Evaluating the Safety and Efficacy of Fractionated Carbon Dioxide Therapy in Postoperative Lower Extremity Wound Healing
Condition: Leg Ulcer
MeSH terms: Leg Ulcer
Study type: Interventional

Summary: 
      This study will evaluate the efficacy and safety of laser therapy on postoperative lower
      extremity wound healing over 12 weeks. The investigators will include adult patients who have
      underwent Mohs Micrographic Surgery on their lower extremities. Patients with poor immune
      systems, current pregnancies, uncontrolled diabetes, lower extremity venous or arterial
      disease will not be included in this study. After surgery patients will be randomized into
      two groups. One group will receive a single laser treatment immediately after their surgery
      on their wound while the other will not. The group not receiving laser therapy will undergo a
      sham laser therapy treatment. Immediately after therapy and 4, 8, and 12 weeks postoperative
      patients will have a follow up visit. During these visits patients wound size will be
      recorded, a photograph will be taken, and the wound temperature will be measured. Patient
      will be given a diary to record any adverse events related to the wound.
    

Detailed description: 
      Background and Significance

      With an aging population, the prevalence of cutaneous malignancies continues to pose
      significant burden in terms of morbidity and economic cost. It is estimated that 5.4 million
      new cases of non-melanoma skin cancers, i.e squamous cell carcinoma (SCC) and basal cell
      carcinoma (BCC), are diagnosed each year. As the incidence of skin cancer increases, the
      prevalence of postoperative lower extremity wounds also increases. Epidemiologic studies
      consistently find up to 10% of BCC and 20% of SCC occur on the lower extremity in both men
      and women, and the largest portion of malignant melanoma cases occurs on the legs of women.
      Lower extremity ulcers are a common postoperative complication of melanoma, BCC and SCC
      treatment, and impose an undue health care burden by negatively impacting patient quality of
      life and increasing costs. Recent reports suggest that lower extremity ulcers cost $10,000
      per patient per year, and patients often reported social isolation and depression, thus
      making an improved treatment protocol for healing lower extremity wounds essential.

      After an acute injury, normal wound healing is usually complete within four weeks and can be
      divided into 4 phases: coagulation, inflammation, formulation of granulation tissue, and
      remodeling or scar formation. The initial steps of coagulation and inflammation involve the
      inhibition of bleeding through activation of the coagulation cascade, release of growth
      factors and cytokines such as platelet-derived growth factor and transforming growth factor
      β, and recruitment of macrophages and fibroblasts. This facilitates removal of foreign bodies
      and bacteria while preparing the wound site for new tissue. Around 5-7 days inflammation
      subsides via apoptosis of proinflammatory cells followed by formation of granulation tissue
      through dermal and epidermal cell migration to the wound bed. Granulation tissue has a high
      metabolic demand that is supplied by angiogenesis (proliferation of new blood vessels).
      Angiogenesis occurs due to local hypoxia during acute tissue injury which stimulates the
      release of several factors such as vascular endothelial growth factor and fibroblast growth
      factor 2. Lastly matrix remodeling and scar formation result in the restoration of primarily
      normal epidermis by replacing the extracellular matrix containing collagen III to primarily
      collagen I and myofibroblast induced tissue contraction.

      Lower extremity ulcers exhibit increased infection risk compared with other body sites, and
      are rarely amenable to surgical closure due to a lack of suitable local skin and poor tissue
      vascularity. As a result, many of these defects are allowed to heal via secondary intention
      healing (SIH).The lower extremity suffers from poor perfusion and hypovascularity, both of
      which impair wound healing in this anatomic site. Therefore, post-surgical wounds on the
      lower extremities frequently convert into chronic wounds, defined as wounds that fail to heal
      within four weeks and show no sign of improvement within eight weeks. This protracted healing
      course drains the medical system of resources and subjects the patient to significant
      discomfort and distress. The major problems reported from patients include pain, immobility,
      sleep disturbances, lack of energy, limitations in work and leisure activities, worry,
      frustration, and lack of self-esteem. Given the problems associated with allowing lower
      extremity ulcers to heal by second intent, strategies that improve ulcer healing would be
      beneficial, improving patient quality of life and preventing further complications.

      Ablative fractional carbon dioxide lasers, such as the CO2RE® (Syneron Candela Corp, Wayland,
      MA), offer a multi-depth pulse technology that delivers a precise fractionated beam pattern
      to treat the epidermis and dermis simultaneously. This precision technology creates areas of
      superficial and deep ablation and coagulation to activate remodeling at several tissue
      depths. The CO2RE® is FDA-approved and has demonstrated efficacy in post-surgical scar
      treatment, although it has not been studied in acute, lower extremity ulcers.

      While the use of AFLs for wounds is novel, there are sufficient reported studies to suggest
      it may be an efficacious intervention to facilitate the healing of lower extremity surgical
      wounds. AFLs create microscopic wounds that can reach greater dermal depths than previously
      attainable with fully ablative devices, and adjacent untreated skin may facilitate rapid
      healing. Histopathologic studies of normal skin treated with AFL demonstrate altered kinetics
      of growth factor and cytokine release, expression of heat shock proteins and matrix
      metalloproteinases. In 3D human organotypic full-thickness skin models, carbon dioxide AF
      therapy resulted in reduced expression of matrix metalloproteinases, and downregulation of
      pro-inflammatory cytokines. Therefore, carbon dioxide AFL may offer significant advantages
      over traditional non-ablative laser technologies.

      Mohs Surgery

      The treatment for BCC and SCC is often surgical. Mohs Micrographic Surgery (MMS) is a
      surgical procedure in which skin cancer cells are removed. Once all visibly cancerous tissue
      is removed, the tissue is examined under a microscope to evaluate for the presence of cancer
      cells at the tissue edges. This allows the surgeon to determine if all of the cancer has been
      removed. After examining the specimen, multiple thin sections of tissue are removed around
      the margins of the wound and then examined under a microscope. If abnormal cells remain,
      further tissue excision is required. This process is continued until no cancerous cells
      remain. This technique allows for preservation of maximum amount of normal tissue and the
      pathologic confirmation of complete cancer excision. MMS is used when there is a high risk of
      recurrence, when the skin cancer is located in a sensitive area such as the nose or lower
      extremities, or the cancer is an aggressive subtype. Complications of MMS include infection,
      hypertrophic scar formation, hypergranulation tissue, and impaired wound healing that can
      result is ulcers persisting up to 7 months.

      Innovation

      This project tests the highly innovative hypothesis that use of the AFL is both safe and
      efficacious for the treatment of post-surgical ulcers. This laser technology has demonstrated
      efficacy for treatment of lower extremity scars, but has not been adequately evaluated in
      ulcers. Due to a unique pattern of injury induced by fractional technology where healthy
      tissue in the vicinity of the ulcer is spared, the use of this technology may demonstrate
      significant benefits as compared to traditional non-ablative lasers and low level light
      systems previously used to treat ulcers.

      Although our proposed study is highly novel, the feasibility of our proposed protocol is
      supported by the fact that the fractional carbon dioxide laser has been shown to improve
      wound healing in scar-related wounds and in post-traumatic wounds of the lower extremity.
      Based on this data, treating acute lower extremity ulcers with ablative fractional carbon
      dioxide laser is expected to improve healing times in lower extremity ulcers occurring as a
      result of cutaneous surgery. This work may lead to the use of ablative fractional laser to
      support the body's regenerative capacity on the lower extremity, improving patient quality of
      life and conserving healthcare resources. The investigators therefore hypothesize that
      ablative fractional laser treatment therapy after cutaneous surgery is a safe and efficacious
      treatment for lower extremity wounds.

      In addition to the novelty of our proposed hypothesis, our study benefits from technical
      innovation in adjudicating ulcer healing, which has previously not been combined with carbon
      dioxide laser technology.

      Preliminary Studies

      The first report of carbon dioxide AFL utilization in wounds was by Schumaker et. al in 2012.
      In their report they described three patients treated with a 10.6-um carbon dioxide AFL
      system for multiple traumatic scars related to blast injury. Incidentally they noted that
      chronic wounds in the treatment sites resolved within 2 weeks of initial therapy. Phillips
      et. al observed similar results in elderly individuals with post traumatic lower extremity
      ulcers. Their report demonstrated greater than 60% resolution of chronic lower-extremity
      ulcers 3 weeks after a single treatment with carbon dioxide AFL therapy. Most recently
      Krakowski et. al demonstrated near complete resolution of two chronic wounds by two months in
      pediatric patients after treatment with CO2 AFL at a pulse energy of 50 mJ and treatment
      density of 5%.

      MMS performed on the nose, like lower extremities, are occasionally allowed to heal by second
      intent and can thus be predisposed to prolonged healing. Our preliminary studies demonstrate
      the effects of carbon dioxide AFL on these wounds. Two patients receiving MMS on the nasal
      ala were studied. One patient receiving carbon dioxide AFL therapy on his postoperative wound
      while the other did not. After three weeks the patient's postoperative wounds were assessed.
      The patient receiving laser therapy had complete epithelialization of his wound, while the
      patient with no treatment had incomplete epithelization. These results suggest the hypothesis
      that the carbon dioxide AFL may be a safe, efficacious treatment for ulcers of the lower
      extremity.

      Design:

      Our study is a prospective, double-blinded, randomized, placebo-controlled trial evaluating
      the efficacy of fractionated carbon dioxide therapy in postoperative lower extremity wound
      healing. This study, including analysis and submission for publication, will occur from
      September 2018 to November 2020. A cohort of 48 patients will be recruited. Eligibility
      criteria will include patients older than 18 years, those with a lower extremity wound as a
      result of Mohs Micrographic Surgery at Saint Louis University Dermatology Des Peres, and a
      postoperative wound greater than 5mm in diameter. Patients must be able to understand the
      informed consent, willing to come to the office for treatments and capable of following
      post-treatment instructions. Exclusion criteria will include pregnancy, immunosuppression,
      uncontrolled diabetes (defined as >7% A1c in the last 3 months), peripheral vascular disease,
      venous insufficiency, or no desire/unable to undergo laser therapy.

      After informed consent is obtained, a screening visit will be performed on their Mohs surgery
      day and patient eligibility will be determined. Then, patients will be randomized 1:1 to a
      treatment or control group via computer software. One arm will receive carbon dioxide AFL
      immediately postoperatively on the wound base. The second arm, which will serve as control,
      will receive sham laser therapy. Both patients will be given identical postoperative wound
      care instructions, including vaseline applied to the wound, a piece of telfa to overlay the
      wound, and paper tape to secure the dressing. Additionally, patients will be advised to avoid
      baths and application of any other products to their wound. Patients will be given a diary to
      record observations about their postoperative wound and to note any adverse events.

      Blinding

      There will be one unblinded member of the team in this study which will be the clinician
      performing laser therapy or sham therapy, who will therefore not be involved in any data
      collection, but will be responsible for reporting any adverse events per IRB protocols at our
      institution. Other members of the research team member will be blinded to patient group
      assignment, and these members of the research team will collect data (see below) at
      subsequent visit. Additionally, patients will be blinded to treatment group. This will be
      achieved by having patients wear safety glasses which blind them and the wound site still
      anesthetized from the operation. Data collection will be done by a separate research team
      member who is blinded to the treatment groups.

      Patient Visits and Data Collection

      Patients will be seen at 4 separate visits. This will include the baseline visit and every 4
      weeks to monitor safety and efficacy endpoints (4, 8 and 12 weeks post-operatively). The
      patient's initial visit will include preoperative screening for eligibility, informed consent
      procedure, and recording of past medical history and physical exam. Once the patient is
      deemed eligible, enrolled, and signed informed consent, they will be randomized to either
      carbon dioxide AFL therapy or sham laser therapy. After the patient undergoes Mohs surgery
      with the resultant ulcer (the defect that typically forms after Mohs), the patient will
      undergo either carbon dioxide laser versus sham laser therapy.

      The investigators will look at the presence or absence of complete healing, wound
      temperature, a digital photograph, quality of life, and adverse events at each visit. Healing
      will be determined by one of the licensed research team members and will be defined by
      complete epithelialization in the absence of scab/eschar. Wound temperature will be recorded
      by non-invasive infrared thermographic camera. A digital photograph will be taken with a
      camera that has an attachment ensuring the same distance and angle at every visit. Quality of
      life will be determined by ED-5Q questionnaire. Adverse events will be recorded by eliciting
      an oral history and review of the patients diary. Adverse events will be recorded as presence
      of absence of specific outcomes. Outcomes that patients will be directly questioned about
      include: crusting (scaly or thickened scar), swelling, burning sensation, xerosis at
      treatment site, pruritus at treatment site, infection, bleeding, hypertrophic or keloid
      scarring, burns, or color changes at treatment site. These data points will be collected at
      every visit, and adjudicated by a member of the research team blinded to the treatment group.
      This member will be a licensed research team member.

      Placebo treatment will consist of directing the laser system at the floor instead of the
      patient's wound site. The patients will be wearing safety glasses and will have their wound
      site still anesthetized from the operation therefore unaware if they are receiving the
      therapy. This group will serve as the control group to the treatment arm in the study.
    

Intervention name(s): CO2RE® (Syneron Candela Corp, Wayland, MA); Sham laser treatment
Intervention type(s): Device; Other
Intervention description(s): The intervention will include a single treatment of a lower extremity wound with ablative fractional carbon dioxide laser after MMS surgery.; A physician who is not blinded will perform a sham laser treatment on blinded subjects.
Other intervention name(s): Ablative fractional carbon dioxide laser
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Leg Ulcer; Lower extremity ulcer; carbon dioxide laser; CO2 Laser; Ablative fractional carbon dioxide lasers