Reduced Hospitalizations and Amputations in Patients with Diabetic Foot Ulcers Treated
with Cyclical Pressurized Topical Wound Oxygen Therapy: Real-World Outcomes
Jessica Izhakoff Yellin,1 Julia A. Gaebler,1 Frank F. Zhou,1
Timothy Niecko,2 Olivia Novins,1 Amelia Ockert,1 Darcy Krzynowek,1 Matthew G. Garoufalis,3 Aliza M. Lee,4 and Robert G. Frykberg5,*,i
1Health Advances LLC, Newton, Massachusetts, USA.
2Niecko Health Economics LLC, Tierra Verde, Florida, USA.
3Department of Podiatry, Jesse Brown VA Medical Center, Chicago, Illinois, USA.
4Department of Podiatry, Salem Veterans Affairs Medical Center, Salem, Virginia, USA.
5Department of Podiatry, Diabetic Foot Consultants, Midwestern University, Glendale, Arizona, USA.
iORCID ID (https://orcid.org/0000-0001-9095-303X).
Background: This study sought to examine the real-world impact of multi- modality cyclical-pressure topical wound oxygen therapy (TWO2) on hospital- izations and amputations in patients with diabetic foot ulcer (DFU) compared with patients without TWO2.
Methods: We conducted a retrospective review of deidentified patient medi- cal records at 2 U.S. Veterans Affairs hospitals between January 2012 and January 2020. DFU patients were assigned to TWO2 or NO TWO2 cohorts based on their treatment records. Patients received appropriate standard of care and may have received other advanced wound treatments, including skin substitutes, negative pressure wound therapy, and growth factors. Pri- mary study outcomes were patients requiring hospitalization and/or ampu- tation within 360 days of initial wound documentation.
Findings: Among unmatched cohorts of 202 patients with DFU (91 TWO2, 111 NO TWO2), 6.6% and 12.1% of TWO2 patients had hospitalizations and amputations, respectively, compared with 54.1% and 41.4% of NO TWO2 patients within 360 days ( p < 0.0001, p < 0.0001), representing 88% and 71% reductions. Among propensity score-matched cohorts of 140 DFU patients (70 TWO2, 70 NO TWO2), compared with NO TWO2, 82% fewer TWO2 patients were hospitalized (7.1% vs. 40.0%, p < 0.0001) and 73% fewer TWO2 patients had amputations (8.6% vs. 31.4%, p = 0.0007). Logistic regression among matched cohorts demonstrated nearly ninefold and fivefold higher risk of hospitalization and amputation, respectively, for NO TWO2 versus TWO2.
Interpretation: This retrospective cohort study demonstrates that treating pa- tients with DFU with TWO2 is associated with significant reductions in hospi- talizations and amputations in the real-world setting.
Keywords: diabetic foot ulcers, topical oxygen therapy, amputations, hospitalizations
Robert G. Frykberg, DPM, MPH
Submitted for publication July 15, 2021.
Accepted in revised form October 19, 2021.
*Correspondence: Department of Podiatry, Diabetic Foot Consultants, 15411 N. Tepic Lane,
Fountain Hills, AZ 85268, USA
(e-mail: [email protected]).
ª Jessica Izhakoff Yellin et al., 2021; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License [CC-BY] (http:// creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduc- tion in any medium, provided the original work is properly cited.
Diabetic foot ulcers (DFUs) are concerning, particularly as nonhealing and recurrent DFUs can lead to hospitalization, amputation, and death.1,2 Estimates of the 5-year mortality rate af- ter lower extremity amputation range from 46% to 57%, depending on the type of amputation.3 As a result, DFUs continue to be a serious and costly condition.4,5 A 2014 study estimated that DFUs cost U.S. public and private payers $9–13 billion per year in addition to costs associated with diabetes.6
Standard of care (SOC) treatment for DFUs is widely accepted to include debridement, effective offloading, treatment of infection, and vascular intervention as required.7,8 However, DFU is a complex condition and despite optimal SOC, many wounds remain difficult to heal or frequen- tly recur.2 While a number of adjunctive thera- pies are available for use, the quality of evidence about their respective efficacy rates is regarded to be low, due primarily to small and poorly de- signed studies, as well as difficulty extrapolating drawn conclusions to the general, real-world DFU population.9,10
Oxygen therapy has been widely studied in the treatment of DFU, as oxygen is critical to the pro- cess of healing a wound.11 Nonetheless, efficacy results from studies of hyperbaric oxygen ther- apy and topical oxygen therapy (TOT) vary, and conclusions regarding effectiveness are inconsis- tent.12–14 A recent double-blind, sham-controlled trial, however, showed significantly improved healing of chronic DFUs with multimodal cyclical pressurized topical wound oxygen therapy (TWO2) at both 12 weeks and 12 months.15
There are several different types of TOTs, each with unique properties in terms of dressings and/or mode of delivery of oxygen topically to the wound bed. These can be categorized as (1) normobaric flow of continuous diffusion of oxygen under pro- prietary dressing devices, (2) low constant pressure devices in a contained chamber, and (3) the device used in this study, incorporating cyclically pres- surized (10–50 mb) and humidified oxygen delivery within a contained chamber or boot.11
Unfortunately, there is a paucity of studies to support the use of TOT within real-world, repre- sentative populations. This study, therefore, sought to evaluate the real-world impact of home- based cyclical pressurized topical wound oxygen therapy on DFUs by analyzing subsequent hospi- talizations and amputations in a large, real-world, representative patient population.
We used deidentified data collected retrospec- tively from patient medical records at two U.S. Veterans Affairs (VA) hospitals. The period of review was January 2012 through January 2020. Patients were identified through a primary diag- nosis of diabetic, ischemic, venous, pressure, and multimorbid wounds (total N = 246). Only patients with a primary diagnosis of DFU (either alone or multimorbid with other wounds) were included in the analysis (N = 202). The protocol was approved by the Institutional Review Board at each facility. Patient medical records were reviewed for de- mographic information such as age, sex, and eth- nicity, wound characteristics, including Wagner classification, wound duration, area, and addi- tional clinical characteristics, including prior amputation, type 1 or 2 diabetes, neuropathy, car- diovascular disease (CVD), peripheral arterial dis- ease (PAD), venous disease, pain level, and stage of kidney disease.
We evaluated the impact of treating chronic DFU with home-based multimodality cyclical pres- sure topical wound oxygen therapy (TWO2), (AOTI Ltd., Galway, Ireland), on hospitalizations and amputations. As is common in clinical practice, study participants may have also received addi- tional adjunctive therapies, including negative pressure wound therapy (NPWT), skin substitutes (SS), and/or growth factors (GF). This study fo- cused on the impact of TWO2 in the real-world setting to corroborate the recent positive find- ings from the aforementioned strictly controlled randomized trial of TWO2 versus sham-treated controls.15
To evaluate the effectiveness of TWO2, we developed two comparison groups. Comparison #1 (C1) compared patients who had ever received TWO2 (TWO2) with those who had never received TWO2 (NO TWO2). Patients in each cohort may have received treatment with additional adjunc- tive therapies, so TWO2 was considered additive to adjunctive treatment in C1. Comparison #2 (C2) compared patients who had received only TWO2 and no other adjunctive wound care therapies (TWO2 ONLY) with those receiving SS, NPWT, and/or GF, but not TWO2 (OTHER TX ONLY), thus evaluating the impact of TWO2 in lieu of other adjunctive treatments. Patients in each co- hort received appropriate SOC irrespective of any adjunctive therapies, including TWO2.
The primary study outcomes were defined as patients with one or more wound-related hospi- talization or amputation within a 1-year analysis period. Medical records were reviewed for presence of wound-related hospitalization or amputation at 90, 180, and 360 days after first documentation of the wound. The presence of a first hospitali- zation or amputation at any time point before or at 360 days classified a patient as having had a hospitalization or amputation within 360 days. Because the study outcomes were patients with wound-related hospitalizations and amputations, no patient was counted for more than one hospi- talization or amputation if multiple such episodes occurred.
Missing data for demographics and clinical characteristics was imputed by the single imputa- tion hot-deck method. This method uses observed values from the sample to impute (fill-in) missing values. In instances of missing outcomes data, we applied the last observation carried forward (LOCF) method, which is a common statistical approach to account for missing follow-up obser- vations.16 We assumed that any patient without follow-up data suggesting a hospitalization or amputation during the 360-day period was cate- gorized as not hospitalized or not amputated.
Baseline demographics and clinical character- istics were assessed by chi-square test for cate- gorical and t-tests for continuous variables. In cases where cell size was small (<5) for categorical assessments chi-square may not be a valid test, thus Fisher’s exact test was used.
When using an observational study design, such as a retrospective cohort study, subjects are not ran- domized to a treatment or control group. Confounding can occur when some of the covariates are related to both the treatment and the outcome. Consequently, there can be systematic differences between the treated subjects and the control subjects.
In the presence of confounding, statistical ap- proaches are required to remove the effects of confounding when estimating the effect of the treatment. Propensity score matching minimizes the effects of confounding by achieving more bal- anced covariates in the absence of a randomized study design.17,18 We, therefore, applied propen- sity score matching by means of a greedy algori- thm to match TWO2 patients to NO TWO2 patients in a 1:1 ratio. Cohorts were matched on age, sex, ethnicity, wound severity, prior amputation, use of offloading, and use of NPWT, SS, or GF.
In addition, the study dichotomous outcomes of wound-related hospitalization versus no hospitali- zation, and amputation versus no amputation were assessed by logistic regression within the matched cohorts for C1 (NO TWO2 vs. TWO2). The logistic model calculated odds ratios (ORs), 95% confidence intervals (CIs), and p-values for the study treat- ment arms (NO TWO2 vs. TWO2). Statistical tests were two-sided, and significance level was set at p < 0.05. Analyses were performed using SAS soft- ware version 9.4.
Role of the funding source
The funders of the study had no role in study design, data analysis, data interpretation, or writ- ing of the report, but did help coordinate data col- lection. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
A total of 202 patients with DFU were identified. For C1, 91 DFU patients qualified as ever receiving TWO2 (TWO2), and 111 patients qualified as never receiving TWO2 (NO TWO2). During the 1-year analysis time frame, patients in each cohort may have been treated with other advanced wound care treatments, including SS, NPWT, and GF. For C2, 58 DFU patients received only TWO2 and no other adjunctive wound care therapies (TWO2 ONLY), and 34 patients received only SS, NPWT, and/or GF, but not TWO2 (OTHER TX ONLY).
Table 1 presents demographic and clinical char- acteristics of unmatched and matched cohorts. For C1, unmatched cohorts of TWO2 versus NO TWO2 were similar on most characteristics, including the use of adjunctive therapies, although statistically significant differences were present for wound se- verity ( p < 0.0001), prior amputation ( p = 0.011), pain level ( p = 0.011), and stage of kidney disease ( p < 0.0001). For C2, unmatched cohorts of TWO2 ONLY versus OTHER TX ONLY were also simi- lar on most characteristics, differing on use of adjunctive therapies, as well as wound severity ( p = 0.0005), pain level ( p = 0.026), stage of kidney disease ( p = 0.0008), and HbA1c ( p = 0.038).
Similarly, C1 is tabulated after application of propensity score matching for age, sex, ethnicity, wound severity, prior amputation, use of offload- ing, and use of NPWT, SS, or GF. After propensity score matching, the TWO2 (n = 70) and NO TWO2 (n = 70) cohorts were well matched on all demogra- phics and clinical characteristics, except for kid- ney disease ( p < 0.0001) and HbA1c ( p = 0.0093).
Table 1. Baseline demographics and clinical characteristics of unmatched and matched cohorts
Unmatched Cohorts Propensity Score Matched Cohorts Comparison #1 (C1) Comparison #2 (C2) Comparison #1 (C1)
Comparison #1 (C1) compares patients who ever received TWO2 (TWO2) to those who never received TWO2 (NO TWO2). Patients in both cohorts may have also received other adjunctive therapy. Comparison #2 (C2) compares patients who only received TWO2 and no other adjunctive therapy (TWO2 ONLY) to those who received NPWT, SS, and/or GF, but not TWO2 (OTHER TX ONLY). Propensity score matching was performed on the following 9 factors; age, sex, ethnicity, wound severity, prior amputation, use of offloading, use of NPWT, use of SS, use of GF. All patients received appropriate SOC.
GF, growth factors; NPWT, negative pressure wound therapy; SD, standard deviation; SOC, standard of care; SS, skin substitutes.
Most of the matched patients were male (97.1% TWO2, 98.6% NO TWO2), and approximately half of patients were white (52.9% TWO2, 48.6% NO TWO2). Many patients also had prior amputa- tion (28.6% TWO2, 28.6% NO TWO2). A large
proportion of patients in each cohort also had CVD (72.9% TWO2, 72.9% NO TWO2), PAD (78.6%
TWO2, 77.1% NO TWO2), and venous disease (40.0% TWO2, 38.6% NO TWO2). On average,
patients in each cohort had a mean diabetes dura- tion of 17.4 years. Average wound duration was similar in the matched cohorts at 194.8 days for TWO2 and 188.6 days for NO TWO2 patients.
During the 12-month observation period, we only had one mortality in the NO TWO2 cohort. There were no instances of mortality in the TWO group.
Outcomes for unmatched cohorts
Table 2 presents outcomes for all cohorts. Within unmatched cohorts for C1, compared with NO TWO2, the proportion of TWO2 patients requiring hospitalization and amputation was 88% lower (6.6% vs. 54.1%, p < 0.0001) and 71% lower (12.1%
- 41.4%, p < 0.0001), respectively, within 360 days
Table 2. Patients with hospitalization and amputation across cohorts
Unmatched Cohorts Propensity Score–Matched Cohorts Comparison #1 (C1) Comparison #2 (C2) Comparison #1 (C1)
Comparison #1 (C1) compares patients who ever received TWO2 (TWO2) to those who never received TWO2 (NO TWO2). Patients in both cohorts may have also received other adjunctive therapy. Comparison #2 (C2) compares patients who only received TWO2 and no other adjunctive therapy (TWO2 ONLY) to those who received NPWT, SS, and/or GF, but not TWO2 (OTHER TX ONLY). Propensity score matching was performed on the following 9 factors; age, sex, ethnicity, wound severity, prior amputation, use of offloading, use of NPWT, use of SS, use of GF. All patients received appropriate SOC.
Within unmatched cohorts for C2, in contrast with OTHER TX ONLY, the proportion of TWO2 ONLY patients with a wound-related hospitali- zation was 88% lower (6.9% vs. 58.8%, p < 0.0001) and the proportion with amputation was 61% lower (13.8% vs. 35.3%, p = 0.016) within 360 days
Outcomes for matched cohorts
Within matched cohorts, TWO2 patients still experienced reduced hospitalizations and ampu- tations versus NO TWO2 within 360 days (Table 2). Compared with NO TWO2, 82% fewer TWO2 patients were hospitalized (7.1% vs. 40.0%, p < 0.0001) and 73% fewer TWO2 patients had an amputation (8.6% vs. 31.4%, p = 0.0007) (Fig. 1).
Regression models in matched cohorts
Logistic regression models were conducted on the dichotomous study outcomes (hospitalization vs. no hospitalization, and amputation vs. no am- putation) within matched cohorts of NO TWO2 and TWO2 patients. The models demonstrated a nearly ninefold greater risk of wound-related hospitalization (OR: 8.667; 95% CI: 3.101, 24.219; p < 0.0001) and nearly fivefold greater risk of amputation (OR: 4.887; 95% CI: 1.840–12.985;
p = 0.0015) for NO TWO2 patients compared with TWO2 within 360 days (Table 3).
This study demonstrates the real-world effec- tiveness of cyclical pressurized topical wound oxygen therapy in reducing wound-related hospi- talizations and amputations for patients with DFU compared with patients who did not receive this intervention. Both amputations and hospitaliza- tions have been shown to contribute substantially to the overall cost burden of an ulcerated patient.4–6 Studies have also demonstrated that the annual cost of care for DFU is higher in patients with am- putation due to increased health care utilization, such as increased provider visits, rehabilitation care, and other medical expenses.19 In 2010, Franklin et al. estimated such costs within the VA to be $60,647 per patient.20 Our results, therefore, support the use of TWO2 in the management of DFU to dramatically improve serious, painful, as well as costly patient outcomes. Equally important, this therapy is self-administered in the comfort of the patient’s own home and does not require fre- quent visits to a specialized unit for such care.
Due to the real-world nature of the data, this study also included background use of other ad- junctive therapies (NPWT, SS, and GF). For C1 (TWO2 vs. NO TWO2), the use of TWO2 was addi- tive to other adjunctive therapies. However, in C2, when patients received TWO2 ONLY or OTHER TX ONLY (including SS, NPWT, and GF), the TWO2 ONLY group still demonstrated a mean- ingful reduction in the proportion of patients with hospitalization (6.9% vs. 58.8%, p < 0.0001) and amputation (13.8% vs. 35.3%, p = 0.016) at 360 days. This suggests that TWO2 confers a signifi- cant benefit alone compared with other adjunctive therapies. These findings demonstrate the real- world, patient-centric clinical value of TWO2 both as adjunctive therapy and as a potential alterna tive to other advanced wound care modalities.
To our knowledge, few other studies have evalu- ated the impact of adjunctive modalities, including TOT, on near-term hospitalizations and amputa- tions. In a retrospective uncontrolled chart re- view evaluating the impact of another type of TOT device on a variety of wound types, the over- all amputation rate for patients treated with TOT was 2.4%.21 Although lower than observed for pa- tients in this study (9–14% across cohorts treated with TWO2), comparisons are difficult to make due to the heterogeneity of woundtypes in theformerstudy. Furthermore, while our average DFU duration was *6 months, the majority of all wounds in the Copeland study were 3 months or less in dura- tion.21 Nonetheless, other controlled studies and several recent RCTs have demonstrated improved healing rates and time to closure of DFUs when using TOT as compared with controls.15,22–24
Figure 1. Matched and unmatched study outcomes. Comparison #1 (C1) compares patients who ever received TWO2 (TWO2) to those who never received TWO2 (NO TWO2). Patients in both cohorts may have also received other adjunctive therapy. Comparison #2 (C2) compares patients who only received TWO2 and no other adjunctive therapy (TWO2 ONLY) to those who received NPWT, SS, and/or GF, but not TWO2 (OTHER TX ONLY). Propensity score matching was performed on the following 9 factors; age, sex, ethnicity, wound severity, prior amputation, use of offloading, use of NPWT, use of SS, and use of GF. All patients received appropriate SOC. GF, growth factor; NPWT, negative pressure wound therapy; SOC, standard of care; SS, skin substitutes.
Table 3. Logistic regression models for matched cohorts
|Comparison #1 (C1)|
|Hospitalization (NO TWO2 vs. TWO2)||8.667||(3.101, 24.219)||<0.0001|
|Amputation (NO TWO2 vs. TWO2)||4.887||(1.840, 12.985)||0.0015|
Study outcomes were assessed through logistic regression models for propensity score–matched cohorts in Comparison #1 (C1). C1 compares patients who ever received TWO2 (TWO2) to those who never received TWO2 (NO TWO2). Patients in both cohorts may have also received other adjunctive therapy. Propensity score matching was performed on the fol- lowing 9 factors; age, sex, ethnicity, wound severity, prior amputation, use of offloading, use of NPWT, use of SS, use of GF.
CI, confidence interval; OR, odds ratio.
In a sham-controlled, double-blinded RCT on the same TWO2 therapy explored in this study, Frykberg et al. found that 56% of TWO2 patients achieved 100% healing at 12 months (vs. 27% in the sham arm, p = 0.013) and only a 5% amputation rate at 1 year from enrollment.15 Our analysis complements Frykberg et al. by showing a signifi- cant reduction in hospitalizations and amputations, also at 12 months, in a large, real-world patient pop- ulation with background use of adjunctive therapies. Taken together, the value of TWO2 is clearly dem- onstrated and warrants close consideration of its foundational role in the treatment of DFU.
Our overall 12-month amputation rate for these chronic DFU patients was 28%, consistently and significantly lower in each of the analyzed cohorts that had used TWO2. The 1-year rates of amputa- tion seen in the cohorts without TWO2 (NO TWO2: 41% unmatched, 31% matched; OTHER TX ONLY: 35%) are fairly comparable with that seen (42.3%) in another recent retrospective study by Blumberg and Warren that also included VA hospitals.25
Similar to our matched NO TWO2 cohort, a 2020 meta-analysis of 21 studies and 6,505 patients by Lin et al. demonstrated on average that nearly 31% of patients with DFU receive amputations.26 Another recent study from the VA indicated that there was an increase in the rate of amputations in veterans during the years 2008 to 2018.27 Inter- estingly, these data are derived from years over- lapping our own patient data and show that the increase in rates came primarily from increases in toe- and transmetatarsal-level amputations.
While our data did not categorize specific levels of amputations performed, modern limb-salvage practice has a relatively low threshold for such minor amputations in the presence of deteriorating diabetic foot wounds.28 This is reflected in recent nation-wide increases in the rate of diabetes- related minor amputations in the United States, manifested as a 50% increase in the total amputa- tion rate in the years 2009–2015.29
The 1-year rate of amputation in our analysis may be the result of several additional factors. First, patients in this study may have had existing, nonhealing wounds before first documentation in their medical records. Second, patients with DFU in this study had high rates of PAD (77–86% across cohorts) as well as prior amputation (27–45% across cohorts). Several studies have shown that PAD and prior amputation are important risk fac- tors for subsequent amputation in DFU.27,30 The patients in our study with high rates of PAD and prior amputation were therefore at higher risk for further amputation.
Renal insufficiency and end-stage renal disease are common complications in diabetes and are of- ten considered to be predictors of failure to heal. As indicated in Table 1, 90 (99%) patients in the TWO2 group had any stage of kidney disease, with almost half having Stage III kidney disease. In contrast, 92 (83%) patients in the No TWO2 group had any stage of kidney disease, with 21 (18.9%) patients within this cohort requiring dialysis. Nonetheless, when including kidney disease stage as a covariate along with treatment in the analysis for both Hospitalization and Amputation outcomes, the kidney disease stage term was nonsignificant at p < 0.05 [Hospitalization p = 0.8218, Amputation = 0.1004].
We also recognize and acknowledge that HbA1c levels were *7–10% higher in our NO TWO2 cohorts (Table 1). Nonetheless, glycohemoglobin levels have long been found to be an inconsistent risk factor for DFU healing as well as risk for am- putation. Accordingly, the aforementioned meta- analysis on risk factors for amputation confirmed that HbA1c level in DFU patients does not affect the incidence of amputation.26
Our study has several limitations inherent to any retrospective cohort analysis. First, we lacked control over the data at the time of documentation. For instance, the analysis could be impacted by missing data over the observation period. To man- age missing data, we used the LOCF method and conservatively assumed that any patient without follow-up data suggesting a hospitalization or am- putation during the 360-day period was cate- gorized as not hospitalized or not amputated. Similarly, due to the nature of medical records, we did not collect data on mortality or level of ampu- tation, as neither was reliably captured within the medical records.
Second, medical records do not capture or ac- count for compliance with prescribed treatments. While patient compliance with TWO2 (and NPWT) is therefore unknown, this uncertainty is also re- flective of and generalizable to a real-world popu- lation of patients with DFU. Third, our study does not evaluate wound healing, but rather mea- sures outcomes in the form of hospitalizations and amputations. Fourth, the medical records follow individual patients, not specific wounds. So, it is possible that a single patient could have additional wounds that contribute to the outcomes of analysis. Finally, treatment selection was based on the clinical judgment of the wound care physician at the time of treatment, which cannot be ascertained through a retrospective chart review, although pa- tients at both treatment facilities had access to all treatments, including TWO2.
This study also demonstrates the benefit of TWO2 across a spectrum of DFU severities. Although most of the patients in this study were categorized as Wagner 1 and 2 upon documentation of their wounds, 20% of analyzed patients (41 of 202) were classified as Wagner 3 and 4 with more severe wounds, reflecting the real- world composition of this VA patient population.
With all severities considered, TWO2 demon- strates a statistically significant benefit over NO TWO2 in reduced incidence of hospitalization and amputation. Specifically, we found a nearly fivefold increased association with amputation and nine- fold increased association with need for hospitali- zation in those patients who did not receive TWO2 compared with those who did.
The results of this study demonstrate that home- based cyclical pressurized topical wound oxygen therapy, when used with or without other adjunc- tive treatments, is associated with significantly re- duced frequency of wound-related hospitalization and amputation for patients afflicted with DFU. Hospitalizations and amputations are not only con- cerning patient outcomes affecting both morbidity and mortality, they are also costly complications that contribute to the significant overall cost burden of DFU on health care resources.4,5 By inference, therefore, cyclical pressurized topical wound oxygen therapy would likely be associated with important quality of life and health economic benefits.
The study protocol will be made available on re- quest from the corresponding author. Deidentified individual participant data that underlie the results reported in this article will be made available with requests accepted immediately after publica- tion, for proposals that set out to achieve aims specified in a methodologically and scientifically sound protocol, and where any mandated VHA ap- proval requirements are met.
J.I.Y., J.A.G., D.K., F.Z., O.N., and A.O. contributed to the conception, design, and analysis of the study. J.I.Y wrote the article. T.N. performed the statistical analysis and contributed to the article and study design. M.G.G. and A.M.L. conducted and oversaw the retrospective data collection at each of the VA sites. J.A.G, D.K., F.Z., O.N., A.O., R.G.F.,
M.G.G., and A.M.L. contributed to the discussion and critically reviewed and provided edits to the article. J.I.Y., J.A.G., R.G.F., M.G.G., and A.M.L. are the guarantors of this work. All authors had full access to the full data in the study and accept responsibility to submit for publication.
ACKNOWLEDGMENTS AND FUNDING SOURCES
The authors would like to thank Despi Herodo- tou (Director of Clinical Development, AOTI) for her help with data collection. This study was spon- sored by AOTI Ltd. (Galway, Ireland). Health Ad- vances received consultative reimbursement from AOTI, and T.N. received consultative reimburse- ment from Health Advances for his independent performance of the statistical analysis. R.G.F. has received research funding from and is a consultant for AOTI. M.G.G. has received research funding and is a consultant for AOTI. A.M.L. has received research funding from AOTI.
AUTHOR DISCLOSURE AND GHOSTWRITING
No other potential conflicts of interest relevant to this article were reported.
ABOUT THE AUTHORS
Jessica Izhakoff Yellin, AB, is a Director at Health Advances, a strategy consulting firm focused exclusively on the health care industry. Julia A. Gaebler, PhD was a Partner at Health Advances. Frank F. Zhou, BA, Olivia Novins, BA, Amelia Ockert, BA, were all Analysts at Health Advances, and Darcy Krzynowek, BA is a Vice President of Health Advances. Timothy Niecko, MS, is Pre- sident, Niecko Health Economics LLC, Matthew G. Garoufalis, DPM is a Podiatrist atthe Jesse Brown VA Medical Center, Chicago, Illinois, Aliza M. Lee, DPM is a Podiatrist at the Salem Veterans Affairs Medical Center, Salem, Virginia, Robert G. Fryk- berg, DPM, MPH, FFPM(Glasg), FRSM is the Medical Director of DM Prevent Diabetic Foot and Wound Centers, and former Chief of the Podiatry section at the Phoenix Veterans Affairs Medical Center in Phoenix, Arizona. He holds Faculty ranks as Adjunct Professor, Midwestern University Pro- gram in Podiatric Medicine as well as Honorary Professor of Podiatric Medicine at NUI Galway.
- Jeffcoate WJ, Vileikyte L, Boyko EJ, Armstrong DG, Boulton Current Challenges and Opportunities in the Prevention and Management of Diabetic Foot Ulcers. Diabetes Care 2018;41:645–652.
- Armstrong DG, Boulton AJM, Bus Diabetic Foot Ulcers and Their Recurrence. N Engl J Med 2017;376:2367–2375.
- Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula WV, Bus Five year mor- tality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res [Internet] 2020 Mar 24 [cited 2021 Mar 18];13. Available from: https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC7092527/
- Driver VR, Fabbi M, Lavery LA, Gibbons The costs of diabetic foot: the economic case for the limb salvage team. Journal of Vascular Surgery 2010;52(3, Supplement):17S–22S.
- Hicks CW, Selvarajah S, Mathioudakis N, et Burden of Infected Diabetic Foot Ulcers on Hos- pital Admissions and Costs. Ann Vasc Surg 2016; 33:149–158.
- Rice JB, Desai U, Cummings AKG, Birnbaum HG, Skornicki M, Parsons NB. Burden of Diabetic Foot Ulcers for Medicare and Private Dia- betes Care 2014;37:651–658.
- Hingorani A, LaMuraglia GM, Henke P, et The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medi- cine. J Vasc Surg 2016;63(2 Suppl):3S–21S.
- Schaper NC, Netten JJ van, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes/Metabolism Research and Reviews 2020;36(S1):e3266.
- Vas P, Rayman G, Dhatariya K, et Effectiveness of interventions to enhance healing of chronic foot ulcers in diabetes: a systematic review. Diabetes/Metabolism Research and Reviews 2020;36(S1):e3284.
- Aldana PC, Khachemoune Diabetic Foot Ulcers: appraising Standard of Care and Reviewing New Trends in Management. Am J Clin Dermatol 2020; 21:255–264.
- Gottrup F, Dissemond J, Baines C, et Use of Oxygen Therapies in Wound Healing. J Wound Care 2017;26(Sup5):S1–S43.
- Fedorko L, Bowen JM, Jones W, et Hyperbaric Oxygen Therapy Does Not Reduce Indications forAmputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: a Pro- spective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care 2016;39:392–399.
- Gordillo GM, Sen Evidence-based recom- mendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. Int J Low Extrem Wounds 2009;8:105–111.
- Smet GHJ de, Kroese LF, Menon AG, et Oxygen therapies and their effects on wound healing. Wound Repair and Regeneration 2017;25:591–608.
- Frykberg RG, Franks PJ, Edmonds M, et A Mul- tinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: the TWO2 Study. Diabetes Care 2020;43:616–624.
- Molenberghs G, Kenward Missing Data in Clinical Studies. John Wiley & Sons; 2007. 529 p.
- The PSMATCH Procedure. In: SAS/STAT® 142 User’s Guide [Internet]. Cary, NC: SAS Institute Inc; Available from: https://support.sas.com/ documentation/onlinedoc/stat/142/psmatch.pdf
- Grip ET, Svensson A-M, Miftaraj M, et Real- World Costs of Continuous Insulin Pump Therapy and Multiple Daily Injections for Type 1 Diabetes: a Population-Based and Propensity-Matched Co- hort From the Swedish National Diabetes Regis- ter. Diabetes Care 2019;42:545–552.
- Margolis DJ, Malay DS, Hoffstad O, et al. Economic burden of diabetic foot ulcers and am- Diabetic Foot Ulcers Data Points #3 (prepared by the University of Pennsylvania DEcIDE Center, under Contract No HHSA29020 0500411). 2011 Jan;AHRQ Publication No. 10(11)- EHC009-2-EF.
- Franklin H, Rajan M, Tseng C-L, Pogach L, Sinha A, Mph M. Cost of lower-limb amputation in U.S. veterans with diabetes using health services data in fiscal years 2004 and 2010. J Rehabil Res Dev 2014;51:1325–1330.
- Copeland K, Purvis A Retrospective Chart Review of Chronic Wound Patients Treated with Topical Oxygen Therapy. Adv Wound Care (New Rochelle) 2017;6:143–152.
- Niederauer MQ, Michalek JE, Liu Q, Papas KK, Lavery LA, Armstrong Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre study. J Wound Care 2018;27(Sup9):S30–S45.
- Blackman E, Moore C, Hyatt J, Railton R, Frye Topical wound oxygen therapy in the treatment of severe diabetic foot ulcers: a prospective controlled study. Ostomy Wound Manage 2010;56:24–31.
- Serena TE, Bullock NM, Cole W, et Topical oxygen therapy in the treatment of diabetic foot ulcers: a multicentre, open, randomised controlled clinical trial. J Wound Care 2021;30(Sup5):S7–S14.
- Blumberg SN, Warren Disparities in initial pre- sentation and treatment outcomes of diabetic foot ulcers in a public, private, and Veterans Admin- istration hospital. Journal of Diabetes 2014;6:68–75.
- Lin C, Liu J, Sun Risk factors for lower extremity amputation in patients with diabetic foot ulcers: a meta-analysis. PLoS One 2020;15:e0239236.
- Cai M, Xie Y, Bowe B, et Temporal Trends in Incidence Rates of Lower Extremity Amputation and Associated Risk Factors Among Patients Using Veterans Health Administration Services From 2008 to 2018. JAMA Netw Open 2021;4: e2033953.
- Frykberg RG, Attinger C, Smeets L, Koller A, Bal A, Kavarthapu Surgical strategies for prevention of amputation of the diabetic foot. Journal of Clinical Orthopaedics and Trauma 2021;17:99–105.
- Geiss LS, Li Y, Hora I, Albright A, Rolka D, Gregg Resurgence of Diabetes-Related Nontrau- matic Lower-Extremity Amputation in the Young and Middle-Aged Adult U.S. Population. Diabetes Care 2019;42:50–54.
- Ferreira L, Carvalho A, Carvalho Short-term predictors of amputation in patients with diabetic foot ulcers. Diabetes & Metabolic Syndrome: clinical Research & Reviews 2018;12:875–879.
THE JOURNAL OF CLINICAL AND APPLIED RESEARCH AND EDUCATION
In This Issue of
Diabetes Care By Max Bingham, PhD
Global Mechanisms Proposed for Cardioprotective Effects of SGLT2 Inhibitors
The beneficial effects of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes are mostly attributed to their ability to enhance glucose excretion and lower hyperglycemia. But they can also promote positive cardiovascular outcomes. Less clear is quite how they manage to achieve the effects, and although many hypothetical mechanisms exist, they only partly explain what might be going on. Avogaro et al. (p. 501) attempt to bring the different strands of evidence to- gether and propose a hypothesis that suggests SGLT2i might modify the trajectory of cell responses to high glucose levels from one of defense to dormancy. They suggest this might be the mechanism that explains the cardiac and renal protective effects of SGLT2i treatments. On that basis they call for dedicated studies to test the hypothesis to ultimately gather the support needed for human studies. They explain that high blood glucose is effectively a toxic environment that likely shifts cell responses to a state of defense characterized by immune responses, anabolic metabolism, inflam- mation, adiposity, and also cardiovascular events. In contrast, they suggest that switching to a dormancy program would curtail many of these issues and that evidence suggests that SGLT2i may actually be able to force this switch—effectively explaining the positive cardiorenal outcomes of
the trials. They acknowledge that most of the cited evidence comes from animal studies but suggest that, together with the more limited human data, the evidence points towards SGLT2i having a dormancy effect at a cellular level. Commenting further, author Angelo Avogaro told us: “There is still a lot to be understood about what SGLT2i do to humans beyond their glycosuric effects. Many hypotheses have been proposed, but we found it fascinating that they may switch the milieu of the cells to a state similar to that observed in mammalian animals during hibernation. If this is the case, this evolutionary hypothesis should be rigorously tested in future studies.”
Oxygen Therapy Improves Diabetic Ulcer Wound Healing: RCT Data
Treating diabetic foot ulcers for 12 weeks with a topical wound oxygen therapy in addition to standard care increases the likelihood that they heal, according to Frykberg et al. (p. 616). Specifically, they found that the therapy resulted in a >4.5-fold increased likelihood of healing compared with placebo and notably could be administered at home by patients. The results come from a double-blind randomized controlled trial (RCT) that compared an oxygen treatment ap- proach (Topical Wound Oxygen [TWO2]) or placebo (circulating air) delivered via a device called a HyperBox (AOTI Ltd., Galway, Ireland). Both approaches were applied on top of standard care for wounds, which were long-standing and had not healed prior to the trial. The company-sponsored trial was stopped early (as planned) after the active treatment showed clear success in healing wounds compared with placebo. Seventy-three individuals had been enrolled up to that point.
The primary outcome was the percentage of ulcers achieving 100% healing at 12 weeks. The authors found that the active treatment had a closure rate of nearly 42%, while the placebo had a closure rate of 13.5%. This resulted in an odds ratio of ~4.5, which was statistically significant, and it increased to 6.0 once ulcer grade was accounted for. Additionally, more than half of ulcers were closed at 12 months after the active treatment but only about one-quarter following placebo. Quality of life measures also improved more following the active treatment. There were high compliance rates in both groups, and no device-related adverse events were experienced in either group. Commenting further, author Robert Frykberg told us: “We believe that in this rather robust double-blinded RCT we have clearly demonstrated the positive effects of cyclical, pressurized topical oxygen therapy in the healing of chronic diabetic foot ulcers. Accordingly, we now have the evidence required to recommend the use of this therapy as an adjunct to good standard care for the management of difficult-to-heal diabetic foot ulcers.”
Avogaro et al. Reinterpreting cardiorenal protection of renal sodium–glucose cotransporter 2 inhibitors via cellular life history reprogramming. Diabetes Care 2020;43:501–507
Kaplan-Meier curve showing the separation between placebo (SC
+ Sham) and active therapy (SC + TWO2) study groups throughout the 12-week trial. SC, standard care.
Frykberg et al. A multinational, multicenter, randomized, double- blinded, placebo-controlled
trial to evaluate the efficacy of cyclical Topical Wound Oxygen (TWO2) therapy in the treatment of chronic diabetic foot ulcers: the TWO2 study. Diabetes Care 2020;43:616–624
A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efﬁcacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study
Robert G. Frykberg,1 Peter J. Franks,2 Michael Edmonds,3 Jonathan N. Brantley,4 Luc Te´ot,5 Thomas Wild,6
Matthew G. Garoufalis,7 Aliza M. Lee,8 Janette A. Thompson,9 Ge´rard Reach,10 Cyaandi R. Dove,11 Karim Lachgar,12 Dirk Grotemeyer,13 and Sophie C. Renton,14 on behalf of the TWO2 Study Group*
Topical oxygen has been used for the treatment of chronic wounds for more than 50 years. Its effectiveness remains disputed due to the limited number of robust high-quality investigations. The aim of this study was to assess the efﬁcacy of multimodality cyclical pressure Topical Wound Oxygen (TWO2) home care therapy in healing refractory diabetic foot ulcers (DFUs) that had failed to heal with standard of care (SOC) alone.
RESEARCH DESIGN AND METHODS
Patients with diabetes and chronic DFUs were randomized (double-blind) to either active TWO2 therapy or sham control therapydboth in addition to optimal SOC. The primary outcome was the percentage of ulcers in each group achieving 100% healing at 12 weeks. A group sequential design was used for the study with three predetermined analyses and hard stopping rules once 73, 146, and ultimately 220 patients completed the 12-week treatment phase.
At the ﬁrst analysis point, the active TWO2 arm was found to be superior to the sham arm, with a closure rate of 41.7% compared with 13.5%. This difference in outcome produced an odds ratio (OR) of 4.57 (97.8% CI 1.19, 17.57), P 5 0.010. After adjustment for University of Texas Classiﬁcation (UTC) ulcer grade, the OR increased to 6.00 (97.8% CI 1.44, 24.93), P 5 0.004. Cox proportional hazards modeling, also after adjustment for UTC grade, demonstrated >4.5 times the likelihood to heal DFUs over 12 weeks compared with the sham arm with a hazard ratio of 4.66 (97.8% CI 1.36, 15.98), P 5 0.004. At 12 months postenrollment, 56% of active arm ulcers were closed compared with 27% of the sham arm ulcers (P 5 0.013).
This sham-controlled, double-blind randomized controlled trial demonstrates that, at both 12 weeks and 12 months, adjunctive cyclical pressurized TWO2 therapy was superior in healing chronic DFUs compared with optimal SOC alone.
1Diabetic Foot Consultants, Midwestern Univer- sity, Glendale, AZ
2Centre for Research and Implementation of Clinical Practice, London, U.K.
3King’s College Hospital, London, U.K.
4McGuire Veterans Affairs Medical Center, Richmond, VA
5Montpellier University Hospital, Montpellier, France
6Medical Center Dessau, Brandenburg Medical School Theodor Fontane, Dessau, Germany 7Edward Hines Jr. VA Hospital, Chicago, IL 8Salem Veterans Affairs Medical Center, Salem, VA
9Washington DC Veterans Affairs Medical Center, Washington, DC
10Hoˆpital Avicenne and Paris 13 University, Bobigny, France
11Advanced Foot & Ankle Center, Las Vegas, NV 12Hoˆpital Simone Veil, Eaubonne, Paris, France 13Hoˆpitaux Robert Schuman – Hoˆpital Kirchberg,
Luxembourg City, Luxembourg
14Northwick Park Hospital, London, U.K.
Received 8 March 2019 andaccepted 3 September 2019
This article contains Supplementary Data online at https://care.diabetesjournals.org/lookup/suppl/ doi:10.2337/dc19-0476/-/DC1.
*A complete list of the TWO2 Study Group collaborators, Steering Committee, and Data Monitoring Committee can be found in the Supplementary Data online.
© 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. More infor- mation is available athttps://www.diabetesjournals.org/content/license.
See accompanying article, p. 515.
With the growing worldwide prevalence of diabetes there has been a resultant increase in the incidence of diabetic foot ulcerations (DFUs) with attendant mor- bidity, mortality, and health care costs (1–3). Common diabetes comorbidities including peripheral neuropathy, defor- mity, and peripheral arterial disease (PAD) are among a number of well- established risk factors for DFUs (2,4). These person-level conditions when combined with numerous underlying cellular or metabolic and ulcer-related factors (hypoxia, inﬂammation, biobur- den, etc.) will quite frequently lead to impaired wound healing and to possible amputation (5,6).
Over the last decade it has become clear that basic standards of care for DFUs mandate rigorous attention to proper de- bridement and off-loading (7–9). While a number of new adjunctive therapies have become available, including growth fac- tors, cellular and acellular tissues, topical negative pressure, oxygen therapies, etc., most therapies suffer from inadequately designed or nongeneralizable studies that cannot attest to their efﬁcacy, safety, and cost-beneﬁt (1,10,11).
Oxygen is an essential component in the wound-healing cascade. Energy me- tabolism (ATP synthesis), reactive oxygen species generation, redox signaling, H2O2 production, antioxidant generation, col- lagen synthesis, deposition of extracel- lular matrix, VEGF gene expression, and angiogenesis are among processes de- pendent on a sufﬁcient supply of oxygen for their activities (12–15).
Hyperbaric oxygen therapy (HBOT) has been studied extensively for its efﬁcacy in healing DFUs and amputation preven- tion, but despite several recent random- ized clinical trials, the results remain inconsistent regarding its effectiveness in healing DFUs (10,16–19). Topical ox- ygen therapies (TOTs), used in clinical practice for .50 years, supply oxygen directly to the hypoxic wound surface without the potential complications posed by HBOT (13,15,20,21). Despite long-standing clinical evidence support- ing the effectiveness of topically applied oxygen for chronic wounds, hyperbaric oxygen proponents have raised concerns about such beneﬁts without systemic hyperoxygenation (22).
To study the effect of topically admin- istered oxygen on cutaneous wounds, Fries et al. (23) conducted a controlled porcine dermal wound-healing experi- ment. They found that topical oxygen increased the wound tissue partial pres- sure of oxygen (PO2) levels 10-fold after 4 min and that repeated treatments ac- celerated wound closure compared with control (air-exposed) wounds. Histological examination showed a stronger presence of VEGF, signs of improved angiogenesis, and more advanced remodeling with bet- ter quality collagen. Their ﬁndings sug- gest several biological mechanisms for the enhanced healing found in other topical oxygen studies. While numerous reports have similarly suggested the po- tential beneﬁts of topical oxygen in heal- ing chronic wounds, its effectiveness in healing DFUs remains disputed due to a combination of poorly designed studies, inconsistent results, and the paucity of ro- bust investigations through randomized controlled clinical trials (RCTs) (15,24–26). In recognition of the need for more rigorous studies of this therapy, a ran- domized, double-blinded, sham-controlled clinical trial was designed to explore the efﬁcacy of cyclical pressurized Topical Wound Oxygen (TWO2) therapy in heal- ing refractory DFUs that had failed to heal with optimal standard of care (SOC) alone. We herein present the results of the TWO2 diabetic foot ulcer study.
RESEARCH DESIGN AND METHODS
The TWO2 study was designed as a pro- spective, multinational, multicenter, double- blinded, placebo-controlled, randomized clinical trial with 17 diabetic foot centers participating across the U.S., U.K., France, Germany, and Luxembourg. The protocol was approved by the governing institu- tional review or local ethics board of each of the participating centers throughout the U.S. and Europe. The study was per- formed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines of the International Conference on Harmonization. Written informed con- sent was provided by all participants prior to performance of study procedures. An independent data monitoring committee and a study steering committee were established to monitor the conduct and analysis of the study.
Sample Size and Design Rationale Limited information was available on RCTs looking at the efﬁcacy of cyclical pressurized topical oxygen for healing DFUs. Aburto and Frye (27), in a ran- domized study of topical oxygen, dem- onstrated better healing in DFU patients after 90 days (90% vs. 40%) compared with the control group. Blackman et al.
(20) enrolled 28 patients with DFUs and obtained a similar result (82.4% vs. 45.5%). In combining the results of these two studies, the control group achieved a healing rate of 9 of 21 (42.8%), and in the active group healing occurred in 23 of 27 (85.2%). Using these ﬁgures, we would anticipate a tentative expected control rate of 43%, and it was proposed that a conservative estimate of difference be- tween groups would be half that experi- enced in these trials at 21%. In order to address the unknown outcomes, we used a group sequential design with three predetermined analysis points. With three analyses, the level of signif- icance needed to be adjusted to maintain the integrity of the analysis. The Pocock stopping boundary method requires a more stringent P value threshold (P , 0.022) at each of the three analysis points to achieve an overall probability of P ,0.05 at the ﬁnal evaluation. For achieve- ment of a minimal level of signiﬁcance between study arms, it was calculated that 110 patients would be required in each study arm (n 5 220). The resultant analyses would therefore be performed after one-third (73), two-thirds (146), and ﬁnally all (220) enrolled patients completed the active phase of the study. Since analysis would be exclusively of the intention-to-treat (ITT) cohort, all pa- tients would be analyzed as per the 12-week primary end point (healed vs. unhealed). Furthermore, no up-rating of this sample size was made to take into consideration patients lost to follow-up.
Inclusion criteria for participation in the trial were as follows: patients with type 1 or 2 diabetes with nonhealing, full-thickness, University of Texas Clas- siﬁcation (UTC) grade 1 or 2 DFU measuring $1 cm2 and ,20 cm2 post- debridement. All ulcers included were to be between 4 weeks and 1 year in duration and to have been receiving stan- dard care for at least 4 weeks. Patients with modest limb ischemia were per- mitted with an ankle brachial index (ABI) .0.7. To account for falsely elevated ABI measurements (7), we performed a secondary conﬁrmatory measurement of distal perfusion adjacent to or distal to the index ulcer in all patients, in- cluding a transcutaneous oxygen pres- sure (TcPO2) .30 mmHg, skin perfusion pressure .30 mmHg, toe pressure .30 mmHg, or a Duplex ultrasound showing biphasic waveforms below the knee. Detailed study enrollment cri- teria can be found in Table 1.
Patients were randomly assigned in a 1:1 ratio double blinded to either the SOC plus sham therapy (SC1Sham) arm or to an SOC plus active TWO2 therapy (SC1TWO2) arm. The randomization list of 220 codes in A or B format was generated by the blinded statistician using a random permuted block design, with blocks of 2, 4, 6, and 8. Study arm allocation was randomly assigned by a centralized study coordinator for each patient at the randomization visit.
All patients were recruited as outpatients in participating wound care centers. At the screening visit and after obtaining informed consent, the pa- tient’s wound was sharply debrided and digitally photographed. All patients were then provided with the same study foam dressings and hydrogel (Kendall; Covidien), instructions, and the study off- loading device (Optima Diab; Salvatelli srl, Civitanova Marche, Italy). After a run-in period of 2 weeks, patients re- turned for their randomization visit. Only if the wound area reduction was ,30% were patients subsequently random- ized double-blind into either the active (SC1TWO2) or sham (SC1Sham) study arm.
The U.S. Food and Drug Administration– cleared, CE-marked TWO2 therapy device (HyperBox; AOTI Ltd., Galway, Ireland) operates by inﬂation of a single- use extremity chamber over the pa- tient’s limb; then, humidiﬁed oxygen is cycled between 10 mb and 50 mb within the chamber. A 10 liters per minute oxygen concentrator was used to provide the oxygen supply rather than oxygen cylinders.
Both the active and sham devices looked and operated identically. How- ever, the sham device did not deliver pressurized oxygen into the extremity chamber, even though values displayed on the device controls looked as if this was being performed. The sham treatment therefore consisted only of unrestricted nonpressurized ambient room air in the nonocclusive extremity chamber.
Delivery, installation, and training on the use of the blinded study device was performed by blinded home equipment providers. No study-related procedures or treatments were provided by these representatives. Patients treated them- selves at home for 90 min daily ﬁve times per week with either the allo- cated TWO2 or sham therapy. Dressing changes were performed at home by either the patient or their personal care- giver. No study therapy was done at the study centers.
Patients visited a local study center weekly for the duration of the study for wound assessment, debridement, and digital wound photographs. Patients re- corded therapy and off-loading compli- ance daily on diary cards that were veriﬁed at each study visit. Additionally, therapy hours were veriﬁed by the TWO2 device itself. The active treatment phase was continued until the ulcer healed or for a maximum of 12 weeks.
Data Collection and Outcome
The treatment phase of the study was 12 weeks. The randomization visit mea- surement after debridement served as the index (baseline) measurement. If mul- tiple ulcers were present, the largest area ulcer at the baseline visit was designated the index ulcer. Weekly digital wound im- ages were transmitted electronically and were assessed for area changes and clo- sure conﬁrmation by a single blinded cen- tral assessor using automated CE-marked wound measurement software (MOWA; Healthpath srl, Rome, Italy).
Once a wound was initially determined to be closed by the blinded study site investigator, that visit served as the ﬁrst of two conﬁrmatory visits. Wound clo- sure (complete epithelialization) was conﬁrmed at the second closure visit 2 weeks later (28). Upon completion of the 12-week treatment phase, patients entered the posttreatment follow-up period for an additional 38 weeks, whereby they returned for wound clo- sure assessment and quality of life (QOL) questionnaires.
The maximum duration for participa- tion in the study was 54 weeks. During the follow-up phase, patients without healed ulcers received standard care according to their clinician’s recommen- dation and were asked not to participate in another wound care trial.
The primary study end point was the percentage of ulcers in each group achieving 100% healing at 12 weeks. Secondary end points included wound area reduction, 12-month in- cidence of both recurrence and com- plete healing, incidence of amputation, Cardiff Wound Impact Schedule (CWIS) QOL assessment, and adverse events (1,28,29).
|Table 1—Inclusion/exclusion criteria
Males and females aged between 18 and 89 years
|Exclusion criteria Evidence of gangrene on any part of affected limb|
|Documented diagnosis of type 1 or 2 diabetes||Documented evidence of osteomyelitis on any part of affected limb|
|Foot ulcer at or below ankle with duration .4 weeks to ,1 year
• If the index ulcer is postamputation, date of surgery must be .30 days
• If .1 ulcer is present, largest is considered as the study index ulcer
• Index ulcer must be $1 cm from any other ulcers present on the foot
|Index ulcer has exposed bone
Active Charcot foot on the study limb
Uncontrolled diabetes: HbA1c .12% (108 mmol/mol) Renal dialysis or creatinine .2.5 mg/dL (221 mmol/L)
|Ulcer size $1 and #20 cm2 after debridement at start of run-in period||Known immune insufﬁciency|
|Ulcer of UTC grade 1A, 1B, 1C, 1D, 2A, 2B, 2C, or 2D||Active treatment for malignancy (not speciﬁc to study limb)|
|ABI .0.7 with a TcPO2 .30 mmHg, skin perfusion .30 mmHg, toe pressure .30 mmHg, or Duplex ultrasound with biphasic waveforms
below the knee
|Chronic steroid use or immunosuppressive agents within the last
3 months or anticipated to require them during the duration of the study
|No planned revascularization procedure or vascular surgery within the last or next 30 days||Subject participated in another investigational device, drug, or biological trial within last 30 days|
|Subject and caregiver willing and able to comply with all speciﬁed care
and visit requirements
|Index ulcer exhibits signs of severe clinical infection that requires
hospitalization or immediate surgical intervention
|Subject has a reasonable expectation of completing the study||Subject is pregnant at the time of screening|
|Subject completed 2-week run-in period with ,30% wound size reduction||Subject has had a deep vein thrombosis within the last 30 days Subject has received growth factor therapy, autologous platelet-rich
plasma gel, bilayered cell therapy, dermal substitute, extracellular matrix, etc., within the screening period
97.8% CIs. For all other analyses, statis- tical signiﬁcance was assessed at the two-sided 5% level (P , 0.05) with 95% CIs provided as appropriate. The stat- istician conducting all analyses was blinded to treatment allocation (with groups identiﬁed as A and B) until results had been ﬁnalized.
Between November 2014 and December 2017, 136 patients were screened for the study. Of these, 63 patients (46%) were excluded from randomization for not meeting the inclusion criteria. Thirty- four patients (25%) returned from the 2-week run-in with wound size reduc- tions $30%, 10 (7%) had ABI values or second vascular assessments out of range, and 19 (14%) either were not willing to comply fully with the protocol or had other laboratory values out of range. Therefore, 73 patients were ran- domized into the active phase of the study (see Fig. 1).
At baseline, 65 patients (89%) had type 2 diabetes and 8 patients (11%) had type 1 diabetes. Fourteen index ulcers (39%) in the active arm, compared with six index ulcers (16%) in the sham arm, were assessed to be UTC grade 2 (penetrating to tendon or capsule). Conversely, 22 ulcers (61%) in the active arm, compared with 31 ulcers (84%) in the sham arm, were assessed to be UTC grade 1 wounds (P 5 0.038). Additionally, 10 patients (28%) in the active arm, compared with 4 patients (11%) in the sham arm, had a previous diagnosis of PAD (P 5 0.066). Seventeen patients (47%) in the active arm had a history of prior amputations on the index limb in contrast to eight (22%) in the sham arm (P 5 0.018) (see Table 2).
At the ﬁrst ITT analysis point of 73 pa- tients, the independent data monitoring committee recommended that enroll- ment should conclude per the predeter- mined stopping rules, as the active arm was shown to be superior to the sham arm for the primary outcome. In the ac- tive arm 15 wounds (41.7%) completely healed versus 5 wounds (13.5%) in the sham arm at 12 weeks [Pearson x2 5 7.27 (1 df), P 5 0.007]. The difference in outcome produced an OR of 4.57 (97.8% CI 1.19, 17.57), P 5 0.010. Examination of the potential confounding by other baseline variables revealed that UTC ul- cer grade substantially changed the OR in favor of the TWO2 group (OR 5 6.00 [97.8% CI 1.44, 24.93], P 5 0.004). The active TWO2 arm showed .3.5 times the likelihood to completely heal over 12 weeks compared with the sham arm with an HR of 3.64 (97.8% CI 1.11, 11.94), P 5 0.013. With inclusion of the UTC ulcer grade into the model, the HR increased to 4.66 (97.8% CI 1.36, 15.98), P 5 0.004. The Kaplan-Meier curve shown in Fig. 2 clearly shows the separation between groups throughout the active phase of the study. The patients then entered into the follow-up phase of the study where they were assessed for index ulcer re- currence, healing, and QOL changes for 12 months post enrollment (see Table 3).
|Table 2—Baseline characteristics
Sham TWO2 (n 5 37)
Age, years, mean (SD) 61.9 (9.5)
Active TWO2 (n 5 36)
Total (n 5 73)
|Sex, male, n (%)||31 (84)||32 (89)||63 (86)||0.53|
|Race, n (%)|
|White/Hispanic||24 (65)||26 (72)||50 (68.5)||0.90*|
|Black||5 (14)||5 (14)||10 (14)|
|Asian||1 (2.7)||2 (5.6)||3 (4.1)|
|American Indian||1 (2.7)||0 (0)||1 (1.4)|
|Not reported||6 (16.2)||3 (8.3)||9 (12.3)|
|Type 2 diabetes, n (%)||33 (89)||32 (89)||65 (89)||0.97|
|BMI (kg/m2), mean (SD)||31.2 (7.6)||30.8 (5.9)||31 (6.8)||0.85|
|Wound area (cm2), mean (SD)||3.22 (2.54)||3.02 (2.66)||3.13 (2.57)||0.74|
|Wound perimeter (cm),
|Ulcer duration (days), mean (SD)||
|Wound classiﬁcation, n (%)|
|UTC grade 1A||27 (73)||20 (56)||47 (64)|
|UTC grade 1B||2 (5.4)||1 (2.8)||3 (4.1)|
|UTC grade 1C||2 (5.4)||1 (2.8)||3 (4.1)|
|UTC grade 2A||4 (10.8)||9 (25)||13 (17.8)||0.04**|
|UTC grade 2B||0 (0)||1 (2.8)||1 (1.4)|
|UTC grade 2C||2 (5.4)||4 (11.1)||6 (8.2)|
|Neuropathic foot, n (%)||29 (78)||28 (78)||57 (78)||0.95|
|Charcot deformity, n (%)||3 (8.1)||1 (2.8)||4 (5.4)||0.32|
|Ulcer location, n (%)||0.32|
|Dorsal foot||5 (13.5)||8 (22.2)||13 (17.8)|
|Leg below malleoli||4 (10.8)||1 (2.8)||5 (6.8)|
|Pedal foot||22 (59.5)||18 (50)||40 (54.8)|
|Toe||6 (16.2)||9 (25)||15 (20.5)|
|Previous history of lower-extremity
amputation, n (%)
|Comorbidities, n (%)|
|Hypertension||30 (81)||28 (78)||58 (79)||0.73|
|Cardiovascular disease||9 (24.3)||13 (36.1)||22 (30.1)||0.27|
|PAD||4 (10.8)||10 (27.8)||14 (19.2)||0.07|
|Venous disease||1 (2.7)||2 (5.6)||3 (4.1)||0.54|
|Renal disease||6 (16.2)||10 (27.8)||16 (21.9)||0.23|
|Neurologic disease||31 (83.8)||28 (77.8)||59 (80.8)||0.52|
|Peripheral edema||1 (2.7)||3 (8.3)||4 (5.4)||0.29|
|Hyperlipidemia||25 (67.6)||23 (63.9)||48 (65.8)||0.74|
|Smoker, n (%)||10 (27)||13 (36)||23 (31.5)||0.41|
|Peripheral arterial circulation parameters
Mean ABI (SD)
Mean toe systolic blood pressure (SD), mmHg
|83.00 (32.75)||84.50 (30.55)||83.77 (30.63)||0.84|
|Blood work values, mean (SD)
Prealbumin, mmol/L 4.29 (1.45) 4.44 (0.93) 4.36 (1.18) 0.61
CRP, nmol/L 140 (173) 65.7 (96.2) 99.6 (139) 0.05
Creatinine, mmol/L 105.2 (30.1) 113.2 (81.3) 108.7 (61) 0.57
HbA1c, % 8.14 (1.49) 8.43 (1.75) 8.25 (1.64) 0.46
HbA1c, mmol/mol 65 (16.3) 69 (19.1) 67 (17.9) 0.46
All comparisons are nonsigniﬁcant except for values in boldface type. *Due to low frequency in each cell, white race was compared with all other races combined. **Due to low frequency in UTC categories, UTC I was compared with UTC II.
Secondary Outcome Measures
At 12 months postenrollment, only 1 of 15 healed ulcers (6.7%) in the active arm recurred, compared with 2 of 5 healed ulcers (40%) in the sham arm, falling just short of statistical sig- niﬁcance (P 5 0.070). In total, 20 (56%) active arm (SC1TWO2) ulcers were closed at 12 months postenrollment compared with 10 (27%) of the sham arm (SC1SHAM) ulcers [x2 (1 df) 5 6.13, P 5 0.013].
Wound Area Reduction
Of the patients with open ulcers at the end of the 12-week active phase, the mean (SD) absolute reduction in ulcer area from baseline was 1.97 (2.75) cm2 for the active arm compared with 0.40 (1.75) cm2 for the sham arm [t (df) 52.12 (35), P 5 0.041].
For the patients with larger open ulcers .4 cm2 at the end of the active phase, the mean (SD) absolute reduction in ulcer area from baseline was 4.12 (1.51) cm2 for the active arm compared with a 1.34 (1.18) cm2 increase for the sham arm [t (df) 5 2.85 (8), P 5 0.021].
The wound care–focused CWIS QOL in- dex improved during the study for pa- tients whose ulcers healed across all functional domains. This positive in- crease was observed in both full and partial responders. The greatest im- provement was seen for the well-being component, with mean (SD) score dif- ference between baseline and the end of 12-week treatment in the active arm of 9.1 (13.9) compared with 20.1 (16.9) in the sham arm [t (df) 5 2.18 (53), P 5 0.033].
TWO2 Therapy and Off-loading Compliance
Therapy compliance in both the active and sham arms was high, with 94% and 96% completing treatments, respectively. Off-loading device compliance in both the active and sham arms was also high, with 97% and 99% using the off-loading .75% of the time.
Events During the study, there were equal num- bers of serious adverse events (10) and adverse events (8) experienced in both study arms. There were no TWO2 device– related adverse events reported. Two index limb amputations (5%) occurred in the active arm compared with three index limb amputations (8%) in the sham arm.
TOT has been reported to improve heal- ing of DFUs in several earlier prospec- tive randomized studies (20,27,30,31). However, these studies suffered from methodological weaknesses, such as a lack of blinding, uncontrolled SOC, or in- appropriate analyses of the ITT populations.
The present TWO2 study has demon- strated, in a randomized, sham-controlled trial, that cyclical pressurized TOT ad- junctive to optimal SOC is significantly superior to standard care alone in heal- ing recalcitrant DFUs within a 12-week home-based treatment period. To this end, trial enrollment was terminated at the ﬁrst predetermined analysis point, since the primary end point had been achieved after the initial 73 randomized patients had completed their 12-week treatment phase.
Despite the loss of 25% of patients in the 2-week run-in period prior to random- ization, a four-and-a-half–fold increased likelihood of healing was achieved at 12 weeks in patients allocated to the active TWO2 therapy. With adjustment for UTC ulcer grade, this effect increased even further. A very high degree of com- pliance with treatment and off-loading was demonstrated in both groups. Clin- ically, the durability of healing as mea- sured by index ulcer recurrence at 12 months was sixfold better than that in the sham group and that seen in other studies (2). Of interest, and distinct from other topical oxygen studies, this RCT allowed for patients with up to UTC grade 2 ulcers with modest degrees of ischemia. Although not statistically signiﬁcant, nearly 28% of patients ran- domized to the active therapy had a prior history of PAD compared with just 10% in the control group. How- ever, despite double-blinded random- ization, a signiﬁcant 47% of active therapy patients had a history of lower- extremity amputations compared with just 22% in the sham arm.
This study is consistent with results reported in several previous studies us- ing topical oxygen in DFU (20,30–32) and venous leg ulcers (33,34), as well as animal studies (23). Several other re- views of this approach have also sug- gested mechanisms of action and putative beneﬁts of topically applied oxygen in the management of chronic wounds (13,15,24,26). Blackman et al. (20), in a prospective open-label study, examined the clinical efﬁcacy of TWO2 therapy in healing DFU patients in a community wound care clinic. Patients were allocated to topical oxygen or oth- erwise treated with advanced moist wound therapy. At 12 weeks, 82.4% of the ulcers in the TWO2 therapy arm and 45.5% in the control arm healed completely (P 5 0.04). Median time to complete healing was 56 days in the active and 93 days in the control arm (P 5 0.013). Another unblinded comparative study investigated the beneﬁts of con- tinuous diffusion of oxygen compared with variable standard care for DFUs (31). Notwithstanding methodological weak- nesses, they found signiﬁcantly faster rates of healing in the topical oxygen group compared with the standard care group and most notably in deeper ulcers. A more recent randomized placebo- controlled trial using a continuous dif- fusion of oxygen device for only UTC grade 1A ulcers reported a higher pro- portion of healed DFUs (32.4% vs. 16.7%, P 5 0.033) and a faster time to closure (P 50.015) in the active group at 12 weeks (30). This study was also planned with a group sequential design; however, their interim analysis end point was not met, and their ITT analysis did not include 35% of randomized patients who were subsequently removed from the trial.
Strengths and Limitations
This TWO2 study followed the guidance for wound-healing therapies put forth by the U.S. Food and Drug Administration (28) as well as subsequent publications from leading authorities calling for more robustly designed sham-controlled RCTs (1,29,35). Nonetheless, and despite ran- domization of known and unknown po- tential confounders between groups, it does have limitations. One is the rela- tively small number of patients included in the primary end point analysis of our ITT population, although the group was similar in size to those of other wound care RCTs (2,36). In a group sequential design study, predetermined hard stop- ping rules are put in place that in our case were met at the ﬁrst analysis point of 73 patients. At that point, the primary outcome was achieved by ﬁnding signif- icantly more patients in the active group had healed compared with the sham- treated group (41.7% vs. 13.5%, P 5 0.007). This approach is used when the magnitude of the treatment effect is uncertain, as it allows for stopping a trial once a wide treatment effect is proven. This also ethically ensures that patients are not further randomized to an inferior arm. In our study, a large margin of effect (68%) and relative performance ratio (309%) were achieved.
|Table 3—Summary of the results: ITT analysis|
|Sham TWO2 Active TWO2||Pearson x2 or OR or|
|(n 5 37) (n 5 36)||HR (97.8% CI), P value|
|Ulcers completely healed at 12 weeks, n (%) 5 (13.5) 15 (41.7)||x2 7.27 (1 df), P 5 0.007|
|By randomized treatment group, univariate||OR 4.57 (1.19, 17.57), P 5 0.010|
|HR 3.64 (1.11, 11.94), P 5 0.013|
|After adjustment for UT grade||OR 6.00 (1.44, 24.93), P 5 0.004|
|HR 4.66 (1.36, 15.98), P 5 0.004|
|Margin of effect/relative performance 68%/309%|
|Ulcer recurrence at 12 months, n (%) 2 (40.0) 1 (6.7)||P 5 0.070|
|Ulcers closed at 12 months, n (%) 10 (27) 20 (56)||P 5 0.013|
|Margin of effect/relative performance 52%/207%|
|Absolute change in ulcer area over 12 weeks, cm2 0.40 (1.75) 1.97 (2.75)||P 5 0.041|
|Absolute change in ulcer area in ulcers .4 cm2 over 12 weeks, cm2 21.34 (1.18) 4.12 (1.51)||P 5 0.021|
|Time to complete wound closure, weeks 6.3 (1.9) 8.2 (4.2)||P 5 0.350|
|CWIS well-being improvement between baseline and week 12 20.1 (16.9) 9.1 (13.9)||P 5 0.033|
|CWIS social life improvement between baseline and week 12 4.1 (12.4) 7.9 (16.9)||P 5 0.340|
|CWIS physical symptom improvement between baseline and week 12 4.6 (11.8) 12.1 (23.2)||P 5 0.130|
|Index limb amputations, n (%) 3 (8) 2 (5)||P 5 0.668|
|TWO2 therapy and off-loading compliance|
|Used TWO2 therapy device 5 days/week, 90 min/day, n (%) 35 (96) 34 (94)||P 5 0.978|
|Used off-loading device .75% of the time, n (%) 36 (99) 35 (97)||P 5 0.984|
Incidence of serious adverse events, n 10 10
Wound infection 2 3
Osteomyelitis 5 2
Hypoglycemic event 1 0
Urinary tract infection 0 2
Signiﬁcant necrotic tissue 1 0
Cardiovascular event 0 1
UTC grade 2 ulceration 0 1
Severe maceration/dermatitis 1 0
Pneumonia 0 1
Incidence of adverse events, n 8 8
UTC grade 1 ulceration 0 3
Ulcer decline 0 2
Minor infection 1 1
Minor osteomyelitis 0 1
Minor necrotic tissue 1 0
Cellulitis 1 0
Swelling/edema 1 1
Maceration 2 0
Dermatitis 1 0
Contusion 1 0
Incidence of adverse device events 0 0
Data are means (SD) unless otherwise indicated. Boldface type indicates signiﬁcant differences.
P 5 0.943
P 5 0.950
The quality of DFU studies is often measured by the results obtained in the control groups. In our sham-treated control group, 13.5% of patients achieved complete ulcer healing within the 12-week outcome period. This rate is similar to that of some studies and lower than others (17,30,37,38). Interestingly, a recent topical oxygen RCT reported an active group healing rate lower than ours at 32.4% and a similar control healing rate (30). For the more chronic ulcers, their placebo arm healing rate dropped to 13.2%. Despite the large margin of effect between our active and sham groups, we attribute our osten- sibly low sham healing rate to the chronicity of the ulcers, complexity of the patients, and the control of, rather than a failure of, SOC treatment. In this regard, the average duration of ulcers enrolled in the trial was .5 months, with a nonsigniﬁcant 14-day longer duration in the control group. After the 2-week run-in period, 25% of enrolled patients were excluded from randomi- zation due to a reduction in wound area $30%. The study off-loading device, itself proven to be as efﬁcacious as gold standard total contact casting (39), may have enabled progress toward healing that excluded patients likely to heal with such standard care alone. This allowed only patients with wounds more difﬁcult to heal (true SOC failures) to be random- ized into this trial. Since there was a very high degree of compliance with both blinded treatments and off-loading throughout the study, we have no reason to believe that the control group healing result was due to any shortcoming in the SOC protocol.
Our sham therapy itself provided nothing more than nonpressurized room air that was free to circulate within the extremity chamber. Room air cannot conceivably be detrimental to the control patients or have a negative impact on ability to heal. Even at the 12-month follow-up evaluation point, long after the active therapy had ended, there was still a clear separation between study groups, with the sham control patients achieving a healing rate of only 27%. Analysis for predictors of healing at 12 weeks resulted only in the treatment effect and UTC ulcer grade being signif- icant. Furthermore, we found no difference in compliance with the therapy or off- loading between study groups. In the ab- sence of otherwise explanatory data to account for the control healing rate, we are left with our presumption that those randomized into the study had ulcers that were truly hard to heal and that the dif- ference in healing rates between active and sham groups was indeed a treatment effect.
The mean age of our study population was ;63 years old, which mirrors that seen in other DFU studies. Eighty-six percent of our study patients were men, likely resulting somewhat from the fact that one-half of the U.S. study sites were Veterans Affairs wound care clinics. Multiple studies have shown DFUs to be more prevalent in men than women to a degree similar to that seen in this RCT (4,10,38). With no signiﬁcant differences in covariates seen between the two study groups, our ﬁndings support the premise that these results are generalizable to simi- larly afﬂicted patient populations.
The results of the TWO2 study demon- strate that cyclical pressurized TOT in conjunction with both optimal off-loading and good standard wound care can heal signiﬁcantly more DFUs at 12 weeks compared with optimal SOC alone. In fact, we found a .4.5-fold increased likelihood of healing within this time period for our actively treated patients. This therapy was safe, without compli- cations, and provided more durable heal- ing for those who had wound closure during active treatment. Uniquely, the therapy has additional beneﬁt in that it can be administered by the patient at home without the expense and difﬁcul- ties of daily travel to a specialized center. In contrast to recently reported systemic HBOT studies (16,18,40), this robust double-blinded, sham-controlled trial provides evidence to support use of this adjunctive cyclical pressurized TOT for chronic DFUs.
Acknowledgments. The authors thank all study patients, clinic personnel, study coordinators, and colleagues who assisted with patient referrals.
Duality of Interest. This study was sponsored by AOTI Ltd. (Galway, Ireland). The sponsor incurred all costs for the study including all institutional fees, monitoring, data warehousing, statistical services, and the provision of study devices and supplies. R.G.F. received research support from thesponsorduringtheconductofthestudy while employed at the Phoenix VA Healthcare System and has received subsequent speaking honoraria. P.J.F., M.E., J.N.B., L.T., T.W., M.G.G., A.M.L., J.A.T.,
G.R., C.R.D., K.L., D.G., and S.C.R. all received research support from the sponsor during the study. No other potential conﬂicts of interest relevant to this article were reported.
Aside from delivery and home setup of study devices, no sponsor employee or agent participated in any aspect of patient care or study treatments.
Author Contributions. R.G.F. assisted with the conception, design, and analysis of the study and wrote the manuscript. P.J.F. provided the sta- tistical design, performed the analyses, and assisted with writing the manuscript. M.E., J.N.B., L.T., T.W., M.G.G., A.M.L., J.A.T., G.R.,
C.R.D., K.L., D.G., and S.C.R. contributed to the discussion and critically reviewed and provided edits to the manuscript. R.G.F. and P.J.F. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this study were presented as a late-breaking abstract at the 78th Scientiﬁc Sessions of the American Di- abetes Association, Orlando, FL, 22–26 June 2018.
- Jeffcoate WJ, Vileikyte L, Boyko EJ, Armstrong DG, Boulton AJM. Current challenges and op- portunities in the prevention and management of diabetic foot ulcers. Diabetes Care 2018;41: 645–652
- Armstrong DG, Boulton AJM, Bus Diabetic foot ulcers and their recurrence. N Engl J Med 2017;376:2367–2375
- International Diabetes Federation. IDF Dia- betes Atlas. 8th ed. Brussels, Belgium, Interna- tional Diabetes Federation, 2017
- Reiber GE, Vileikyte L, Boyko EJ, et Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Di- abetes Care 1999;22:157–162
- Frykberg RG, Banks Challenges in the treat- ment of chronic wounds. Adv Wound Care (New Rochelle) 2015;4:560–582
- Lobmann R, Schultz G, Lehnert Proteases and the diabetic foot syndrome: mechanisms and therapeutic implications. Diabetes Care 2005;28: 461–471
- Hingorani A, LaMuraglia GM, Henke P, et The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg 2016;63(Suppl.):3S–21S
- Snyder RJ, Frykberg RG, Rogers LC, et The management of diabetic foot ulcers through optimal off-loading: building consensus guide- lines and practical recommendations to improve outcomes. J Am Podiatr Med Assoc 2014;104: 555–567
- International Diabetes IDF Clini- cal Practice Recommendation on the Diabetic Foot: A Guide for Health Care Professionals, Brussels, Belgium, International Diabetes Feder- ation, 2017
- Game FL, Apelqvist J, Attinger C, et al.; International Working Group on the Diabetic Effectiveness of interventions to enhance healing of chronic ulcers of the foot in diabetes: a systematic review. Diabetes Metab Res Rev 2016;32(Suppl. 1):154–168
- Elraiyah T, Tsapas A, Prutsky G, et al. A systematic review and meta-analysis of adjunc- tive therapies in diabetic foot J Vasc Surg 2016;63:46S–58S.e1-2
- Gordillo GM, Sen Revisiting the essential role of oxygen in wound healing. Am J Surg 2003; 186:259–263
- Howard MA, Asmis R, Evans KK, Mustoe Oxygen and wound care: a review of current therapeutic modalities and future direction. Wound Repair Regen 2013;21:503–511
- Gordillo GM, Roy S, Khanna S, et Topical oxygen therapy induces vascular endothelial growth factor expression and improves closure of clinically presented chronic wounds. Clin Exp Pharmacol Physiol 2008;35:957–964
- Gottrup F, Dissemond J, Baines C, et Useof oxygen therapies in wound healing. J Wound Care 2017;26:S1–S43
- Fedorko L, Bowen JM, Jones W, et al. Hy- perbaric oxygen therapy does not reduce indi- cations for amputation in patients with diabetes with nonhealing ulcers of the lower limb: a pro- spective, double-blind, randomized controlled clinical trial. Diabetes Care 2016;39:392–399
- Lo¨ndahl M, Katzman P, Nilsson A, Hammarlund Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care 2010;33:998–1003
- Santema KTB, Stoekenbroek RM, Koelemay MJW, et al.; DAMO2CLES Study Group. Hyper- baric oxygen therapy in the treatment of ische- mic lower-extremity ulcers in patients with diabetes: results of the DAMO2CLES multicenter randomized clinical Diabetes Care 2018;41: 112–119
- Game FL, Attinger C, Hartemann A, et al.; International Working Group on the Diabetic IWGDF guidance on use of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev 2016; 32(Suppl. 1):75–83
- Blackman E, Moore C, Hyatt J, Railton R, Frye Topical wound oxygen therapy in the treat- ment of severe diabetic foot ulcers: a prospective controlled study. Ostomy Wound Manage 2010; 56:24–31
- Gordillo GM, Sen CK. Evidence-based recom- mendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. Int J Low Extrem Wounds 2009;8:105–111
- Feldmeier JJ, Hopf HW, Warriner RA III, Fife CE, Gesell LB, Bennett UHMS position state- ment: topical oxygen for chronic wounds. Un- dersea Hyperb Med 2005;32:157–168
- Fries RB, Wallace WA, Roy S, et al. Dermal excisional wound healing in pigs following treat- ment with topically applied pure Mutat Res 2005;579:172–181
- Orsted HL, Poulson R, Baum J, et al.; Advisory Evidence-based practice standards for the use of topical pressurised oxygen therapy. Int Wound J 2012;9:271–284
- Leslie CA, Sapico FL, Ginunas VJ, Adkins Randomized controlled trial of topical hyperbaric oxygen for treatment of diabetic foot ulcers. Diabetes Care 1988;11:111–115
- de Smet GHJ, Kroese LF, Menon AG, et al. Oxygen therapies and their effects on wound Wound Repair Regen 2017;25:591–608
- Aburto I, Frye C. A randomized controlled trial to evaluate different treatment regimes with topical wound oxygen (TWO2) on chronic Oral presentation at the 6th Interna- tional Symposium on Diabetic Foot, 11–14 May 2011, Noordwijkerhout, the Netherlands
- S. Food and Drug Administration. Guid- ance for industry, chronic cutaneous ulcer and burn woundsddeveloping products for treatment [Internet], 2006. Available from https://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ucm071324.pdf. Accessed 8 February 2019
- Bolton Quality randomized clinical trials of topical diabetic foot ulcer healing agents. Adv Wound Care (New Rochelle) 2016;5:137–147
- Niederauer MQ, Michalek JE, Liu Q, Papas KK, Lavery LA, Armstrong Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a ran- domised, double-blind, multicentre study. J Wound Care 2018;27:S30–S45
- Yu J, Lu S, McLaren AM, Perry JA, Cross Topical oxygen therapy results in complete wound healing in diabetic foot ulcers. Wound Repair Regen 2016;24:1066–1072
- Niederauer MQ, Michalek JE, Armstrong DG. A prospective, randomized, double-blind multicenter study comparing continuous diffusion of oxygen therapy to sham therapy in the treatment of diabetic foot ulcers. J Diabetes Sci Technol 20×17;11:883–891
- Tawﬁck W, Sultan S. Does topical wound oxygen (TWO2) offer an improved outcome over conventional compression dressings (CCD) in the management of refractory venous ulcers (RVU)? A parallel observational comparative Eur J Vasc Endovasc Surg 2009;38:125–132
- Tawﬁck WA, Sultan Technical and clinical outcome of topical wound oxygen in comparison to conventional compression dressings in the management of refractory nonhealing venous ulcers. Vasc Endovascular Surg 2013;47:30–37
- Centers for Medicare & Medicaid Decision memo for hyperbaric oxygen (HBO) therapy (section C, topical oxygen) (CAG-00060R) [Internet], 2017. Available from https://www.cms.gov/medicare-coverage-database/details/nca- decision-memo.aspx?NCAId5286&bc5AAAA AAAAQAAA&. Accessed 8 February 2019
- Zelen CM, Serena TE, Denoziere G, Fetterolf A prospective randomised comparative par- allel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J 2013;10:502–507
- Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic foot ulcers receiving stan- dard A meta-analysis. Diabetes Care 1999;22:692–695
- Marston WA, Hanft J, Norwood P, Pollak R; Dermagraft Diabetic Foot Ulcer Study Group. The efﬁcacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized Diabetes Care 2003;26:1701–1705
- Piaggesi A, Goretti C, Iacopi E, et al. Com- parison of removable and irremovable walking boot to total contact casting in ofﬂoading the neuropathic diabetic foot ulceration. Foot Ankle Int 2016;37:855–861
- Margolis DJ, Gupta J, Hoffstad O, et al. Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a co- hort Diabetes Care 2013;36:1961– 1966
S Y S TEMA TIC REVIEW OR MET A – AN ALY SIS
Topical oxygen therapy for diabetes-related foot ulcers: A systematic review and meta-analysis
Shivshankar Thanigaimani1,2 | Tejas Singh1,3 | Jonathan Golledge1,2,3
1The Queensland Research Centre for Peripheral Vascular Disease (QRC-PVD), College of Medicine and Dentistry, James Cook University, Queensland, Australia
2The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia
3The Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, Queensland, Australia
Jonathan Golledge, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.
Email: [email protected]
Funding from James Cook University (Strategic Research Investment Fund) and Queensland Government supported this work. JG holds a Practitioner Fellowships from the National Health and Medical Research Council (1117061) and a Senior Clinical Research Fellowship from the Queensland Government, Australia. The funders played no role in study design, conduct, data collection, analysis and interpretation, and did not assist in preparation or review of this manuscript.
1 | INTRODUCTION
Diabetes-related foot ulceration (DFU) is one of the top 10 causes of global disability.1 About 6.3% of the global popu- lation (approximately 440 million people) are estimated to be affected by DFU.2 In the United States, it has been estimated that managing DFU costs between US$28 and 97 billion per year.3 The 5-year mortality of patients with a DFU has been reported to be 31% which is comparable with a group or pa- tients with a range of different cancers.4 DFUs re-occur in more than 50% within 3 years and many remain unhealed with conventional therapies for extended periods.5,6 Topical oxygen therapy has been proposed as a treatment for DFU by improving tissue oxygenation and collagen synthesis, pro- moting angiogenesis, enhancing the function of fibroblast and leukocytes, and inhibiting microbial growth.7,8 These proposed beneficial effects of topical oxygen therapy would be expected to improve wound healing. The clinical efficacy of this treatment in healing DFUs is however controversial.9 A position statement from the Undersea and Hyperbaric
| 1 of 10
Medical Society (UHMS) stated that topical oxygen therapy is emerging as a potential treatment for chronic wounds, but that the therapeutic efficacy is not adequately supported by scientific evidence for guideline recommendation.10,11 Since then, a number of randomised controlled trials have, however, reported beneficial effects of topical oxygen therapy.12-17
A number of prior systematic reviews have examined the evidence on topical oxygen therapy in treating DFU. These have included both randomised and non-randomised trials and not performed meta-analyses.18,19 This has made it diffi- cult to draw firm conclusions on the evidence for this treat- ment. Furthermore, recently two further randomised trials had been reported that were not included in the previous sys- tematic reviews.14,16 The aim of this systematic review was to perform an up to date assessment of the evidence for topical oxygen therapy in treating DFU through a pooled analysis of findings from randomised control trials.
2 | METHODS
2.1 | Search strategy
This systematic review was performed according to the 2015 Preferred Reporting Items for Systematic Review and Meta- Analysis Protocols (PRISMA-P) statement.20 The study pro- tocol was registered with PROSPERO (CRD42021214994). The literature search was conducted by two authors (ST and TS) to identify randomised controlled trials that evaluated the effect of topical oxygen therapy in people with a DFU. The PubMed and Cochrane databases were searched to include all relevant publications until the 14th October 2020. The search strategy used terms similar or synonymous to ‘Topical oxy- gen therapy’ and ‘DFU’ as given in the supplementary mate- rial. References from the included studies were also searched for potential studies to be included. No language restrictions were applied.
2.2 | Inclusion and exclusion criteria
Inclusion required the studies to be randomised controlled trials that tested the efficacy of topical oxygen therapy as a treatment for DFU and compared against placebo or no ac- tive/sham treatment. Non-randomised or cohort studies, reviews and case reports were excluded. Included studies were identified by two authors (ST and TS) and reviewed by a third author (JG) to confirm the eligibility for inclusion. Discrepancies were resolved through discussion.
2.3 | Data extraction
The full texts of included studies were independently as- sessed by two investigators (ST and TS) to extract study design, number of people who were screened, randomised and completed follow-up, intervention method and duration, primary outcome, and qualitative and quantitative methods of assessing the DFU. Age, sex, current smoking, ankle– brachial index (ABI), toe pressure, transcutaneous oxygen pressure, HbA1c levels, duration of wound, prior history of revascularisation procedures, lower extremity amputation, hypertension, cardiovascular disease, metformin prescription and safety data were also extracted. Extracted data were dis- cussed in a meeting with another researcher (JG) and finally agreed through consensus.
2.4 | Quality assessment
Two authors (ST and TS) independently assessed the risk of bias of all included studies. A modified version of the Cochrane Collaboration’s tool was used which assessed re- porting of concealment of random allocation of participants, random sequence generation method, sample size calcula- tions, reporting of statistical analysis methods, percentage of participants lost to follow-up and intent-to-treat analysis.21 The modifications included the addition of assessments of how DFU was defined and wound size measured. Any dis- crepancies were resolved through discussion between the au- thors. Assessment scores with <50%, 50%–75% and >75% were considered to have high, moderate and low risk of bias, respectively.
2.5 | Outcomes and data analysis
The primary outcome was complete ulcer healing, defined as complete epithelialisation, following topical oxygen ther- apy compared to control or sham treatment at the end of the follow-up period. The secondary outcome was any am- putation including toe, trans-metatarsal and below, through or above knee amputations. To consistently take account of missing data due to loss to follow-up, two types of out- come analyses were planned as previously described.22 In the main analysis, patients who were lost during follow-up were considered to have achieved full ulcer healing (best- case scenario). In a sensitivity analysis, all participants lost to follow-up were considered to have not achieved full ulcer healing (worst-case scenario). A minimum of three studies were required to be eligible for meta-analysis of the primary or secondary outcomes. Due to anticipated statistical het- erogeneity, random-effects models using Mantel–Haenszel’s method were used. Data were expressed as risk ratio (RR) with 95% confidence intervals (CI). Leave-one-out sensitiv- ity analyses, by removing studies individually, were per- formed for the main analysis to assess the contribution of any single study towards the overall outcomes. A separate sensitivity analyses of studies deemed to be at low risk of bias were also planned if enough eligible studies were iden- tified. The I2 index was used to assess the degree of statisti- cal heterogeneity between studies, with I2 ≥75% accepted to denote high heterogeneity. Funnel plots of the effect size versus the standard error of mean (SEM) of the log- transformed effect were plotted as scatterplot to assess po- tential publication bias. In addition, the rank correlation test was used to estimate the effects of smaller studies. Number needed to treat (NNT) was calculated using the formula [1/ (Experimental event rate)-(Control event rate)] to report the number of patients needed to be treated with the intervention to achieve one additional positive outcome. All analyses were conducted using the ‘meta’ and ‘metafor’ packages of R software version 3.4.4. A p value of <0.05 was considered as statistically significant.
3. | RESULTS
3.1 | Study selection
The literature search identified 719 studies, of which 665 unique records were assessed. In all, 96 studies that investi- gated any form of oxygen therapy were selected for full-text assessment (\* MERGEFORMAT Figure 1). Finally, six tri- als were deemed eligible based on the inclusion criteria.12-17
3.2 | Study characteristics
The characteristics of the included studies are summarised in Table S1. Among the six RCTs, four were conducted in the United States,12,13,15,16 one in Canada17 and one was a multi-centre trial that were conducted in the United States, Germany, the United Kingdom and France.14 Eligibility for inclusion typically required a diagnosis of type 1 or 2 dia- betes mellitus and a non-healing, full thickness wound that could be categorised as class 1A or above of the University of Texas classification of DFUs and a duration of at least 4 weeks and <52 weeks or wound sizes ranging from 1.5 cm2 to 10 cm2 (see Table S1). Studies provided a variable duration
FIGURE 1 Preferred Reporting Items of Systematic Review and Meta-analyses (PRISMA) flow diagram. A total of 719 studies were screened and 6 trials were included. DFU – Diabetes-related foot ulcer; RCT – Randomized controlled trials of usual standard of care of 1,12,13 215,16 or 4 weeks14 before considering the DFU non-healing as part of the eligibility criteria. In one trial, potential participants were excluded if the DFU was considered only neuropathic in aetiology with no contribution of ischaemia unless the ulcer had failed to heal with 12 weeks of optimum management.17 Patients were followed up while the topical oxygen therapy was delivered in all included studies for between 4 and 12 weeks. In one study, patients were also followed for 12 months after the topical oxygen therapy concluded.14
3.3 | Interventions tested and controls
Topical oxygen therapy was delivered using a variety of different Food and Drug Administration approved devices
TABLE 1 Baseline patient characteristics in the included studies
BMI, kg/ m2
Duration of diabetes, months
Duration of ulcer, mean±S.D
Prior revascularisation procedures, %
|Driver 2013||TOT||70.6||58.6±7.1||NA||NA||NA||NA||20 months||NA|
|Yu 2016||TOT||85||57.0±9.5||NR*||NR*||8.6±2.3||NR||47.4±23.4 wks||NR|
|Niederauer||TOT||79.7||56.1±10.1||NR||NR||8.4 ± 1.6||NR||131.6±89.2 days||NR|
|2018||Control||75||56.6±14.4||NR||NR||8.3 ± 2.0||NR||143.8±97.7 days||NR|
Abbreviations: %, Percentage; *, Measured but not reported; BMI, Body mass index; CVD, Cardiovascular disease; HTN, Hypertension; mmHg: Millimetres of mercury; NR, Not reported; NRC, Not reported correctly; sABI, Ankle Brachial Index; SD, Standard deviation; TcPo2, Transcutaneous oxygen pressure; TOT, Topical oxygen therapy.
To convert percentage HbA1c values to mmol HbA1c per mol Hb, use the following equation 10.93 × % HbA1c – 23.5 mmol/mol.
TABLE 2 Quality assessment of all included studies
Patient subset definition
|Mentioned the number of patients who completed the study||
Random sequence generation
Allocation of random sequence concealed
Sample size estimate not reached
Abbreviations: %, Percentage; 0.5 = Unclear; 0 = No; 1 = Yes; ITT, Intent to treat.
which supplied ≥98% transdermal continuous oxygen at flow rate of 3–15 ml/hr, including the TransCu O2® System,15,16 Natrox Oxygen Delivery System (ODS)17 and continuous tissue oxygen insufflation with Epiflo® oxy- gen generators provided by Neogenix, LLC.1312 One study tested variable oxygen flow using the cyclical Topical Wound Oxygen therapy device.14 Most studies delivered oxygen at atmospheric pressure using a single-use system,
but in one study, oxygen was delivered intermittently using a multi-use system at variable pressure and flow rate14 (Table S2). Three studies provided standard of care with- out any sham device for control participants12,13,17 and three studies used sham devices along with standard of care in control participants.14-16 This affected investigator, partici- pant and assessor blinding that was reflected in the quality assessment of these studies.
|History of lower extremity
Toe pressure, mmHg
Follow-up period (weeks)
Ulcer site (%)
|NA||NA||NA||NA||NA||NR||NR||NR||12||At or below the malleoli|
|NA||NA||NA||NA||NA||NR||NR||NR||At or below the malleoli|
|NR||NR||NR||NR||1.0±0.1||NR||NR||NR||12||Weight bearing (79.7)|
|NR||NR||NR||NR||1.0±0.2||NR||NR||NR||Weight bearing (73.6)|
|47.2||78||36||NR||1.1±0.2||84.5±30.5||NR||78%||52||Dorsal foot (22.2),|
|Leg below malleoli (2.8),|
|Pedal foot (50),|
|21.6||81||24||NR||1.0±0.2||83.0±32.7||NR||78%||Dorsal foot (13.5),|
|Leg below malleoli (10.8),|
|Pedal foot (59.5),|
Blinding of participants
Blinding of assessors
|Blinding of outcome assessment||HbA1c values reported||
Baseline wound size reported
|Verified wound measurement method||
3.4 | Patient characteristics
The baseline participant characteristics are shown in \* MERGEFORMAT Table 1. The wound duration, HbA1c levels, ABI, smoking status, prior history of amputation and revascularisation procedures, toe pressure, transcutane- ous pressure, neuropathy and ulcer site are illustrated in \* MERGEFORMAT Table 1. Reporting of ulcer aetiology was limited in the included studies and those that reported ABI or toe pressure suggested that majority of the included par- ticipants had non-ischaemic ulcers. Only one study reported body mass index, prior history of lower extremity amputa- tions and toe pressure.14 Four studies reported the duration of ulcers in the included participants.13,14,16,17 Only one study reported smoking history and prevalence of neuropathy14 and none of the trials reported prior history of revascularisation procedures, transcutaneous oxygen pressures, duration of di- abetes and prescription of metformin and cost-effectiveness of topical oxygen therapy compared to other contemporary treatments.
3.5 | Risk of bias of included studies
Three studies were assessed as at low risk of bias,14-16 one study was assessed at moderate risk of bias12 and two assessed as at high risk of bias13,17 (\* MERGEFORMAT Table 2). All studies reported the population included, the number of participants who completed the study and the baseline wound size.12-17 Five studies reported the HbA1c levels of the participants.12,14-17 Two trials determined the wound size by measuring the length, width and depth with a ruler.12,13 One trial measured wound size using automated CE-marked wound measurement software,14 one trial measured maxi- mum perpendicular length and width of the wound17 and two trials measured wound size using planimetric analysis.15,16 Three trials blinded both the participants and assessors.14-16 Three trials used intent-to-treat analyses.12,14,16 Two trials re- cruited the required population size based on a sample size estimate.14,15 Only one trial clearly reported the random se- quence generation.14
3.6 | Effect of topical oxygen therapy on complete ulcer healing
Overall, five 13-17 of the six trials reported that topical oxygen therapy significantly increased the proportion of participants that achieved ulcer healing by comparison to controls. The main meta-analysis of all six trials, includ- ing 267 participants undergoing topical oxygen therapy and 263 controls, suggested that topical oxygen therapy resulted in greater likelihood of ulcer healing compared to controls (RR 1.94; 95% CI 1.19, 3.17). The included trials had moderate statistical heterogeneity (I2 = 57%;
\* MERGEFORMAT Figure 2). The worst-case scenario sensitivity analysis suggested, similar to the main analysis, that topical oxygen therapy resulted in greater likelihood of ulcer healing compared to controls but with a lower RR (RR 1.57; 95% CI 1.07, 2.30) (Figure S1). The funnel plots were asymmetrical suggesting a risk of publication bias (\* MERGEFORMAT Figure 3). The correlation rank test suggested the possibility of small study effects (p = 0.05). Leave-one-out sensitivity analyses showed that removal of any single study did not affect the significance of the find- ings (\* MERGEFORMAT Table 3). Meta-analysis of three studies that were assessed as low risk of bias with 183 inter- vention participants and 182 controls suggested that topi- cal oxygen therapy resulted in greater likelihood of ulcer healing compared to controls (RR 2.37; 95% CI 1.52, 3.68) (Figure S2). Meta-regression suggested no significant rela- tionship between the benefit achieved with topical oxygen therapy and the length of follow-up in the included studies (R2 = 26.6%, p = 0.16, \* MERGEFORMAT Figure 4). The number needed to treat to achieve one additional positive outcome was 5.33.
3.7 | Effect of topical oxygen therapy on amputation
Only two studies reported the requirement for amputation.12,14 One trial reported no amputations in the intervention group as compared to one amputation in the control participants
FIGURE 2 Forest plot suggesting a significant benefit of topical oxygen therapy in healing of diabetes-related foot ulcers.
RR: Risk ratio; CI: Confidence interval; Ne: Number of experimental events; Nc: Number of control events
FIGURE 3 Funnel plot using Egger’s test suggesting a potential publication bias due to asymmetry in the observed outcomes
TABLE 3 Leave-one-out sensitivity analysis of the main analysis (best-case scenario approach)
Abbreviations: CI, Confidence interval; I , Heterogeneity index.
during 12-week follow-up.12 Another trial reported two am- putations in the intervention group compared to three ampu- tations in the control participants. In this study, although the intervention was undertaken for 12 weeks, the patients were followed up for up to 12 months.14 Meta-analysis was not eligible due the absence of sufficient studies reporting this outcome.
3.8 | Serious adverse events with topical oxygen therapy
Three studies reported safety data and noted a similar num- ber of serious adverse events in both intervention and control participants.12,14,16 Two studies reported mortality rates.14,16 One trial reported no deaths in the intervention group as com- pared to two deaths in control participants after 12 weeks.16 Another trial reported two deaths each in intervention and control groups after 12-month follow-up.14 Although none of the included studies perform economic analyses, three stud- ies stated that it would be cost-effective compared to hyper- baric oxygen therapy.15-17
4 | DISCUSSION
This systematic review and meta-analysis suggested that topical oxygen therapy improved the healing of DFUs, as evidenced by an approximate twofold increased likelihood of ulcer healing. Sensitivity analyses suggested that the findings
FIGURE 4 Meta-regression suggesting no significant effect of varying follow-up period on treatment outcomes (R2 = 26.6%, p = 0.16)
were robust. Analysis of secondary outcomes of amputations was not possible due to limited number of studies; however, two studies that reported amputations showed no significant differences.12,14 Serious adverse events were reported to be similar between intervention and control groups. The in- cluded DFUs appeared to be non-healing neuropathic ulcers based on the ABI reported in the studies. Overall, the find- ings of this meta-analysis suggest that topical oxygen therapy could be considered for the treatment of non-healing neu- ropathic DFUs, although due to the heterogeneity between studies and small sample sizes of included trials the findings should be interpreted cautiously.
The cost of treating a DFU has been reported to be be- tween £3,339 23 and £20,351 per patient depending on the interventions used and ulcer chronicity.24 A simulation model using inputs from peer-reviewed journal publications and publicly available documents reported that 5-year cost per person treated with continuous delivery of topical ox- ygen was £2,770 less than negative pressure wound ther- apy.25 Furthermore, topical oxygen therapy can be provided at the patient’s home, rather than a hospital setting, unlike hyperbaric oxygen therapy. Hyperbaric oxygen therapy, an established treatment for non-healing DFU in some coun- tries, is normally delivered for 1 to 2 months three to four times per week at a central facility. The cost of a course of hyperbaric oxygen therapy has been estimated as £3000 per patient.26 In contrast, the included trials showed that the topical oxygen therapy enables the patients to be home based for most of the treatment period by providing equip- ment that can deliver continuous oxygen therapy for a few weeks before being replaced (Table S2). Therefore, topical oxygen therapy has the potential to provide an easy-to-use and more cost-effective means of delivery oxygen to treat DFUs.
Hyperbaric oxygen therapy has been reported to have some complications such as those related to barotrauma, such as pneumothorax and ear drum rupture. Safety data were only available from three of the trials included in this systematic review which reported no excess of serious ad- verse events12,14,16 (Table S3). None of the trials reported cost-effectiveness analyses and this information will likely have an important impact on implementation of this treat- ment. Future trials are needed to provide cost-effectiveness and further safety analyses.
This meta-analysis and the included trials had a number of limitations and potential biases that should be acknowledged. First, all the included trials were relatively small making it difficult to draw any reliable conclusions. Reporting of par- ticipant risk factors, prior treatment and adverse events was generally limited making it difficult to draw conclusions on the generalisability of findings.14 None of the studies reported economic analyses which has important implications for im- plementation. Furthermore, there was significant clinical heterogeneity due to differences in duration of treatment and follow-up, and poor reporting of the presence of peripheral ischaemia. Funnel plots suggested the possibility of publica- tion bias. There was heterogeneity in the characteristics of the included patients and design of the studies. This should be taken into account in applying the results of this systematic review. Furthermore, ischaemic DFUs do not appear to have been included and requirement for amputation was poorly reported. Finally, both Driver et al12,13 and Niederauer and colleagues15,16 reported two studies included in this meta- analysis. We were unable to clarify whether there was an overlap in the participants reported in these trials. The leave- one-out sensitivity analysis suggested that the findings that topic oxygen therapy significantly increased the likelihood of ulcer healing remained following removal of individual trials. In view of the small number of trials, however, further assess- ment of the effectiveness of topical oxygen therapy in larger populations of patients is advisable before widespread use.
In conclusion, this systematic review suggested that topi- cal oxygen therapy improved the likelihood of DFU healing; however; its effect on requirement for amputation is unclear. Further clinical trials adequately powered to test the effect of this treatment on amputation, its value in treating ischaemic ulcers and its cost-effectiveness are needed. A large clinical trial including heterogeneous DFUs would also help provide confidence that the findings are repeatable and can be widely applied.
CONFLICT OF INTEREST
Dr. Shivshankar Thanigaimani was involved in the study conceptualisation, keyword search, full-text screening, data extraction, data analysis and manuscript preparation and editing. Dr. Tejas Singh was involved in data extrac- tion, validation and manuscript preparation and editing. Prof. Jonathan Golledge was involved in the study concep- tualisation, data validation, supervision, manuscript prepa- ration and editing, critical assessment of the manuscript and funding acquisition.
Jonathan Golledge https://orcid.org/0000-0002-5779-8848
- Larsson J, Apelqvist J. Towards less amputations in diabetic pa- tients. Incidence, causes, cost, treatment, and prevention–a Acta Orthop Scand. 1995;66(2):181-192.
- Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Global epidemiology of diabetic foot ulceration: a systematic review and meta-analysis (†). Ann Med. 2017;49(2):106-116.
- Nussbaum SR, Carter MJ, Fife CE, et An economic evaluation of the impact, cost, and medicare policy implications of chronic nonhealing wounds. Value Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research. 2018;21(1):27-32.
- Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula WV, Bus Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res. 2020;13(1):16.
- Boulton AJM, Vileikyte L, Ragnarson-Tennvall G, Apelqvist
- The global burden of diabetic foot disease. The Lancet. 2005;366(9498):1719-1724.
- Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367-2375.
- de Smet GHJ, Kroese LF, Menon AG, et Oxygen thera- pies and their effects on wound healing. Wound Repair Regen. 2017;25(4):591-608.
- Gordillo GM, Sen CK. Evidence-based recommendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. Int J Low Extrem Wounds. 2009;8(2):105-111.
- Mutluoglu M, Cakkalkurt A, Uzun G, Aktas Topical oxygen for chronic wounds: a PRO/CON debate. J Am Coll Clin Wound Spec. 2014;5(3):61-65.
- Feldmeier JJ, Hopf HW, Warriner RA 3rd, Fife CE, Gesell LB, Bennett UHMS position statement: topical oxygen for chronic wounds. Undersea Hyperb Med. 2005;32(3):157-168.
- UHMS Position Topical oxygen for chronic wounds. Undersea Hyperb Med. 2018;45(3):379-380.
- Driver VR, Reyzelman A, Kawalec J, French A prospec- tive, randomized, blinded, controlled trial comparing transder- mal continuous oxygen delivery to moist wound therapy for the treatment of diabetic foot ulcers. Ostomy Wound Manage. 2017;63(4):12-28.
- Driver VR, Yao M, Kantarci A, Gu G, Park N, Hasturk H. A prospective, randomized clinical study evaluating the effect of transdermal continuous oxygen therapy on biological processes and foot ulcer healing in persons with diabetes mellitus. Ostomy/ Wound Management. 2013;59(11):19-26.
- Frykberg RG, Franks PJ, Edmonds M, et A multinational, mul- ticenter, randomized, double-blinded, placebo-controlled trial to evaluate the efficacy of cyclical topical wound oxygen (TWO2) therapy in the treatment of chronic diabetic foot ulcers: the TWO2 study. Diabet Care. 2020;43(3):616-624.
- Niederauer MQ, Michalek JE, Armstrong A prospective, ran- domized, double-blind multicenter study comparing continuous diffusion of oxygen therapy to sham therapy in the treatment of diabetic foot ulcers. J Diabet Sci Technol. 2017;11(5):883-891.
- Niederauer MQ, Michalek JE, Liu Q, Papas KK, Lavery LA, Armstrong Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo con- trol: a randomised, double-blind, multicentre study. J wound care. 2018;27(Sup9):S30-S45.
- Yu J, Lu S, McLaren AM, Perry JA, Cross KM. Topical oxygen therapy results in complete wound healing in diabetic foot ulcers. Wound Repair Regen. 2016;24(6):1066-1072.
- Nataraj M, Maiya AG, Karkada G, et al. Application of topical oxygen therapy in healing dynamics of diabetic foot ulcers – a sys- tematic review. Rev Diabet Stud. 2019;15:74-82.
- Vas P, Rayman G, Dhatariya K, et al. Effectiveness of interven- tions to enhance healing of chronic foot ulcers in diabetes: a sys- tematic review. Diabetes/Metabolism Res Rev. 2020;36(S1):e3284.
- Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1.
- Higgins JPT, Altman DG, Gotzsche PC, et The cochrane collab- oration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
- Golledge J, Singh TP. Systematic review and meta-analysis of clinical trials examining the effect of hyperbaric oxygen therapy in people with diabetes-related lower limb ulcers. Diabet Med. 2019;36(7):813-826.
- Sedory Holzer SE, Camerota A, Martens L, Cuerdon T, Crystal- Peters J, Zagari Costs and duration of care for lower extremity ulcers in patients with diabetes. Clin Ther. 1998;20(1):169-181.
- Ramsey SD, Newton K, Blough D, et al. Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care. 1999;22(3):382-387.
- Chan BC, Campbell An economic evaluation examin- ing the cost-effectiveness of continuous diffusion of oxygen therapy for individuals with diabetic foot ulcers. Int Wound J. 2020;17(6):1791-1808.
- Abidia A, Laden G, Kuhan G, et The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: A double- blind randomised-controlled trial. Eur J Vasc Endovasc Surg. 2003;25(6):513-518.
Additional supporting information may be found online in the Supporting Information section.
How to cite this article: Thanigaimani S, Singh T, Golledge J. Topical oxygen therapy for diabetes- related foot ulcers: A systematic review and meta- analysis. Diabet Med. 2021;00:e14585. https://doi. org/10.1111/dme.14585
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Oxygen Therapy and Wound Management: Thinking Outside the Chamber
Oxygen is a vital component of basic and advanced wound healing. It plays a major part in intricate cellular processes involved with healing all types of wounds. Understanding the pathophysiology of a hypoxic situation at the tissue level is vital in establishing the types of wounds that will benefit from oxygen therapy. The options for comprehensive therapy are discussed in depth; indications such as venous leg ulcers and chronic venous insufficiency, as well as diabetic foot ulceration are also reviewed in this article. A summary of recent topical oxygen therapy evidence is presented, as well as the myths surrounding oxygen therapy. This guide is aimed at providing support for clinicians wishing to incorporate oxygen into their practice.
Advanced, or ‘smart’, technology continues to be utilized in all facets of healthcare, up to and including
for delivery of oxygen to the body. And while the use of smart technology is said to make life increasingly more convenient from both a personal and professional standpoint, it does not relieve wound care providers of having to understand the many nuances associated with caring for patients living with hard-to- heal wounds. From the mechanism of action and the administration of oxygen therapy, to the available research that offers proven pros and cons to oxygen’s use, providers must be comprehensively well versed with this modality regardless of how much today’s technology might be able to ‘think’ for us humans. What’s more, topical oxygen presents a myriad of challenges despite how sophisticated today’s technology is. This continues to place emphasis on the basic facts and best practices surrounding this important life-sustaining element.
Oxygen’s Important Role
Oxygen is crucial in all phases of the wound healing cascade of events. Cellular and biological processes depend on oxygen, especially during the repair process. These include cell proliferation, angiogenesis, collagen deposition, resistance to infection, and protein synthesis needed to restore tissue integrity and function.1 Tissue oxygenation can trigger healing responses as well. Oxygen keeps cells nourished, oxidizes food during cellular respiration, is involved in the production of cell energy, and is an overall essential element to wound healing.2 Hypoxia, a lower level of oxygen than normal, is caused when there’s an impaired delivery of oxygen or an impaired cellular oxygen uptake.2 In the human body, normal blood oxygen level is categorized in the 94 – 98% range, while levels below 90% are considered dangerous and require intervention.3
Negative Effects of Decreased Oxygen
Limiting oxygen to the cells could have negative consequences, such as impaired healing and respiratory issues. Consider chronic obstructive pulmonary disease (COPD), which compromises lung function due to damage to the airways that renders breathing difficult. As COPD and breathing difficulties advance, a lack of oxygen to vital organs could lead to hypoxia. Symptoms include shortness of breath, frequent respiratory infection, fatigue, lower-extremity swelling, and reduced muscle strength.
Another condition that restricts the flow of oxygen and can impact wound healing is obstructive sleep apnea (OSA), a serious disorder that causes breathing to stop repeatedly during sleep when the body should be receiving extra oxygen. If left untreated, OSA can lead to hypertension, development of diabetes, heart conditions, and strokes, among other maladies. The importance of recognizing diminished oxygen levels has led clinicians to utilizing the delivery of oxygen as a treatment. COPD patients, depending on severity, can be prescribed supplemental oxygen, while patients with OSA can be treated with positive airway pressure devices that prevent breathing interruption.
Another form of oxygen as a treatment is hyperbaric oxygen therapy (HBOT), the roots of which actually date back to the 1600s. In the late 1930s, the military began using hyperbaric chambers to treat deep-sea divers who experienced decompression sickness. In 1967, the Undersea Medical Society, now known as the Undersea and Hyperbaric Medical Society (UHMS), was founded and later reviewed available evidence supporting the use of HBOT for a number of conditions. A listing of approved indications for HBOT by the U.S. Food & Drug Administration includes4
Approved Indications for HBOT:
- Air and gas bubbles in blood vessels
- Anemia (severe anemia when blood transfusions cannot be used)
- Burns (severe and large burns treated at a specialized burn center)
- Carbon monoxide poisoning
- Crush injury
- Decompression sickness
- Gas gangrene
- Hearing loss (complete hearing loss that occurs suddenly and without any known cause)
- Infection of the skin and bone (severe)
- Radiation injury
- Skin graft flap at risk of tissue death
- Vision loss (when sudden and painless in one eye due to blockage of blood flow)
- Wounds (non-healing, diabetic foot ulcers)
It is reported that there are more than 8 million chronic wounds that are more likely to be stuck in the inflammatory phase.5 The longer that it takes to manage these wounds effectively will increase likelihood of complications – time is tissue.
Options for Comprehensive Treatment
An arsenal of modalities is available that can impact cellular dysfunction in chronic wounds. These modalities could include electrical stimulation, high frequency ultrasound, low frequency contact and non-contact ultrasound, low level laser, shockwave therapy, pulse lavage, negative pressure wound therapy, diathermy, deep oscillation devices, and others that can be conducted in conjunction with sharp debridement, compression, and complete decongestive therapy (CDT). The goal with these modalities mainly includes the ability to ‘jump start’ chronic wounds into the progressive healing cascade and removing nonviable tissue to alter the wound environment.
Altering the chronic wound environment can move the wound along the healing path. Chronic wounds have an alkalic pH level of 7.15- 8.9, while wounds that make progress have a much lower pH level.6 If we are successful in decreasing the pH level by one numeric point, this increases the oxygenation level at the wound dramatically.6 Necrotic tissue is a medium for bacteria to proliferate and produce inflammatory mediators that inhibit healing. Without adequate local tissue oxygenation, the respiratory burst is impaired and the result is increased susceptibility to infection.7
Clinicians should also aim to assess arterial perfusion in lower-extremity wounds to establish adequate delivery of oxygen-rich blood to tissue. The delivery of oxygen is dependent on adequate blood flow at the capillary level. Without adequate perfusion, tissue death is eminent as the environment could become ischemic. Acute hypoxia is needed for cellular signaling, but chronic hypoxia will maintain the wound in an inflammatory phase. Treatment through revascularization can reestablish adequate levels of oxygen delivery to tissue.
Another important and often missed component in wound care is recognizing the negative effects of edema. Edema impairs the healing process because it delays the delivery of oxygen and nutrients to tissue. The endothelial glycocalyx plays an important role in fluid management, but increases endothelial cell permeability and leukocyte infiltration when injured. There’s also an increase in inflammatory cytokines, matrix metalloproteinases, reactive oxygen and nitrogen species, iron deposition, and tissue metabolites.8 When interstitial space increases due to endothelial glycocalyx damage or with an edematous condition, the distance from the capillaries to the cells requiring oxygen increases, therefore delaying oxygen transport. This increase in diffusion distance robs the wound of oxygen, which ultimately impairs the healing cascade of events. Patients with chronic venous leg ulcers (VLUs) and edematous lower extremities suffer from frequent infections, skin changes, and poor outcomes.
Chronic Edema and VLUs
Studies have validated the fact that patients with chronic edema have a difficult time healing. Rafetto et al. describe that the incidence of VLUs is 70 – 80% of all clinical ulcers, with recurrence rates of 50 – 70% at 6 months.8 VLUs pose a significant problem to our population, but new findings indicate that the numbers will continue to increase. The standard of care for VLUs consists of compression. With the recent changes in the Starling principle, it is understood that the lymphatic system is responsible for removing fluid and resolving edema. If a patient has a healthy lymphatic system, edema management will not pose a problem. However, if a patient’s lymphatic system fatigues, fails, or is damaged, any long- standing VLU edema will lead to a condition known as phlebolymphedema. A condition that indicates venous damage, phlebolymphedema when present with ulcers will lead to difficult healing due to the presence of stagnant protein-rich fluid and due to the longstanding fluid volume within the lower extremities. Essentially, the lymphatic system is working overtime and eventually fails. Margolis et al. discuss a prognostic model for VLUs, indicating that a wound that is < 10 cm2 and less than 12 months old at the first visit has a 29% chance of not healing by 24th week of care, while a wound > 10cm2 and > 12 months old has a 78% chance of not healing.9 This could be our answer as to why VLU patients with prolonged unresolved edema could have a poor chance of healing. If patients with VLUs have a lymphatic system that fails due to prolonged edema, compression will not suffice as the standard of care. The treatment at this point, along with compression, should be aimed at moving lymph to another quadrant with a normal lymphatic system. A 2022 article indicates that all edema is related to lymphatic dysfunction, whether transient or permanent, thereby creating a lymphedema continuum.10 Untreated lymphatic dysfunction will also lead to an increase in diffusion distance, thus decreasing the amount of oxygen delivered to the skin and/ or wound.
The Impact of CVI
In their 2020 study, Dean et al. established that lower-extremity lymphedema is predominantly caused by chronic venous insufficiency (CVI) and not the commonly encountered cancer.11 This also underscores that when the cause of edema is not addressed properly, patients will encounter frequent infections, chronic wounds, and other complications while not allowing oxygen to diffuse adequately. Tests such as transcutaneous oximetry (PtcO2) can assess the peri-wound oxygen tension of wounds. Fife et al. determined oxygen tension < 40mm Hg to be defined as tissue hypoxia.12
Patients with edema, inflammation, and/ or infection could have initial Ptc02 readings < 30 mm Hg, due to the increased diffusion distance. When adding supplemental oxygen under normobaric conditions, if the PtcO2 is > 100mm Hg, there could be an edematous condition at fault, as opposed to an arterial condition, decreasing the delivery of O2. Noting the important role of oxygen throughout the healing process, focusing on adequate arterial perfusion and decreasing the diffusion distance of edematous legs can be of value to bringing wounds out of the inflammatory phase and into the proliferative phase. Additionally, wound bed oxygenation can increase by revascularization, debridement of necrotic tissue, address infection, and address edema.
A study published in 2003 found that the percent change in wound area at 4 weeks in those who healed was 82%, whereas the percent change in wound area was 25% in those who failed to heal.13 The percent change in foot ulcer area after 4 weeks of observation is a robust predictor of healing at 12 weeks. This study concluded that this can serve as a clinical decision point in care for diabetic foot ulcers to identify patients who may not respond to standard care requiring additional treatments. If limited or no progress is made at 4 weeks, it is recommended to reassess the wound for arterial perfusion, infection, and other factors that delay healing and potentially consider the use of advanced modalities.
If ischemia impairs the delivery of oxygen, a vascular referral is of importance, whereas edematous lower extremities require appropriate compression to decrease the larger diffusion distance to improve oxygenation.
The Emergence of Topical Oxygen Therapy
Topical oxygen therapy (TOT) is another valuable option that has been available for some time, but early research was lacking. As such, TOT was often labeled as ‘topical hyperbaric oxygen therapy’, which is incorrect based on its function.
More recently, there has been a great deal of available research on the effectiveness of TOT and its ability to help heal chronic wounds. TOT is not likely to replace HBOT, but should continue to produce optimal evidence-based results. What follows is a list of top challenges that exist related to the use of TOT.
Top 10 Challenges of Oxygen Therapy
The use of TOT at Home Doesn’t Alter Treatment at an Outpatient Wound Clinic
During the past 3 years, I’ve had the opportunity to use long wave infrared thermography and Near Infrared Spectroscopy on chronic hard to heal wounds. Medical thermography has over 800 published articles and this allows me to not only look for physiological anomalies in the nonvisible light spectrum but also to assess tissue oxygenation. These objective findings assist providers with their clinical assessments, while requesting further objective tests, validates treatment interventions and utilized in preventative measures not only for pressure injury but also for patients with diabetes. As we consider chronic wounds to have a decrease in oxygenation in the wound bed, I am also noting a decrease in thermal energy when imaging chronic wounds, classifying them in a hypoperfusion state. Thermographically, it is evident that technology can assist us with determining which wounds may not progress due to a lack of oxygen, whether the lack of oxygen is due to arterial disease of a problem with increased diffusion distance, as in an edematous extremity. In addition, dehiscence of incisions may occur when there’s increased diffusion distance, therefore minimizing the amount of oxygen needed to maintain surgical incision health.
Patients can utilize TOT at home and continue wound care treatments at an outpatient clinic and/ or with home health, without altering the plan of care. Providers can continue treatment, such as debridement and other modalities, just as if they were performing HBOT treatment. The only exception would be negative pressure wound therapy and/ or occlusive dressings, as oxygenation might not reach the wound bed due to the occlusive barrier. To be mindful of successful interventions, chronic wounds could require additional modalities, as long as the basic tenets of wound care have been implemented and not overlooked.
Recent TOT Evidence
There is growing evidence of the benefits of TOT. A sampling of studies includes:
Benefits of TOT
- Evidence of TOT promoting collagen formation and VEGF expression promoting angiogenesis26
- Use of a special probe to measure the superficial pO2 at the center of the wound (2mm depth) after exposure to topical oxygen27
- A comparison of a variety of chronic wounds being treated with HBOT versus TOT for 14 weeks and assessing healing outcomes19
- A study that examined VLUs being treated with TWO2 versus compression28
- A report that TOT can generate sustained increased in wound pO2 supporting angiogenesis and increased VEGF29
- A DFU study noting that at 12 weeks with TWO2 with a mean baseline wound area of 1 cm2, there was a healing rate of 82.4%, with a median of 56 days to heal; versus the control group with a mean baseline wound area of 1.4 cm2, there was a healing rate of 45.5%, with 93 median days to heal in the standard of care group30
- A study of VLUs with > 2 years onset, with no improvement over the previous year, demonstrating improved healing rates and median time to heal when using TWO231
- A multinational, multicenter, randomized, double- blinded, sham-controlled trial supporting cyclical pressurized TOT for the treatment of DFUs32
TOT Being Misunderstood
As indicated by a recent consensus statement on guidelines for the use of TOT in the treatment of hard-to-heal wounds25, there’s a growing body of evidence suggesting that topical oxygen is valuable in healing DFUs.
As with any product, following manufacturer’s indications to ensure proper use is imperative. Indications for TOT includes the use for chronic, hard-to-heal wounds such as DFUs, VLUs, pressure ulcers (stage 3 – 4), and post- surgical and burn wounds. TCOT and/ or CDO list indications to treat such as skin ulcerations resulting from diabetes, venous stasis, post- surgical infections, gangrenous lesions, pressure ulcers, infected residual limbs, skin grafts, burns, and frostbite. Research lists wound types that are indicated and/ or have demonstrated successful outcomes for TOT,21 including diabetic ulcers, vascular ulcers, post-surgical infections, pressure injuries, amputations and infected stumps, skin grafts, ischemic tissues, burns, and frostbite. The utilization of various products and modalities as intended could alter the healing trajectory of chronically stalled hard-to-heal wounds.
Understanding TOT Contraindications
Contraindications for topical oxygen include:
- Inadequate perfusion to support wound healing
- Acute thrombophlebitis
- Ulcers due to Raynaud’s disease
- Presence of necrotic tissue if debridement is not Necrotic wounds with eschar or slough
- Wounds with fistulas or deep sinus tracts with unknown depth
- Wound dressings that are occlusive, including the use of petrolatum products
Also consider including untreated osteomyelitis, and malignant wounds.
TOT Safety & Precautions
Although there are benefits for using oxygen in the wound management field, the hazards and side effects of oxygen must be considered. Oxygen should be administered cautiously, as with any medication.
Generally, oxygen supports combustion, so smoking should not be permitted near the source of oxygen and it should be kept away from any heat source. Ensure that any electrical equipment involved is in safe working condition. Unlike precautions and possible complications with HBOT, TOT presents no risk for oxygen toxicity, ear barotrauma, pneumothorax, temporary change in vision, or a decrease in glucose levels. Devices that are worn continuously are recommended to be disconnected during a shower or bath. A recent systematic review and meta-analysis study on the efficacy and safety of TOT for DFUs concluded that TOT is effective and safe for chronic DFUs.23 Another 2022 study describes TOT to be considered safe with no known risks to the patient above moist wound therapy alone with no reported serious adverse events or reactions in the literature.21,24
Failing to Recognize and Address Importance of Oxygen
Oxygen levels affect the quality of new blood vessel growth, collagen formation, and the signaling of growth factors. Chronic wounds are found to have low oxygen levels. Adequate circulation should be determined with objective testing in lower-extremity wounds to ensure there’s oxygenation and nutrients reaching tissue. The importance of oxygen is also recognized in the numerous biological processes occurring throughout the healing cascade, such as cell proliferation, angiogenesis, protein synthesis, and resistance to infection, which are required for restoration of tissue function and integrity.21,22
Uncertainty About TOT Changing Wound Environment
It is known that chronic wound beds have higher-than-normal pH levels. Dissemond et al. acknowledge that pH values influence wound healing and that insight into this allows for more individualized therapy.14 Percival et al. mention how pH has been shown to affect matrix metalloproteinase activity (MMP), tissue inhibitors of MMP, fibroblast activity, keratinocyte proliferation, microbial proliferation, and immunological responses in a wound.15
The pH of chronic wounds has been described to be between 7.15 and 8.9 (7 being neutral, above that as alkaline and below as acidic). For perspective, a pH of 4 is 10 times as acidic as a pH of 5, representing a 10-fold in H+ concentrations.16 The same study describes how pH level decreased as the wound progresses.17 Since there’s a higher number of MMP and necrotic tissue in the wound bed, there’s also an increased metabolic load resulting in tissue hypoxia.18
The pH also influences oxygen release to the tissue. By lowering the pH, there’s an increase of oxygen diffusion. Tissue oxygen tension (pO2) > 40mmHg increases the likelihood of healing. Gordillo demonstrated that tissues must have a pO2 of at least 40 mmHg to promote the production of VEGF, collagen, and restore angiogenesis.19 Fries et al. utilized a special probe at a depth of 2mm in the center of a wound, to determine if TOT raises pO2 levels. Another study utilized an oxygen aerosol delivery system, which could continue to answer questions on oxygenation penetration.20
Understanding Available TOT
There are various types of topical oxygen therapy (TOT) delivery systems, including intermittent TOT, continuous TOT (TCOT), and continuous diffusion of oxygen (CDO), to deliver oxygen to the tissue. There are differences, however, in how oxygen is supplied to the wound bed and the equipment. TOT uses a high-flow oxygen concentrator connected to a disposable boot or bag, supplying oxygen to the area for 90 minutes, five days per week. The pressure on one device that’s available cannot be controlled, while the other device can control the pressure from 0 – 50 mmHg to help oxygen diffusion to the wound bed. The concentrator is connected to a power source and it’s capable of being used at multiple settings, including the patient’s home. The patient will be immobile during therapy. While oxygen could desiccate a wound bed, a humidifier is utilized to maintain the moisture level inside this boot or bag. Oxygen transfer requires the wound to be moist. One product utilizes non- contact cyclical compression to aid in edema management and the use of humidification, to maintain a moist wound barrier to aid in oxygen diffusion while preventing desiccation.
TCOT uses oxygen generators to continuously provide oxygen from the air to the wound 24 hours per day, 7 days per week. Tubing can be placed within a wound dressing. This continuous system requires a minimum relative humidity level and the level of humidity must be met for normal operation. CDO is a lightweight, handheld device using an oxygen generator providing continuous delivery of oxygen to the wound bed. It delivers oxygen via a cannula that is placed under a moist wound dressing indicated for 24 hours, 7 days per week therapy time. There are two types of CDO systems available: CDO with oxygen distribution system. These systems will produce oxygen even at lower levels of humidity.
Realizing TOT is Not HBOT
Topical oxygen is not and should not be classified in the same category as HBOT, nor ‘soft’ or ‘mild’ chambers. Although HBOT and TOT interventions deliver oxygen to the wound bed, HBOT mechanism of action is to deposit an increase of oxygen to the wound bed, HBOT mechanism of action is to deposit an increase of oxygen to the wound through the plasma as the patient breathes 100% oxygen. On the contrary, TOT is diffusing oxygen across the wound bed and can be utilized in various settings, including the patient’s home, making it convenient when there are barriers such as lack of transportation, rising gasoline prices, the pandemic, lack of resources, and no access to advanced modalities.
Topical oxygen pressures are slightly higher than normobaric pressure, equivalent up to 1.1 atmosphere absolute (ATA). HBOT pressures will be higher than normobaric pressures consisting of >1.4 ATA with treatments typically ranging from 2-3.0 ATA. There’s data indicating the effectiveness of TOT, especially for treating DFUs. But if the goal is to increase the tissue pO2 to a hyperoxygenated level systemically, HBOT will be the choice.
- Castilla DM, Liu Z-J, Velazquez Oxygen: implications for wound healing. Adv Wound Care (New Rochelle). 2012;1(6):225-30.
- MacIntyre Tissue hypoxia: implications for the respiratory clinician. Respir Care. 2014;59(10):1590-6.
- Aviles F, Whitten-Byles D. Oxygen & wound healing: going beyond hyperbaric therapy. TWC. 2018;12(11):14-21.
- Hyperbaric oxygen therapy: get the FDA. 2021. Accessed online: www.fda.gov/ consumers/consumer-updates/hyperbaric-oxygen-therapy-get-facts
- Nussbaum SR, Carter MJ, Fife CE, et al. An economic evaluation of the impact, cost, and medicare policy implications of chronic nonhealing Value Health. 2018;21:27-32.
- Gethin, (2007). The significance of surface pH in chronic wounds. Wounds UK. 3.
- Cole Wound care update: the role of topical oxygen therapy in the treatment of wounds. Lower Extremity Review. 2020; 12(5):35-8.
- RaffettoJD, Ligi D, ManiscalcoR, KhalilRA,Mannello, F. Why venous leg ulcers have difficulty healing: overview on pathophysiology, clinical consequences, and treatment. J Clin 2020;10(1):29.
- Margolis DJ, Allen-Taylor L, HoffstadO, BerlinJA. The accuracy of venous leg ulcer prognostic models in a wound care Wound RepairRegen. 2004;12(2):163-8.
- HettrickH, Aviles Jr. F. All edema is lymphedema: progressing lymphedema and wound management to an integrated model of Wound ManagPrev. 2022;68(1):8-15.
- DeanSM, ValentiE, HockK, LefflerJ, CompstonA, AbrahamWT. The clinical characteristics of lower extremity lymphedema in 440 patients. J VascSurgVenous LymphatDisord. 2020;8(5):851-9.
- FifeCE, SmartDR, SheffieldPJ, HopfHW, HawkinsG, Clarke Transcutaneous oximetry in clinical practice: consensus statements from an expert panel based on evidence.Undersea HyperbMed. 2009;36(1),43-53.
- Sheehan P, Jones P, Giurini JM, Caselli A, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Plastic and Reconstructive Surgery. 2006 Jun;117(7 Suppl):239S-244S. DOI: 1097/01.prs.0000222891.74489.33. PMID: 16799391.
- Dissemond, , Witthoff, M., Brauns, T. C., Haberer, D., &Goos, M. (2003). pH-Wertdes Milieus chronischerWunden. UntersuchungenimRahmeneinermodernenWundtherapie [pH values in chronic wounds. Evaluation during modern wound therapy]. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandteGebiete, 54(10), 959–965.
- Percival, L., McCarty, S., Hunt, J. A., & Woods, E. J. (2014). The effects of pH on wound healing, biofilms, and antimicrobial efficacy. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society, 22(2), 174–186.
- Tsukada K, Tokunaga K, Iwama T, Mishima Y (1992) The pH changes of pressure ulcers related to the healing process of wounds. Wounds 4(1): 16–20.
- Solomon E, Schmidt R, Adragna P (1990) Human Anatomy and 2nd International edn. Saunders, USA.
- Hunt TK, Beckert S (2005) Therapeutical and practical aspects of oxygen in wound In: Lee B (ed) The Wound Management Manual. McGraw-Hill Medical, New York.
- Gordillo GM, Roy S, Khanna S, et Topical oxygen therapy induces vascular endothelial growth factor expression and improves closure of clinically presented chronic wounds. Clin Exp PharmacolPhysiol2008;35:957–964.
- Petri M, Stoffels I, Jose J, et Photoacoustic imaging of real-time oxygen changes in chronic leg ulcers after topical application of a haemoglobin spray: a pilot study. J Wound Care. 2016; 25(2):87–91.
- Oropallo A, Andersen Topical Oxygen. [Updated 2021 Sep 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
- Oxygen: Implications for Wound Healing Diego M. Castilla,1 Zhao-Jun Liu,1,2 and Omaida C. Velazquez1,2, ADVANCES IN WOUND CARE, VOLUME 1, NUMBER 6 j 225-230 Copyright ª 2012 by Mary Ann Liebert, DOI: 10.1089/wound.2011.031.
- Sun, K., Li, R., Yang, X. L., & Yuan, L. (2022). Efficacy and safety of topical oxygen therapy for diabetic foot ulcers: An updated systematic review and meta-analysis. International wound journal, 10.1111/iwj.13830. Advance online publication.
- Kalliainen, K., Gordillo, G. M., Schlanger, R., & Sen, C. K. (2003). Topical oxygen as an adjunct to wound healing: a clinical case series. Pathophysiology : the official journal of the International Society for Pathophysiology, 9(2), 81–87.
- Serena, E., Andersen, C., Cole, W., Garoufalis, M., Frykberg, R., &Simman, R. (2022). Guidelines for the use of topical oxygen therapy in the treatment of hard-to-heal wounds based on a Delphi consensus. Journal of wound care, 31(Sup3), S20–S24.
- Scott, G., & Reeves, (2005). 051 Topical Oxygen Alters Angiogenesis Related Growth Factor Expression in Chronic Diabetic Foot Ulcers. Wound Repair and Regeneration, 13(2), A4-A27.
- Fries RB, Wallace WA, Roy S, et al. Dermal excisional wound healing in pigs following treatment with topically applied pure oxygen. Mutat Res. 2005; 579(1-2):172-81. Epub 2005 Aug 18. PMID: 16105672.
- Tawfick W, Sultan Does topical wound oxygen (TWO2) offer an improved outcome over conventional compression dressings (CCD) in the management of refractory venous ulcers (RVU)? A parallel observational comparative study. Eur J VascEndovasc Surg 2009;38:125–132.
- Gordillo GM, Sen Evidence-based recommendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. Int J Low Extrem Wounds 2009;8:105–111.
- Blackman E, Moore C, Hyatt J, Railton R, Frye Topical wound oxygen therapy in the treatment of severe diabetic foot ulcers: a prospective controlled study. Ostomy Wound Manage 2010; 56:24–31.
- Tawfick WA, Sultan Technical and clinical outcome of topical wound oxygen in comparison to conventional compression dressings in the management of refractory nonhealing venous ulcers. Vasc Endovascular Surg 2013;47:30–37.
- Frykberg, G., Franks, P. J., Edmonds, M., Brantley, J. N., Téot, L., Wild, T., Garoufalis, M. G., Lee, A. M., Thompson,
- A., Reach, G., Dove, C. R., Lachgar, K., Grotemeyer, D., Renton, S. C., & TWO2 Study Group (2020). A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study. Diabetes care, 43(3), 616–624.
The Top Ten Tips For Optimizing Oxygen Therapy in Your Practice
Editorial Summary Oxygen therapy is a well evidenced modality of care in clinical wound practice. It can provide many benefits, such as a reduction in hospitalizations and amputations for diabetic foot ulceration patients. This article provides a practical top ten tips for the methods of optimization of oxygen therapy in your practice; taking into account factors for delivery of this modality such as activity, wound impacting factors; comfort, economic impact; geographic factors, capable participation level; compliance/ adherence, number of wounds and severity, and active infections, all of which will be discussed in this article to improve patient care delivery.
This article is the second of two I have written on oxygen therapy for Wound Masterclass; the first, ‘Optimizing Oxygen Therapy in Your Clinical Wound Practice’, published in the inaugural May – June issue, provided a concise background and overview to this modality. This second article is intended to complement the first with a practical ‘Top Ten Tips’ of use to the clinican, in introducing this modality to their practice and how to approach the various factors involved.
1. Activity Level How active is my patient?
If they need to be active because they are still working and supporting a family you may want to consider a portable continuous diffusion device. Are they retired and have a more sedentary lifestyle, where at home delivery devices that are not as mobile may be used? Is the mobility from some delivery systems beneficial for the patient, or will the ambulation and freedom from a more portable device enable your patient to partake in more activities than you recommend? The boot systems and chambers are great for providing guaranteed non ambulatory stationary time when activity restriction is desired. The pressurized system requires the patient to sit near the condenser unit, ensuring that during device use they cannot do much, thus allowing protected offloading time. If they do need to be mobile, the continuous delivery systems offer that freedom. If you want to limit mobility, the boot/ sleeve systems require close association to the base unit and do not allow free movement while on therapy.
2. Wound Impacting Factors
Some of the delivery systems differ in the ability to move edema during use, adding the benefit of fluid control. The cyclic pressurized TOT delivery system (not the continuous flow TOT systems) has the added benefit of sequential non-contact compression of the limb, which helps to reduce peripheral edema in addition to the oxygen, and promotes arterial blood flow. Wound bed dryness is another consideration. Topical oxygen requires delivery to the wound surface and requires a moist wound environment; HBOT delivers the oxygen systemically and does not have this requirement. Dry wound beds will have an issue with the diffusion of oxygen, and thick gel wound care products will inhibit diffusion of the oxygen molecules. Pressurized cyclical TOT has the added benefit of adding humidification for oxygen diffusion. Keep in mind, moist wound environments have better outcomes compared to dry wound therapy.
For some, group settings have a positive impact on patients, while it makes others withdraw from social interactions because of the wounds. HBOT requires frequent interactions in a facility and may utilize multi-place units or single full body chambers, which have the additional claustrophobic issue. If the patient is not comfortable, they will not use the therapy and thus the treatment is ineffective. It has been well documented that oxygen therapy reduces wound pain; this benefit is achieved from both HBOT and TOT. Physical discomfort may come from devices that require seals (TOT boots/ sleeves) to achieve pressure, or from prolonged stationary positions (HBOT and high/ low pressurized TOT systems) for 60120 minutes at a time. The TOT systems have less noticeable negative side effects during use compared to HBOT, which can cause temporary myopia, glycemic control issues, middle ear barotrauma, pulmonary oxygen toxicity, and CNS oxygen toxicity.
4. Economic Impact to the Patient
Can your patient afford to drive or take transportation daily to your office or treatment facility, if HBOT is the recommendation? Does their insurance plan cover the therapy or is it an out-of-pocket expense? Can they maintain their job occupation under the therapy, or do they need to take time away in order to utilize the therapy?
5. Geographic Location
Where is the patient located? What if your patient is in a rural area and can only make infrequent appointments? Don’t forget about the homebound patients who cannot leave, and telehealth patients who prefer to stay virtual. HBOT requires daily transportation to a specific location. TOT devices can be used at home and do not require transportation, and can also be used in skilled facilities and inpatient settings.
6. Capable Participation Level
How involved is your patient in their care? Are they capable of performing their own dressing changes and therapy or do they rely on others to help, and are they capable of helping with the therapy prescribed? Patients that cannot perform their own care but have no problem getting transportation may do better with HBOT. Pressurized TOT systems are daily applications; patients or caregivers that can participate in donning and doffing of boot/chamber delivery systems daily will find benefit from this therapy. Continuous TOT device systems may stay in place in the dressing for 1 – 2 weeks and do not need to be changed as often, but do require batteries that need to be charged/ changed often, which can also be problematic. Cognition deficiencies pose wound care problems in general with dressing changes, without the added daily application or battery changes.
7. Compliance/ Adherence
No matter which therapy you think would be best, it all comes down to your patient’s willingness to participate. If you know your patient misses recommended appointments but oxygen therapy is indicated, then a system which requires the least amount of patient involvement would likely work better. Continuous diffusion systems do not need to be changed/ used daily and do not require daily transportation to another location. Home health agencies can preform the dressing changes and they are user friendly, for the more independent individual.
8. Number of Wounds and Severity
Let’s face it, some patients unfortunately have more than one wound or wounds that are very large. Continuous TOT devices are designed for single wounds or smaller wounds grouped together. They rely on tubing under occlusive dressing to deliver the oxygen. Larger wounds and patients with multiple wounds need a larger surface area of coverage, which would best be found from the pressurized devices and HBOT.
9. Active Infection
All oxygen delivery systems can be used in conjunction with treated infections but are not a substitute for antibiotic therapy. HBOT has the added benefit of being synergistic with some antibiotics due to its systemic delivery where the TOT do not, and HBOT also has a specific indication for osteomyelitis. HBOT has the strongest evidence of support with severe infections to include necrotizing and clostridial. Cyclic pressurized TOT systems, along with HBOT, have been shown to increase local wound partial oxygen tension. Increasing the wound oxygen tension has a direct effect on leukyocyte activity in clearing the infection. Activated neutrophils produce NADPH oxidase to generate reactive oxygen species, which also consumes the available oxygen. Between the cellular activity needed to fight an infection, the now increased metabolic demand of oxygen to heal damage tissue, and bacterial or fungi consumption thereof, the wound tends to be depleted of available oxygen creating a hypoxic like environment. Chronic wounds with suspected biofilms will have a chronic increase of neutrophils, thereby high oxygen consumption that continues to impede wound healing.
10. Dressing Compatibility
HBOT can be used with any dressing choice. Topical delivery systems cannot be used in conjunction with gels, as they hinder the oxygen from getting into the wound bed (they can be wiped out before device use for the noncontinuous delivery devices). Continuous non pressurized devices require occlusive dressings to keep the oxygen locally and if not kept in check can lead to maceration of the periwound. Pressurized systems can go through breathable dressings like unna boots, compression systems, and even TCC.
Cyclical Pressurized TOTNon-cyclical pressurized TOTContinuous non-pressurized TOT HBOT ACTIVITY LEVEL DESIRED 60-90 minutes daily stationary time 60-90 minutes daily stationary time Allows 24 hour mobilityUp tp 2 hours daily stationary time PROMOTES OFFLOADING OF WOUND AREA DURING USE Highly likelyHighly likelyNoneLikely EDEMA CONTROL YesLittleNoneLittle HUMIDIFICATION YesNoYesNo NEEDS INTACT VASCULATURE FOR DELIVERY NoNoNoYes LOCATION COMFORT Home basedHome basedHome basedFacility based only PHYSICAL COMFORT Limited-Stationary near deviceLimited-stationary near device Allows flexibility in positioning Limited-facility arranged setting WOUND COMFORT Evidence of pain reductionEvidence of pain reductionEvidence of pain reductionEvidence of pain reduction DEVICE DELIVERY DISCOMFORT Some maySome mayLess likelyMore likely ADDITIONAL COSTS Some insurance coverageSome insurance coverageSome insurance coverageMost insurance coverage. Requires daily transportation to a facility LOCATION OF THERAPY Medical settings Home useMedical settings Home useNo restriction on locationOnly at a HBOT facility PATIENT PARTICIPATION Self care Care giver Self care Care giver Self care Care giver H/H agency Rely on facility Rely on transportation DEVICE USE REQUIRES Ability to preform donning and doffing Breathable dressing Ability to preform donning and doffing Breathable dressing Daily charging of batteries Disposable unit for application Occlusive dressing A health care professional COMPLIANCE Patient dependant unless in a facility Patient dependant unless in a facility Patient dependantPatient dependant Transportation dependant VARIABLE WOUND SIZES YesYes No, limited to smaller wounds Yes WOUND DEPTH AllAllAllDeeper wounds ACTIVE INFECTION Yes with infection treatmentYes with infection treatmentYes with infection treatmentYes with infection treatment DRESSING SELECTION Flexible (remove or use with breathable dressing) Flexible (remove or use with breathable dressing) OcclusiveFlexible OINTMENTS/ GEL USE Must be wiped off prior to useMust be wiped off prior to use NoYes
VOLUME 46 | SUPPLEMENT 1
12. Retinopathy, Neuropathy, and Foot Care:
Standards of Care in Diabetes 2023
Nuha A. ElSayed, Grazia Aleppo, Vanita R. Aroda,
Raveendhara R. Bannuru, Florence M. Brown, Dennis Bruemmer Billy S. Collins, Christopher H. Gibbons, John M. Giurini,
Marisa E. Hilliard, Diana Isaacs, Eric L. Johnson, Scott Kahan, Kamlesh Khunti, Jose Leon, Sarah K. Lyons, Mary Lou Perry,
Priya Prahalad, Richard E. Pratley, Jane Jeffrie Seley, Robert C. Stanton, Jennifer K. Sun, and Robert A. Gabbay, on hehalf of the American Diabetes Association
Diabetes Care 2023;46(Suppl. 1):S203-S215 | https://doi.org/10.2337/dc23-S012
12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes-2023
Diabetes Care 2023;46(Suppl. 1):5203-5215 I https://doi.org/10.2337/dc23-5012
The American Diabetes Association (ADA) “Standards of Care in Diabetes” in cludes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guide lines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for up dating the Standards of Care annually, or more frequently as warranted. For a de tailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
For prevention and management of diabetes complications in children and adoles cents, please refer to Section 14, “Children and Adolescents.”
Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes, with prevalence strongly related to both the duration of diabetes and the level of glycemic control (1). Diabetic retinopathy is the most frequent cause of new cases of blindness among adults aged 20-74 years in developed countries. Glaucoma, cataracts, and other eye disorders occur earlier and more frequently in people with diabetes.
In addition to diabetes duration, factors that increase the risk of, or are associ ated with, retinopathy include chronic hyperglycemia (2,3), nephropathy (4), hyper tension (5), and dyslipidemia (6). Intensive diabetes management with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset and progression of diabetic retinopathy, reduce the need for future ocular surgical procedures, and potentially improve patient-reported visual function (2,7-10). A meta-analysis of data from cardiovascular outcomes studies showed no association between glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment and retinopathy per se, except through the association between retinopathy and average AlC reduction at the 3-month and 1-year follow up. Long-term impact of improved glycemic control on retinopathy was not studied
Nuha A. EISayed, Grazia Aleppo,
Vanita R. Aroda, Raveendhara R. Bannuru, Florence M. Brown, Dennis Bruemmer, Billy 5. Collins, Christopher H. Gibbons, John M. Giurini, Marisa E. Hilliard,
Diana Isaacs, Eric L. Johnson, Scott Kahan, Kamlesh Khunti, Jose Leon, Sarah K. Lyons, Mary Lou Perry, Priya Prahalad,
Richard E. Pratley, Jane Jeffrie Seley, Robert C. Stanton, Jennifer K. Sun, and Robert A. Gabbay, on behalf of the American Diabetes Association
Disclosure information for each author is available at https://dai.org/10.2337/dc23-SDIS.
Suggested citation: EISayed NA, Aleppo G, Aroda VR, et al., American Diabetes Association. 12. Retinopathy, neuropathy, and foot care: Standards of Care in Diabetes-2023. Diabetes Care 2023; 46(Suppl. 1}:5203-5215
© 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www. diabetesjournals.org/journals/pages/license.
in these trials. Retinopathy status should be assessed when intensifying glucose lowering therapies such as those using GLP-1 RAs, since rapid reductions in AlC can be associated with initial worsening of retinopathy (11).
The preventive effects of therapy and the fact that individuals with prolifera tive diabetic retinopathy (PDR) or macu lar edema may be asymptomatic provide strong support for screening to detect diabetic retinopathy. Prompt diagnosis allows triage of patients and timely in tervention that may prevent vision loss in individuals who are asymptomatic despite advanced diabetic eye disease.
Diabetic retinopathy screening should be performed using validated approaches and methodologies. Youth with type 1 or type 2 diabetes are also at risk for compli cations and need to be screened for dia betic retinopathy (12) (see Section 14, “Children and Adolescents“). If diabetic retinopathy is evident on screening, prompt referral to an ophthalmologist is recom mended. Subsequent examinations for individuals with type 1 or type 2 diabe tes are generally repeated annually for individuals with minimal to no retinop athy. Exams every 1-2 years may be cost-effective after one or more normal eye exams. In a population with well controlled type 2 diabetes, there was little risk of development of significant retinopathy within a 3-year interval af ter a normal examination (13), and less frequent intervals have been found in simulated modeling to be potentially ef fective in screening for diabetic retinop athy in individuals without diabetic retinopathy (14). However, it is impor tant to adjust screening intervals based on the presence of specific risk factors for retinopathy onset and worsening retinopathy. More frequent examina tions by the ophthalmologist will be re quired if retinopathy is progressing or risk factors such as uncontrolled hyperglyce mia, advanced baseline retinopathy, or diabetic macular edema are present.
Retinal photography with remote read ing by experts has great potential to pro vide screening services in areas where qualified eye care professionals are not readily available (15-17). High-quality fun dus photographs can detect most clinically significant diabetic retinopathy. Interpreta tion of the images should be performed by a trained eye care professional. Retinal
photography may also enhance efficiency and reduce costs when the expertise of ophthalmologists can be used for more complex examinations and for therapy (15,18,19). In-person exams are still nec essary when the retinal photos are of unacceptable quality and for follow-up if abnormalities are detected. Retinal pho tos are not a substitute for dilated com prehensive eye exams, which should be performed at least initially and at yearly intervals thereafter or more frequently as recommended by an eye care profes sional. Artificial intelligence systems that detect more than mild diabetic retinopa thy and diabetic macular edema, autho rized for use by the U.S. Food and Drug Administration (FDA), represent an alter native to traditional screening approaches
(20). However, the benefits and optimal utilization of this type of screening have yet to be fully determined. Results of all screening eye examinations should be documented and transmitted to the refer ring health care professional.
Type 1 Diabetes
Because retinopathy is estimated to take at least 5 years to develop after the on set of hyperglycemia, people with type 1 diabetes should have an initial dilated and comprehensive eye exami nation within 5 years after the diagnosis of diabetes (21).
Type 2 Diabetes
People with type 2 diabetes who may have had years of undiagnosed diabetes and have a significant risk of prevalent diabetic retinopathy at the time of diag nosis should have an initial dilated and comprehensive eye examination at the time of diagnosis.
Individuals who develop gestational dia betes mellitus do not require eye ex aminations during pregnancy since they do not appear to be at increased risk of developing diabetic retinopathy during pregnancy (22). However, individuals of childbearing potential with preexisting type 1 or type 2 diabetes who are plan ning pregnancy or who have become pregnant should be counseled on the baseline prevalence and risk of devel opment and/or progression of diabetic retinopathy. In a systematic review and meta-analysis of 18 observational studies of pregnant individuals with preexisting
type 1 or type 2 diabetes, the prevalence of any diabetic retinopathy and PDR in early pregnancy was 52.3% and 6.1%, re spectively. The pooled progression rate per 100 pregnancies for new diabetic reti nopathy development was 15.0 (95% Cl
9.9-20.8), worsened nonproliferative
diabetic retinopathy was 31.0 (95% Cl 23.2-39.2), pooled sight-threatening pro gression rate from nonproliferative dia betic retinopathy to PDR was 6.3 (95% Cl 3.3-10.0), and worsened PDR was 37.0
(95% Cl 21.2-54.0), demonstrating that close follow-up should be maintained during pregnancy to prevent vision loss
(23). In addition, rapid implementation of intensive glycemic management in the setting of retinopathy is associ ated with early worsening of retinop athy (24).
A systematic review and meta-analysis and a controlled prospective study dem onstrate that pregnancy in individuals with type 1 diabetes may aggravate reti nopathy and threaten vision, especially when glycemic control is poor or retinop athy severity is advanced at the time of conception (23,24). Laser photocoagu lation surgery can minimize the risk of vision loss during pregnancy for individ uals with high-risk PDR or center-involved diabetic macular edema (24). Anti-vascular endothelial growth factor (anti-VEGF) med ications should not be used in pregnant individuals with diabetes because of the oretical risks to the vasculature of the developing fetus.
Two of the main motivations for screen ing for diabetic retinopathy are to pre vent loss of vision and to intervene with treatment when vision loss can be pre vented or reversed.
Two large trials, the Diabetic Retinopa thy Study (DRS) in individuals with PDR and the Early Treatment Diabetic Reti nopathy Study (ETDRS) in individuals with macular edema, provide the strongest support for the therapeutic benefits of photocoagulation surgery. The DRS (25) showed in 1978 that panretinal photo coagulation surgery reduced the risk of severe vision loss from PDR from 15.9% in untreated eyes to 6.4% in treated eyes with the greatest benefit ratio in those with more advanced baseline disease (disc neovascularization or vitre ous hemorrhage). In 1985, the ETDRS also verified the benefits of panretinal photocoagulation for high-risk PDR and in older-onset individuals with severe
nonproliferative diabetic retinopathy or less-than-high-risk PDR. Panretinal laser photocoagulation is still commonly used to manage complications of dia betic retinopathy that involve retinal neovascularization and its complications. A more gentle, macular focal/grid laser photocoagulation technique was shown in the ETDRS to be effective in treating eyes with clinically significant macular edema from diabetes (26), but this is now largely considered to be second-line treatment for diabetic macular edema.
Anti-Vascular Endothelial Growth Factor Treatment
Data from the DRCR Retina Network
(formerly the Diabetic Retinopathy Clini cal Research Network) and others dem onstrate that intravitreal injections of anti–VEGF agents are effective at re gressing proliferative disease and lead to noninferior or superior visual acuity outcomes compared with panretinal la ser over 2 years of follow-up (27,28). In addition, it was observed that individuals treated with ranibizumab tended to have less peripheral visual field loss, fewer vitrectomy surgeries for secondary com plications from their proliferative dis ease, and a lower risk of developing diabetic macular edema. However, a potential drawback in using anti-VEGF therapy to manage proliferative disease is that patients were required to have a greater number of visits and received a greater number of treatments than is typically required for management with panretinal laser, which may not be opti mal for some individuals. The FDA has approved aflibercept and ranibizumab for the treatment of eyes with diabetic retinopathy. Other emerging therapies for retinopathy that may use sustained intravitreal delivery of pharmacologic agents are currently under investigation. Anti-VEGF treatment of eyes with non proliferative diabetic retinopathy has been demonstrated to reduce subse quent development of retinal neovascu larization and diabetic macular edema but has not been shown to improve visual outcomes over 2 years of therapy and therefore is not routinely recom mended for this indication (29).
While the ETDRS (26) established the
benefit of focal laser photocoagulation surgery in eyes with clinically significant macular edema (defined as retinal edema
located at or threatening the macular center), current data from well-designed clinical trials demonstrate that intravi treal anti-VEGF agents provide a more effective treatment plan for center involved diabetic macular edema than monotherapy with laser (30,31). Most patients require near-monthly adminis tration of intravitreal therapy with anti VEGF agents during the first 12 months of treatment, with fewer injections needed in subsequent years to maintain remission from central-involved diabetic macular edema. There are currently three anti VEGF agents commonly used to treat eyes with central-involved diabetic macular edema-bevacizumab, ranibizumab, and atlibercept (1)-and a comparative effec tiveness study demonstrated that atliber cept provides vision outcomes superior to those of bevacizumab when eyes have moderate visual impairment (vision of 20/50 or worse) from diabetic macular edema (32). For eyes that have good vision (20/25 or better) despite diabetic macular edema, close monitoring with initiation of anti-VEGF therapy if vision worsens provides similar 2-year vision outcomes compared with immediate initi ation of anti-VEGF therapy (33).
Eyes that have persistent diabetic macu lar edema despite anti-VEGF treatment may benefit from macular laser photo coagulation or intravitreal therapy with corticosteroids. Both of these therapies are also reasonable first-line approaches for individuals who are not candidates for anti-VEGF treatment due to systemic considerations such as pregnancy.
Lowering blood pressure has been shown to decrease retinopathy progression, although tight targets (systolic blood pressure <120 mmHg) do not impart additional benefit (8). In individuals with dyslipidemia, retinopathy progression may be slowed by the addition of feno fibrate, particularly with very mild non proliferative diabetic retinopathy at baseline (34,35).
Diabetic neuropathies are a heteroge neous group of disorders with diverse clinical manifestations. The early rec ognition and appropriate management of neuropathy in people with diabetes is important. Points to be aware of in clude the following:
- Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropa thies may be present in people with diabetes and may be treatable.
- Up to 50% of diabetic peripheral neu ropathy may be asymptomatic. If not recognized and if preventive foot care is not implemented, people with dia betes are at risk for injuries as well as diabetic foot ulcers and amputations.
- Recognition and treatment of au-
symptoms, reduce sequelae, and im prove quality of life.
Specific treatment to reverse the un derlying nerve damage is currently not available. Glycemic control can effec tively prevent diabetic peripheral neu ropathy (DPN) and cardiac autonomic neuropathy (CAN) in type 1 diabetes (36,37) and may modestly slow their progression in type 2 diabetes (38), but it does not reverse neuronal loss. Treat ments of other modifiable risk factors (including lipids and blood pressure) can aid in prevention of DPN progression in type 2 diabetes and may reduce disease progression in type 1 diabetes (39-41). Therapeutic strategies (pharmacologic and nonpharmacologic) for the relief of painful DPN and symptoms of autonomic neurop athy can potentially reduce pain (42) and improve quality of life.
Diabetic Peripheral Neuropathy
Individuals with a type 1 diabetes dura tion 2′.5 years and all individuals with type 2 diabetes should be assessed an nually for DPN using the medical history and simple clinical tests (42). Symptoms vary according to the class of sensory fi bers involved. The most common early symptoms are induced by the involve ment of small fibers and include pain and dysesthesia (unpleasant sensations of burning and tingling). The involve ment of large fibers may cause numb ness and loss of protective sensation (LOPS). LOPS indicates the presence of distal sensorimotor polyneuropathy and is a risk factor for diabetic foot ulceration. The following clinical tests may be used to assess small- and large-fiber func tion and protective sensation:
- Small-fiber function: pinprick and temperature sensation.
- Large-fiber function: lower-extremity
reflexes, vibration perception, and 10-g monofilament.
- Protective sensation: 10-g mono filament.
These tests not only screen for the presence of dysfunction but also predict future risk of complications. Electrophysi ological testing or referral to a neurolo-
tonomic neuropathy may improve gist is rarely needed, except in situations
where the clinical features are atypical or the diagnosis is unclear.
In all people with diabetes and DPN, causes of neuropathy other than diabetes should be considered, including toxins (e.g., alcohol), neurotoxic medica tions (e.g., chemotherapy), vitamin B12 deficiency, hypothyroidism, renal disease, malignancies (e.g., multiple myeloma, bronchogenic carcinoma), infections (e.g., HIV), chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis (43). See the American Diabetes Association position statement “Diabetic Neuropathy” for more details (42).
Diabetic Autonomic Neuropathy
Individuals who have had type 1 diabe tes for 2:5 years and all individuals with type 2 diabetes should be assessed an nually for autonomic neuropathy (42). The symptoms and signs of autonomic neuropathy should be elicited carefully during the history and physical examina tion. Major clinical manifestations of diabetic autonomic neuropathy include resting tachycardia, orthostatic hypoten sion, gastroparesis, constipation, diarrhea, fecal incontinence, erectile dysfunction, neurogenic bladder, and sudomotor dysfunction with either increased or decreased sweating. Screening for symp toms of autonomic neuropathy includes asking about symptoms of orthostatic in tolerance (dizziness, lightheadedness, or weakness with standing), syncope, exer cise intolerance, constipation, diarrhea, urinary retention, urinary incontinence, or changes in sweat function. Further testing can be considered if symptoms are present and will depend on the end organ involved but might include cardio vascular autonomic testing, sweat testing, urodynamic studies, gastric emptying, or endoscopy/colonoscopy. Impaired coun terregulatory responses to hypoglycemia in type 1 and type 2 diabetes can lead to hypoglycemia unawareness but are not directly linked to autonomic neuropathy.
Cardiovascular Autonomic Neuropathy. CAN is associated with mortality independently of other cardiovascular risk factors (44,45). In its early stages, CAN may be completely asymptomatic and detected only by decreased heart rate variability with deep breathing. Advanced disease may be associated with resting tachycardia (>100 bpm) and orthostatic hypoten sion (a fall in systolic or diastolic blood
pressure by >20 mmHg or >10 mmHg, respectively, upon standing without an appropriate increase in heart rate). CAN treatment is generally focused on allevi ating symptoms.
Gastrointestinal Neuropathies. Gastrointes tinal neuropathies may involve any por tion of the gastrointestinal tract, with manifestations including esophageal dysmotility, gastroparesis, constipation, diarrhea, and fecal incontinence. Gastro paresis should be suspected in individu als with erratic glycemic control or with upper gastrointestinal symptoms with out another identified cause. Exclusion of reversible/iatrogenic causes such as medi cations or organic causes of gastric outlet obstruction or peptic ulcer disease (with esophagogastroduodenoscopy or a barium study of the stomach) is needed before considering a diagnosis of or specialized testing for gastroparesis. The diagnostic gold standard for gastroparesis is the measurement of gastric emptying with scintigraphy of digestible solids at 15-min intervals for 4 h after food intake. The use of 13C octanoic acid breath test is an ap proved alternative.
Genitourinary Disturbances. Diabetic auto nomic neuropathy may also cause geni tourinary disturbances, including sexual dysfunction and bladder dysfunction. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation (42). Female sex ual dysfunction occurs more frequently in those with diabetes and presents as decreased sexual desire, increased pain during intercourse, decreased sexual arousal, and inadequate lubrication (46). Lower urinary tract symptoms manifest as urinary incontinence and bladder dys function (nocturia, frequent urination, urination urgency, and weak urinary stream). Evaluation of bladder func tion should be performed for individuals with diabetes who have recurrent uri nary tract infections, pyelonephritis, in continence, or a palpable bladder.
Near-normal glycemic control, imple mented early in the course of diabetes, has been shown to effectively delay or prevent the development of DPN and CAN in people with type 1 diabetes (47-50). Although the evidence for the benefit of near-normal glycemic control is not as strong that for type 2 diabetes, some studies have demonstrated a mod est slowing of progression without rever sal of neuronal loss (38,51). Specific glucose-lowering strategies may have dif ferent effects. In a post hoc analysis, par ticipants, particularly men, in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial treated with insulin sensitizers had a lower inci dence of distal symmetric polyneuropathy over 4 years than those treated with insu lin/sulfonylurea (52). Additionally, recent evidence from the Action to Control Car diovascular Risk in Diabetes (ACCORD) trial showed clear benefit of intensive glucose and blood pressure control on the preven tion of CAN in type 2 diabetes (53).
Dyslipidemia is a key factor in the development of neuropathy in people with type 2 diabetes and may contrib ute to neuropathy risk in people with type 1 diabetes (54,55). Although the ev idence for a relationship between lipids
and neuropathy development has be come increasingly clear in type 2 diabe tes, the optimal therapeutic intervention has not been identified. Positive effects of physical activity, weight loss, and bar iatric surgery have been reported in indi viduals with DPN, but use of conventional lipid-lowering pharmacotherapy (such as statins or fenofibrates) does not appear to be effective in treating or preventing DPN development (56).
Blood Pressure Control
There are multiple reasons for blood pressure control in people with diabetes, but neuropathy progression (especially in type 2 diabetes) has now been added to this list. Although data from many studies have supported the role of hy pertension in risk of neuropathy devel opment, a recent meta-analysis of data from 14 countries in the International Prevalence and Treatment of Diabetes and Depression (INTERPRET-DD) study re vealed hypertension as an independent risk of DPN development with an odds ratio of 1.58 (57). In the ACCORD trial, intensive blood pressure intervention decreased CAN risk by 25% (53).
Neuropathic pain can be severe and can impact quality of life, limit mobility, and contribute to depression and social dys function (58). No compelling evidence exists in support of glycemic control or lifestyle management as therapies for neuropathic pain in diabetes or predia betes, which leaves only pharmaceutical interventions (59). A recent guideline by the American Academy of Neurology rec ommends that the initial treatment of pain should also focus on the concurrent treatment of both sleep and mood dis orders because of increased frequency of these problems in individuals with DPN (60).
A number of pharmacologic therapies exist for treatment of pain in diabetes. The American Academy of Neurology update suggested that gabapentinoids, serotonin-norepinephrine reuptake inhibi tors (SNRls), sodium channel blockers, tricyclic antidepressants (TCAs), and SNRI/ opioid dual-mechanism agents could all be considered in the treatment of pain in DPN (60). These American Academy of Neurology recommendations offer a sup plement to a recent American Diabetes Association pain monograph, although
some areas of disagreement exist, particu larly around SNRl/opioid dual-mechanism agents (61). A recent head-to-head trial suggested therapeutic equivalency for TCAs, SNRls, and gabapentinoids in the treatment of pain in DPN (62). The trial also supported the role of combination therapy over monotherapy for the treat ment of pain in DPN.
Gabapentinoids. Gabapentinoids include
several calcium channel a2-o subunit li gands. Eight high-quality studies and seven medium-quality studies support the role of pregabalin in treatment of pain in DPN. One high-quality study and many small studies support the role of gabapentin in the treatment of pain in DPN. Two medium-quality studies suggest that micro gabalin has a small effect on pain in DPN
(60). Adverse effects may be more severe in older individuals (63) and may be at tenuated by lower starting doses and more gradual titration.
SNRls. SNRls include duloxetine, venla
faxine, and desvenlafaxine, all selective SNRls. Two high-quality studies and five medium-quality studies support the role of duloxetine in the treatment of pain in DPN. A high-quality study supports the role of venlafaxine in the treatment of pain in DPN. Only one medium-quality study sup ports a possible role for desvenlafaxine for treatment of pain in DPN (60). Adverse events may be more severe in older peo ple but may be attenuated with lower doses and slower titration of duloxetine. Tapentadol and Tramadol. Tapentadol and tramadol are centrally acting opioid anal gesics that exert their analgesic effects through both µ-opioid receptor agonism and norepinephrine and serotonin reuptake inhibition. SNRl/opioid agents are probably effective in the treatment of pain in DPN. However, the use of any opioids for man agement of chronic neuropathic pain carries the risk of addiction and should be avoided. Tricyclic Antidepressants. Tricyclic anti depressants have been studied for treat ment of pain, and most of the relevant data was acquired from trials of ami triptyline and include two high-quality studies and two medium-quality stud ies supporting the treatment of pain in DPN (60,62). Anticholinergic side effects may be dose limiting and restrict use in individuals 2′.65 years of age.
Sodium Channel Blockers. Sodium channel blockers include lamotrigine, lacosamide, oxcarbazepine, and valproic acid. Five medium-quality studies support the role
of sodium channel blockers in treating pain in DPN (60).
Capsaicin. Capsaicin has received FDA ap proval for treatment of pain in DPN using an 8% patch, with one high-quality study reported. One medium-quality study of 0.075% capsaicin cream has been re ported. In patients with contraindica tions to oral pharmacotherapy or who prefer topical treatments, the use of topical capsaicin can be considered.
Carbamazepine and a-Lipoic Acid. Carba
mazepine and a-lipoic acid, although not approved for the treatment of painful DPN, may be effective and considered for the treatment of painful DPN (41,54,56).
Treating orthostatic hypotension is chal lenging. The therapeutic goal is to mini mize postural symptoms rather than to restore normotension. Most patients re quire both nonpharmacologic measures (e.g., ensuring adequate salt intake, avoid ing medications that aggravate hypoten sion, or using compressive garments over the legs and abdomen) and pharmaco logic measures. Physical activity and ex ercise should be encouraged to avoid deconditioning, which is known to ex acerbate orthostatic intolerance, and volume repletion with fluids and salt is critical. There have been clinical studies that assessed the impact of an approach incorporating the aforementioned non pharmacologic measures. Additionally, supine blood pressure tends to be much higher in these individuals, often requir ing treatment of blood pressure at bed time with shorter-acting drugs that also affect baroreceptor activity such as guan facine or clonidine, shorter-acting calcium blockers (e.g., isradipine), or shorter acting [3-blockers such as atenolol or metoprolol tartrate. Alternatives can in clude enalapril if an individual is unable to tolerate preferred agents (64-66). Midodrine and droxidopa are approved by the FDA for the treatment of ortho static hypotension.
Treatment for diabetic gastroparesis may be very challenging. A low-fiber, low-fat eating plan provided in small frequent meals with a greater proportion of liquid calories may be useful (67-69). In addi tion, foods with small particle size may improve key symptoms (70). With drawing drugs with adverse effects on
gastrointestinal motility, including opioids, anticholinergics, tricyclic antidepressants, GLP-1 RAs, and pramlintide, may also improve intestinal motility (67,71). How ever, the risk of removal of GLP-1 RAs should be balanced against their potential benefits. In cases of severe gastroparesis, pharmacologic interventions are needed. Only metoclopramide, a prokinetic agent, is approved by the FDA for the treatment of gastroparesis. However, the level of evidence regarding the benefits of meto clopramide for the management of gas troparesis is weak, and given the risk for serious adverse effects (extrapyramidal signs such as acute dystonic reactions, drug-induced parkinsonism, akathisia, and tardive dyskinesia), its use in the treat ment of gastroparesis beyond 12 weeks is no longer recommended by the FDA. It should be reserved for severe cases that are unresponsive to other thera pies (71). Other treatment options in clude domperidone (available outside the U.S.) and erythromycin, which is only effective for short-term use due to tachy phylaxis (72,73). Gastric electrical stimula tion using a surgically implantable device has received approval from the FDA, although its efficacy is variable and use is limited to individuals with severe symp toms that are refractory to other treat ments (74).
In addition to treatment of hypogonadism if present, treatments for erectile dys function may include phosphodiester ase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses. As with DPN treatments, these interventions do not change the underlying pathol ogy and natural history of the disease process but may improve a person’s qual ity of life.
Foot ulcerations and amputations are common complications associated with diabetes. These may be the consequences of several factors, including peripheral neuropathy, peripheral arterial disease (PAD), and foot deformities. They rep resent major causes of morbidity and mortality in people with diabetes. Early recognition of at-risk feet, preulcerative lesions, and prompt treatment of ulcer ations and other lower-extremity com plications can delay or prevent adverse outcomes.
Early recognition requires an under
standing of those factors that put peo ple with diabetes at increased risk for ulcerations and amputations. Factors that are associated with the at-risk foot include the following:
- Poor glycemic control
- Peripheral neuropathy/LOPS
- Foot deformities (bunions, hammer- toes, Charcot joint, etc.)
- Preulcerative corns or calluses
- Prior ulceration
- Prior amputation
- Nephropathy (particularly individuals on dialysis or posttransplant)
Identifying the at-risk foot begins with a detailed history documenting diabetes control, smoking history, exercise toler ance, history of claudication or rest pain, and prior ulcerations or amputations. A thorough examination of the feet should be performed annually in all people with diabetes and more frequently in at-risk individuals (75). The examination should include assessment of skin integrity, as sessment for LOPS using the 10-g mono filament along with at least one other neurological assessment tool, pulse ex amination of the dorsalis pedis and pos terior tibial arteries, and assessment for foot deformities such as bunions, ham mertoes, and prominent metatarsals, which increase plantar foot pressures and increase risk for ulcerations. At-risk individuals should be assessed at each visit and should be referred to foot care specialists for ongoing preventive care and surveillance. The physical examina tion can stratify patients into different categories and determine the frequency of these visits (76) (Table 12.1).
Evaluation for Loss of Protective Sensation
The presence of peripheral sensory neu ropathy is the single most common com ponent cause for foot ulceration. In a multicenter trial, peripheral neuropathy was found to be a component cause in 78% of people with diabetes with ulcer ations and that the triad of peripheral sensory neuropathy, minor trauma, and foot deformity was present in >63% of participants (77). All people with dia betes should undergo a comprehensive foot examination at least annually, or
more frequently for those in higher-risk categories (75,76).
LOPS is vital to risk assessment. One of the most useful tests to determine LOPS is the 10-g monofilament test. Studies have shown that clinical exami nation and the 10-g monofilament test are the two most sensitive tests in iden tifying the foot at risk for ulceration
(78). The monofilament test should be performed with at least one other neu rologic assessment tool (e.g., pinprick, temperature perception, ankle reflexes, or vibratory perception with a 128-Hz tuning fork or similar device). Absent monofilament sensation and one other abnormal test confirms the presence of LOPS. Further neurological testing, such as nerve conduction, electromyography, nerve biopsy, or intraepidermal nerve fi ber density biopsies, are rarely indicated for the diagnosis of peripheral sensory neuropathy (42).
Evaluation for Peripheral Arterial Disease
Initial screening for PAD should include a history of leg fatigue, claudication, and rest pain relieved with dependency. Physical examination for PAD should include assessment of lower-extremity pulses, capillary refill time, rubor on dependency, pallor on elevation, and ve nous filling time (75,79). Any patient ex hibiting signs and symptoms of PAD should be referred for noninvasive arte rial studies in the form of Doppler ultra sound with pulse volume recordings. While ankle-brachia! indices will be calculated, they should be interpreted carefully, as they are known to be inac curate in people with diabetes due to
noncompressible vessels. Toe systolic blood pressure tends to be more accurate. Toe systolic blood pressures <30 mmHg are suggestive of PAD and an inability to heal foot ulcerations (80). Individuals with abnormal pulse volume recording tracings and toe pressures <30 mmHg with foot ulcers should be referred for immediate vascular evaluation. Due to the high prevalence of PAD in people with dia betes, it has been recommended by the Society for Vascular Surgery and the American Pediatric Medical Associa tion in their 2016 guidelines that all people with diabetes >50 years of age should undergo screening via noninva sive arterial studies (79,81). If nor mal, these should be repeated every 5 years (79).
All people with diabetes (and their families), particularly those with the aforementioned high-risk conditions, should receive general foot care edu cation, including appropriate manage ment strategies (82-84). This education should be provided to all newly diag nosed people with diabetes as part of an annual comprehensive examination and to individuals with high-risk conditions at every visit. Recent studies have shown that while education improves knowl edge of diabetic foot problems and self care of the foot, it does not improve behaviors associated with active participa tion in their overall diabetes care and to achieve personal health goals (85). Evi dence also suggests that while patient and family education are important, the knowledge is quickly forgotten and needs to be reinforced regularly (86).
Table 12.1-lnternational Working Group on the Diabetic Foot risk stratification system and corresponding foot screening frequency
Category Ulcer risk Characteristics Examination frequency*
0 Very low No LOPS and No PAD Annually
LOPS or PAD
Every 6-12 months
LOPS + PAD, or
LOPS + foot deformity, or PAD + foot deformity
Every 3-6 months
3 High LOPS or PAD and one or more of the following: Every 1-3 months
Adapted with permission from Schaper et al. (76). LOPS, loss of protective sensation; PAD, peripheral artery disease. *Examination frequency suggestions are based on expert opinion and patient-centered requirements.
Individuals considered at risk should understand the implications of foot de formities, LOPS, and PAD; the proper care of the foot, including nail and skin care; and the importance of foot inspec tions on a daily basis. Individuals with LOPS should be educated on appropriate ways to examine their feet (palpation or visual inspection with an unbreakable mirror) for daily surveillance of early foot problems. Patients should also be educated on the importance of refer rals to foot care specialists. A recent study showed that people with diabetes and foot disease lacked awareness of their risk status and why they were be ing referred to a multidisciplinary team of foot care specialists. Further, they ex hibited a variable degree of interest in learning further about foot complica tions (87).
Patients’ understanding of these issues
and their physical ability to conduct proper foot suNeillance and care should be as sessed. Those with visual difficulties, physi cal constraints preventing movement, or cognitive problems that impair their ability to assess the condition of the foot and to institute appropriate responses will need other people, such as family members, to assist with their care.
The selection of appropriate footwear and footwear behaviors at home should also be discussed (e.g., no walking barefoot, avoiding open-toed shoes). Therapeutic footwear with custom-made orthotic devices have been shown to re duce peak plantar pressures (84). Most studies use reduction in peak plantar pressures as an outcome as opposed to ulcer prevention. Certain design features of the orthoses, such as rocker soles and metatarsal accommodations, can reduce peak plantar pressures more significantly than insoles alone. A systematic review, however, showed there was no signifi cant reduction in ulcer incidence after
18 months compared with standard insoles and extra-depth shoes. Fur ther, it was also noted that evidence to prevent first ulcerations was non existent (88).
Treatment recommendations for people with diabetes will be determined by their risk category. No-risk or low-risk individuals can often be managed with
education and self-care. People in the moderate- to high-risk category should be referred to foot care specialists for further evaluation and regular surveil lance as outlined in Table 12.1. This in cludes individuals with LOPS, PAD, and/ or structural foot deformities, such as Charcot foot, bunions, or hammertoes. Individuals with any open ulceration or unexplained swelling, erythema, or in creased skin temperature should be re ferred urgently to a foot care specialist or multidisciplinary team.
Initial treatment recommendations should include daily foot inspection, use of moisturizers for dry, scaly skin, and avoidance of self-care of ingrown nails and calluses. Well-fitted athletic or walking shoes with customized pressure relieving orthoses should be part of ini tial recommendations for people with increased plantar pressures (as demon strated by plantar calluses). Individuals with deformities such as bunions or hammertoes may require specialized footwear such as extra-depth shoes. Those with even more significant de formities, as in Charcot joint disease, may require custom-made footwear.
Special consideration should be given to individuals with neuropathy who pre sent with a warm, swollen, red foot with or without a history of trauma and without an open ulceration. These indi viduals require a thorough workup for possible Charcot neuroarthropathy (89). Early diagnosis and treatment of this condition is of paramount importance in preventing deformities and instability that can lead to ulceration and amputa tion. These individuals require total non weight-bearing and urgent referral to a foot care specialist for further manage ment. Foot and ankle X-rays should be performed in all individuals presenting with the above clinical findings.
There have been a number of devel
opments in the treatment of ulcerations over the years (90). These include negative-pressure therapy, growth fac tors, bioengineered tissue, acellular ma trix tissue, stem cell therapy, hyperbaric oxygen therapy, and, most recently, topi cal oxygen therapy (91-93). While there is literature to support many modalities currently used to treat diabetic foot wounds, robust randomized controlled trials (RCTs) are often lacking. How ever, it is agreed that the initial treat ment and evaluation of ulcerations
include the following five basic prin ciples of ulcer treatment:
- Offloading of plantar ulcerations
- Debridementofnecrotic,nonviable tissue
- Revascularization of ischemic wounds when necessary
- Management of infection: soft tissue or bone
- Use of physiologic, topical dressings
However, despite following the above principles, some ulcerations will become chronic and fail to heal. In those situa tions, advanced wound therapy can play a role. When to employ advanced wound therapy has been the subject of much discussion, as the therapy is often quite expensive. It has been determined that if a wound fails to show a reduc tion of 50% or more after 4 weeks of appropriate wound management (i.e., the five basic principles above), consid eration should be given to the use of advanced wound therapy (94). Treat ment of these chronic wounds is best managed in a multidisciplinary setting.
Evidence to support advanced wound
therapy is challenging to produce and to assess. Randomization of trial partici pants is difficult, as there are many variables that can affect wound heal ing. In addition, many RCTs exclude certain cohorts of people, e.g., individu als with chronic renal disease or those on dialysis. Finally, blinding of participants and clinicians is not always possible. Meta-analyses and systematic reviews of obseNational studies are used to deter mine the clinical effectiveness of these modalities. Such studies can augment for mal RCTs by including a greater variety of participants in various clinical settings who are typically excluded from the more rigidly structured clinical trials.
Advanced wound therapy can be cat
egorized into nine broad categories (90) (Table 12.2). Topical growth factors, acel lular matrix tissues, and bioengineered cellular therapies are commonly em ployed in offices and wound care cen ters to expedite healing of chronic, more superficial ulcerations. Numerous clinical reports and retrospective studies have demonstrated the clinical effectiveness of each of these modalities. Over the years, there has been increased evidence to support the use of these modalities.
Nonetheless, use of those products or agents with robust RCTs or system atic reviews should generally be pre ferred over those without level 1 evidence (Table 12.2).
Negative-pressure wound therapy was
first introduced in the early to mid- 1990s. It has become especially useful in wound preparation for skin grafts and flaps and assists in the closure of deep, large wounds (95,96). A variety of types exist in the marketplace and range from electrically powered to mechanically
powered in different sizes depending upon the specific wound requirements.
Electrical stimulation, pulsed radio frequency energy, and extracorporeal shockwave therapy are biophysical mo dalities that are believed to upregulate growth factors or cytokines to stimulate wound healing, while low-frequency non contact ultrasound is used to debride wounds. However, most of the studies advocating the use of these modalities have been retrospective observational or poor-quality RCTs.
Hyperbaric oxygen therapy is the de livery of oxygen through a chamber, ei ther individual or multiperson, with the intention of increasing tissue oxygena tion to increase tissue perfusion and neovascularization, combat resistant bac teria, and stimulate wound healing. While there had been great interest in this modality being able to expedite healing of chronic diabetic foot ulcers (DFUs), there has only been one positive RCT published in the last decade that re ported increased healing rates at 9 and 12 months compared with control subjects (97). More recent studies with significant design deficiencies and par ticipant dropouts have failed to provide corroborating evidence that hyperbaric oxygen therapy should be widely used for managing nonhealing DFUs (98,99). While there may be some benefit in prevention of amputation in selected chronic neuroischemic ulcers, recent stud ies have shown no benefit in healing DFUs in the absence of ischemia and/ or infection (93,100).
Topical oxygen therapy has been studied rather vigorously in recent years, with several high-quality RCTs and at least five systematic reviews and meta analyses all supporting its efficacy in healing chronic DFUs at 12 weeks (19,20,30-34,91,92,101-105). Three
types of topical oxygen devices are available, including continuous-delivery, low-constant-pressure, and cyclical pressure modalities. Importantly, topical oxygen therapy devices provide for home-based therapy rather than the need for daily visits to specialized cen ters. Very high participation with very few reported adverse events combined with improved healing rates makes this therapy another attractive option for ad vanced wound care.
If DFUs fail to heal despite appropriate wound care, adjunctive advanced thera pies should be instituted and are best managed in a multidisciplinary manner. Once healed, all individuals should be enrolled in a formal comprehensive prevention program focused on reducing the incidence of recurrent ulcerations and subsequent amputations (75,106,107).
- Solomon SD, Chew E, Duh EJ, et al. Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care 2017;40:412- 418
- Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, et al. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986
- Stratton IM, Kohner EM, Aldington SJ, et al. UKPDS 50: risk factors for incidence and progression of retinopathy in type II diabetes over 6 years from diagnosis. Diabetologia 2001;44:156-163
- Estacio RO, McFarling E, Biggerstaff S, Jeffers BW, Johnson D, Schrier RW. Overt albuminuria predicts diabetic retinopathy in Hispanics with NIDDM. Am J Kidney Dis 1998;31:947-953
- Yau JWY, Rogers SL, Kawasaki R, et al.; Meta Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35: 556-564
- Eid S, Sas KM, Abcouwer SF, et al. New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism. Diabetologia 2019;62:1539-1549
- UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853
- Chew EV, Ambrosius WT, Davis MD, et al.; ACCORD Study Group; ACCORD Eye Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-244
- Writing Team for the DCCT/EDIC Research Group; Gubitosi-Klug RA, Sun W, Cleary PA, et al. Effects of prior intensive insulin therapy and risk factors on patient-reported visual function outcomes in the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. JAMA Ophthalmol 2016;134:137-145
- Aiello LP, Sun W, Das A, et al.; DCCT/EDIC Research Group. Intensive diabetes therapy and ocular surgery in type 1 diabetes. N Engl J Med 2015;372:1722-1733
- Bethel MA, Diaz R, Castellana N, Bhattacharya I, Gerstein HC, Lakshmanan MC. HbA1c change and diabetic retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: a meta-analysis and meta-regression. Diabetes Care 2021;44:290-296
- Dabelea D, Stafford JM, Mayer-Davis EJ, D’Agostino R, Dolan L, Imperatore G, et al. Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood. JAMA 2017;317:825-835
- Agardh E, Tababat-Khani P. Adopting 3-year screening intervals for sight-threatening retinal vascular lesions in type 2 diabetic subjects without retinopathy. Diabetes Care 2011;34:1318-1319
- Nathan DM, Bebu I, Hainsworth D, et al.; DCCT/EDIC Research Group. Frequency of evidence based screening for retinopathy in type 1 diabetes. N Engl J Med 2017;376:1507-1516
- Silva PS, Horton MB, Clary D, et al. Identification of diabetic retinopathy and ungradable image rate with ultrawide field imaging in a national teleophthalmology program. Ophthalmology 2016; 123:1360-1367
- Bragge P, Gruen RL, Chau M, Forbes A, Taylor HR. Screening for presence or absence of diabetic
retinopathy: a meta-analysis. Arch Ophthalmol 2011;129:435-444
- Walton OB 4th, Garoon RB, Weng CY, et al. Evaluation of automated teleretinal screening program for diabetic retinopathy. JAMA Ophthalmol 2016;134:204-209
- Daskivich LP, Vasquez C, Martinez C Jr, Tseng CH, Mangione CM. Implementation and evaluation of a large-scale teleretinal diabetic retinopathy screening program in the Los Angeles County Department of Health Services. JAMA Intern Med 2017;177:642-649
- Sim DA, Mitry D, Alexander P, et al. The evolution of teleophthalmology programs in the United Kingdom: beyond diabetic retinopathy screening. J Diabetes Sci Technol 2016;10:308-317
- Abramoff MD, Lavin PT, Birch M, Shah N, Folk JC. Pivotal trial of an autonomous Al-based diagnostic system for detection of diabetic retinopathy in primary care offices. NPJ Digit Med 2018;1:1-8
- Hooper P, Boucher MC, Cruess A, Dawson KG, Delpero W, Greve M, et al. Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of diabetic retinopathy. Can J Ophthalmol 2012; 47(2 Suppl):S1-S54
- Gunderson EP, Lewis CE, Tsai AL, et al. A 20-year prospective study of childbearing and incidence of diabetes in young women, controlling for glycemia before conception: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Diabetes 2007;56:2990-2996
- Widyaputri F, Rogers SL, Kandasamy R, Shub A, Symons RCA, Lim LL. Global estimates of diabetic retinopathy prevalence and progression in pregnant women with preexisting diabetes: a systematic review and meta-analysis. JAMA Ophthalmol 2022;140:486-494
- Diabetes Control and Complications Trial Research Group. Effect of pregnancy on micro vascular complications in the diabetes control and complications trial. Diabetes Care 2000;23: 1084-1091
- The Diabetic Retinopathy Study Research Group. Preliminary report on effects of photo coagulation therapy. Am J Ophthalmol 1976;81: 383-396
- Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796-1806
- Gross JG, Glassman AR, Jampol LM, et al.; Writing Committee for the Diabetic Retinopathy Clinical Research Network. Panretinal photo coagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA 2015;314:2137-2146
- Sivaprasad S, Prevost AT, Vasconcelos JC, et al.; CLARITY Study Group. Clinical efficacy of intravitreal aflibercept versus panretinal photo coagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial. Lancet 2017;389:2193-2203
- Maturi RK, Glassman AR, Josic K, et al.; DRCR Retina Network. Effect of intravitreous anti-vascular endothelial growth factor vs sham treatment for prevention of vision-threatening complications of
diabetic retinopathy: the Protocol W randomized clinical trial. JAMA Ophthalmol 2021;139:701-712
- Elman MJ, Bressler NM, Qin H, et al.; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118:609-614
- Mitchell P, Bandello F, Schmidt-Erfurth U,
et al.; RESTORE study group.The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118:615-625
- Wells JA, Glassman AR, Ayala AR, et al.;
Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015; 372:1193-1203
- Baker CW, Glassman AR, Beaulieu WT, et al.; DRCR Retina Network. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. JAMA 2019;321:1880-1894
- Chew EV, Davis MD, Danis RP, et al.; Action to Control Cardiovascular Risk in Diabetes Eye Study Research Group. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) eye study. Ophthalmology 2014;121:2443-2451
- Shi R, Zhao L, Wang F, et al. Effects of lipid lowering agents on diabetic retinopathy: a Meta analysis and systematic review. Int J Ophthalmol 2018;11:287-295
- Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep 2014;14:528
- Martin CL, Albers JW; DCCT/EDIC Research Group. Neuropathy and related findings in the diabetes control and complications trial/ epidemiology of diabetes interventions and complications study. Diabetes Care 2014;37:31-38
- lsmail-Beigi F, Craven T, Banerji MA, et al.;
ACCORD trial group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 2010;376:419-430
- Bashir M, Elhadd T, Dabbous Z, et al. Optimal glycaemic and blood pressure but not lipid targets are related to a lower prevalence of diabetic microvascular complications. Diabetes Metab Syndr 2021;15:102241
- Look AHEAD Research Group. Effects of a
long-term lifestyle modification programme on peripheral neuropathy in overweight or obese adults with type 2 diabetes: the Look AHEAD study. Diabetologia 2017;60:980-988
- Callaghan BC, Reynolds EL, Banerjee M, et al. Dietary weight loss in people with severe obesity stabilizes neuropathy and improves symptomatology. Obesity (Silver Spring) 2021;29: 2108-2118
- Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care 2017;40:136-154
- Freeman R. Not all neuropathy in diabetes is of diabetic etiology: differential diagnosis of diabetic neuropathy. Curr Diab Rep 2009;9:423-431
- Pop-Busui R, Evans GW, Gerstein HC, et al.; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care 2010;33:1578-1584
- Pop-Busui R, Cleary PA, Braffett BH, et al.; DCCT/EDIC Research Group. Association between cardiovascular autonomic neuropathy and left ventricular dysfunction: DCCT/EDIC study (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications). J Am Coll Cardiel 2013;61:447-454
- Smith AG, Lessard M, Reyna S, Doudova M, Singleton JR. The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy. J Diabetes Complications 2014;28:511-516
- Diabetes Control and Complications Trial (DCCT) Research Group. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995;38:869-880
- CDC Study Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia 1998; 41:416-423
- Albers JW, Herman WH, Pop-Busui R, et al.; Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Diabetes Care 2010; 33:1090-1096
SO. Pop-Busui R, Low PA, Waberski BH, et al.; DCCT/EDIC Research Group. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). Circulation 2009;119:2886-2893
- Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev 2012;6:CD007543
- Pop-Busui R, Lu J, Brooks MM, et al.; BARI 2D Study Group. Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the Bypass Angioplasty Revascular ization Investigation 2 Diabetes (BARI 2D) cohort. Diabetes Care 2013;36:3208-3215
- Tang Y, Shah H, Bueno Junior CR, et al. Intensive risk factor management and cardio vascular autonomic neuropathy in type 2 diabetes: the ACCORD trial. Diabetes Care 2021;44:164-173
- Callaghan BC, Xia R, Banerjee M, et al.; Health ABC Study. Metabolic syndrome components are associated with symptomatic polyneuropathy independent of glycemic status. Diabetes Care 2016;39:801-807
- Andersen ST, Witte DR, Dalsgaard EM, et al. Risk factors for incident diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes
followed for 13 years: ADDITION-Denmark. Diabetes Care 2018;41:1068-1075
- Afshinnia F, Reynolds EL, Rajendiran TM, et al. Serum lipidomic determinants of human diabetic neuropathy in type 2 diabetes. Ann Clin Transl Neural 2022;9:1392-1404
- Lu Y, Xing P, Cai X, et al. Prevalence and risk factors for diabetic peripheral neuropathy in type 2 diabetic patients from 14 countries: estimates of the INTERPRET-DD study. Front Public Health 2020;8:534372
- Sadosky A, Schaefer C, Mann R, et al. Burden of illness associated with painful diabetic peripheral neuropathy among adults seeking treatment in the US: results from a retrospective chart review and cross-sectional survey. Diabetes Metab Syndr Obes 2013;6:79-92
- Waldfogel JM, Nesbit SA, Dy SM, et al. Pharmacotherapy for diabetic peripheral neuro pathy pain and quality of life: a systematic review. Neurology 2017;88:1958-1967
- Price R, Smith D, Franklin G, et al. Oral and topical treatment of painful diabetic polyneuropathy: practice guideline update summary: report of the AAN Guideline Subcommittee. Neurology 2022;98:31-43
- Pop-Busui R, Ang L, Boulton AJM, et al. Diagnosis and Treatment of Painful Diabetic Peripheral Neuropathy. Arlington, VA, American Diabetes Association, 2022
- Tesfaye S, Sloan G, Petrie J, et al.; OPTION-OM trial group. Comparison of amitriptyline supple mented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-OM): a multicentre, double-blind, randomised crossover trial. Lancet 2022;400:68Q-690
- Dworkin RH, Jensen MP, Gammaitoni AR, Olaleye DO, Galer BS. Symptom profiles differ in patients with neuropathic versus non-neuropathic pain. J Pain 2007;8:118-126
- Briasoulis A, Silver A, Yano Y, Bakris GL. Orthostatic hypotension associated with baro receptor dysfunction: treatment approaches. J Clin Hypertens (Greenwich) 2014;16:141-148
- Figueroa JJ, Basford JR, Low PA. Preventing and treating orthostatic hypotension: as easy as A, B, C. Cleve Clin J Med 2010;77:298-306
- Jordan J, Fanciulli A, Tank J, et al. Manage ment of supine hypertension in patients with neurogenic orthostatic hypotension: scientific statement of the American Autonomic Society, European Federation of Autonomic Societies, and the European Society of Hypertension. J Hypertens 2019;37:1541-1546
- Camilleri M, Parkman HP, Shafi MA, Abell TL; American College of Gastroenterology. Clinical guideline: management of gastroparesis. Am J Gastroenterol 2013;108:18-37
- Parrish CR, Pastors JG. Nutritional manage ment of gastroparesis in people with diabetes. Diabetes Spectr 2007;20:231-234
- Parkman HP, Yates KP, Hasler WL, et al.; NIDDK Gastroparesis Clinical Research Consortium. Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis. Gastroenterology 2011;141:486-498, 498.el-498.e7
- Olausson EA, Sti:irsrud S, Grundin H, lsaksson M, Attvall S, Simren M. A small particle size diet reduces upper gastrointestinal symptoms in patients with diabetic gastroparesis: a randomized
controlled trial. Am J Gastroenterol 2014;109: 375-385
- Umpierrez GE (Ed.) Therapy for Diabetes Mellitus and Related Disorders. 6th ed. Arlington, VA, American Diabetes Association; 2014
- Sugumar A, Singh A, Pasricha PJ. A sys tematic review of the efficacy of domperidone for the treatment of diabetic gastroparesis. Clin Gastroenterol Hepatol 2008;6:726-733
- Maganti K, Onyemere K, Jones MP. Oral erythromycin and symptomatic relief of gastro paresis: a systematic review. Am J Gastroenterol 2003;98:259-263
- McCallum RW, Snape W, Brody F, Wo J, Parkman HP, Nowak T. Gastric electrical stimulation with Enterra therapy improves symptoms from diabetic gastroparesis in a prospective study. Clin Gastroenterol Hepatol 2010;8:947-954; quiz e116
- Boulton AJM, Armstrong DG, Albert SF, et al.; American Diabetes Association; American Association of Clinical Endocrinologists. Compre hensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care 2008;31: 1679-1685
- Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ; IWGDF Editorial Board. Practical guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev 2020;36(Suppl. 1):e3266
- Reiber GE, Vileikyte L, Boyko EJ, et al. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care 1999;22:157-162
- Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care 2000;23:606-611
- Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Pediatric Medical Association and the Society for Vascular Medicine. J Vase Surg 2016;63(Suppl.): 3S-21S
- Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vase Endovasc Surg 2019;58(1S): Sl-S109.e33
- American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care 2003;26:3333-3341
- Reaney M, Gladwin T, Churchill S. Information about foot care provided to people with diabetes with or without their partners: Impact on recommended foot care behavior. Appl Psychol Health Well-Being 2022;14:465-482
- Heng ML, Kwan YH, llya N, et al. A collaborative approach in patient education for diabetes foot and wound care: A pragmatic randomised controlled trial. Int Wound J 2020; 17:1678-1686
- Bus SA, Lavery LA, Monteiro-Soares M, et al.; International Working Group on the Diabetic Foot. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev 2020;36(Suppl. 1):e3269
- Goodall RJ, Ellauzi J, Tan MKH, Onida S, Davies AH, Shalhoub J. A systematic review of the impact of foot care education on self efficacy and self care in patients with diabetes. Eur J Vase Endovasc Surg 2020;60:282-292
- Yuncken J, Williams CM, Stolwyk RJ, Haines TP. People with diabetes do not learn and recall their diabetes foot education: a cohort study. Endocrine 2018;62:250-258
- Walton DV, Edmonds ME, Bates M, Vas PRJ, Petrova NL, Manu CA. People living with diabetes are unaware of their foot risk status or why they are referred to a multidisciplinary foot team. J Wound Care 2021;30:598-603
- Bus SA, van Deursen RW, Armstrong DG, Lewis JE, Caravaggi CF; International Working Group on the Diabetic Foot. Footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in patients with diabetes: a systematic review. Diabetes Metab Res Rev 2016;32(Suppl. 1):99-118
- Rogers LC, Frykberg RG, Armstrong DG, et al. The Charcot foot in diabetes. Diabetes Care 2011; 34:2123-2129
- Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle) 2015;4:560-582
- Carter MJ, Frykberg RG, Oropallo A, Sen CK, Armstrong DG, Nair HKR, et al. Efficacy of topical wound oxygen therapy in healing chronic diabetic foot ulcers: systematic review and meta-analysis. Adv Wound Care (New Rochelle). 21 June 2022 [Epub ahead of print]. DOI: 10.1089/wound.2022. 0041
- Frykberg RG, Franks PJ, Edmonds M, et al.; TWO2 Study Group. A multinational, multicenter, randomized, double-blinded, placebo-controlled trial to evaluate the efficacy of cyclical topical wound oxygen (TWO2) therapy in the treatment
of chronic diabetic foot ulcers: the TWO2 study. Diabetes Care 2020;43:616-624
- Boulton AJM, Armstrong DG, Li:indahl M, et al. New Evidence-Based Therapies far Complex Diabetic Foot Wounds. Arlington, VA, American Diabetes Association, 2022
- Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care 2003;26:1879- 1882
- Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care 2008;31:631-636
- Argenta LC, Morykwas MJ, Marks MW, DeFranzo AJ, Molnar JA, David LR. Vacuum assisted closure: state of clinic art. Plast Reconstr Surg 2006;117(Suppl. ):1275-1425
- Li:indahl M, Katzman P, Nilsson A, Hammarlund
C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care 2010;33:998-1003
- Santema KTB, Stoekenbroek RM, Koelemay MJW, et al.; DAMO2CLES Study Group. Hyperbaric oxygen therapy in the treatment of ischemic lower- extremity ulcers in patients with diabetes: results of the DAMO2CLESmulticenter randomized clinical trial. Diabetes Care 2018;41:112-119
- Fedorko L, Bowen JM, Jones W, et al. Hyperbaric oxygen therapy does not reduce indications for amputation in patients with diabetes with nonhealing ulcers of the lower limb: a prospective, double-blind, randomized controlled clinical trial. Diabetes Care 2016;39: 392-399
- Lalieu RC, Brouwer RJ, Ubbink DT, Hoencamp R, Bol Raap R, van Hulst RA. Hyperbaric oxygen therapy for nonischemic diabetic ulcers: a sys tematic review. Wound Repair Regen 2020;28: 266-275
- Niederauer MQ, Michalek JE, Liu Q, Papas KK, Lavery LA, Armstrong DG. Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre study. J Wound Care 2018;27(Suppl. 9):530- 545
- Serena TE, Bullock NM, Cole W, Lantis J, Li L, Moore S, et al. Topical oxygen therapy in the treatment of diabetic foot ulcers: a multicentre, open, randomised controlled clinical trial. J Wound Care 2021;30(Suppl. 5):57-514
- Sun XK, Li R, Yang XL, Yuan L. Efficacy and safety of topical oxygen therapy for diabetic foot ulcers: an updated systematic review and meta analysis. Int Wound J. 5 May 2022 [Epub ahead of print]. DOI: 10.1111/iwj.13830
- Frykberg RG.Topical wound oxygen therapy
in the treatment of chronic diabetic foot ulcers. Medicina (Kaunas) 2021;57:917
- Sethi A, Khambhayta Y, Vas P. Topical oxygen therapy for healing diabetic foot ulcers: a systematic review and meta-analysis of randomised control trials. Health Sci Rep 2022;3:100028
- van Netten JJ, Price PE, Lavery LA, et al.; International Working Group on the Diabetic Foot. Prevention of foot ulcers in the at-risk patient with diabetes: a systematic review. Diabetes Metab Res Rev 2016;32(Suppl. 1):84-98
- Frykberg RG, Vileikyte L, Boulton AJM,
Armstrong DG. The at-risk diabetic foot: time to focus on prevention. Diabetes Care 2022;45: e144-e145
Efficacy of Topical Wound Oxygen Therapy in Healing Chronic Diabetic Foot Ulcers: Systematic Review and Meta-Analysis
Marissa J. Carter,1,* Robert G. Frykberg,2 Alisha Oropallo,3 Chandan K. Sen,4 David G. Armstrong,5
Harikrishna K.R. Nair,6 and Thomas E. Serena7
1Strategic Solutions, Inc., Bozeman, Montana, USA.
2Diabetic Foot Consultants, Midwestern University, Glendale, Arizona, USA.
3Department of Vascular Surgery, Donald and Barbara Zucker School of Medicine, Hofstra/Northwell Health, Hempstead, New York, USA.
4Indiana Center for Regenerative Medicine and Engineering, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
5Department of Surgery, Keck School of Medicine of University of Southern California, Los Angeles, California, USA. 6Wounds Malaysia, Wound Care Unit, Department of Internal Medicine, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia. 7SerenaGroup Research Foundation, Cambridge, Massachusetts, USA.
Objective: To conduct a systematic review and meta-analysis of recently published randomized controlled trials (RCTs) that employed the use of topical oxygen therapy (TOT) as an adjunct therapy in the treatment of Wagner 1 and 2 diabetic foot ulcers.
Approach: Following a literature search of eligible studies from 2010 on- ward, four RCTs were included. Studies were analyzed for patient and wound characteristics, outcomes, risk of bias, and quality of the evidence assessed using the Grading of Recommendations Assessment, Development, and Evalua- tion (GRADE) methodology. A random-effects meta-analysis for complete wound healing was carried out due to statistical heterogeneity of included studies.
Results: Risk of bias judgment (RoB2 analysis) resulted in one low-risk trial and three trials with some risk. One study was determined to be the origin of the statistical heterogeneity. Pooled results showed statistical significance with a risk ratio (RR) of 1.59 (95% confidence interval [CI]: 1.07–2.37; p = 0.021). Sensitivity analysis, based on imputed values for missing outcomes, demonstrated that both the RR and 95% CIs changed little. The GRADE ratings for each do- main were as follows: (a) risk of bias: moderate (3); (b) imprecision: mod- erate (2), high (1); (c) inconsistency: low (2), high (1); (d) indirectness:
moderate (2), high (1); and (e) publication bias: moderate (1), high (2). Overall, the evidence was moderate.
Innovation: Our study shows that TOT is a viable diabetic foot ulcer therapy. Conclusions: These data support the use of TOT for the treatment of chronic Wagner 1 or 2 diabetic foot ulcers in the absence of infection and ischemia.
Keywords: diabetic foot ulcer, topical oxygen therapy, systematic review, meta-analysis
Open camera or QR reader and scan code to access this article and other resources online.
Marissa J. Carter, PhD, MA
Submitted for publication March 8, 2022.
Accepted in revised form May 13, 2022.
*Correspondence: Strategic Solutions, Inc., 37 Voyager Lane, Bozeman, MT 59718, USA
(e-mail: [email protected]).
ª Marissa J. Carter et al., 2022; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License [CC-BY-NC] (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are cited.
ADVANCES IN WOUND CARE, VOLUME 00, NUMBER 00 1
2022 by Mary Ann Liebert, Inc. DOI: 10.1089/wound.2022.0041
Diabetes-related foot ulcers (DFUs), affect- ing up to one third of patients with diabetes during the course of their disease, have long been con- sidered major precursors to lower extremity am- putation, whether of neuropathic, ischemic, or neuroischemic etiology.1,2 A recent systematic re- view reported a worldwide prevalence of DFU of 6.3%, with the highest prevalence being 13% in North America.3 Another report found the global burden of diabetes-related lower extremity com- plications to be high, with a crude estimate of DFUs affecting 18.6 million persons.4 The costs of treat- ing chronic DFUs are commensurate with the frequent complexity of the problem itself. A 2014 U.S.-based administrative database study found that such costs can range from $9 to $13 billion, and the excess health care costs of DFU approximately double the cost of treating diabetes itself.5
The rapid growth of the global population with diabetes will lead to a greater number of pa- tients suffering from DFUs and a concomitant increase in global amputation rates. Current pro- tocols for managing acute or chronic DFUs focus on thorough systematic assessment, debridement, ef- fective offloading, wound bed preparation, and re- vascularization, as necessary.6–8 Unfortunately, many DFUs are refractory to optimal standard of care (SOC) as defined by healing less than 50% in 4 weeks. These patients require reassessment of vascular, nutritional, and infection status; exami- nation of the effectiveness of debridement and off- loading regimens; and reevaluation of renal status, diabetic control, residual small artery disease (not amenable to intervention), or other significant metabolic abnormalities that may adversely affect wound healing. These patients are likely to benefit from advanced wound healing therapies, such as topical oxygen therapy (TOT).7,9,10
When TOT was introduced to clinical practice over 50 years ago, practitioners initially viewed it as a controversial therapy, due to the sparse evi- dence supporting its use. Technological advances in delivery systems and recent clinical trials sug- gest that TOT is a viable advanced treatment mo- dality for DFUs.10–15
There are several types of TOT devices on the market, including continuous diffusion of oxy- gen (CDO) delivery systems, devices delivering low constant pressure O2 (at 22 mmHg), and a system that delivers cyclically pressurized oxygen (from 10 to 50 mb above atmospheric pressure).10,16 CDO devices, delivering a low constant flow of pure oxygen at 3–15 mL/h, are designed for continu- ous ambulatory use through proprietary wound
dressings, whereas the latter two devices de- liver oxygen within a flexible, disposable extremity chamber used in the home.
Early clinical studies on TOT lacked scientific rigor. For example, a poorly designed, unblinded, and inadequately powered trial published in 1988 compared 12 hospitalized patients with chronic DFUs who received 14 days of topical ‘‘hyperbaric’’ oxygen therapy with 16 similar patients treated with standard care. The investigators reported no difference in healing outcomes after 2 weeks of treatment, and they concluded that TOT pro- vided no appreciable benefit in the treatment of DFUs.17
Despite this early report, several reviews, ob- servational human studies, and preclinical animal work suggested a positive wound healing benefit associated with TOT.18–24 A very compelling ani- mal study was published by Fries et al. in 2017 that clearly demonstrated an upregulation of growth factors and significant increases in tissue level oxygen partial pressures after treatment with TOT compared with control wounds.19 Furthermore, these physiological attributes were corroborated by clinical as well as histological evidence of improved healing in the oxygen-treated wounds.
The last decade, however, has given rise to several more robust randomized controlled trials (RCTs) that demonstrate the efficacy of TOT in treatment of chronic DFUs compared with controls treated with SOC alone.11–15 Additionally, several recent independent systematic reviews and meta- analyses validate the additional benefit of TOT in this regard.25–27 These systematic reviews, how- ever, were fairly heterogeneous in the types of studies analyzed and did not include the most re- cent RCT published in 2021.13
Our aim in this systematic review and meta- analysis was to provide a rigorous assessment of recently reported RCTs comparing adjunctive TOT with control patients receiving SOC for the treat- ment of chronic DFUs. Distinct from the several other systematic reviews, we include only robust prospective RCTs with primary outcomes of com- plete healing at 12 weeks. Complete healing (or complete wound closure), as used in this analy- sis, is defined as complete reepithelialization with no further evidence of drainage nor visible granulation tissue. To avoid potential duplication of patient data, we have specifically excluded those publications with reported interim data. The data from studies evaluating CDO and cy- clically pressurized systems were included and pooled. There were too few studies to perform separate meta-analyses.
TOT has had a checkered history as an adjunc- tive therapy in wound healing in part due to the development of the technology itself. Recent ad- vances have made the devices more robust and reliable with the potential to accelerate wound healing in chronic diabetic foot ulcers. By con- ducting a systematic review of all the relevant RCTs using the most conservative outcome of complete wound healing at a minimum of 12 weeks, we demonstrate that more robust devices do have the ability to improve wound healing in less severe chronic diabetic foot ulcers.
CLINICAL PROBLEM ADDRESSED
Chronic diabetic foot ulcers are an unfortunate but common complication of diabetes. While con- sistent SOC can heal many DFUs given enough time, a substantial proportion of these wound types are stuck in the inflammatory phase of wound healing and need an adjunctive treatment to ad- dress the issue(s) so that the wound can tran- sition to the proliferative phase. While a variety of treatments have demonstrated efficacy in this regard, many are expensive, and some are not available to all patients. Given that TOT is a pos- sible adjunctive therapy for DFUs, we decided to formally assess the RCTs conducted to date using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), including meta-analysis, to determine if this mode of therapy can be recommended.
MATERIALS AND METHODS
The study was performed according to the 2015 Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement28 and was registered at PROSPERO (CRD42021259090).
Studies involving patients with chronic DFUs using TOT (intermittent or continuous application of oxygen) in addition to SOC (debridement, off- loading, and moist wound care) in any health care setting were eligible provided that they were RCTs. Data of studies with 20 patients or fewer or with- out primary outcomes of healing at 12 weeks were excluded from the assessment.
The following databases were used in the search:
- Cochrane Central Register of Controlled Trials
- Cochrane Database of Systematic Reviews
- Health Technology Assessment Database
- International Clinical Trials Registry Plat- form Search Portal.
The following search terms were used: Topical Oxygen OR Topical Wound Oxygen OR Continuous Diffusion of Oxygen OR Continuous Topical Oxy- gen OR Topical Hyperbaric Oxygen OR High- Pressure Cyclical Oxygen AND Clinical Trial OR Trial OR Placebo OR Random.
In addition, the full-text document (e.g., journal article or clinical study report) had to be available and published after January 1, 2010. Any language was permissible provided that English titles and abstracts were available and indicated potential relevance.
Figure 1 summarizes the literature search and study selection process. On October 20, 2021, 2 authors conducted the literature search, which yielded 51 clinical trials and 240 publications with 11 RCTs (14 publications) meeting search criteria (Table 1). All members of the study team discussed the search results and reached a consensus that four studies met the predefined inclusion criteria (Supplementary Tables S1 and S2).11–13,15
Data extraction and risk of bias analysis
The primary outcome of interest was complete wound healing (skin reepithelialization without drainage or dressing requirements confirmed at two consecutive study visits 2 weeks or more apart) at 12 weeks with the following secondary out- comes collected if available: wound-related pain, readmission to the hospital, health-related quality of life, dependence on outside help or need for care, adherence to prescribed therapy, and adverse events (AEs), including amputation and mortality. SOC in treatment of DFUs includes debride- ment as necessary (typically sharp debridement), offloading of plantar ulcers, appropriate dressings to maintain a moist wound care bed, and infec- tion control. Reporting should include debridement type and frequency, as well as details of dressings and offloading. Although findings were not tabu-
lated, we noted if details were missing.
Two reviewers independently extracted key study metrics and outcomes, and a third member checked congruity of the data. A consensus among the team members was reached that only complete wound healing was a useful outcome, as not all studies provided other wound healing outcomes.
Figure 1. PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analysis.
The risk of bias analysis used the RoB2 approach developed by the Cochrane group.29 The same re- viewers who extracted the data carried out the risk of bias analysis independently. The senior sys- tematic reviewer/statistician adjudicated differ- ences in assessment for each domain for each study and reviewed the overall results.
Meta-analysis was conducted for complete
significant. Heterogeneity was explored by sys- tematically omitting one of the included studies. The effect measure used was relative risk, and the analysis was conducted using MedCalc and SPSS (v 28.0).
Table 1. Literature search data
Parameter Clinical Trials Publications
Unique results from search terms 51 240
wound healing at 12 weeks using all eligible stud-
ies, as only one study was low risk. A fixed-effects
Those involving gaseous, topically applied oxygen
model (inverse variance method; Mantel–Haenszel) was used when heterogeneity was judged nonsig- nificant, including the I2 and Cochran’s Q metrics. A random-effects model (DerSimonian and Laird method) was used when heterogeneity was judged
RCTs meeting criteria 11 14
Completed with full-text publication 4 10a
aTwo clinical trials had multiple publications. Only one reference from each study contained the primary outcomes used in the meta-analysis. Refer to Supplementary Tables S1 and S2.
RCT, randomized controlled trial.
The primary sensitivity analysis was carried out using a modified jump-to-reference ( J2R) ap- proach,30 in which subjects lost to follow-up or withdrawals due to other reasons for the complete wound healing outcome in the TOT group were assumed to have had the same proportional out- comes as the control/sham/SOC only group. Since outcomes for subjects withdrawn from the studies depend on the reason why the subjects were with- drawn, for serious adverse events (SAEs) or AEs in which the event was serious enough that a subject was withdrawn from the study, the event would likely have affected the wound healing trajectory in an adverse manner. For nonserious AEs or most other reasons for withdrawals, the wound healing trajectory would likely have been similar to the healing rate of the uncensored control/sham/SOC only group.
Thus, the algorithm for a secondary sensitivity analysis was implemented first for the control/ sham/SOC only group as: (a) index wounds of subjects who had an SAE/AE that forced with- drawal or caused a voluntary withdrawal by the subject were scored as not healed; death was scored as not healed. If insufficient data were reported to enable a determination, then the algorithm as- sumed that this category was 0; (b) all other index
wounds were scored as healed/not healed according to the J2R method, which uses complete case re- sults. The adjusted healing rate thus obtained was then used as the J2R value for the TOT group. When calculating the number of subjects in a sen- sitivity analysis, if fractions were involved, num- bers of subjects were rounded up or down to integers depending on whether the fraction was
>0.5 or not.
Grading of Recommendations Assessment, Development, and Evaluation
Three team members evaluated independently the body of evidence using the GRADE methodol- ogy.31 Consensus among all authors determined recommendations.
Three of the four studies had larger and similar numbers of enrolled participants (N = 130–146), whereas the Frykberg RCT15 was smaller (N = 73) (Table 2). The mean wound age was comparable among all studies, although the Driver study11 enrolled smaller area wounds on average (Table 2). All RCTs had a study length of 12 weeks.
Table 2. Characteristics of included studies
RCT Study Design
No. of Subjects Randomized
|Study Duration, Weeks||
|Driver||2017||• Subject blinded||130||12||22 Wound clinics||• Active: 65b||• Class: UT 1A||• Active: 12|
|et al.11||• Assessor blinded
• 2 Groups
|• Activea: 66
• Shama: 64
|(United States and Canada)||• Sham: 63b||• Mean wound age: Active:
17.7 weeks; Sham: 14.9
|• SOC: 17|
|• Mean wound area: Active:
2.0 cm2; Sham: 2.3 cm2
|Niederauer||2018||• Subject blinded||146||12||34 Wound clinics||• Active: 74||• Class: UT 1A||• Active: 22|
|et al.12||• Assessor blinded||• Active: 74||(United States)||• Sham: 72||• Mean wound age: Active:||• SOC: 19|
|• 2 Groups||• Sham: 72||18.8 weeks; Sham: 20.5|
|• Mean wound area: Active:
3.5 cm2; Sham: 3.9 cm2
|Frykberg||2020||• Subject blinded||73||12||17 Diabetic||• Active: 36||• Class: UT 1A–D, 2A–D||• Active: 3|
|et al.15||• Assessor blinded||• Active: 36||foot centers||• Sham: 37||• Mean wound age: Active:||• SOC: 4|
|• 2 Groups||• Sham: 37||(United States,||22.9 weeks; Sham: 24.9|
|• Mean wound area: Active:
3.0 cm2; Sham: 3.2 cm2
|Serena||2021||• No blinding||145||12||19 Wound clinics||• Active: 81||• Class: Wagner 1 or 2||• Active: 15|
|et al.13||• 2 Groups||• Active: 81||(United States)||• SOC: 64||• Mean wound age: Active:||• SOC: 12|
|• SOC: 64||24.5 weeks; SOC: 23.8|
|• Mean wound area: Active:
2.9 cm2; SOC: 3.5 cm2
aActive group defined as the group allocated to the intervention; sham group defined as the group allocated to SOC alone using a sham device.
bSubjects randomized and also received allocated treatment. SOC, standard of care; UT, University of Texas.
Table 3. Complete wound healing outcomes and safety analysis of included studies
|Study||Year||Outcome Dataa||Safety Results||Healing Confirmation Visit|
|Driver et al.11||2017||• Activeb: 35/65 (54%)
• Shamb: 31/63 (49%)
• p = 0.42
|• SAEs: Active: 12; Sham: 13
B All unrelated/unlikely related to device
• AEs: Active: 53 Sham: 55
|2 Weeks after initial healing date|
Niederauer et al.12 2018 • Active: 24/74 (32%)
- Sham: 12/72 (17%)
- p = 027
Frykberg et al.15 2020 • Active: 15/36 (41%)
- Sham: 5/37 (14%)
- p = 007
Serena et al.13 2021 • Active: 36/81 (44%)
- SOC: 18/64 (28%)
- p = 04
aBased on proportions of wounds healed at 12 weeks.
B 1 Probably related to SOC
B 3 Possibly related to device
- Infections: Active: 3; Sham: 10
- AEs: Active: 11; Sham: 13
B Related to study wound: Active: 6; Sham: 10
- SAEs: Active: 10; Sham: 10
- AEs: Active: 8; Sham: 8
- Index limb amputations: Active: 2; Sham: 3
- AEs: Active: 41; SOC: 32
- Severe/life-threatening AEs: Active: 7; SOC: 8
- Possibly/probably related to product: Active: 1; SOC: 12 AEs
Follow-up telephone call/12-week durability visit
2 Weeks after initial healing date
2-Week confirmation visit (T.E. Serena, pers. comm.)
bActive group defined as the group allocated to the intervention; sham group defined as the group allocated to SOC alone using a sham device. AE, adverse event; SAE, serious adverse event.
The difference between intervention and SOC groups in terms of complete wound healing ranged from 5% to 27% (all rates had higher healing rates compared with the SOC group), but only the Driver trial reported statistically nonsignificant results (Table 3). AEs were similar in both groups for all studies, although the absolute rates varied con- siderably.
Risk of bias analysis
There were eight disagreements between the two reviewers regarding judgment of the five do- mains for the four studies, half of which were for the Driver study.11 There was also a disagreement about the overall judgment for the Driver trial.11 After adjudication, this resulted in one low-risk trial and three trials with some risk (Table 4).
Since only one study was low risk, meta-analysis proceeded with all eligible studies. A random-effects model was chosen because there was substan- tial heterogeneity (I2: 55.7%; p = 0.081). The simple explanation for the origin of the heterogeneity was the Driver study,11 as its removal resulted in no heterogeneity.
The pooled results showed statistical signifi- cance with a risk ratio (RR) of 1.59 (95% confi- dence interval [CI]: 1.07–2.37; p = 0.021) (Fig. 2 and
Table 5). A funnel plot suggested that the magni- tude of the intervention response varied consider- ably with the degree of precision (Fig. 3).
Sensitivity analysis using imputed values for missing outcomes, which was based on random- effects models, demonstrated that despite some fairly high levels of missing outcomes in three studies, neither the pooled estimate or 95% CIs changed substantially (Table 6) ( p = 0.039).
Grading of Recommendations Assessment, Development, and Evaluation
The ratings for each domain were as follows: (a) risk of bias: moderate (3); (b) imprecision: moderate (2), high (1); (c) inconsistency: low (2), high (1); (d) indirectness: moderate (2), high (1); and (e) publi- cation bias: moderate (1), high (2). All agreed that the overall evidence was moderate. Based on our meta-analysis and GRADE review, the study panel agreed that TOT can be recommended for the in- dication of chronic DFUs that have not responded to an initial trial of effective offloading and sharp debridement in the absence of infection and ischemia.
Our systematic review of RCT evidence for TOT indicates that it is a viable treatment for Wagner 1
Table 4. Final summary table risk of bias judgment for complete wound healing outcome at 12 weeks
|Study||Domain 1||Domain 2||Domain 3||Domain 4||Domain 5||Overall|
|Driver et al.11||Low risk||Low risk||Some concerns||Low risk||Low risk||Some concerns|
|Frykberg et al.15||Low risk||Low risk||Low risk||Low risk||Low risk||Low risk|
|Niederauer et al.12||Some concerns||Low risk||Some concerns||Low risk||Low risk||Some concerns|
|Serena et al.13||Low risk||Some concerns||Some concerns||Low risk||Low risk||Some concerns|
Figure 2. Forest plot for the random-effects model including all studies.
Figure 3. Funnel plot of the magnitude of the intervention response in- cluding all studies.
and 2 DFUs. The meta-analysis supports efficacy in the defined populations under study; that is, chronic nonischemic DFUs of at least 4 weeks duration and not adequately responding to SOC alone. Our recommendation corroborates and is consistent with the other aforementioned system- atic reviews that also support TOT for the treat- ment of chronic DFUs.25–27 Additional studies are needed to clarify the indications for use and effi- cacy in other wound types.
The meta-analysis demonstrated that, even in the presence of statistical heterogeneity addressed using random-effects models, results were statis- tically significant and remained so when apply- ing reasonable sensitivity analysis. While other systematic reviews have already reported positive findings,25–27 our study was the first to analyze only RCTs, including the most recent trial,13 and we applied the most rigorous form of risk of bias analysis, GRADE, and meta-analysis.
It is interesting to note that if the Driver study11 is removed from meta-analysis, there is no het- erogeneity, and a fixed-effects model is possible with extremely statistically significant results. One possible reason for the failure to achieve sta-
tistical significance in the Driver study11 could be premature failure of the active device, Epiflo™ (Neogenix, formerly Ogenix, Beachwood, OH). This older continuous topical oxygen (CTO) device uses an electrochemical generator to produce oxygen at a flow rate of 3 mL/h. While the device has a blinking red light that indicates when the power is on, it does not contain an alarm or indicator to notify the patient or provider that the generator is not functioning properly. If the device fails, the patient and clinician may believe that the device is working properly, even though it is no longer gen- erating oxygen. In addition, CTO devices may not function in regions with low humidity levels.32
These weaknesses may explain the poorer re- sults in the CTO clinical trials compared with the other systems. While the trial was generally well designed, the control group achieved nearly a 50% closure rate at 12 weeks compared with 54% in the active group. This would ostensibly indicate that those ulcers enrolled would have been as likely to heal with SOC as with active therapy. Further- more, the authors acknowledged that they specifi- cally excluded patients with typical comorbidities
Table 5. Results of the random-effects model including all studies
Table 6. Sensitivity analysis of the complete wound healing outcome using a random-effects model
|Driver et al.11||35/65||31/63||1.09||0.78–1.53||35.2||Study||TOT||SOC||Ratio||95% CI||%|
|Niederauer et al.12||24/74||12/72||1.95||1.06–3.59||22.2||Driver et al.11||41/65||38/63||1.05||0.80–1.37||33.9|
|Frykberg et al.15||15/36||5/37||3.08||1.25–7.60||13.7||Niederauer et al.12||26/74||13/72||1.95||1.09–3.48||23.3|
|Serena et al.13||36/81||18/64||1.58||1.00–2.51||28.8||Frykberg et al.15||15/36||5/37||3.08||1.25–7.60||14.8|
|Total||110/256||66/236||1.59||1.07–2.37||100.0||Serena et al.13||38/81||19/64||1.58||1.02–2.46||28.0|
Total 120/256 75/236 1.59 1.02–2.48 100.0
CI, confidence interval; TOT, topical oxygen therapy.
seen in patients with DFU (ischemia, renal insufficiency, etc.) and patients with deeper ulcers that would be consid- ered more difficult to heal.11
The current SARS-Cov-2 pandemic has resulted considerable disruption to wound care especially for patients par- ticularly for treatments that involve wound care clinics and hospitals.33 Con- sequently, treatments that can be con- ducted in the patient’s home care setting may have some advantage,34 including
TOT for treatment of DFUs. It remains unknown whether the economics of using TOT are favorable since no studies have been published on the sub- ject. Although any advanced therapy will be more costly initially, long-term benefits are almost uni- formly supportive of such therapies since they heal wounds faster and avoid hospitalizations and am- putations. Indeed, a recent publication supports this premise.35
There are some limitations to this meta- analysis. First, complete wound healing was the only common endpoint available for this review and meta-analysis. The U.S. Food and Drug Ad- ministration favors this endpoint36; however, the analysis was unable to assess patient-centered outcomes, such as quality of life or wound-associated pain, or clinical endpoints of interest, such as pre- vention of infection or amputation. Second, there is invariably some heterogeneity in applying SOC for DFU treatment even in RCTs in which there is considerable training and assessment at each participating site; examples include types of dressings, debridement frequencies, and types of permissible offloading. Within a trial, heterogene- ity is usually minimal due to randomization pro- cedures, but between trials, differences can be a factor in determining what the overall SOC healing rate is over the length of the study.
However, what really matters is the difference between the treatment groups in regard to healing rates rather than absolute values. SOC can also be insufficiently detailed in the study publication, which is a reporting issue; for example, only two of the trials described debridement, and offloading details were missing in one trial. This can lead to uncertainty in regard to study assessment, partic- ularly for assessors not familiar with the trials. Third, our recommendations are limited to Wagner grade 1 or 2 DFUs: none of the clinical trials in- cluded more severe ulcers. Similarly, the trials primarily treated chronic uninfected ulcers with adequate perfusion. Therefore, the conclusions do not extend to infected or ischemic ulcers. Last, our recommendations are based on only four RCTs; more well-conducted trials would be likely to strengthen or amend our conclusions.
In conclusion, this systemic review and meta- analysis supports the use of TOT as an adjunctive therapy in the treatment of Wagner 1 and 2 DFUs that have not responded to preliminary treatment with optimal SOC alone.
Marissa Carter: Data curation (lead), formal analysis (lead), investigation (supporting), meth- odology (lead), supervision (equal), visualization (supporting), writing—original draft (supporting), and writing–review and editing (equal). Robert Frykberg: Data curation (supporting), formal analysis (supporting), investigation (lead), meth- odology (supporting), writing—original draft (sup- porting), and writing—review and editing (equal). Alisha Oropallo: Data curation (supporting), for- mal analysis (supporting), investigation (supporting), methodology (supporting), writing—original draft (supporting), and writing—review and editing (equal). Chandan Sen: Investigation (supporting), methodology (supporting), and writing—review and editing (equal).
David Armstrong: Data curation (supporting), investigation (supporting), and writing—review and editing (equal). Harikrishna Nair: Writing— original draft (supporting) and writing—review and editing (equal). Thomas Serena: Conceptuali- zation (lead), funding acquisition (lead), supervision (equal), visualization (supporting), writing—original draft (supporting), and writing—review and editing (equal). Marissa Carter takes full responsibility for the work, the study design, had access to data, and made the decision to submit and publish the article.
ACKNOWLEDGMENTS AND FUNDING SOURCES
The authors acknowledge the valuable input of Prof. Michael Edmonds (Kings College Hospital, London, United Kingdom) and the editorial assis- tance of Kristen Eckert, Strategic Solutions, Inc. The study was funded by SerenaGroup Research Foundation (Cambridge, MA); the study sponsor’s role was to organize the study and maintain flow of work, not to influence how decisions were taken.
AUTHOR DISCLOSURE AND GHOSTWRITING
M.J.C.: Has received an honorarium from EO2 Concepts. R.G.F.: Has received research support and consulting fees from Advanced Oxygen Ther- apy, Inc. A.O.: Has received research support from EO2 Concepts. C.K.S.: No conflicts of interest. D.G.A.: No conflicts of interest. H.K.R.N.: No con- flicts of interest. T.E.S.: Has received research support from Inotec and EO2 Concepts. The con- tent of this article was expressly written by the authors listed. No ghostwriters were used to write this article.
ABOUT THE AUTHORS
Marissa J. Carter, PhD, is president of Stra- tegic Solutions and is a clinical trial designer and biostatistician with considerable experience in wound care. Robert G. Frykberg, DPM, recently retired from his longstanding position as Chief of Podiatry at the Phoenix VA Medical Center but
continues to hold the academic rank of Professor, University of Arizona College of Medicine-Phoenix. Alisha Oropallo, MD, is a vascular surgeon and wound care physician, and the medical director of the Comprehensive Wound Healing Center and Hyperbarics at Northwell Health. Chandan K. Sen, PhD, is a J. Stanley Battersby Chair and Professor of Surgery, Director of the Indiana Cen- ter for Regenerative Medicine and Engineering (ICRME), and Editor-in-Chief of Advances in Wound Care.
David G. Armstrong, DPM, is an interna- tionally recognized leader in the field of podiatric surgery, diabetic foot, limb preservation, tissue repair, and wound healing. Harikrishna K.R. Nair, MD, is well-known expert in the field of wound healing and is head of the Wound Care Unit, Department of Internal Medicine, Kuala Lumpur Hospital, Malaysia. Thomas E. Serena, MD, is founder and Medical Director of The SerenaGroup, a family of wound, hyperbaric and research com- panies, and a recognized leader in medical wound research and clinical trials.
Supplementary Table S1 Supplementary Table S2
- Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation: basis for Diabetes Care 1990;13:513–521.
- Armstrong DG, Boulton AJM, Bus Diabetic foot ulcers and their recurrence. N Engl J Med 2017;376:2367–2375.
- Zhang P, Lu J, Jing Y, et al. Global epidemi- ology of diabetic foot ulceration: a systematic review and meta-analysis. Ann Med 2017;49: 106–116.
- Zhang Y, Lazzarini PA, McPhail SM, et al. Global disability burdens of diabetes-related lower- extremity complications in 1990 and Dia- betes Care 2020;43:964–974.
- Rice JB, Desai U, Cummings AK, et al. Burden of diabetic foot ulcers for medicare and private in- Diabetes Care 2014;37:651–658.
- Schaper NC, van Netten JJ, Apelqvist J, et al. Practical Guidelines on the prevention and man- agement of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev 2020;36(Suppl 1):e3266.
- Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: a clinical prac- tice guideline by the Society for Vascular Surgery in collaboration with the American Po- diatric Medical Association and the Society for Vascular Medicine. J Vasc Surg 2016;63(2 Suppl): 3S–21S.
- American Diabetes 11. Microvascular complications and foot care: standards of medi- cal care in diabetes–2021. Diabetes Care 2021; 44(Suppl 1):S151–S167.
- Frykberg RG, Banks Challenges in the treatment of chronic wounds. Adv Wound Care (New Ro- chelle) 2015;4:560–582.
- Frykberg Topical wound oxygen therapy in the treatment of chronic diabetic foot ulcers. Medi- cina (Kaunas) 2021;57:917.
- Driver VR, Reyzelman A, Kawalec J, et al. A prospective, randomized, blinded, controlled trial comparing transdermal continuous oxygen deliv- ery to moist wound therapy for the treatment of diabetic foot ulcers. Ostomy Wound Manage 2017; 63:12–28.
- Niederauer MQ, Michalek JE, Liu Q, et al. Con- tinuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre J Wound Care 2018;27(Suppl 9):S30–S45.
- Serena TE, Bullock MN, Cole W, et Topical oxygen therapy in the treatment of diabetic foot ulcers: a multicentre, open, randomised controlled clinical trial. J Wound Care 2021;30(Suppl 5): S1–S8.
- Yu J, Lu S, McLaren AM, et Topical oxygen therapy results in complete wound healing in di- abetic foot ulcers. Wound Repair Regen 2016;24: 1066–1072.
- Frykberg RG, Franks PJ, Edmonds M, et al. A multinational, multicenter, randomized, double- blinded, placebo-controlled trial to evaluate the efficacy of cyclical topical wound oxygen (TWO2) therapy in the treatment of chronic diabetic foot ulcers: the TWO2 Study. Diabetes Care 2020;43: 616–624.
- Gottrup F, Dissemond J, Baines C, et Use of oxygen therapies in wound healing. J Wound Care 2017;26(Suppl 5):S1–S43.
- Leslie CA, Sapico FL, Ginunas VJ, et Rando- mized controlled trial of topical hyperbaric oxy- gen for treatment of diabetic foot ulcers. Diabetes Care 1988;11:111–115.
- Blackman E, Moore C, Hyatt J, et al. Topical wound oxygen therapy in the treatment of se- vere diabetic foot ulcers: a prospective controlled Ostomy Wound Manage 2010;56:24–31.
- Fries RB, Wallace WA, Roy S, et Dermal ex- cisional wound healing in pigs following treat- ment with topically applied pure oxygen. Mutat Res 2005;579:172–181.
- Gordillo GM, Roy S, Khanna S, et Topical ox- ygen therapy induces vascular endothelial growth factor expression and improves closure of clini- cally presented chronic wounds. Clin Exp Phar- macol Physiol 2008;35:957–964.
- Kalliainen LK, Gordillo GM, Schlanger R, et Topical oxygen as an adjunct to wound healing: a clinical case series. Pathophysiology 2003;9: 81–87.
- Gordillo GM, Sen Evidence-based recom- mendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. Int J Low Extrem Wounds 2009;8:105–111.
- Hirsh F, Berlin SJ, Holtz Transdermal oxygen delivery to diabetic wounds: a report of 6 cases. Adv Skin Wound Care 2009;22:20–24.
- Sen CK, Khanna S, Gordillo G, et Oxygen, ox- idants, and antioxidants in wound healing: an emerging paradigm. Ann N Y Acad Sci 2002;957: 239–249.
- Nataraj M, Maiya AG, Karkada G, et al. Applica- tion of topical oxygen therapy in healing dynamics of diabetic foot ulcers—a systematic review. Rev Diabet Stud 2019;15:74–82.
- Thanigaimani S, Singh T, Golledge J. Topical ox- ygen therapy for diabetes-related foot ulcers: a systematic review and meta-analysis. Diabet Med 2021;38:e14585.
- Connaghan F, Avsar P, Patton D, et Impact of topical oxygen therapy on diabetic foot ulcer healing rates: a systematic review. J Wound Care 2021;30:823–829.
- Moher D, Shamseer L, Clarke M, et Preferred reporting items for systematic review and meta- analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1.
- Sterne JAC, Savovic´ J, Page MJ, et RoB 2: a revised tool for assessing risk of bias in rando- mised trials. BMJ 2019;366:l4898.
- Cro S, Morris TP, Kenward MG, et al. Sensitivity analysis for clinical trials with missing continuous outcome data using controlled multiple imputa- tion: a practical Stat Med 2020;39:2815– 2842.
- Siemieniuk R, Guyatt G. What is GRADE? BMJ Best Practice. https://bestpractice.bmj.com/info/ us/toolkit/learn-ebm/what-is-grade/ (last accessed February 2, 2022).
- Neyerlin KC, Gasteiger HA, Mittelsteadt CK, et al. Effect of relative humidity on oxygen reduction kinetics in a J Electrochem Soc 2005;152:A1073.
- Driver VR, Couch KS, Eckert KA, et The impact of the SARS-CoV-2 pandemic on the management of chronic limb-threatening ischemia and wound care. Wound Repair Regen 2022;30:7–23.
- Kaufman H, Gurevich M, Tamir E, et Topical oxygen therapy used to improve wound healing in a large retrospective study of wounds of mixed aetiology. Wounds Int 2021;12:63–68.
- Yellin JI, Gaebler JA, Zhou FF, et al. Reduced hospitalizations and amputations in patients with diabetic foot ulcers treated with cyclical pressurized topical wound oxygen therapy: real-world Adv Wound Care (New Rochelle) 2021. [Epub ahead of print]; DOI: 10.1089/wound.2021.0118.
- S. Food and Drug Administration. Guidance for Industry: Chronic Cutaneous Ulcer and Burn Wounds–Developing Products for Treatment, 2006. www.fda.gov/downloads/drugs/guidancecompliance regulatoryinformation/guidances/ucm071324.pdf (last accessed February 2, 2022).
Adjunct Intermittent Topical Oxygen Therapy Promotes Closure in Calciphylaxis Wounds Laurin Mejia, Ph.D., PA-C, CWS1 , Karin Zachow, MD, CWS 1 1 Bruce W Carter VA Medical Center, Miami, FL.
Introduction: Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare disorder that presents with painful, necrotic, ischemic skin and tissue lesions resulting from reduced blood flow. Most often noted in patients with end-stage renal disease (ESRD) who are undergoing hemodialysis, it is highly lethal and poorly understood. While there is no recognized standard of care for treatment, sodium thiosulfate (STS) injections and hyperbaric oxygen therapy (HBOT) are often trialed in addition to standard evidence-based wound care. Methods: A 64-year old male patient with ESRD, on hemodialysis (HD) 3 times weekly, presented with multiple large, necrotic, painful, eschar-covered wounds to his lower extremities in the setting of significant edema, present for 5-months. The wounds were previously diagnosed as calciphylaxis by punch biopsy. The patient did not tolerate intralesional STS injections or compression garments secondary to pain, and refused HBOT due to time constraints from his thrice weekly HD. The patient agreed to daily Intermittent Topical Oxygen Therapy (ITOT), in which he applied a sleeve over his lower legs with an occlusive seal that filled with hyper concentrated oxygen for 90-minutes daily. The ITOT was an adjunctive therapy, enabling the wound care team to continue applying and revising primary dressing plans throughout the treatment course, which included sharp debridement every 1-2 weeks, with antimicrobial absorbent primary and secondary dressings changed every 2-3 days. Primary and secondary dressings were not removed during ITOT therapy. Results: The patient reported decreased wound pain, and all wounds were completely reepithelialized after 118 days. The patient continued applying the ITOT daily, and at last follow-up on day 366, the wounds remained closed with no recurrence or new lesions. Discussion: Calciphylaxis continues to present a devastating and difficult-to-treat wound disorder. These results demonstrate a safe and user-friendly adjunct therapy that can supplement evidence-driven wound care in devastating cases of calciphylaxis, without disrupting basic wound care goals such as debridement and bioburden management. As the mechanism of action in topical oxygen and hyperbaric oxygen diverges, these results support further investigation to determine if ITOT provides a basis for which treatment can be built upon in calciphylaxis patients.
Calciphylaxis is a rare, dangerous, and poorly understood condition that results in painful, ischemic, necrotic skin lesions. Sometimes, pain will precede these lesions. This most commonly occurs in patients with end stage renal disease (ESRD) on hemodialysis, however, exceptional cases do occur in patients without renal disease. Calciphylaxis has a high rate of mortality, ranging 40-80% in the literature1 , and death is mostly caused by secondary infection. The eschar-covered lesions are a result of ischemia caused by calcification, fibrosis, and thrombus formation in the arterioles and capillaries of the dermis and subcutaneous tissue2 . Diagnosis is typically clinical, however biopsy findings can confirm diagnosis and include arteriolar calcification, subintimal fibrosis, and thrombotic occlusion, often requiring special stains such as von Kossa or Alizarin red3 . Some variables that are thought to contribute to vessel calcification in calciphylaxis include comorbid conditions including autoimmune disease and malignancy, chronic kidney disease-mineral bone disorder, hyperparathyroidism, vitamin D administration, irregularities in calcium, phosphate, medication regimen, inhibitors of vascular calcification, and chronic inflammation. Treatments targeting these features will sometimes benefit patients, however there are still no definitive guidelines for calciphylaxis treatment. Typically, the initial approach includes pain control, wound care, and managing risk factors. Other common components of treatment include sodium thiosulfate, parathyroidectomy, surgical debridement, and hyperbaric oxygen therapy (HBOT).
Oxygen and Wound Healing
Oxygen is a critical component that is required during all phases of wound healing 4 . In HBOT sessions, patients breath in concentrated, 100% oxygen at high pressures 4 , increasing dissolved oxygen in the plasma and thereby increasing oxygen delivery to the wound. Wound HBOT is typically prescribed daily for 30 minutes or more, for at least 3 weeks. HBOT is currently considered second-line for recalcitrant calciphylaxis. High cost and frequency of treatments create obstacles for patients, especially those already attending thrice weekly hemodialysis. Furthermore, there are numerous absolute and relative contraindications to HBOT, including but not limited to untreated pneumothorax, COPD, incompatible implanted devices, seizure disorders, eustachian tube dysfunction, claustrophobia, and insulin-dependent diabetes 5 . Alternatively, intermittent Topical Oxygen Therapy (ITOT) provides an excellent option for oxygen therapy that is effective, more affordable, and accessible. This is a portable product that the patient operates independently, in their own home, recommended 90 minutes daily, five times a week. During the therapy, the patient applies a patch or sleeve over the wound. The patch or sleeve connects to a small oxygen concentrator that concentrates oxygen from air, an oxygen tank is not required. The concentrated oxygen fills the patch or sleeve, delivering oxygen via non-contact, adjustable cyclical compression. In cases with significant pain, the compression firmness can be reduced and adjusted as pain improves. Studies show that the partial pressure of oxygen in the wound tissue increased by 10-fold after only 4 minutes of treatment. Furthermore, wound recurrence was significantly reduced with continued use of the ITOT after wound closure 6 . This therapy only requires a gas-permeable dressing, so the oxygen sleeve or patch can be applied directly over intact dressings with no need for dressing change or wound care at the time of daily therapy.
ITOT provides a user friendly, effective, and accessible wound oxygen therapy. Here, we demonstrate that employment of ITOT as an adjunctive therapy for calciphylaxis wound treatment, in a patient who declined HBOT, contributed to swift, successful wound closure and pain relief. Continued use of ITOT after wound closure also has prevented recurrence in this patient 1+ year after wound closure. Continued exploration of ITOT in additional cases of calciphylaxis and non-uremic calciphylaxis, as well as other ischemic wound etiologies is warranted. Furthermore, as the mechanisms of ITOT is independent of oxygen intake in the lungs, it would provide valuable information to explore the efficacy of ITOT vs HBOT for wound therapy in patients with gas-exchange diseases such as COPD or asthma, which are relative contraindications in HBOT
We would like to thank the invaluable members of the Miami VA Wound Clinic, Dr. Matthew Hardy, MD, CWSP, Davis Cheung, RN, CWS, Theresa Hernandez, RN, CWS, Pedro Claverol-Gil, RN, and Immaculata Sablan, LPN. We would also like to thank our help representatives of Advanced Oxygen Therapy Inc. (AOTI).
1. Kodumudi, V., Jeha, G.M., Mydlo, N. et al. Management of Cutaneous Calciphylaxis. Adv Ther 37, 4797– 4807 (2020). https://doi.org/10.1007/s12325-020-01504-w 2. McCarthy JT, El-Azhary RA, Patzelt MT, Weaver AL, Albright RC, Bridges AD, Claus PL, Davis MD, Dillon JJ, El-Zoghby ZM, Hickson LJ, Kumar R, McBane RD, McCarthy-Fruin KA, McEvoy MT, Pittelkow MR, Wetter DA, Williams AW. Survival, Risk Factors, and Effect of Treatment in 101 Patients With Calciphylaxis. Mayo Clin Proc. 2016 Oct;91(10):1384-1394. doi: 10.1016/j.mayocp.2016.06.025. PMID: 27712637. 3. Chen TY, Lehman JS, Gibson LE, Lohse CM, El-Azhary RA. Histopathology of Calciphylaxis: Cohort Study With Clinical Correlations. Am J Dermatopathol. 2017 Nov;39(11):795-802. doi: 10.1097/DAD.0000000000000824. PMID: 29053546. 4. Thackham, J.A., McElwain, D.S. and Long, R.J. (2008), The use of hyperbaric oxygen therapy to treat chronic wounds: A review. Wound Repair and Regeneration, 16: 321-330. https://doi.org/10.1111/j.1524- 475X.2008.00372.x 5. Lam, Gretl BA; Fontaine, Rocky CHT; Ross, Frank L. MD; Chiu, Ernest S. MD Hyperbaric Oxygen Therapy: Exploring the Clinical Evidence, Advances in Skin & Wound Care: April 2017 – Volume 30 – Issue 4 – p 181- 190 doi: 10.1097/01.ASW.0000513089.75457.22 6. Frykberg RG, Franks PJ, Edmonds M, Brantley JN, Téot L, Wild T, Garoufalis MG, Lee AM, Thompson JA, Reach G, Dove CR, Lachgar K, Grotemeyer D, Renton SC; TWO2 Study Group. A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study. Diabetes Care. 2020 Mar;43(3):616-624. doi: 10.2337/dc19-0476. Epub 2019 Oct 16. PMID: 31619393.
Topical oxygen therapy in the patient of chronic diabetic leg & foot ulcer
V. Saxena, R. Saxena, A.P.S. Suri, G.D. Ramchandani, S.S. Dariya, S. Suri, R. Ramchandani, G. Mathur, G. Suri, K.K. Pareek, P. Saxena
Topical oxygen therapy in the patient of chronic diabetic leg & foot ulcer . 1 2 Santokba Durlabhji Memorial Hospital, Jr. Resident – Department of Medicine, Jaipur, India. Saxena Diabetes Care Centre, Director Department of Diabetology 3 4 & Foot Care, Ajmer, India. Director Diabetic foot care & wound care centre-, Diabetic Foot Care, New Delhi, India. Director Ramchandani Diabetes Clinic, 5 6 Department of Diabetology, Kota, India. SMS Hospital, Consultant Physician & Diabetologist, Jaipur, India. Holy Help Hospital, Consulting Physician, Hisar, India 7 8 9 IMS & SUM Hospital, Resident Department Of medicine, Bhuvneshwar, India. S.N.Pareek Memorial Hospital, Honorary Physician-, Kota, India. Diabetic foot 10 care & wound care centre-, Diabetic Foot care, New Delhi, India. S.N.Pareek Memorial Hospital, Director & in charge Department of 11 Medicine, Kota, India. SMS Medical College & Hospital, Sr. Professor- Department of Medicine, Jaipur, India..
Aim of the study was to heal chronic non healing DFU with Topical oxygen delivery device with standard Care.
Diabetes mellitus is a metabolic disorder associated with so many complications including diabetic foot syndrome. International Diabetes Federation (IDF) 2021 data reveals that globally 537 million people are suffering from disease & estimated to reach up to 783 million in 2045. In Indian subcontinent (SEA) about 90 million people in the year 2021 estimated to reach 152 million in the year 2045.  Diabetic foot syndrome characterized by infection; soft tissue damage & diabetic foot ulcer (DFU) due to diabetic peripheral neuropathy . The prevalence of DFU in type 2 diabetes is 6.4% globally, with 6.38% in South India, and 14.30% in North India. DFU increases risk for lower extremity amputations  Many surgical and non-surgical treatments are available to tackle this problem including wound debridement, skin grafting, revascularization, frequent dressing of the wound site with offloading of foot and ultimately amputation in very severe cases to save the life of patient. Primary factor enhancing wound healing process, is oxygen. Hyperbaric oxygen therapy shown benefits in wound healing with adverse effect oxygen toxicity & barotrauma. Topical oxygen therapy (TOT) are safer alternative. It bypasses oxygen transport system & creating oxygen-rich wound bed environment & improved pH levels, helps to cure infection, enhance wound healing & rate of wound closure in chronic non-healing DFUs 
The 15-patient included in the study were between 45 to 64 years with chronic non-healing diabetic foot ulcer (duration more than 3 months &Texas grade -1 to grade IV) between November 2021 to May 2022. They received topical oxygen therapy (TOT) from two centres from North India with oxygen concentrator through the device named oxygen boot. Other group include 16 patients treated as standard care of diabetic foot management named standard care group. The primary outcome measure assessed was the rate of wound healing or wound closure. After opening the dressing from the wound, topical oxygen therapy given by oxygen boot, lasted for 90 minutes & oxygen given at 1 atmospheric th pressure through oxygen concentrator for six weeks’ time with off on every 7 day. TOT given on outpatient basis or at the home of patient. Standard best practice of wound care management followed to all patients. Standard best practice of wound care like dressing with hydro gel and calcium alginate sheaths was done to all wounds after debridment. Offloading done with standard posterior POP slab. Empirical therapy of antibiotics was advised to all patients according to culture & sensitivity reports.- All wounds included in study were Texas grade -1 to grade IV st th-In each patient’s follow-up of culture & sensitivity done on day 1, 7& 21.-Blood perfusion was normal in all patient, ABI was normal i.e.between 0.8-1.2-Neurological assessment by VPT, severe diabetic peripheral neuropathy presents i.e., VPT threshold between 42 to 45-Creatinine was between 1.2 to 2.6 mg%.-All patient on anti-platelets therapy advised Rivaroxaban 2.5 mg + aspirin 75 mg-All patients on OHA with basal insulin or Mixtared. Data were prospectively obtained on wound size, duration of Ulcer, glycaemic control, neuropathy assessment by vibration perception test (VPT), vascular assessment by ABI & colour Doppler, renal function etc.
In TOT group Wound granulated in 4 weeks and reduction in bio film by 1weak.Smell of wound reduced after 4-5 sitting with size of wound reduced by more than 50 % of surface area by 4 to 6 weeks & complete healing of wound in 60 % of patient in the study time frame within 8 to 10 weeks. 4 patient in 10 to 12 weeks & 2 patients require skin grafting after coming of granulation. Healing time is about 2 to 4 weeks early then standard group.
The application of topical oxygen therapy (TOT) in patients with Texas grade I to 4 of chronic diabetic foot ulcers improves wound healing.In Grade 1 & 2 complete healing of ulcer & in higher grade reduction of size up[to 50 to 80 % along with depth of ulcer in study time frame i.e. 8 to 10 weeks. The topical oxygen therapy represents a potentially exciting new technology to decrease healing time and to promote wound closure in patients with nonhealing DFUs. More studies are needed to determine the benefits of topical oxygen, but our current results are extremely promising. Conflict of Interest: I have no potential conflict of interest to disclose.
CONFLICT OF INTEREST: NO CONFLICT OF INTEREST
References: 1. IDF diabetes atlas – 10 edition 2021.Across the globe http://www.diabetesatlas.org/across-the-globe.html. 2.Jakosz N. IWGDF guidelines on the prevention and management of diabetic foot disease (book review). Wound practice and research. Wound Repair Regen. 2019; 27(3):144. [Google Scholar 3.Shahi SK, Kumar A, Kumar S, Singh SK, Gupta SK, Singh TB. Prevalence of diabetic foot ulcer and associated risk factors in diabetic patients from North India. J Diabet Foot Compl. 2012;4(3):83–91. [Google Scholar] 4.Demling RH. Nutrition, anabolism, and the wound healing process: anverview. Eplasty. 2009;9:e9. [PMC free article] [PubMed] [Google Scholar