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Abstract
Introduction Diabetic foot ulcer (DFU), one of the most common and serious consequences of diabetes, affects many individuals and often leads to amputation, death and other disastrous outcomes. Diabetic foot ulcers have a relatively poor response to therapy, which increases the likelihood of recurrence. Cold atmospheric plasma (CAP) therapy is an emerging treatment method for DFU that can reduce bacterial loads and speed up the healing of chronic wounds. Although some studies have reported that CAP could improve the wound healing speed compared with conventional traditional therapy, the samples in these studies are small and not sufficiently representative. The purpose of the current systematic review and meta-analysis is to evaluate the effectiveness and safety of CAP in DFU treatment and provide a scientific basis for its clinical application.
Methods and analysis The following databases will be searched: Wanfang, China Biology and Medicine CD, Embase, PubMed and The Cochrane Library. We will retrieve publications, conference documents, current trials and internal reports written in English or Chinese related to the effect of CAP therapy on wound healing in patients with diabetic foot ulcers up to 30 June 2022. The selected articles will be read independently by two reviewers, and valid information such as first author, publication date and outcome indicators will be extracted. Researchers will also assess the quality of the literature using the Cochrane risk-of-bias tool 2. RevMan 5.3.5, EndNote X7 and STATA V.13.0 will be used for data analysis.
Ethics and dissemination No ethical review is necessary for this systematic review because it is based on previously published data and does not include patient intervention. A peer-reviewed publication will publish the findings of this investigation.
- Diabetic foot
- General diabetes
- Information management
Data availability statement
Data are available in a public, open access repository.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Strengths and limitations of this study
This study presents a thorough meta-analysis of the effect of cold atmospheric plasma therapy on wound healing in patients with diabetic foot ulcers for the first time.
Subgroup and sensitivity analyses will be used to explore sources of heterogeneity.
There may be a language bias because we will only include articles that were published in English and Chinese.
Introduction
According to the International Diabetes Federation, approximately 537 million adults (aged 20–79) worldwide suffered from diabetes in 2021, with approximately 6.7 million people dying as a result of diabetes or its complications.1 Diabetic foot ulcer (DFU) is one of the most devastating consequences of diabetes and a substantial contributor to disability. Studies have reported that the lifetime prevalence of DFUs is 19%–34%, and the recurrence rate of ulcers following wound healing is as high as 40%.2 Patients with DFUs have a 2.5-fold higher 5-year mortality risk than patients with diabetes without foot ulcers, and the 5-year mortality rate after amputation is more than 70%.2 The cost of DFU treatment is close to the total cost of other diabetes complications,3 which places a great economic burden on the patient’s family and society.4
Cold atmospheric plasma (CAP) is a novel therapeutic technique that has been reported to have a positive impact on wound healing.5 6 Preliminary clinical trials suggested that CAP can decrease bacterial load and accelerate the healing of chronic wounds without causing any obvious negative effects on healthy tissues.7–11 Moreover, research on diabetes-affected animals indicated that CAP therapy can hasten wound healing, result in epidermis formation, neovascularisation and cell proliferation, and boost transforming growth factor release.12
Studies on the treatment of diabetic foot with CAP are gaining traction.12–15 Amini MR claimed that applying CAP directly to diabetic foot can minimise the size of the wounds.13 A prospective, randomised, patient-blinded clinical trial designed by Jonas Hiller15 demonstrated that CAP-mediated stimulation of granulation vascularisation and re-epithelialisation in the diabetic foot appeared to be significantly dependent on activation of critical growth factors, such as FGF-2 and VEGF-A, and interleukins. However, the sample size of these studies is limited and not sufficiently representative. There is still a lack of reliable evidence to support the efficacy of CAP in the treatment of diabetic foot ulcers. This study aims to examine the effect of CAP therapy on wound healing in patients with diabetic foot ulcers and provide a basis for clinical application.
Methods
Search strategy
We will search the PubMed, Cochrane Library, MEDLINE, Embase, Ovid and Chinese Biological Medicine databases for relevant randomised controlled trials (RCTs) (up to 30 June 2022). After retrieving the articles, we will manually review the reference lists to compile a thorough collection of RCTs on the use of CAP therapy for the treatment of DFUs.
The following search terms will be used: ‘Diabetic foot’, ‘diabetic feet’, ‘foot ulcer, diabetic’, ‘foot, diabetic’, ‘feet, diabetic’, ‘cold atmospheric plasma therapy’, ‘Cold atmospheric plasma’ and ‘CAP’.
A draft of our retrieval strategy has been provided as online supplemental file 1 (as an example, using PubMed).
Supplemental material
Selection criteria
The inclusion criteria will be as follows: (1) RCT that assessed the effectiveness of CAP versus conventional therapy in patients with diabetes; (2) the included patients were all patients with diabetes with chronic foot ulcer and surgical foot trauma; (3) literature or research published in Chinese or English and (4) outcomes included ulcer healing time, ulcer size change, formation of granulation tissue, quality of life, patient satisfaction, resource use, amputation rate and treatment-related side effects. The primary outcome is the rate of complete ulcer healing and complete wound closure, which is defined as 100% re-epithelialisation without the need for drainage or dressing (oedema, infection, pain, bleeding).
The exclusion criteria will be as follows: (1) non-RCTs; (2) CAP was not evaluated against conventional therapy and (3) studies that were not human studies (ie, vitro or animal).
Patient and public involvement
This study involves no patients or members of the public in its conception, execution, or reporting.
Manual search for more information
We will manually search for conference papers, ongoing legal cases, internal reports and other papers. If the information in the post is not clear enough, we will make an effort to contact the authors for further details.
Collection and analysis of data
Selection of studies
To determine whether the references will ultimately be used in the research, two reviewers will independently screen the title of each reference. In the screening process, Endnote X7 document management software will be used. The author will be contacted if more details are needed. If there are differing viewpoints, another reviewer will make the final decision. We will also record the reasons for the exclusion of the literature. The PRISMA flowchart (online supplemental file 2) describes the selection method in detail.
Supplemental material
Extraction and handling of data
The following data will be extracted from the included studies by two independent reviewers: first author, publication date, country of publication, research type, sample size and outcome measures. If research data are missing, we will make an effort to contact the relevant author to request additional study data. Disagreements between reviewers will be resolved by discussion.
Assessment of risk of bias
Two researchers will read the included articles independently, and the latest version of the Cochrane risk-of-bias tool 2 (ROB 2)16 will be used to assess the bias of each involved study. According to the ROB 2, bias will be assessed across five distinct domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome and selection of the reported results. Based on the above five domains, the risk of bias will be judged as low, high or some concerns, and the overall risk of bias of the assessment results will be predicted. Disagreements among the two researchers will finally be resolved by consulting the corresponding author. If an RCT has ‘some concerns’ about the risk of bias in three or more areas, it will be excluded from the systematic review due to the high risk of bias.
Data synthesis and analysis
Once the necessary information is extracted, reviewers will determine whether a meta-analysis is feasible. Review manager was used to analyse and synthesise data. The 95% CI will be used, and mean differences will be calculated for continuous variables. For dichotomous outcomes, the relative risk will be calculated. The χ2 and I2 tests will be used to evaluate the heterogeneity of the data. Fixed effects models will be employed for analysis when heterogeneity is not significant (p≥0.10, I2≤50%), while random effects models will be used when heterogeneity is significant (I2>50% or p<0.10).
Missing data
If there are missing research data, we will make an effort to get in touch with the relevant author to request additional information. We will endeavour to use the data we have for our analysis and take measures to address the potential effects of missing data if the authors cannot be reached or further information cannot be acquired.
Assessment of heterogeneity
The χ2 and I2 tests will be used to evaluate the heterogeneity of the data. Fixed-effects models will be used when the heterogeneity between studies is minimal (I2<50% and p>0.1); otherwise, random effects models will be employed, and subgroup analysis or meta-regression analysis will be performed to investigate the source of heterogeneity.
Evaluation of publication bias
Funnel plots and STATA V.13.0 will be used to assess the publication bias of the included articles. In studies with at least 10 trials, funnel plots were used for publication bias assessment, whereas in studies with fewer than 10 trials, STATA V.13.0 will be used for publication bias assessment.
Subgroup analysis
If there is significant heterogeneity among the included studies, subgroup analysis will be used to explore the sources of heterogeneity. We will divide the data into different units based on the different experimental design schemes or the specific baseline of the included people (such as wound size, bacterial clearance rate and different observation time) and then compare them across subgroups to explore factors that might influence the results.
Sensitivity analysis
To determine the robustness of the conclusions, a sensitivity analysis will be conducted. We will exclude high deviation risk studies, missing data studies and outliers and reanalyse whether the conclusions have changed to check the robustness of the conclusions of the systematic review.
Discussion
One of the most frequent and challenging issues for patients with diabetic foot ulcers is difficulty in wound healing. Repeated infections and long-term non-healing wounds will worsen public health and cause significant economic losses.17 In recent years, plasma medicine has developed into an innovative field of medical research. CAP is one of the best plasma sources for the characterisation of living surfaces and has been found to have anti-inflammatory, antimicrobial and antitumour effects.18 CAP can promote wound healing through its specific mode of action without causing damage to human tissues,19 accelerate wound healing in diabetic animals, lead to epidermal formation, neovascularisation and cell proliferation and increase the release of transforming growth factor.12 A team of researchers claimed that CAP treatment can accelerate the wound healing of diabetic foot ulcers by regulating the level of inflammatory factors and bacterial load,13 while another study claimed that CAP is an effective treatment option for diabetic foot ulcers in terms of wound reduction and antibacterial effects.20
Although some studies have indicated that CAP therapy could have positive benefits on wound healing and bacterial decrease in diabetic foot, the sample size of these studies was limited and not sufficiently representative. The results of this research will present a scientific basis for the treatment of diabetic foot with CAP therapy. Bias and significant heterogeneity could emerge as the investigation progresses; therefore, we will conduct subgroup analysis and sensitivity analysis where appropriate to explore the sources of heterogeneity as much as possible and ensure the reliability of the results.
Data availability statement
Data are available in a public, open access repository.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors ZL: writing—original draft preparation and review—editing. JY, QZ, SF and XQ: writing—review. QC: supervision and review.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.