Prevention of Vascular Graft Infection With Hypochlorous Acid

Background Infection of prosthetic bypass grafts is a major concern in patients who undergo vascular surgical procedures, since they are associated with significant mortality, morbidity and healthcare costs. Vascular prosthetic graft infections (VGI) are known to occur in 0.5% to 5.0% of intracavity grafts and in as many as 6% of extra-cavity grafts which involve surgery in the groin. VGI rates are higher in critical limb ischemia and in emergent procedures.

Infections of aortic grafts have a mortality rate of between 24 and 75%, and lower limb graft infections have amputation rates of up to 70%.

Intraoperative contamination of vascular grafts is considered to be the most common source of graft infection. Hematogenous spread from infections in other areas such as pneumonia, urinary tract, gastrointestinal tract, etc. are much less common than intraoperative contamination and are more likely in the early post-operative period.

Reducing VGI has clear benefits for the patient and also for the healthcare system. A Cochrane review on the prevention of surgical site infection was unable to identify any clear evidence for lavage of the wound, however it did suggest that the use of antibacterial solutions compared to non-antibacterial solutions may reduce surgical site infections. Hypochlorous acid (HOCl) is an antimicrobial solution that occurs naturally in the human body in white cells as a defence against bacteria. HOCl ultimately degrades to saline and water and leaves no residual harmful chemicals.

HOCl has been used in a number of clinical evaluations in patients with different medical conditions to reduce the risk of subsequent infection, including patients with perforated appendicitis, peritonitis from different sources, and coronary artery bypass graft surgery. There have been no concerns with patient safety and the studies do suggest efficacy in these different clinical conditions. Hypochlorous acid is also widely used in the management of patients with chronic wounds and burns in Canada. There has been no evaluation of its use in preventing VGI. A Canadian manufacturer of hypochlorous acid, Sterasure Inc (now Biomiq Inc), has produced a version of hypochlorous acid in sterile packaging, that is ideal for use in the operating room. This sterile product has Health Canada approval for use in wound care and soft tissue irrigation in chronic and acute wounds. It does not have explicit Health Canada approval for the use in the prevention of VGI and health Canada approval is being sought for its use in this clinical trial. There are no published data on the use of HOCl to prevent vascular graft infection. The cost of the sterile preparation of hypochlorous acid is <$50 per 500 ml.

HOCl has the potential to reduce bacterial contamination in wounds at the end of prosthetic vascular graft implant procedures, and to therefore reduce the frequency of VGI. In order to be able to fully evaluate HOCl as a lavage solution to prevent VGI, it is important to obtain data on the event rate of VGI with the use of HOCl as a lavage solution at the completion of surgery.

In order to ensure that accurate data are obtained on VGI rates, it is important that a standardized method be used to determine VGI. Validated criteria from the Management of Aortic Graft Infection Collaboration (MAGIC) have been developed for the diagnosis of vascular graft/endograft infection. The rates of VGI in a Canadian population are not known when these criteria are applied, hence the need to establish the VGI rate using these criteria with standard of care, as well as the rates of VGI with the use of HOCl. With these data the sample size analysis for a randomized controlled trial (RCT) to assess the efficacy of HOCl in preventing VGI could then be established.

The rate of VGI is not captured in current data collection for Quality Improvement at Hamilton Health Sciences (HHS). These processes capture surgical complications up to 30 days post procedure and do not specifically capture data on prosthetic graft infections. There is no infrastructure in place to evaluate such complications out to 12 months or beyond. Baseline data for this complication are not available at HHS, hence the need to obtain accurate VGI rates using MAGIC criteria with the current standard of care as well as the data with an intervention such as hypochlorous acid wound lavage.

Based on currently published rates of VGI, using inconsistent criteria for VGI, it is estimated that that a sample size to test this hypothesis would be anywhere from 3,000 to 23,000 patients. In order to determine the feasibility of conducting such a large RCT, the first step is to conduct a pilot RCT. A pilot RCT will inform the feasibility of conducting a large RCT in terms of VGI rates, patient recruitment, adherence of the surgical team to using the intervention, and the applicability of the data collection tools.

The ultimate hypothesis of this research is that lavage of surgical wounds with HOCl prior to closure, following the insertion of prosthetic vascular grafts, can reduce the rate of VGI. This inexpensive preventative measure has the potential to result in significant patient benefit and significant cost savings to healthcare.

Aims

• Primary aims - To conduct a pilot randomized controlled trial of the use of hypochlorous acid wound lavage versus current standard of care with no lavage, in patients who have prosthetic vascular grafts inserted, to assess the feasibility of a large RCT, by establishing -

• The VGI rates in the study population using the MAGIC criteria
• The VGI rates with the use of a hypochlorous acid lavage which would enable an appropriate sample size calculation for a large RCT
• To assess the feasibility of recruiting patients for such a study
• The adherence of the surgical team with the lavage protocol
• The feasibility of the data collection tool for determining the outcomes of VGI
• The feasibility of the data collection tool for evaluating the costs associated with VGI
• Secondary aims

• To capture the costs associated with treating patients VGI, in order to assess potential savings to the healthcare system associated with lower rates of VGI

Method

Study design

• A pilot randomized controlled trial of wound lavage with hypochlorous acid compared to no lavage after the insertion of a prosthetic vascular graft to the abdominal or lower limb arteries.

Patients

• Sample size - 500 consecutive patients who meet the criteria for the study
• Patients will be followed for 12 months following the surgery to determine if VGI has occurred

Interventions Patients in the treatment group will have a lavage of their wounds with hypochlorous acid just prior to closure which will occur in the normal manner. Patients in the control group will have their wounds closed in the current standard of care with no lavage of their wound.

Randomization Recruited patients will receive a trial number in continuous sequence. Using a random number generator, each patient trial number will be allocated to either the active hypochlorous acid wound lavage study arm or the no wound lavage study arm. This allocated study arm will be placed into an opaque, sealed envelope for each trial number that will only be opened during the surgical procedure for the patient with that trial number.

Method of lavage of the wounds

• A sterile preparation of each lavage solution will be used for this study
• A total of 500 ml of lavage solution will be used for the abdominal cavity lavage and 500 ml will be used for each leg or groin wound
• The lavage will be placed into the abdominal cavity or the leg wounds after the procedure has been completed and prior to abdominal cavity or limb wound closure. For each leg wound part of the solution will be dispersed from each wound into the tunnel where the graft has been placed
• The solution will be manually dispersed or dispersed with an irrigation syringe through the abdominal cavity and leg wounds, and will be left to sit in situ for 2 minutes and will then be aspirated with suction
• This will be repeated a second time and up to 100 ml of solution will be reserved for lavage of the superficial part of the wound in the abdominal cavity or the leg
• Normal closure will occur following the lavage. In abdominal wound closure, once the muscular layer has been closed, the lavage will occur in the subcutaneous layer with the remaining solution prior to closure of this layer and skin. In the leg wounds, once the deepest layer has been closed, the wound lavage with the remaining solution will occur.

Criteria to diagnose VGI The following validated criteria from the Management of Aortic Graft Infection Collaboration for criteria for the diagnosis of vascular graft/endograft infection21, will be used to make a diagnosis of prosthetic graft infection.

MAGIC major criteria

• Pus (definite by microscopy) around graft or in aneurysm sac at surgery
• Open wound with exposed graft or communicating sinus
• Fistula development, e.g., aorto-enteric
• Graft insertion in an infected site, e.g., fistula, mycotic aneurysm, or infected pseudo-aneurysm
• Peri-graft fluid on CT scan > 3 months after insertion
• Peri-graft gas on CT scan > 7 weeks after insertion
• Increase in peri-graft gas volume demonstrated on serial imaging
• Microorganism recovered from an explanted graft
• Microorganism recovered from an intra-operative specimen
• Microorganism recovered from a percutaneous aspirate of peri-graft fluid MAGIC minor criteria
• Localised clinical features of VGI, e.g., erythema, warmth, swelling, purulent discharge, and pain
• Fever > 38 degrees Celsius with VGI as most likely cause
• Other -

o suspicious peri-graft gas/fluid/soft tissue inflammation

o aneurysm expansion

o pseudo-aneurysm formation

o focal bowel wall thickening

• discitis/osteomyelitis
• suspicious metabolic activity on Fluorodeoxyglucose Positron Emission Tomography (FDG PET) /Computed Tomography (CT)
• radiolabelled leucocyte uptake
• Blood culture(s) positive and no apparent source except for VGI
• Abnormally elevated inflammatory markers with VGI as the most likely cause, e.g., Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), and white cell count

Data for costs of treating VGI

• In patients who develop VGI, the following data will be documented in order to determine the impact and cost of VGI -

o Additional treatment including investigations, medical treatment, procedures and surgery

o Outcomes including death or amputation

o Length of hospital stay

o Ability to return to original accommodation on discharge

• The costs will be calculated using current standard rates for investigations such as CT scan, MRI scan, white cell scan etc.; medical and surgical procedures; hospital stay in standard ward, ICU, rehabilitation unit or long term care; and other significant costs that are identified.

Feasibility data from the pilot RCT • The following data will be collected in relation to the feasibility of conducting a larger RCT

• The number of patients who met the criteria for the study but declined to consent to the study
• The number of occasions that the surgical team did not adhere to the study arm protocol
• The need for modification to the data collection tools for both the study outcome and the costs of VGI treatment

Sample size and statistics

• A pilot RCT is needed to establish the feasibility of conducting a full RCT as it relates to VGI rates, patient recruitment, feasibility of adherence to the treatment and the data collection tools.
• Accurate data are needed to be able to determine the feasibility of mounting a full RCT to assess the hypothesis of this study.

Adverse events

• Adverse events that are not part of the normal expected course of care for the patient's medical condition will be documented, the seriousness will be determined and the probability of being related to the use of lavage solution will be determined by the Investigator team.
• A Data Safety and Monitoring Board will be established to review any potential adverse events and patient safety issues throughout the study.

Data storage Data collected as part of the study will be in an electronic form in the software REDCap and will be de-identified data. A Study Key of patient identifiers will be kept separately in RedCap. Once all of data for the study have been collected and validated, the Study key will be deleted. Individual patients will have a study number, but no identifiers in the stored data.

Data will be stored for 15 years from the completion of the study.

Resources for the study

• The sterile HOCl to be used in this study will be provided by the manufacturer Sterasure Inc (now Biomiq Inc), Kitchener, Ontario and will be bottled in sterile bottles and packaging

Inclusion criteria

• Patients undergoing elective or emergent open insertion of prosthetic vascular grafts to the abdominal and/or lower limb vessels, including all prosthetic bypass grafts and patch grafts
• Patients 18 years of age or older
• Able to provide informed consent in English

Exclusion criteria

• Patients undergoing vascular surgery that does not involve the insertion of a prosthetic graft to the abdominal and/or lower limb vessels by an open operation
• Patients under the age of 18 years
• Patients who are unable to provide informed consent in English