INTRODUCTION
Chronic ulcers affect 6.5 million individuals, and of these, 5 million suffer with ulcers of the lower extremities.1 Often related to diabetes, vascular and/or neuropathic conditions, or infection, approximately 50% of these ulcers take longer than 4 weeks to heal.2 After healing, lower extremity ulcers have extremely high recurrence rates: 70% to 96% of venous leg ulcers (VLUs) reoccur within 2 to 3 months of healing3 while 40% of diabetic foot ulcers (DFUs) reoccur within 1 year.4 Leg and foot ulcers represent a substantial portion of the health care cost burden associated with treatment, conservatively estimated to be nearly $32 billion among Medicare beneficiaries receiving care in outpatient settings.5 This cost does not account for home-based care or out-of-pocket supplies purchased by individuals. Care of DFUs alone can increase costs by $9 billion to $13 billion in excess of typical diabetes mellitus care costs, which are estimated to increase to $2.1 trillion to $2.4 trillion in 2030 from $1.3 trillion in 2015.6 These economic figures do not account for the costs of human suffering and negative impact on physical activity and health-related quality of life.7,8 Health care costs and human suffering are increased when ulcers become chronic and recalcitrant to treatment. Unfortunately, incidence, prevalence, and morbidity associated with chronic ulcers are expected to increase as a result of the growing aging population suffering with vascular disorders, diabetes, and obesity.2 Further, impaired functional status of these patients often limits wound self-management and can hamper treatment effectiveness, reducing healing outcomes.
Research on chronic wound populations shows high physical and functional morbidity. Findings from studies of physical complaints show pain affects between 48% and 94% of individuals seeking wound care in outpatient and community nursing clinics.9-11 It is a widely held belief that the sensory neuropathy that often accompanies foot ulcers leads to an "insensate" foot; paradoxically, pain is present in up to 75% of individuals with diabetes-related foot ulcers.12 Pain and other uncomfortable symptoms such as itch, tingling, and achiness are also prevalent in patients with healed ulcers.13 Research also shows a high number of individuals with VLUs and DFUs are physically deconditioned, less physically active, have poor balance and gait abnormalities, and are slower walkers.14,15 These individuals are at high risk for falling and sustaining injuries16 and have poor health-related quality of life owing to a number of factors including pain, decreased physical function, social isolation, and wound severity.11,17,18
While nonpharmacologic interventions such as exercise and physical activity play a role in ulcer prevention and healing,19 our research focuses on a patient population at highest of risk for developing ulcers-those with recently healed ulcers. These patients often experience other distressing symptoms such as pain and have low physical activity levels.20 The intervention framework selected for this study is based on cooling theory and its influence on pain reduction, espousing that skin over the healed ulcer site is highly susceptible to reulceration due to numerous factors including poor tissue remodeling and aberrant inflammation from venous and diabetic disease processes that can elevate skin temperature and subsequently induce chronic pain.21,22 Cooling has been found to decrease foot and leg temperatures in patients with chronic wounds; it is also postulated to mitigate metabolic demands and abnormal cytokine production preventing tissue autolysis, along with reducing oxidative stress by increasing total antioxidant status.23,24
There are also benefits in reducing pain through affecting nociceptor function and slowing nerve transmission velocity in pain fibers.13,25 Pain, in particular, is known to negatively influence physical activity in patients with chronic venous disease.26 In an attempt to address pain and physical activity, we developed a topically applied cooling patch as part of our MUSTCOOL intervention and posited that if pain was reduced, individuals would feel better and become more physically active. To explore this assumption, we evaluated the efficacy of the MUSTCOOL intervention to determine whether it prevents ulcer recurrence in individuals with recently healed VLUs or DFUs when compared to a placebo (noncooling) patch.27
METHODS
A longitudinal randomized controlled trial design guided data collection and analysis. The target population comprised consented individuals with VLUs (n = 82) or DFUs (n = 58) that had healed up to 6 weeks prior to study enrollment. Patients were recruited through wound center referrals and advertisements placed in outpatient clinics in 2 US Southeastern states. Inclusion criteria were 18 years and older, an ankle-brachial index of 0.8 to 1.3 mm Hg to confirm artery blood flow sufficiency, English speaking, and agreed to attend 4 study visits. Exclusion criteria were cognitive impairment measured with the Mini-Cog28 (score of <=2 with an abnormal clock draw), inflammatory or vascular conditions such as cold hypersensitivity, chronic regional pain syndrome, Lupus erythematosus, multiple sclerosis, receiving chemotherapy, or required physical assistance to perform study-related procedures.
Study Procedures
A permuted block randomization strategy developed by the study statistician was used to assign participants with newly healed VLUs and DFUs to either the cooling or placebo group. Randomization was stratified by ulcer type. The principal investigator (T.J.K.) and external consultants were masked to treatment assignment. To minimize the likelihood that the mask could be broken (eg, the next treatment assignment could be guessed), the block size was varied. At baseline, the research assistant consented, determined eligibility, enrolled, collected baseline data such as demographics, pain and physical activity, and then instructed participants on treatment procedures and provided all study supplies (eg, patches). The primary outcomes were pain and physical activity. For the analysis of continuous efficacy outcome measures (change from baseline), we had 85% power to detect a difference of 0.59 seconds (Cohen's d) between the treatment and control groups for VLU (80/group) and DFU (60/group) assuming [alpha]= .05 (type I error rate), 2-sided independent sample t-test comparison of means, and equality of variance between groups. Occurrence of VLU is twice that of DFU; hence the difference in sample size determination. A CONSORT diagram (Figure) shows enrollment, allocation, and follow-up of participants.
The Medical University of South Carolina institutional review board (study #Pro00064441) approved this research conducted between July 2016 and March 2020. The study conformed to the Declaration of Helsinki and was conducted in compliance with Good Clinical Practices of the International Conference of Harmonization. Participants provided written informed consent, received US $250 in compensation, and were informed that all data would remain confidential in a password-protected database Research Electronic Data Capture (REDCap) (https://www.project-redcap.org/).
Intervention
The self-management components of the MUSTCOOL intervention were completed by participants in both the cooling and placebo groups. Prophylactic maintenance component consisted of patch application (glycerin cooling or cotton-filled placebo) at a consistent time (eg, 7 PM) for 30 minutes to the affected leg or foot skin with legs elevated. The dosing for prophylactic maintenance was 3 times each week. In addition, a preventive bolus was administered over 5 consecutive days when increased temperature measured via a skin thermometer for 2 consecutive days above baseline was noted. The cooling patch was a 3 x 5 flexible, half-inch-thick glycerin-based sheet hydrogel that did not freeze to a solid state. We previously conducted extensive safety testing of the material without adverse events (eg, skin injury).29 The placebo patch was identical to the glycerin patch but was cotton filled (manufactured by the same company). Both patches were covered with a protective polyethylene fabric that could be laundered and stored in the freezer. Participants received freezer thermometers to make sure freezer temperature was maintained at 0[degrees]F. Once removed from the freezer, the placebo patch warmed to room temperature within 2 minutes. The patches were anchored to the site with a tubular retainer made of an expandable elastic latex-free stretch net. Participants recorded the date and time the patch was applied on a written log. The other MUSTCOOL component was self-use of standard of care; the VLU group wore compression stockings and elevated legs and the DFU group wore therapeutic footwear, per their health care provider recommendations.
Participants were asked to stop applying the patch and contact study personnel immediately if the ulcer returned or if a new ulcer developed elsewhere on the participant's leg or foot. During study month 1, weekly supportive phone calls were made to participants by study personnel, and then bimonthly thereafter. These calls included fidelity monitoring for adherence to the patch application procedure, protocol deviations, and adverse events.
Data Collection and Outcome Measures
Demographic characteristics measured were age, race, sex, education level, employment status, type of job, depression measured with the Geriatric Depression Scale,30 weight, and body mass index (kg/m2). Pain was measured with the Brief Pain Inventory (BPI)31 (Cronbach's [alpha] 0.88) and reported as change in worst and least pain, and pain right now from baseline to end of study at 6 months. The BPI also assesses pain severity and intensity with an average score calculated for both subscales: pain severity (4 items rated from 0 = no pain to 10 = pain as bad as you can imagine; and pain interference (7 items rated from 0 = does not interfere to 10 = completely interferes). Higher scores indicate worse interference and severity. We also collected data on pain descriptors common in patients with venous disease and diabetes/neuropathic disorders such as ache, burning, and numbness sensations.
Physical activity was assessed using the patient-reported International Physical Activity Questionnaire (IPAQ)32 (pooled Spearman R 0.81) calculated as metabolic equivalent of tasks (METs) minutes per week. The total MET is the sum of MET minutes per week spent walking, moderate-intensity activity, and vigorous-intensity minutes (with the different activities weighted differently). Scoring of high, moderate, or low physical activity levels is based on time and intensity of various types of activity. Objective physical activity data were captured using the Yamax Power Walker EX-510 3D accelerometer (Yamax Corp, Tokyo, Japan), a user-friendly activity tracker that recorded daily steps and time/duration. The Yamax pedometer has undergone validity studies and has also shown to be accurate in measuring physical activity among older adults.33,34 These 3 outcomes were assessed at baseline, and months 1, 3, and 6 during study visits at the Research Nexus, study clinics, or during home visits.
Data Analysis
The primary efficacy outcomes were changes in pain and physical activity from baseline to the primary endpoint at 6 months post-baseline (continuous). In analysis of the continuous efficacy outcome measures, we compared unadjusted mean differences in pain (BPI scores) for 3 individual subscores "worst pain," "least pain," and "pain right now" and composite scores (mean of subscores) via paired t tests (or equivalently nonparametric Wilcoxon signed rank test) between the (cooling vs placebo) groups for VLU and DFU participants who provided both baseline and 6-month measures. Physical activity in MET minutes per week, captured by the IPAQ, was calculated as MET at 6 months minus MET at baseline and was computed as per instructions (http://www.ipaq.ki.se); negative numbers indicate a decrease in METs. Median MET minutes were compared via quantile regression, while Fisher's exact tests were used to compare physical activity categories between the groups and general linear models were used for comparison of change in steps via pedometer counts and activity time over 6 months. All statistical analyses were performed using SAS Statistical Software Version 9.4 (Copyright (C) 2016 by SAS Institute Inc, Cary, North Carolina). A 2-sided P < .05 was considered statistically significant.
RESULTS
The samples sizes were 15 and 28 in intervention and placebo control groups for healed VLUs and 12 and 15 for healed DFUs, respectively. Demographic data are shown in Table 1. The VLU group was slightly older (mean age 64.1 years) than the DFU group (58.4 years). The majority of the DFU group (75.9%) were males compared to the VLU group (50.7%). Most participants in both groups were married, had a least a high school education, were retired, were obese (body mass index >30), and had average scores on the Geriatric Depression Scale less than 2, indicating no depression/normal. No significant differences were noted in any of the demographic characteristics.
Pain
At baseline (Table 2), there were no significant differences between group composite scores for pain severity (VLU placebo control 0.6, and cooling intervention 0.8; DFU placebo 0.3, intervention 1.0, respectively) or pain interference (VLU placebo control 0.7, intervention 0.7; DFU 0.3, intervention 0.8, respectively). More healed VLU participants endorsed having discomfort/pain from the healed ulcer over the past month at baseline-38.1% in the VLU placebo group and 48.8% in the intervention group compared to 24.1% with healed DFUs in the placebo group and 37.9% in the intervention group. Few individuals in both groups were taking medications or receiving treatments at baseline for pain. At baseline, the commonly reported pain descriptors reported by 5 or more individuals for 11 symptoms in either placebo or intervention groups for healed VLUs included aching, burning, numb, sharp pain, shooting pain, tenderness, and throbbing. Aching, sharp shooting, and throbbing symptoms were found in the healed DFU intervention or placebo groups. At study completion, no pain descriptors had more than 5 participant reports (Table 3). Table 3 shows comparisons of changes/differences in scores from baseline to 6-month end of study for the BPI worst pain, least pain, and pain right now items. Difference scores showed slight reductions (scored as "a little bit" with negative scores indicating improvement) between placebo and intervention groups for healed VLU pain severity (-0.5) and interference (-0.9) and healed DFU pain severity (-0.3) and interference (-0.2), respectively; none were statistically significantly different (all P > .16).
Physical Activity
Few participants completed both baseline and 6-month follow-up for the IPAQ (Table 3). Difference changes in MET minutes per week were low (several were 0) for the placebo and cooling groups for both healed VLU and DFU participants; no significant differences were noted. At baseline (Table 2), participants largely fell into the inactive/sedentary activities category, with median 2544 MET minutes for the VLU cooling group (n = 34/42, 81.0%) versus 2514 METs in the control (n = 29/40; 72.5%). Similarly, findings indicated 699 versus 2735 MET minutes for DFU (n = 26/48, 89.7%) and (n = 22/29, 75.9%) control groups, respectively. Steps taken for both VLU and DFU placebo and intervention groups showed no statistically significant differences in average steps over 6 months; however, improvements were noted in both VLU groups, although minimal. Pedometer use was more consistent for both groups compared to completion of the IPAQ. Overall, 47 out of the VLU sample used the accelerometer between 3 and 24 weeks, 4 used it 3 to 5 weeks, 12 used it 11 to 20 weeks, and 31 used it 21 to 24 weeks. Among controls, 6 used it 11 to 19 weeks and 17 used it 21 to 24 weeks; among the intervention group, 4 used it 3 to 5 weeks, 6 used it 12 to 20 weeks, and 14 used it 21 to 24 weeks. Overall, 30 out of the DFU sample used the pedometer between 3 and 24 weeks; 6 used it 3 to 9 weeks, 9 used it 11 to 16 weeks, and 15 used it 23 or 24 weeks. Among controls, 2 used it 9 weeks, 4 used it 13 to 16 weeks, and 8 used it 23 to 24 weeks; among the intervention group, 4 used it 3 to 10 weeks, 5 used it 11 to 14 weeks, and 7 used it 24 weeks.
DISCUSSION
We studied individuals with recently healed venous and diabetic/neuropathic foot ulcers and compared pain and physical activity outcomes using a cooling intervention developed to prevent ulcer recurrence and mitigate negative symptoms post-healing versus a sham patch. We targeted this population because rates of ulcer recurrence associated with VLUs and DFUs are high and in response developed our MUSTCOOL leg and foot ulcer prevention intervention27 as a self-management approach to reduce the incidence of reulceration and reduce subsequent negative physical symptoms, including pain. Conventional prevention treatments include leg compression, proper footwear, and underlying disease management35; however, there has been much less focus on self-management approaches to mitigate negative symptoms such as pain that can further impair functional outcomes in population with chronic conditions. We did not find substantial changes in pain after leg and foot ulcers healed. Pain severity and interference, while endorsed, were minimal at baseline, even less so for the DFU group.
Pain is a common physical complaint often associated with chronic wounds and has been found to be as high at 94% in a study of 73 patients seeking care in a vascular clinic11 and ranged from 48% to 81% (average 74%) in a study of symptom clusters in 318 patients with VLUs recruited from hospital outpatient and community nursing clinics.10 Paradoxically, pain has been found in up to 75% of individuals with diabetes-related foot ulcers.12 It is a widely held belief that sensory neuropathy often accompanies DFUs, leading to an "insensate" foot or lack of sensation; however, this claim is unsupported. We surmised pain would continue post-healing, but this was not the case and we did not have data about pain experienced while having the ulcer. Unfortunately, we were unable to find studies that reported pain specifically after wound healing to draw comparisons with our findings.
Our data suggest a large portion of the VLU and DFU groups are inactive; this finding is consistent with prior research that shows a high number of individuals with chronic ulcers are physically deconditioned, less active, have poor balance and gait abnormalities, and are slower walkers.14,15 In a study of 106 individuals with VLUs, 60 (44%) reported falling during the study period and 47 (78%) had a history of repeated falls.16 In a study of physical function of individuals with DFUs presenting for surgery to treat infection, 70% (n = 49/92) scored 2 standard deviations below the US population mean on the Patient Reported Outcomes Measurement Information System (PROMIS) for physical function.36 We measured physical activity with the IPAQ that measured MET minutes per week at baseline and end of study. Few individuals improved in their overall activity level for METs (minutes per week); however, few participants completed the questionnaire at 6-month end of study. One MET is defined as approximately 1 kcal/kg/h and includes activities such as sleeping, lying quietly, or meditating.37 Activities achieving levels of moderate-intensity physical activity typically include brisk walking, swimming leisurely, or cycling leisurely, whereas activities achieving vigorous-intensity physical activity include jogging, cycling fast, or playing a game of football. Sedentary activities typically include lying, sitting, eating, or standing quietly.38
We observed good adherence (>60% of completers used it through study completion) to pedometer use for steps taken and time engaged in walking; steps taken and time did improve in the VLU group more so than the DFU group, but improvements were noted. Anecdotally during end of study interviews, participants said they liked feedback from the device because it helped "motivate" them to walk more. Nevertheless, both groups largely fell into the inactive/sedentary activities category. While minimal gains were achieved among some participants, we assert that even small increases such as 10 additional minutes of walking or an additional 350 to 1100 steps/day may suggest clinically important improvements in populations with chronic diseases such as chronic obstructive pulmonary disease.39 We also acknowledge that additional research is needed to support the clinical relevance of the time and step counts in a posthealing ulcer population.
While physical activity and other nonpharmacologic interventions play a role in wound healing, our research focused on prevention of VLU and DFU recurrence using a topically applied cooling patch to augment standard of care that included compression, leg elevation, and therapeutic footwear. Consistent inspection, skin care, and trauma prevention over the healed site are critical nursing care recommendations because the ulcer continues to remodel during the final stage of healing. Evidence suggests that aberrant inflammation may play a role in poor remodeling in individuals with venous disease and/or diabetes, placing the healed area at risk for reulceration.
Strengths and Limitations
The strengths of our study include the use of a well-established, self-management approach that incorporates self-report, monitoring, and application of an evidence-based cooling intervention intended to augment standard of care. To enhance rigor, we selected a randomized controlled trial and implemented consistent fidelity monitoring. This study is our second randomized controlled trial of the MUSTCOOL intervention. In the first, we provided standard-of-care devices and supplies that included compression wraps, leg elevator pillows, and skin care products as part of the study intervention. In this second trial, a more "real-world" approach was used in which we instructed participants to "do what your health care provider prescribed/recommended" after the ulcer healed. Weaknesses include our inability to accurately assess adherence to standard of care, which could have influenced findings. Those who adhered less than 85% of the time to the treatment protocol may have experienced a less robust response. Anecdotally, we observed during study visits that many of the study participants did not consistently wear compression stockings or therapeutic footwear, which may have influenced their overall disease management outcomes such as edema, thus limiting the efficacy of our intervention. Our sample sizes were small and there were fewer participants with DFUs, which we anticipated (~70% to 80% of all lower extremity ulcers are VLUs while <30% are DFUs).
CONCLUSIONS
Health care providers play a major role in wound management, which includes recommendations for improvements in postwound healing, adherence to standard of care, and meticulous self-inspection over the healed site. Despite the existence of guideline-guided care for prevention,35,40 ulcer recurrence rates remain high. In this study we posited that augmenting care with our evidence-based self-management MUSTCOOL intervention, pain would be reduced and consequently physical activity, specifically walking, would be enhanced. However, we were unable to support this pain assumption chiefly because the population experienced low to no pain at study onset. We wish to emphasize MUSTCOOL is intended to augment standard of care; it was not designed to replace intervention for wound prevention. Nonetheless, our previous work supports that adherence to the MUSTCOOL intervention for at least 85% of the time decreased the risk of ulcer recurrence from 18% to 7% (P = .012), and provided clinically relevant improvements in pain, cramping, ache, itch, and throb, the 5 most commonly-reported distressing symptoms associated with venous disease.27,41 Thus we suggest nurses and other health care providers recommend the use of the cooling patch in patients with venous disease or have a recently healed VLU and with these distressing symptoms consider use of MUSTCOOL for VLU prevention and/or symptom management. Recommendations for further study in DFU patients are warranted.
ACKNOWLEDGMENT
The authors thank Dana E. King, MD (independent medical monitor), Debra Miller-Cox, MD (wound specialist advisor), Mary Hanley, DO (wound specialist advisor), and Carolyn Horne, PhD, RN (nursing science advisor) for their support of this project.
REFERENCES