Antimicrobial Hernia Repair Device Development
The Antimicrobial Hernia Repair Device (AHRD) (Cook Biotech Incorporated, West Lafayette, IN, USA) consists of a textured, multilayered SIS lyophilized sheet with raised-walled craters of approximately 12 mm in diameter. A controlled volume of gentamicin sulfate suspension in a solution of poly-polyDL-Lactide-Co-Glycolide (PLGA) in acetone is deposited into the craters on the device and dried to form controlled-release disks each containing 4.56 mg antibiotic (Figure 1). The disks are placed on one side of the graft only, the side oriented away from the bowel, to reduce the risk of the PLGA exacerbating adhesion formation to the viscera. During device development, plasma gentamicin was designed to peak at 4-6 hours after implantation and then gradually decline over a span of 5 days. The device delivers the antibiotic locally at a peak minimal inhibitory concentration (MIC) > 10:1 with the average MIC exceeded for over 24 hours and is therefore capable of delivering relatively high local doses of drug without causing systemic toxicity.
This was a prospective, multicenter, single-arm pilot study designed to evaluate the safety and efficacy of the AHRD. The study was approved by the Institutional Review Boards of all participating institutions (Nova Scotia Health Authority Research Ethics Board, Providence Health Care Research Institute, and National Research Ethics Service Liverpool East)
and adhered to the STROBE guidelines. All patients provided written informed consent and were recruited for study inclusion between August 2015 and February 2017. The study was registered at www.clinicaltrials.gov as NCT02401334.
A predefined number of up to 30 patients at 3 clinical sites in the United Kingdom and Canada was chosen as the sample size for this pilot study. The clinical sites were chosen from centres with previous extensive experience of using SIS in ventral hernia repair. No power calculation was performed, as there was no control arm and this study was a pilot study designed to gather initial outcomes data to inform a subsequent pivotal study. Patients were screened sequentially for eligibility at each site. Inclusion criteria included patients over 21 years old with a ventral or incisional hernia that was to be surgically corrected with open surgery. Patients were required to have a Class II, Class III, or Class IV surgical field at the time of the operation, as defined clinically using the investigator’s best judgement.
Patients were excluded from the study if they were pregnant, had a known allergy to porcine products, had a body mass index (BMI) < 25 kg/m2, body weight < 45 kg, glycosylated hemoglobin (Hgb A1c) > 10%, albumin < 2.5 g/dL or pre-albumin < 5.0 mg/dL. Patients were also excluded if they had an existing serum gentamicin level of > 2 mg/L on the morning of surgery or any of the following contraindications to gentamycin: renal insufficiency (as determined by an estimated glomerular filtration rate (GFR) < 60 mL/min/1.73 m2), allergy to aminoglycosides, or myasthenia gravis. Patients with dirty-infected (Class IV) surgical fields required pre-operative culture and sensitivity of the contaminating organism demonstrating sensitivity to gentamicin sulfate.
Peri- and post-operative patient care, including the use of peri-operative antibiotics, was conducted in accordance with surgeon discretion and institutional standard of care. However, if applicable, complete removal of all infected mesh was required during the same procedure prior to implanting the AHRD. Device placement required an overlap of greater than 4 cm in all dimensions, but the surgical plane into which the device was implanted was variable based on surgeon preference and individual patient requirements. Graft fixation was completed using interrupted unbraided sutures. Abdominal wall reconstruction required complete fascial coverage of the graft, using anterior components separation if necessary. Closed suction drains were utilized at the surgeon’s discretion. Primary skin closure was achieved in all patients. Perioperative antibiotics, method of skin closure and wound dressings, and the use of negative pressure therapy were at the discretion of the surgeon.
The primary outcome of the study was the incidence of surgical site infection as defined by the Centers for Disease Control and Prevention. Secondary outcomes included other procedural and post-operative adverse events related to the device or to the procedure, and hernia recurrence through one year.
To determine the systemic absorption and effect of gentamicin on the patient, serum gentamicin levels were obtained 24 hours following graft implantation and incidence of nephrotoxicity (as determined by immediate impairment of kidney function) was assessed. Other adverse events related to the device or to the procedure were also recorded. Patients were followed daily in hospital then and at 2 weeks, 1 month, 3 months, 6 months and 12 months. A Data Safety Monitoring Board (DSMB) consisting of independent physicians and statisticians who were not investigators in the study, nor had a real or perceived conflict of interest with the conduct and administration of the study, were convened on a regular basis to evaluate the clinical study progress and review adverse events.
Continuous variables were summarized using means and standard deviations, and categorical variables were summarized with frequencies and percentages. All enrolled patients were used to describe the outcomes.