A META-ANALYSIS: THE UTILIZATION OF NEGATIVE PRESSURE WOUND THERAPY IN DIABETIC FOOT ULCERS

ABSTRACT


INTRODUCTION
Diabetes mellitus has a global prevalence of more than 500 million individuals.In the year 2019, diabetes was the primary reason for 1.5 million fatalities, and 48% of all diabetes-related deaths took place prior to individuals reaching the age of 70 years.It is associated with a significant consequence known as diabetic foot ulcers or DFUs.DFUs exhibit a significant degree of chronicity and morbidity, frequently presenting with complications such as infections that can progress to osteomyelitis and necessitate amputations.Comorbidities are associated with a decline in immune function and the ability to repair wounds. 1,2he five-year survival rate for amputations connected to diabetes is 40%, which exceeds the mortality rate observed in numerous cancer cases.Diabetic foot is a prevalent complication of diabetes mellitus that arises from elevated blood glucose levels.This condition manifests as peripheral nerve and vascular impairments, leading to dry and irritated skin on the foot.Ultimately, this can progress to the formation of non-healing ulcers, significantly diminishing the quality of life for affected individuals.][5][6][7][8][9] Negative pressure wound therapy (NPWT) is a therapeutic technique that can be utilized to manage superficial wounds and promote the removal of exudate from deep wounds.The intervention can efficiently remove necrotic tissue and wound fluids, promote granulation tissue formation, reduce bacterial infection, and accelerate the wound healing process. 10egative Pressure Wound Therapy (NPWT) is a mechanical device consisting of a tube connected to a suction apparatus.The present technique induces a subatmospheric pressure gradient between the site of injury and the surrounding environment, thereby promoting the elimination of exudate and accelerating the wound-healing process. 11he previous case report has investigated NPWT successfully as a wound healing treatment for diabetic foot.Negative Pressure Wound Therapy (NPWT) has proven to be a highly effective treatment for improving skin survival and accelerating wound healing across various wound types.NPWT's mechanisms are diverse, with a biological role that includes macrodeformation, micro-deformation, fluid removal, wound contraction promotion, and the creation of a warm, moist, and enclosed wound environment.It also supports angiogenesis, granulation tissue growth, and inhibits bacterial growth These advantages result in reduced dressing change frequency, minimized wound exposure, lower infection risk, optimal conditions for subsequent skin transplantation, and an increased success rate for skin graft procedures. 12he author intends to conduct a systematic review and meta-analysis to further explore aspects related to wound healing rate, the rate of amputations, and the occurrence of adverse events following the application of NPWT for diabetic foot ulcers.

METHODS
The search platforms chosen for this investigation were Embase, Pubmed, and the Cochrane Library databases.The search keywords utilized were "negative pressure wound therapy" OR "vacuum-assisted closure therapy," OR "diabetes" OR "diabetic foot," OR "chronic wound" OR "morbidity" OR "Quality-adjusted life year." The inclusion criteria in the study were as follows: The researchers conducted a systematic search of databases, resulting in the identification of relevant publications that were subsequently compiled by two scholars.Duplicate articles were eliminated, and an initial screening phase involved the assessment of titles and abstracts of the publications.
Subsequently, a more thorough review of the complete texts was performed, and the papers were categorized based on predetermined criteria for inclusion or exclusion.In cases where the researchers did not reach a consensus during the screening phase, an impartial third party was consulted to assist in resolving any disagreements.The dataset comprised a wide range of parameters obtained through extensive text analysis, including factors such as authorship, publication date, the number of patients who received the intervention, gender distribution, levels of glycosylated hemoglobin, duration of the intervention, age, body mass index (BMI), location and size of the ulcers, and the duration of followup.The data underwent a transformation process to make it more suitable for subsequent synthesis.For instance, metrics that were initially expressed as a proportion of the entire body of literature were converted into specific patient counts.
The synthesis was conducted using RevMan version 5.4 and R statistical software.The statistical measures employed for reporting continuous variables were the weighted mean difference (WMD) and the 95% confidence interval (CI).Binary variables, on the other hand, were reported using the odds ratio (OR) and the 95% CI.The statistical data was displayed using a forest plot, with a significance level of α=0.05.The examination of literature heterogeneity was conducted using I2 analysis and Q calibration.The heterogeneity in the data was indicated by an I 2 value greater than 25% or a significant P value.The random effects model analysis was employed when heterogeneity was seen among studies.
On the other hand, in situations where there was an absence of heterogeneity.In order to address the potential presence of variability in the literature, a sensitivity analysis was performed utilizing the exclusion strategy.This involved carefully excluding each study one by one.

RESULTS
The current study encompassed an initial assessment of 291 publications and subsequently underwent a sequence of procedures, which included confirming duplication, conducting primary screening, and re-screening.Ultimately, seven papers were deemed suitable for inclusion in the research, with a combined sample size of 890 participants.The screening process is visually represented in Figure 1.

Figure 1. PRISMA Flow Chart
The critical characteristics of the seven randomized controlled trials (RCTs) in this study are succinctly summarized in Table 1.The participants' age span ranged from 50 to 69 years.The duration of the interventions varied from one week to 56 days.Furthermore, the observation period's duration exhibited variability, with a minimum of two weeks and a maximum of six months.The tabulated data can be found in Table 1.This study focused on the investigation of a meta-analysis conducted in multiple nations.Two of the studies took place in Europe, with one conducted in Poland and the other in Germany.Three research investigations were carried out in India, while one study was performed in Pakistan, and an additional study was undertaken in New Zealand.The main treatment intervention applied to the participants in To gather data on patient amputation rates, a set of four studies was conducted.The analysis revealed no statistically significant heterogeneity among the studies included in the research.The findings indicate that there is no statistically significant reduction in the amputation rate with the use of NPWT (Odds Ratio [OR] = 0.01, 95% Confidence Interval [CI]: 0.00 to 0.02, p = 0.81).
this study was Negative Pressure Wound Treatment (NPWT).In each of the research studies, the control group received standard wound care, which included regular topical dressing, traditional wound dressing, and SWMC.

Wound Healing Rate
After completing a comprehensive review of the available literature, it was discovered that four studies have provided data on the markers of wound healing rate displayed by the participants.The existing body of research provides evidence of statistical heterogeneity, as evidenced by an odds ratio (OR) of 0.77 95% (CI) [0.65, 0.90], p=0.01, and an I 2 value of 73%, which means the result shows the statistically significant of NPWT treatment for DFUs.The results suggest that the patient had a positive impact on wound healing after the utilization of NPWT.

Incidence of Adverse Events
Two investigations have successfully identified the variables that exhibit associations with the incidence rate of adverse patient events.The conducted studies did not exhibit substantial statistical heterogeneity, as indicated by an I 2 value of 0% and a P-value of 0.23.The results obtained from the comprehensive analysis using a random effect model (odds ratio [OR] = 0.01, 95% [CI]: 0.00 to 0.04), p=0.23.The result shows no statistical significance of NPWT in reducing incident adverse events.While, The psychological impact of diabetic foot issues can be profound.It often results in emotional distress, anxiety, and depression for individuals dealing with these complications.The fear of amputation, pain, and the challenges of managing the condition can take a toll on a person's mental well-being.Additionally, the lifestyle changes required to manage diabetic foot problems, such as restricted mobility and potential dependency on others for care, can lead to feelings of frustration and a reduced quality of life.The psychological impact of diabetic foot issues should not be underestimated, and addressing the emotional well-being of individuals is an important aspect of their overall care.][22][23] In patients diagnosed with diabetes, elevated blood glucose levels give rise to atypical cell proliferation, impairment of vascular endothelial cells, alterations in the micro-environment, and an inflammatory reaction within the peripheral nerves and blood vessels.Several factors are crucial in the complex healing process of diabetic foot ulcers (DFU). 24,20 e primary approaches for treating diabetic foot ulcers involve surgical removal of damaged tissue, alleviating pressure on weight-bearing areas, addressing lower extremity ischemia and foot infections, and promptly referring patients to multidisciplinary care, constituting the initial treatment protocols. 20iabetic Foot Ulcer (DFU) is considered one of the most concerning complications of type 2 diabetes mellitus.DFU is a condition affecting the feet of diabetic individuals and is characterized by sensory, motor, autonomic neuropathy, as well as macrovascular and microvascular issues.Several factors contribute to the development of DFU, including elevated blood sugar levels, neuropathy, joint limitations, and deformities.The diagnostic process for DFU typically starts with a medical history, which includes details about previous ulcers, amputations, injuries, and the patient's diabetes history.Physical examination involves assessing vascular health, neurological and musculoskeletal function, as well as evaluating the presence of any infections.Effective management of DFU often requires a multidisciplinary approach. 25abetic foot ulcers are a prevalent and perilous manifestation of diabetes, arising from a combination of causes, including repetitive stress, inadequate glucose management, and neuropathy.Associated immunological deficits are known to result in the swift development of deep-tissue infections via the formation of skin ulcers.The diagnostic process encompasses clinical assessment, culture and sensitivity testing, radiography, and imaging techniques.The comprehensive management of diabetic foot ulcers (DFU) encompasses many interventions, such as antibiotic therapy, surgical debridement, meticulous wound care, and metabolic optimization. 26,27uscle flaps are commonly used to reconstruct infected wounds due to their ability to enhance vascular perfusion and fill empty spaces.However, The utilization of muscle flaps to address large diabetic foot ulcers (DFUs) presents challenges in individuals with limited blood circulation in their lower limbs. 28Complications of diabetic foot ulcer commonly connected with muscle flaps include hematoma formation, wound dehiscence, flap loss seroma development, fat necrosis, scarring, and delayed healing, rendering them less preferable in specific scenarios. 29The conventional method for managing foot wounds often entails the utilization of moistto-dry dressings and the implementation of skin grafts.Nevertheless, This method has certain disadvantages, including a prolonged healing period, an elevated risk of infections, heightened levels of discomfort, and difficulties in promoting the optimal formation of granulation tissue when tendons, bones, or implants are exposed. 30ertain surgeons may opt for extracting extensor tendons and employ methods such as negative pressure wound therapy (NPWT) or moist dressings to facilitate the formation of granulation tissue, which might result in enduring impairment and deformation of the foot. 30,31egative pressure wound therapy (NPWT) is a therapeutic approach that utilizes differential internal and exterior pressures to promote the removal of deeply buried necrotic tissue and wound fluids.This strategy has been shown to successfully reduce the occurrence of wound infection and promote a favorable moist wound environment, hence facilitating wound healing. 32However, the signs presented regarding the repercussions of this phenomenon in clinical practice demonstrate a significant degree of variability . 33 In the previous study, it was stated that Negative Pressure Wound Therapy (NPWT) outperforms traditional methods in the treatment of diabetic foot ulcers.NPWT not only reduces the time to rehospitalization but also lowers the risk of amputation or surgical removal of the diabetic foot.Despite the higher costs associated with NPWT, the approach proves to be cost-effective.It is essential to emphasize the importance of employing proper therapy techniques and selecting patients judiciously. 34nother study provided an explanation that NPWT has brought about a significant transformation in the management of challenging and persistent wounds.It also serves as an adjunct therapy for preparing wounds before surgical procedures like skin grafts and flap surgery, contributing to improved wound healing rates.

Amputation Rate
This chapter provides a comprehensive overview of the NPWT device's composition, mechanism of action, application techniques, advantages, suitable use cases, restrictions, potential side effects, and innovative developments. 35owever, it's important to note that while NPWT is a valuable tool for wound healing, it may pose challenges in treating wounds with inadequate tissue oxygenation, such as diabetic foot ulcers.NPWT can reduce tissue oxygenation in wound areas due to the external compression applied by the foam and tubing.The foot, being particularly sensitive to ischemia, and considering that diabetes often coincides with atherosclerosis, caution is necessary when applying NPWT to diabetic foot ulcers to minimize compression pressure. 35he result of this study shows the positive impact of NPWT as a promising intervention to promote the healing rate for chronic wounds such as diabetic foot ulcers with (OR) of 0.77 95% (CI) [0.65, 0.90], p=0.01.This result was supported by research from Liu et al. 36 who conducted a meta-analysis that identified 11 randomized controlled trials (RCTs) and included 1044 patients.Moreover, a significant proportion of these articles exhibited a deficiency in giving full explanations of the randomized techniques and processes.Specifically, only three studies included specific information addressing allocation concealment.The present study included nine randomized controlled trial (RCT) articles published within the past decade, which specifically examined the application of negative pressure wound therapy (NPWT). 37In the realm of wound care, conventional methodologies have involved the implementation of various dressings to facilitate and accelerate the wound healing process.However, it is imperative to recognize that these dressings tend to adhere to the wound's scab, perhaps causing harm to the formation of granulation tissue during dressing replacement.Consequently, there exists a potential for impeding the overall progress of wound healing.Numerous studies have provided evidence supporting the efficacy of Negative Pressure Wound Therapy (NPWT) in enhancing the wound microenvironment, modulating microvascular hemodynamics, mitigating wound infections, and facilitating the regeneration of endothelial cells. 38The findings of this meta-analysis revealed that the most commonly seen adverse effects during treatment were wound edema, bleeding, pain, and infection.
The results of this study suggest that the utilization of NPWT did not lead to a greater prevalence of unfavorable consequences.However, it is imperative to highlight that no statistically significant difference was seen between the two treatment regimens.The current study did not incorporate a statistical analysis of the negative pressure value employed in the Negative Pressure Wound Therapy (NPWT) approach.Numerous studies have provided evidence regarding the importance of maintaining a negative pressure range of 50-200 mmHg to manage excessive bleeding and effectively promote optimal wound healing.Moreover, accurate identification and management of infections in cases of diabetic foot infection, along with the administration of suitable antibiotic therapy, are of utmost importance. 39It is critical to prioritize the optimization of blood glucose levels as a key factor in improving wound healing and reducing the harmful effects on cellular immunity, thereby lowering susceptibility to infections. 40he study provides detailed information on the challenges and complications associated with DFUs, the diagnostic process, and various treatment methods, with a specific focus on NPWT.The study the need for further research, particularly in exploring the impact of NPWT on gene expression in diabetic patients, which can be considered a novel area of investigation.The article hints at a novel aspect by suggesting that NPWT may impact gene expression in individuals with diabetes.This potential influence on gene expression could open up new avenues for research into the underlying mechanisms of NPWT in wound healing.Future research could delve into optimizing the application of NPWT in terms of negative pressure levels.Future research could explore whether tailoring NPWT parameters to individual patient characteristics could enhance its effectiveness and to explore emerging or innovative therapeutic approaches for diabetic foot ulcers.
The limited number of studies to analyze has a possible impact on this metaanalysis's result, resulting in a potential bias.In order to conduct a thorough analysis of the effectiveness of Negative Pressure Wound Therapy (NPWT), additional samples are necessary.Additionally, a recent study has shown evidence that negative pressure wound therapy (NPWT) can impact gene expression alterations in persons diagnosed with diabetes.This discovery implies that exploring the influence of NPWT on gene expression holds potential as a fruitful area of investigation for future research within the discipline.Further research is needed to confirm this finding.

CONCLUSION
This meta-analysis aims to assess the effectiveness and safety of negative pressure wound therapy (NPWT) in managing diabetic foot ulcers (DFUs).The result of our analysis shows that NPWT has a significant effect on the healing rate.These findings of our study indicate that the application of NPWT is a viable strategy for expediting the process of wound healing in diabetic foot ulcers.NPWT can be a promising intervention for patients with diabetic foot ulcers to reduce morbidity.Nevertheless, it is imperative to meticulously manage and adjust the negative pressure value to mitigate any potential risk of bleeding in the wound.To confirm these findings, further research is needed.
(a) The study employed a randomized controlled trial (RCT) design, with a publication period spanning from 2013 to 2022.(b) The participants were diagnosed with DF.(c) The study was conducted and reported in the English language.(d) The patient had a medical procedure known as negative pressure debridement, which is also commonly referred to as vacuum negative pressure therapy.(e) The study assessed many indicators, including wound healing rate, incidence of adverse responses, and amputation rate.The criteria for exclusion were as follows: (a) Studies conducted in languages other than English.(b) Studies with a sample size of less than 10 participants.(c) Foot trauma not caused by diabetes.(d) Studies that do not include outcome measures or have incomplete data.

Figure 2 .
Figure 2. Adverse Event After Intervention

Table 1 .
Characteristics of Study