Abstract
Purpose:
The purpose of this study was to test our MUSTCOOL cooling patch intervention on the incidence of venous leg (VLU) and diabetic foot ulcer (DFU) recurrence over a previously healed wound.
Design:
6-month randomized controlled trial.
Subjects and Setting:
The target population was individuals with previously healed ulcers receiving care in outpatient wound centers in the Southeastern region of the U.S. participated in the trial. The sample comprised 140 individuals with recently healed ulcers, their average age was 62.4 years (SD 12 yrs.); 86 (61.4%) were male; and 47 (33.6%) were Black or African American.
Methods:
Participants were randomized to the MUSTCOOL or placebo patch. Both groups received instructions to apply the patch 3 times per week, and engage in standard of care including compression and leg elevation (VLU) or therapeutic footwear and hygiene (DFU). Demographic data were collected at baseline, and incidence measures taken at 1, 3, and 6 months. We also studied whether new ulcers developed on the adjacent leg or foot. Data were reported in frequencies/percentages.
Results:
One hundred seventeen participants (84%) were analyzed who completed 6 months of study participation. Thirteen percent (9/69) and 17% (12/69) developed a recurrent or new VLU, respectively; 29% (14/48) and 13% (6/48) developed a recurrent or new DFU, respectively. One person in the DFU group developed both a recurrent and new ulcer. For 9 recurrent VLUs, 6 (66.7%) recurred in the MUSTCOOL group and 3 (33.3%) receiving the placebo. Of the 15 recurrent DFUs (includes individual that developed both a recurrent and new ulcer), 10 (66.7%) recurred in the MUSTCOOL group and 5 (33.3%) receiving the placebo.
CONCLUSIONS:
While the incidence of ulcer recurrent was slightly higher in the MUSTCOOL group, this finding was not considered clinically relevant. Overall ulcer recurrence during the 6-month study period was lower than reports in the literature, the time frame in which recurrence rates are highest.
Trial registration:
The study was prospectively registered with ClinicalTrials.gov on December 10, 2015 (Identifier: NCT02626156) https://clinicaltrials.gov/ct2/show/NCT02626156.
Keywords: Venous leg ulcers, diabetic foot ulcers, incidence, recurrence, cooling intervention
Introduction
One hundred fifty million individuals world-wide1 are affected by some type of wound, about half (71 million) of which are lower extremity ulcers of the legs and feet related to chronic conditions such as diabetes mellitus, and vascular and/or neuropathic disorders.2 Venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs) represent a substantial portion of the cost burden associated with wound care.3 Treatment costs approximate $20 - 25 billion in annual expenditures in the United States.4 This figure does not account for the costs of human suffering and the negative impact on physical activity and health related quality of life.
Many individuals with lower extremity ulcers experience multiple new and recurrent ulcers in their lifetimes that take months or years to heal. While recent figures are unavailable, once healed, VLUs and DFUs show extremely high recurrence rates. Data suggest 70 – 96% of VLUs recur within 2 to 3 months of healing;5-7 conservative estimates show the five-year cumulative DFU recurrence rate is 66%.8,9 If even half of these new and recurrent ulcers could be prevented, $10 billion on expenditures for hospital and outpatient wound care would be saved and associated suffering eliminated.
Cooling interventions to mitigate the inflammatory response have been used for centuries as a treatment modality for musculoskeletal injuries and acute inflammatory conditions.10 The application of ice and other cold devices reduces the abnormal metabolic rate within tissue, and impedes the destruction of otherwise uninjured adjacent tissue by limiting injury. However, cooling in response to chronically inflamed scar tissue that continues to remodel is not as well established because the physiological mechanisms associated with remodeling leg and foot ulcer tissue are poorly understood.11 For acute injuries, cooling causes an initial vasoconstriction in skin blood vessels, which results in decreased local blood flow to the area. Cooling also prevents localized fluid leakage from the microcirculation and thus reduces inflammation, clinical characterized by edema and redness. Our early research conducted in populations with VLUs shows skin heats up before it breaks down Specifically skin temperature is increased by approximately 1.8°C in venous disease-affected skin and spikes prior to ulceration.12 Following this line of reasoning, prophylactically cooling a focal or localized area of affected skin reduces the risk of skin changes and ulceration by reducing microcirculatory blood flow, vessel permeability, and tissue metabolism.13-15 To date, limited research has been conducted on methods to reduce the incidence of recurrence of VLUs and DFUs. To address this gap and building on our preliminary work, the purpose of our study was to determine the influence of a cooling intervention (MUSTCOOL) on the incidence of recurrence and the development of new ulcers on untreated areas of the same and contralateral legs and feet in a clinic population of patients with newly healed VLUs and DFUs during our 6-month study.
Methods
This was a 6-month longitudinal randomized controlled trial (RCT) performed at four participating study sites within the US between July 2016 – March 2020. The study protocol was reviewed and approved by the Medical University of South Carolina Institutional Review Board (IRB #Pro00064441), conformed to the 1975 Declaration of Helsinki, and was conducted in compliance with Good Clinical Practices (GCP) of the International Conference of Harmonization (ICH).
Sample and setting
Eligibility criteria included individuals with a VLU or DFU healed within 42 days of enrollment, 18 years of age and older, ankle brachial index (ABI) 0.8- 1.3mmHg to confirm lack of mixed artery-venous disease (cooling could substantially compromise skin blood flow), English speaking, and agreed to attend four study visits. Individuals were excluded from study participation if they had open VLUs or DFUs, cognitive impairment (Mini-Cog score of ≤2 with an abnormal clock draw)16, chronic inflammatory or vascular conditions where blood flow of skin may have been impaired such as Lupus erythematosus, Raynaud’s, and scleroderma, chronic regional pain syndrome, multiple sclerosis, hypersensitivity to cold, currently receiving chemotherapy, or required assistance to physically perform required protocol activities.
We recruited the majority of individuals from wound care provider referrals. A study webpage was created in which a REDCap (Research Electronic Data Capture) survey (https://www.project-redcap.org/) was made accessible to interested individuals to self-prescreen through a series of ‘yes’ and ‘no’ questions. If pre-screening indicated potential eligibility, individuals were contacted by study personnel, and provided an overview of the protocol, study aims, and information about study visits and procedures. If individuals were interested in participation, a baseline study clinic visit was scheduled.
Study Procedures
At the baseline visit, written informed consent was obtained prior to performing eligibility screening and any data collection procedures. As part of the eligibility screening process, a Mini-Cog assessment was performed to rule out cognitive impairment, ABIs were performed on individuals who did not have ABI results in their electronic health record (EHR) within the past 12 months, and the skin area over the healed ulcer was visually inspected for intact dermis. When available, the date of discharge from wound care was used as the ulcer healing date or if the discharge data was unavailable, participant recall of wound closure was used. Participants also completed a checklist that screened for medical exclusions. After screening, eligible participants completed baseline measures, received study instructions, and were randomly allocated to the MUSTCOOL or placebo control interventions. During the baseline visit, participants completed a 12-item verbal test to demonstrate understanding of study procedures and were corrected if 100% successful completion was not achieved. They were also observed using study equipment, providing a return demonstration of certain study procedures such as measuring skin temperature.
Interventions
The MUSTCOOL intervention and the placebo control interventions included a 3 X 4 inch patch applied to the healed VLU or DFU; both were designed by Southwest Technologies (Kansas City, MO, USA). The MUSTCOOL patch was made from a ½ inch sheet hydrogel containing glycerin and the placebo patch was made from cotton batting; both were covered with a polyethylene fabric. The safety and tolerability of both have been previously reported.14 Participants were instructed to apply the patch every other day to the recently healed ulcer area, using stretch net stocking to anchor it in place for 30 minutes while lying in a supine position and legs elevated approximately 10 inches from the level of the heart. The patch was to be stored in a plastic bag in the freezer set at 0°C, and prior to use, removed from the freezer bag to acclimate for 2 minutes, and then placed directly over the healed ulcer. Participants who had difficulty assuming the supine position were instructed to recline in a semi-upright position, and if possible, to use pillows to raise their feet. On treatment days (every other day), participants were asked to document this procedure on their study log by making a checkmark.
All participants were instructed to measure skin temperature over the recently healed ulcer site upon waking every morning using a handheld infrared thermometer (TempTouch, San Antonio, TX) and record it on a study log throughout the 6-month study period. Skin temperature increase have been found to be a strong predictor of DFUs.17 The average of the first 28 days of these morning measurements was considered the ‘baseline’ skin temperature. During study months 2 through 6, participants were asked to monitor the morning skin temperature over the affected area and to compare it to the baseline temperature. If the morning temperature reached or exceeded the baseline temperature by 2°C for two consecutive days participants were instructed to modify the regimen and perform 5 consecutive days of 30-minute patch applications (both placebo and MUSTCOOL) and then resume to every other day. During study month 1, weekly supportive phone calls were made to participants by study personnel, and then monthly thereafter. Participants were asked to stop applying the patch and to contact study personnel immediately if the ulcer returned or if a new ulcer developed elsewhere on the treatment or non-treatment contralateral leg or foot.
We tracked any ulcers that developed during the course of the study, assessed during phone calls, reviewed from recorded data on study logs, and then corroborated from participant reports during return visits at months 1, 3 and 6. Leg and foot skin was assessed during each visit. Participant fidelity to the protocol was assessed during phone calls and in-person study visits by asking participants about frequency of use of the intervention, time of application, leg elevation, and other related procedures.
Sample Size Determination
The primary outcome was recurrence of at least one VLU or DFU over the previously ulcerated skin during the study period. Based on a two-group continuity corrected Chi-square test of equal proportions, with 52 participants per group we had 81% power to detect a difference in proportions with an odds ratio for recurrence of VLU or DFU of 3.5, assuming 25% of participants would experience a recurrent ulcer in the MUSTCOOL group18 compared to 54% in the placebo group12,13, drop-out rate anticipated to be 20% per group13, α = 0.05 (Type I error rate), and two-sided test for intention to treat (ITT) analysis. Figure 1 shows eligibility, randomization, and retention of participants (CONSORT diagram). A computer-generated permuted block randomization strategy was used to assign enrolled patients to the MUSTCOOL or placebo control groups across all participating study sites. Randomization was stratified by ulcer type (VLU or DFU). The block size was varied to minimize the likelihood that the blind would be broken, e.g., the next treatment assignment could be guessed. The Principal Investigator (TK) and all members of the study team who performed visits and data collection procedures were blinded to treatment allocation. To ensure concealment, after baseline measures were collected, another member of the research team (project director) (MM) performed the randomization, and the enrolled participant was then provided with all study materials including the patches and instructions. In addition, user access to the randomization electronic case record form in the study database was restricted to the project director who was also a member of the study’s Data and Safety Monitoring Committee (DSMC). The study blind was unmasked for the members of the DSMC during their semi-annual meetings to monitor the study’s risk profile and to provide recommendations to both the Principal Investigator and IRB regarding study modification and continuance.
Figure 1. CONSORT Participant Flow Diagram.
Abbreviations
VLU: Venous leg ulcer
DFU: Diabetic foot ulcer
PI: Principal Investigator
Data analysis
Descriptive statistics were used to characterize the sample in terms of demographic and clinical features, ulcer recurrence or new ulcer development, and time to new/recurrent ulcer overall or by intervention/control group using frequency distributions and proportions or means with standard deviations and medians as appropriate. All statistical analyses were conducted using SAS Statistical Software Version 9.4 (Copyright © 2016 by SAS Institute Inc., Cary, NC, USA).
Results
One hundred forty participants were randomized to either the placebo control group (n=69) or the intervention (n=71), and 117 individuals (84%) completed the trial. The average age of participants was 62.4 years (SD 12 yrs); 86 (61.4%) were male; 47 (33.6%) were Black or African American; 7 (5%) Hispanic or Latinx. A majority of participants (n= 78, 55.7%) were married; 39 (27.9%) had attended or graduated from college; 62 (44.3%) were retired; 63 (45%) reported current or former job involved manual labor; and 60 (42.9%) were rural US Census designation (Table 1). Clinical characteristics included mean body mass index of 34.8 (SD 9.7). The top 3 comorbid conditions were hypertension (n=102, 72.9%), diabetes mellitus (n=81, 57.9%), and arthritis (n=57, 40.7%). The top 3 medications taken were antihypertensives (n= 99, 70.7%), cholesterol lowering medications (n= 68, 48.6%), and insulin (n = 50, 35.7%).
Table 1.
Demographic Characteristics Overall and by Treatment Group
| Characteristic | Overall (N=140) |
Intervention Cryotherapy (n=71) |
Control TAU (n=69) |
p-value |
|---|---|---|---|---|
| Age | 62.4 ± 12.9 | 61.6 ± 13.8 | 63.3 ± 12.0 | .431 |
| Sex | .831 | |||
| Male | 86 (61.4) | 43 (60.6) | 43 (62.3) | |
| Female | 54 (38.6) | 28 (39.4) | 26 (37.7) | |
| Race | .101 | |||
| Black or African American | 47 (33.6) | 28 (39.4) | 19 (27.5) | |
| White | 91 (65.5) | 41 (57.7) | 50 (72.5) | |
| Ethnicity: Hispanic or Latino | 7 (5.0) | 6 (8.5) | 1 (1.4) | .057 |
| Marital status: | .978a | |||
| Never married | 21 (15.0) | 11 (15.5) | 10 (14.5) | |
| Married | 78 (55.7) | 39 (54.9) | 39 (56.5) | |
| Widowed | 15 (10.7) | 8 (11.3) | 7 (10.1) | |
| Separated | 6 (4.3) | 5 (7.0) | 1 (1.4) | |
| Divorced | 18 (12.9) | 7 (9.9) | 11 (15.9) | |
| Resides with significant other | 2 (1.4) | 1 (1.4) | 1 (1.4) | |
| Education | .059b | |||
| 8th grade or less | 4 (2.9) | 3 (4.2) | 1 (1.4) | |
| Some high school | 7 (5.0) | 3 (4.2) | 4 (5.8) | |
| High school graduate | 51 (36.4) | 31 (43.7) | 20 (29.0) | |
| Some college | 39 (27.9) | 21 (29.6) | 18 (26.1) | |
| College graduate | 25 (17.9) | 6 (8.5) | 19 (27.5) | |
| Post graduate and/or higher level degree | 14 (10.0) | 7 (9.9) | 7 (10.1) | |
| Employment status | .184c | |||
| Employed full-time | 35 (25.0) | 16 (22.5) | 19 (27.5) | |
| Employed part-time | 7 (5.0) | 3 (4.2) | 4 (5.8) | |
| Volunteer full-time | 1 (0.7) | — | 1 (1.4) | |
| Volunteer part-time | 1 (0.7) | 1 (1.4) | — | |
| Not employed | 33 (23.6) | 21 (29.6) | 12 (17.4) | |
| Retired | 62 (44.3) | 29 (40.8) | 33 (47.8) | |
| Student | 1 (0.7) | 1 (1.4) | — | |
| How would you describe your current or former job? | .168 | |||
| Professional | 49 (35.0) | 22 (31.0) | 27 (39.1) | |
| Technical | 24 (17.1) | 11 (15.5) | 13 (18.8) | |
| Manual | 63 (45.0) | 34 (47.9) | 29 (42.0) | |
| Other | 4 (2.9) | 4 (5.6) | — | |
| US Census designation: | .945 | |||
| Rural | 60 (42.9) | 31 (43.7) | 29 (42.0) | |
| Urbanized area | 63 (45.0) | 31 (43.7) | 32 (46.4) | |
| Urban cluster | 17 (12.1) | 9 (12.7) | 8 (11.6) | |
| Body mass index | 34.8 ± 9.7 34.8 [28.1- 39.7] |
34.4 ± 10.4 34.3 [27.9 - 39.5] |
35.2 ± 8.9 35.5 [28.5 - 40.2] |
.518 |
| Top co-morbid conditions | ||||
| Hypertension | 79.2% (102/140) | |||
| Diabetes | 57.9% (81/140) | |||
| Arthritis | 40.7% (57/140) | |||
| Other medical issue | 28.6% (40/140) | |||
| Varicose veins | 24.3% (34/140) | |||
| Top medications | ||||
| Antihypertensives | 70.7% (99/140) | |||
| Cholesterol | 48.6% (68/140) | |||
| Insulin | 35.7% (50/140) | |||
| Diuretics | 35.7% (50/140) | |||
| Diabetes pills | 33.6% (47/140) |
All values expressed as n(%), mean ±s.d., or median[Q1 - Q3]
P-values obtained from pooled t-test, Wilcoxon Rank Sum test or Chi-squared test
P-value for comparison of Never married vs Married or Residing with significant other vs. Separated, divorced, or Widowed
P-value for comparison of High school or less vs. At least some college
P-value for comparison of Employed full- or part-time vs. Not employed, Volunteer or Student vs. Retired
Ulcer development
Forty two of 117 (35.8%) individuals developed an ulcer during the study period; among those with a previous VLU, 21/69 (30.4%) developed a recurrent or new ulcer and in those with a previous DFU 21/48 (43.7%) developed a recurrent ulcer. Overall 26/60 (43.3%) patients in the MUSTCOOL groups (both VLU and DFU) developed recurrent or new ulcers compared to 16/57 (28.1%) in the placebo control group (p = .085). Among VLUs, 13/35 (37.1%) developed a recurrent or new ulcer in the MUSTCOOL group compared to 8/34/ (23.5%) in the placebo control group (p = .219). Among DFUs, in the MUSTCOOL group 13/25 (52.0%) developed a recurrent or new ulcer compared to 8/23 (34.8%) in the placebo control group (p = .230).
Among individuals with previous VLUs (Table 2), 9/69 (13%) developed a recurrent ulcer during the 6-month study period, 12/69 (17.4%) developed a new ulcer, and none developed both types. Of the 9 recurrent VLUs, 6/9 (66.7%) recurred in the MUSTCOOL group compared to 3/9 (33.3%) in the placebo control group. Of the new ulcers, 7/12 (58.3%) developed in the MUSTCOOL group compared to 5/12 (47.7%) in the placebo control group. The time to recurrence did not vary based on group; ulcers recurred during months 3 to 6 in both groups (50% (3/6) in the placebo group versus 5/11 (45%) in the MUSTCOOL group).
Table 2.
Mean Time (with standard deviation [std] and median) to Venous Leg Ulcer (VLU) Development and Proportions Overall and Between Treatment Groups
| Previous VLU group (N = 69) | Overall N=21 |
Placebo Control (n=8) |
MUSTCOOL (n=13) |
|---|---|---|---|
| Developed ulcers | 30.4% (21/69) | 23.5% (8/34) | 37.1% (13/35) |
| Recurrent | 13.0% (9/69) | 8.8% (3/34) | 17.1% (6/35) |
| New | 17.4% (12/69) | 14.7% (5/34) | 20.0% (7/35) |
| Recurrent ulcers | 42.9% (9/21) | 33.3% (3/9) | 66.7% (6/9) |
| Time to ulcer recurrence [days: mean ± std (median)] | 81.0 ± 55.5 (80) | 98.7 ± 36.3 (84) | 72.2 ± 64.2 (50.5) |
| Baseline – end of Month 1 | 33.3% (3/9) | 0 | 3 |
| End of Month 1 to end of Month 2 | 0 | - | - |
| End of Month 2 to end of Month 3 | 33.3% (3/9) | 2 | 1 |
| End of Month 3 to end of Month 6 | 33.3% (3/9) | 1 | 2 |
| New ulcers* | 57.1% (12/21) | 41.7% (5/12) | 58.3% (7/12) |
| Time to ulcer development [days: mean ± std (median)] | 117.3 ± 58.7 (144) | 98.8 ± 63.6 (105) | 132.2 ± 56.9 (151) |
| Baseline – end of Month 1 | 16.7% (2/12) | 1 | 1 |
| End of Month 1 to end of Month 2 | 8.3% (1/12) | 0 | 1 |
| End of Month 2 to end of Month 3 | 0 | - | - |
| End of Month 3 to end of Month 6 | 75% (9/12) | 4 | 5 |
| Number of ulcers (per participant) | |||
| 1 ulcer | 75.0% (9/12) | 5 | 4 |
| 2 ulcers | 16.7% (2/12) | 0 | 2 |
| 3 ulcers | 8.3% (1/12) | 0 | 1 |
Note.
includes 4 new ulcers on non-treatment (contralateral) leg
Among individuals with previous DFUs (Table 3), 14/48 (29.2%) developed a recurrent ulcer, 6/48 (12.5%) developed a new ulcer, and 1/48 (2.1%) developed both a recurrent and new ulcer. Of the 15 recurrent DFUs (this statistic includes the participant that developed both a recurrent and new ulcer), 10/15 (66.7%) recurred in the MUSTCOOL group compared with 5/15 (33.3%) in the placebo group. Most recurrent and new ulcers developed in both during the first 2 months of the study, with 6/9 (66.7%) on the treatment foot in the placebo group versus 7/12 (58.3%) in the treatment foot in the MUSTCOOL group. The distribution of new ulcers between treatment groups and leg or foot is shown in Table 4.
Table 3.
Mean Time (with standard deviation [std] and median) to Diabetic Foot Ulcer (DFU) Development and Proportions Overall and Between Treatment Groups
| Previous DFU Group (N = 48) | Overall N=21 |
Control TAU (n=8) |
Intervention Cryotherapy (n=13) |
|---|---|---|---|
| Developed ulcers | 43.8% (21*/48) | 34.8% (8/23) | 52.0% (13/25) |
| Recurrent | 31.3% (15/48) | 21.7% (5/23) | 40.0% (10/25) |
| New | 14.6% (7/48) | 17.4% (4/23) | 12.0% (3/25) |
| Recurrent ulcers | 71.4% (15/21) | 33.3% (5/15) | 66.7% (10/15) |
| Time to ulcer recurrence [days: mean ± std (median)] | 48.5 ± 34.0 (43) | 45.0 ± 47.5 (43) | 50.3 ± 28.1 (55.5) |
| Baseline – end of Month 1 | 40.0% (6/15) | 2 | 4 |
| End of Month 1 to end of Month 2 | 21.4% (3/15) | 2 | 1 |
| End of Month 2 to end of Month 3 | 35.7% (5/15) | 0 | 5 |
| End of Month 3 to end of Month 6 | 6.7% (1/15) | 1 | 0 |
| New ulcers** | 36.8% (7/19) | 57.1% (4/7) | 42.9% (3/7) |
| Time to ulcer development [days: mean ± std (median)] | 55.3 ± 52.3 (21) | 59.0 ± 60.4 (56.5) | 50.3 ± 51.7 (21) |
| Baseline – end of Month 1 | 57.1% (4/7) | 2 | 2 |
| End of Month 1 to end of Month 2 | 0 | - | - |
| End of Month 2 to end of Month 3 | 0 | - | - |
| End of Month 3 to end of Month 6 | 42.9% (3/7) | 2 | 1 |
| Number of ulcers (per patient) | |||
| 1 ulcer | 57.1% (4/7) | 3 | 1 |
| 2 ulcers | 42.9% (3/7) | 1 | 2 |
Note:
1 patient with both, recurrent and new ulcer, counted in both sections
includes 1 new ulcer on non-treatment contralateral leg
Table 4.
Distribution of New ulcers Between Treatment Groups and Leg (treatment leg [TL] or foot [TF] and Non-Treatment Contralateral Leg [NTL] or Foot [NTF]
| New ulcers | Placebo Control (n=9) |
MUSTCOOL (n=10) |
|---|---|---|
| Venous leg ulcers | ||
| Baseline – end of Month 1 | 1 (TL) | 1 (TL) |
| End of Month 1 to end of Month 2 | 0 | 1 (TL) |
| End of Month 2 to end of Month 3 | 0 | 0 |
| End of Month 3 to end of Month 6 | 4 (2 TL; 2 NTL) | 5 (3 TL; 2 NTL) |
| Diabetic foot ulcers | ||
| Baseline – end of Month 1 | 2 (2 TF) | 2 (1 TF; 1 NTF) |
| End of Month 1 to end of Month 2 | 0 | 0 |
| End of Month 2 to end of Month 3 | 0 | 0 |
| End of Month 3 to end of Month 6 | 2 (2 TF) | 1 (TF) |
Abbreviations
TL: Treatment leg
NTL: Non-treatment leg
TF: Treatment foot
NTF: Non-treatment foot
Among patients with VLUs and DFUs, most of the reported causes of recurrent ulcers were unknown (14/23; 60.8%). However, the remainder (9/23; 39%) were attributed to trauma, swelling, and ill-fitting footwear. Causes of new ulcers that developed on the treatment leg or foot were unknown (5/13; 38.5%); the most commonly reported known causes were trauma and swelling (3/13; 23%). New ulcers that developed on the non-treatment contralateral leg, 5/9 (55.6%) were from unknown causes. Trauma (4/9; 44%) was indicated as the most common reason for developing a new ulcer on the contralateral leg (non-treatment leg).
Time to recurrence
Recurrence at 3 months was 8.7% (6/69) and at 6 months, 13.0% (9/69) in the VLU group and the time to ulcer recurrence [days: mean ± standard deviation (std) (median) was 81 ± 55.5 days. For participants with DFUs, recurrence at 3 months was 29% (14/48) and at 6 months, 31% (15/48). The mean time to ulcer recurrence was 48.5 days ± 34 days.
Discussion
Our 6-month randomized controlled trial investigated the influence of our MUSTCOOL small cooling patch intervention comprised of a sheet hydrogel compared to a cotton-filled placebo patch applied to the site of previously healed VLUs and DFUs, the two most common types of lower extremities ulcers, on reducing the incidence of ulcer recurrence. We studied these two ulcer types because they represent the most common ulcers of the lower extremities particularly VLUs, which account for majority (~90%) of all lower extremity ulcers.19 Our findings suggest the cooling patch did not lower VLU or DFU recurrences more than the placebo patch over the 6-month study period. Nevertheless, median recurrence rates in the MUSTCOOL group were lower than the placebo group.
Recurrence rates for VLUs at 3 months range from 22%18 to as high as 70%5; ours was 8.7%. At 6 months our rate increased slightly to 13% compared to 39% reported in a study by Finlayson and colleagues.18 Studies published within the past 5 years to which we could compare our findings were difficult to locate; we selected the 5-year time frame because new studies reported study population demographics over this time period (obesity, multiple chronic conditions, immobility, age) similar to ours. The mean time to recurrence in our study was 81 days compared with 42 weeks in the Finlayson study.18 It is difficult to compare recurrence rates and times to recurrence among the studies because individuals were given different treatments for VLU (surgical procedures, phlebotonic medications, for example) and engaged in varying levels/types of compression therapy (hallmark of prevention), leg elevation, skin care and exercise. Reports of engagement in compression therapy range from 10% – 86%.20 Findings from a recent summation analysis that included 34 cohorts of patients treated for chronic venous disease and post thrombotic syndrome showed moderately good compliance with compression stockings (66.3%).21 Compliance was not defined in their review. While we instructed participants to document on the study log what they did specific to standard of care (wore compression stockings, elevated legs, performed skin care), few recorded this information, thus we were unable to draw conclusions about whether engagement influenced our study findings.
The DFU recurrent rate in our study was 29% at 3 months as compared to 60% reported by Dubsky and colleagues22 and our 6-month recurrence rate was 31% compared with 53% reported in a study by Galea and colleagues.23 In a 34-week incidence study conducted by Petersen and colleagues24 28.7% experienced a DFU recurrence. The authors did not report the breakdown over time and we are unable to compare their findings with our rates measured at 3- and 6-months. Our data suggest the MUSTCOOL intervention reduced the incidence of DFUs, similar to a recurrence rate that reported in the Petersen study, although most (48%) of the DFUs in their study occurred at a new location on the contralateral foot; only 17% recurred over the recently healed location. We point out that more DFUs (10/15) recurred in the MUSTCOOL group in our study, compared 5 in the placebo control group. Similar to VLUs, DFU participant reporting of engagement in standard of care including the wearing of therapeutic footwear and socks and daily foot hygiene was inconsistent and could not be factored into the analysis to determine influence on DFU recurrence. The mean time to onset of a DFU recurrence was 48.5 days; we could find no recent study to use as a comparison.
We also assessed the incidence of new ulcers on areas of the lower legs and feet that did not receive the interventions and found there were more new ulcers compared to recurrent ulcers in the group with VLUs. Of note, there were no clinically relevant differences in the number of new ulcer (7 compared 5) in MUSTCOOL or placebo groups, respectively. To explain why new ulcers might develop adjacent to previously healed ulcers, we explored the literature on patient engagement in guideline-recommended preventive measures and found that adherence is as low as 27%.25 Reasons cited for non-adherence were lack of patient knowledge in wearing compression stockings and lack of education by professionals during delivery of care.26 Data from our previous cooling efficacy study indicated 85% of participants were adherent to standard of care.14 This wide variability in reported adherence rates makes it difficult to draw conclusions regarding outcomes on new ulcers. We were unable to find data on physiological causes to explain new ulcers that developed on the non-treatment areas (same and contralateral leg or foot) aside from lack of patient engagement or worsening of disease.
While we could not establish statistically significant differences between the MUSTCOOL and placebo interventions for the VLU and DFU groups, we observed slightly higher numbers of recurrent and new ulcers in the MUSTCOOL groups. Participants in the MUSTCOOL groups had slightly higher reports of traumatic injuries and swelling; however, these were not deemed clinically relevant. Overall, the MUSTCOOL intervention did not reduce the incidence of both VLU and DFU recurrence compared to placebo over the 6-month study period.
Strengths and Limitations
The intent of this study aim was to report the incidence of VLU and DFU recurrence in response to the MUSTCOOL intervention compared to placebo. We were able to provide recent incidence data on a non-pharmacological method aimed to reduce VLU and DFU recurrence; we showed the incidence of recurrence in both of our study populations was lower than reports in the literature. Limitations included difficulty assessing participant engagement in standard of care, an important component of our study. We identified several participants who reported they could not afford to purchase therapeutic footwear or compression stockings due to costs, thus the likelihood of their use of standard of care was minimal. It is important to note that the MUSTCOOL protocol was complementary to standard of care and not intended as a stand-alone intervention.
Conclusion
Notably absent from the literature are new approaches to prevent the frequent recurrence of VLU and DFU in at risk populations. Coupled with daily standard of care, our MUSTCOOL intervention, utilizing a cooling gel patch applied every other day to a recently healed lower-leg VLU or foot DFU, minimally reduced the incidence of recurrence during the 6-month study period, the time frame in which recurrence rates are the highest. When the ulcer did recur, time to onset was often delayed, but this could not be confirmed in DFU recurrence. We hypothesize that cooling may ameliorate the aberrant inflammatory response during tissue remodeling in the types of wounds we studied, thus decreasing this physiological risk factor for recurrence. However, this mechanism of cooling action did not result in prevention of recurrence. Due to poor reporting from participants, we were unable to determine engagement in standard of care thus we could not analyze the influence on recurrence. Nonetheless, 70% of participants with recently healed VLUs and 56% of those with DFUs remained ulcer-free during the 6-month study period.
Acknowledgements:
The authors thank Dr. Dana E. King MD (independent medical monitor), Dr. Debra Miller-Cox (wound specialist advisor), MD, Dr. Mary Hanley, DO (wound specialist advisor), and Dr. Carolyn Horne, PhD, RN (nursing science advisor) for their support of this project.
Sources of funding: Research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health under Award Number R01NR015647, and, in part, by the National Center for Advancing Translational Sciences of the National Institutes of Health under Grant Number UL1 TR001450. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Conflict of Interest Disclosure Statement:
The authors have no conflicts of interest to report.
Contributor Information
Teresa J. Kelechi, Medical University of South Carolina, College of Nursing, 99 Jonathan Lucas Street, MSC 160, Charleston, SC 29425, US.
Mohan Madisetti, Medical University of South Carolina, Charleston, SC.
Margaret Prentice, Medical University of South Carolina, Charleston, SC.
Martina Mueller, Medical University of South Carolina, Charleston, SC.
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