Does Debridement Improve Clinical Outcomes in People With Diabetic Foot Ulcers Treated With Continuous Diffusion of Oxygen?

Objective. This post hoc analysis evaluates the association between the frequency of diabetic foot ulcer (DFU) debridement and the proportion of ulcers treated with active continuous diffusion of oxygen (CDO) that heal in a 12-week evaluation period. Materials and Methods. There were 146 patients with DFUs (77% men; average age, 56.3 ± 12.4 years) enrolled in a double-blind, placebo-controlled, randomized study to receive either active CDO or an otherwise fully operational placebo device. Patients were followed for 12 weeks or until wound closure. All patients received identical offloading, dressings, and follow-up. Ulcer debridement was left to the discretion of the treating physician and recorded from physician self-report as a dichotomous variable. Results. A significantly higher proportion (204%) of ulcers healed in the CDO group compared with the placebo (46.2% vs. 22.6%, respectively; P = .016). The relative performance of active CDO over placebo became greater when frequent debridement was used (51.2% vs. 21.3%, respectively; P = .006). Conclusions. A significantly greater percentage of healing was recorded in patients receiving active CDO therapy than those receiving a placebo device in addition to standard wound care with identical dressings, debridement recommendations, and offloading. The relative performance of CDO appears to increase with the use of frequent debridement. 

RELATED CONTENT

Surgical Debridement With a Scalpel

Operative Management of Abdominal Wound Dehiscence: Outcomes and Factors Influencing Time to Healing in Patients Undergoing Surgical Debridement With Primary Closure

A Novel TCC Using a Moldable Wooden Construct Heals Diabetic Foot Wounds: A Pilot Study

There is a worldwide epidemic of diabetes and diabetes-related complications. Foot ulcers are one of the most common complications in patients with diabetes, leading to amputation and hospitalization.^1-3 While a variety of treatments have been associated with diabetic foot ulcer (DFU) healing, debridement, including enzymatic, autolytic, larval, and surgical, is one of the most common components of the DFU treatment plan.^4,5 There are several theoretical reasons to debride a DFU. Debridement changes the wound environment by removing necrotic debris, senescent cells, infected tissue, and biofilm that may impair healing. At the same time, debridement can convert a stagnant, chronic ulcer to a more biologically active acute wound.⁶ 

Several studies^4,7,8 have suggested DFUs receiving serial surgical debridement heal faster and a higher proportion of these DFUs heal. For instance, Steed et al⁷ reported data from a post hoc analysis of a multicenter, randomized, controlled trial (RCT) studying topically applied recombinant human platelet-derived growth factor (rhPDGF) versus a placebo that showed centers with the highest rates of DFU healing had the highest frequency of debridement, and centers with the lowest healing rates had the lowest rates of debridement among patients who received rhPDGF. Similarly, among patients who received the placebo, sites with the lowest debridement had the lowest healing rates.⁷ Even though there are important limitations to previous studies,^4,7,8 the body of work in this area supports the importance of debridement as a component of the overall DFU treatment strategy. Wilcox et al⁸ reviewed the serial surgical debridement of nearly 155 000 patients with more than 312 000 total wounds. They⁸ identified a healing rate more than 3-fold greater in people with chronic wounds debrided weekly than those treated less often. While aforementioned works have suggested a positive healing signal through the use of serial debridement and many guidelines endorse the practice,^9-11 a relative paucity of evidence to support its use still exists. 

Oxygen has been shown to be an essential component in multiple mechanisms of action required for wound healing.^10-12 Depressed levels of oxygen have been shown^13,14 to be a rate-limiting step in these mechanisms. Conversely, increasing oxygen levels has been shown^13,14 to result in increased, and often proportional, levels of activity in these mechanisms of action. Aside from general cell metabolism and energy production, these mechanisms of action, and corresponding rates of action, affected by oxygen levels in the tissue include cell proliferation and reepithelialization,^13,15 collagen synthesis and tensile strength,^14,16,17 angiogenesis,^18,19 antibacterial activity through respiratory burst,^20-22 and growth factor signaling transduction.^23,24 Damaged tissue in chronic wounds has increased oxygen demands and can achieve improved healing through enhancement of local oxygen availability with oxygen therapy.^22,25,26 

Continuous diffusion of oxygen or continuously diffused oxygen (CDO) uses pure, humidified oxygen to treat a wound by continuously supplying oxygen directly to the affected tissue within a moist wound therapy (MWT) dressing; simply put, CDO is MWT plus oxygen. This allows for sustained delivery of oxygen to the tissue (24 hours daily, 7 days weekly), full patient mobility during treatment, and application of the therapy in virtually any setting. In CDO therapy, oxygen is introduced into the wound bed through the dressing and into the surface of the tissue. Anything that can impair the transport of oxygen into the wound bed, such as slough or eschar, theoretically would negatively impact the effectiveness of CDO therapy. Aggressive debridement removes or minimizes these barriers to oxygen transport and would allow the optimal transport of oxygen into the tissue.

The aim of this study is to evaluate the association between DFU debridement and the proportion of ulcers that heal with and without active CDO therapy in a 12-week evaluation period.

This is a post hoc analysis that investigates the effect of debridement in a 12-week, randomized, double-blinded, placebo-controlled study that was conducted at 34 sites in the continental United States to evaluate a topically applied CDO therapy device (OxySpur Oxygen Diffusion Dressing; EO2 Concepts, San Antonio, TX) to heal DFUs (ClinicalTrials.gov Identifier NCT01645891). The study was approved by Schulman Associates Institutional Review Board, Inc (IRB No. 201202439; Cincinnati, OH). The inclusion/exclusion criteria and methods for this study previously have been described in greater detail in a separate publication.¹² 

After initial screening for eligibility and obtaining informed consent, a patient history and baseline assessment were obtained, including ankle-brachial index (ABI); ulcer duration, location, and size; patient age, ethnicity, and gender; and glycated hemoglobin. Inclusion criteria included patients aged 30 to 90 years with a University of Texas Wound Classification System grade 1A DFU lasting 30 to 365 days duration and an ulcer size ranging from 1.5 cm² to 10 cm². Before randomization, patients were subjected to a 2-week run-in period during which they received standard of care dressings, debridement, and offloading. If there was a wound area reduction >50% during the run-in period, patients were excluded from the study.

Patients were then randomized to either the treatment arm with an active CDO device (henceforth, the active arm) or the control arm using a placebo CDO device (henceforth, the placebo arm). All devices in both arms were set to 3 mL/hour of oxygen flow and were functional in that they produced oxygen and displayed the oxygen flow rate. The only difference was the placebo device did not have any oxygen flowing out of the oxygen supply port (Figure 1).  

Standard of care in both treatment arms was identical. All patients received a standard regimen consisting of wound cleansing, moist wound care, offloading, and, as appropriate, aggressive surgical debridement. Dressings in both arms were restricted to a single foam (XTRASORB Foam; Integra Life Sciences Corp, Plainsboro, NJ) covered by an occlusive barrier (Tegaderm; 3M, St Paul, MN) to eliminate dressing variability. Optionally, a calcium alginate (MAXORB Extra Wound Dressing; Medline Industries, Inc, Northfield, IL) could be used for control of excessive exudate. The DH Offloading Walker (Össur, Reykjavík, Iceland) was used for offloading. All ulcers were surgically debrided to a bleeding base as necessary; the number of debridements was not limited, but debridement usually was performed once weekly at the discretion of the treating physician. The physician was free to determine the type of surgical debridement.

Patients were followed for the treatment phase of 12 weeks or until the wound closed, whichever event occurred first. During the treatment phase, patients had weekly visits that included ulcer assessment, debridement, digital photograph for ulcer size determination via planimetric analysis, documentation of adverse events, and a dressing change with reapplication of the study device. The authors used a calibrated imaging guide template developed in-house for scaling, a digital 35-mm camera (EOS Rebel T2i; Canon, Tokyo, Japan) with ring flash for the pictures, and processed the images using Fiji ImageJ open source software package. The primary efficacy outcome was complete wound closure defined as complete reepithelialization with no drainage as assessed by the treating clinician and confirmed by a blinded observer. 

Statistical methods
The sample size justification assumed that 82.4% of patients in the active and 45.5% in the placebo arms would experience wound closure during the 12-week study period. With 2-sided testing and an overall significance level of 5%, this study would achieve 90% power with 41 patients per treatment arm. The study failed to cross the boundary at midpoint; at the interim analysis of primary outcome based on 42 patients (21 per arm), 52.4% of active and 38.1% of placebo patients experienced wound closure (P = .54). In a conditional power calculation, the authors concluded that if the efficacy specified in the protocol was experienced in the remainder of the study, then the total sample size required to reach 90% power would be 100, or 50 per arm.

Continuous variables and outcomes were summarized with the sample sizes, means, and standard deviations, and categorical outcomes were summarized with frequencies and percentages. At baseline, both treatment arms were contrasted on the mean of continuously distributed outcomes with t tests and on proportions with Fisher’s exact test. For all analyses and graphics, R and SAS (SAS Institute, Cary, NC) were used. 

At baseline, both treatment arms were similar in regard to age, ethnicity, gender, ulcer size, ulcer duration, glycated hemoglobin, ABI, ulcer location (weightbearing or not), and patients experiencing no pain in the ulcer between Site X, which utilized debridement significantly less, and the other 33 sites (Table 1). Baseline characteristics did not vary significantly by treatment arm¹² or site, with the exception of ethnicity; Site X had a predominantly Hispanic patient population. The effect of ethnic orientation on the primary outcome for patients who completed the study is shown in Table 2. Additional results, such as the effects of wound chronicity, wound size, adverse events, and other variables on clinical outcomes, are reported and discussed in the previous publication.¹² This paper focuses on the effect of debridement on outcomes with CDO therapy.

The effect of debridement was examined by comparing the frequency of self-reported ulcer debridement to outcomes. Debridement frequency is defined as the percentage of patient visits that reported debridement. All sites except 1 demonstrated a high debridement frequency, averaging 92% to 100% debridement of all patient visits. The exception was 1 site that debrided patients only 41.3% of visits; this site (Site X) was a high-enrolling site, and the results there were markedly different from the sites that debrided ulcers more frequently. Figure 2 shows the results obtained from Site X compared with all Other Sites, as well as the overall study results for all sites. Site X did not show a statistically significant difference between the active and placebo arms (P = .63). Analyzing the data for all other sites without Site X, referred to as Other Sites, shows the frequency of debridement of all visits was 98.4%, which was more than twice that of Site X. The outcomes for sites that debrided frequently (Other Sites) are marginally improved for the active arm as compared with the overall study results (All Completed), closing 51.2% of DFUs and placebo closing 21.3% (P = .006). The relative efficacy of the active versus placebo improved from 204% to 240% for sites that debrided ulcers more frequently.

Examining debridement rates across arms and outcomes (excluding Site X), Table 3 shows the frequency of debridement was high for all patients who completed the study. The rates ranged from 98% to 100% regardless of patient arm or whether the ulcer closed. For the patients that did not complete the study, the debridement rates were slightly lower yet substantially similar between the arms (92.0% and 89.5% for active and placebo, respectively). 

The patients at Site X were nearly all of Hispanic ethnicity (95.5%). Figure 3 shows the results for only the Hispanic population obtained from Site X compared with those for all Other Sites and the overall study results for all sites. For the Hispanic population, analyzing the data for all Other Sites (without Site X) shows the frequency of debridement was 97.9% of all visits, which was more than twice that of Site X. The outcomes for sites that debrided frequently (Other Sites) significantly improved for the active arm as compared with the overall study results (All Completed) in the Hispanic population, closing 81.8% of DFUs and placebo closing 21.4% (P = .005). The relative efficacy of the active versus placebo improved from 220% to 382% for sites that debrided ulcers more frequently in the Hispanic population.

The use of frequent debridement has been associated with a higher proportion of DFUs healing in several reports.^8,27 Since CDO is, in essence, MWT plus oxygen, having a clean wound is essential to allow optimal access for oxygen to penetrate the tissue. The same argument can be made for platelet-derived growth factor or cellular- and tissue-based wound care products. Any barrier, such as detritus or film, will hinder the access of oxygen, growth factors, or stem cells to the wound bed. In the case of CDO, it stands to reason that devitalized tissue will reduce the ability of oxygen to penetrate the wound and will lower the resulting oxygen concentrations available to living cells in the wound bed below the barrier. The results shown in Figure 2 appear to support this hypothesis, suggesting infrequent debridement may negatively impact performance. 

Site X debrided at a frequency of less than half that of the Other Sites and showed no statistical difference between the active and placebo arms in the primary outcome of full wound closure. However, for the Other Sites that debrided nearly every visit (Table 3), using a per protocol analysis, the active arm significantly outperformed the placebo arm by a relative difference of 240%, with active CDO closing more than half (51.6%) of the wounds and the placebo closing less than one quarter (21.3%, P = .006). For all Other Sites, there was no significant variability between treatment arms or outcomes in the rate of debridement (Table 3), so debridement did not play a role in affecting the results for the sites except Site X. Site X accounted for 14.3% of patients who completed the study and had a dramatic effect on overall performance and debridement levels for the study, as seen by comparing the results in Table 3. Excluding Site X results, the absolute overall debridement levels increased by 8.4%, the absolute performance of the active CDO group increased by 5.0%, and the relative performance of the active versus placebo increased by 36.0%. 

Since the patient population at Site X were mostly of Hispanic ethnicity (95.5%), there was an even more dramatic impact of debridement on the results for the Hispanic patients as shown in Figure 3. Excluding Site X results, the absolute overall debridement levels increased by 22.6%, the absolute performance of the active CDO group increased by 26.8%, and the relative performance of the active versus placebo increased by 162%. These results suggest frequent and aggressive debridement improves the performance of CDO. 

There are several strengths and limitations to consider in this study. Most of the published work^4,7,8 that evaluated debridement and DFU healing are from post hoc analyses of phase 3 and 4 RCTs and relied on self-reported debridement. There were no objective measures or blinded reviewer assessment of the quality or depth of debridement. The only variable is frequency of debridement as a percent of the total number of visits in the study. Because there was a very high rate of self-reported debridement except for 1 study site, the sample size for “low-debrided wounds” was small. However, the strengths of the study include the high-quality design with blinding of patients and physicians, consistency of dressings and offloading that were used as the standard of care for both treatment arms, strict screening criteria, and use of a run-in period to evaluate chronicity of wounds. In addition, because these data were from an RCT, patients were clearly characterized, and there was no difference between groups.

In this double-blinded study, a significantly greater percentage of healing in patients receiving CDO therapy compared with a placebo device providing standard wound therapy with identical dressings, debridement, and offloading was reported. The relative performance of CDO appears to increase with the use of frequent debridement; the association of frequent debridement with better outcomes has been reported.¹² Frequent debridement may be even more important with CDO since it allows greater access of the continuous flow of oxygen to the affected tissues.

Authors: Lawrence A. Lavery, DPM, MPH¹; Mark Q. Niederauer, PhD²; Klearchos K. Papas, PhD³; and David G. Armstrong, DPM, MD, PhD⁴

Affiliations: ¹Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, TX; ²EO2 Concepts, San Antonio, TX; ³University of Arizona, Tucson, AZ; and ⁴Department of Surgery, Southwestern Academic Limb Salvage Alliance (SALSA) Keck School of Medicine of USC, Los Angeles, CA 

Correspondence: Lawrence A. Lavery, DPM, MPH, Department of Plastic Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390; larry.lavery@utsouthwestern.edu

Disclosure: This research was funded by EO2 Concepts Inc (San Antonio, TX). Dr. Lavery received research funding from EO2 Concepts, Osiris Therapeutics Inc (Columbia, MD), Integra Life Sciences (Plainsboro, NJ), Cardinal Health (Dublin, OH), and Avazzia (Dallas, TX) and is a consultant for Boehringer Ingelheim (Ingelheim am Rhein, Germany), MedImmune (Gaithersburg, MD), Medline Industries (Northfield, IL), Bayer AG (Leverkusen, Germany), and EO2 Concepts. Dr. Niederauer is an employee of EO2 Concepts. Dr. Papas received research support from EO2 Concepts. Dr. Armstrong is a consultant for EO2 Concepts.