Evaluating the Role of Hyperbaric Oxygenation Therapy in Improving Diabetic Foot Ulcer Healing: A Systematic Review

Search strategy

On December 20, 2023, a search was done on three databases: PubMed, Cochrane, and ClinicalKey. The keywords used in the search were: “treatment outcome” AND “hyperbaric oxygenation” AND “diabetic foot ulcers.” No date filters were applied to any of the searches; however, language and study design filters were utilized. Only clinical trials and randomized controlled trials (RCTs) written in English were selected. Table 1 shows the details on the search strategy and its results. All results were recorded into Google Sheets, and all authors independently searched for relevant studies. Any disagreements were discussed via a presentation of the conflicting topics involving all the authors, and these were then resolved through thorough research and with scientific evidence.

Table 1.

Search strategies used in each database and results

Study eligibility criteria

Studies included in this review were clinical trials or RCTs which used HBOT to treat DFU. Since this review aimed to answer a therapeutic question, clinical trials and RCTs conducted on patients were deemed the most suitable for addressing this inquiry. Meanwhile articles written in any other language besides English were excluded to prevent any misinterpretation or misunderstanding. Additionally, other study types, and studies that did not focus on the healing of DFU using HBOT were excluded altogether.

Data extraction

The following aspects were extracted from any eligible studies: (1) author and year of publication, (2) country of origin, (3) population (total subjects, sex, age), (4) intervention (total days of treatment, specific method, pressure and time per therapy), and (5) control. As for the outcome, the following were extracted from the included studies: post-treatment ulcer condition and amputation rate from HBOT and control groups.

Critical appraisal of included studies

All included studies were appraised in accordance to the 2020 JBI Checklist for Randomized Controlled Trials [8]. This checklist has been described as a well-documented tool developed by experts, offering detailed guidance and transparency in critically appraising studies. However, one limitation of the checklist is that it lacks examples for each step and this may introduce subjectivity. Additionally, the presentation of results requires further elaboration to improve clarity [9].

Search result and study characteristics

The literature search process in all three databases yielded a grand total of 1,665 results; all these records were obtained exclusively from database sources only. Automation tools in the form of search filters in each database were used, and the application of language and study type filters resulted in a total of 1,583 records being deemed ineligible and thus removed. An additional 19 duplicate records were removed, and the resulting 63 titles and abstracts were screened. Out of these, 35 records were initially deemed eligible for further review. However, three records could not be retrieved, and upon further assessment, one study was excluded as it was still ongoing and had yet to present its final findings. Additionally, seven studies were retrospective cohorts rather than RCTs or clinical trials, nine studies discussed chronic wounds but did not focus on DFUs, three studies treated DFUs but did not use HBOT, and four studies were incomplete. After these exclusions, a final total of eight articles were included in this review. This entire process was summarized as a PRISMA flowchart in Fig. 1.

Fig. 1.

Preferred Reporting Items for Systematic Review and Meta-Analysis flowchart. Summarizing the identification process of studies for this review. DFU, diabetic foot ulcer; HBOT, hyperbaric oxygen therapy; RCTs, randomized controlled trials.

All included studies obtained informed consent from their human subjects and ethical clearance. Characteristic details of each included study are presented in Table 2.

Table 2.

Characteristics of included studies

Study outcomes

Table 3 summarizes the outcomes of the included studies, with the majority indicating that HBOT demonstrates the ability to heal DFUs effectively and reduce the risk of complications, notably amputation. While these findings strongly suggest the potential of HBOT in replacing standard DFU therapy regimens, further exploration is required to ascertain its effectiveness compared to other potential alternative methods such as photodynamic therapy, non-thermal plasma therapy, or electrostimulation therapy. Notably, half of the included studies used HBOT as an adjunctive therapy, while the other half employed it as a standalone treatment. Since this review exclusively focused on studies that used HBOT, it is essential to consider the potential of other therapies which may require further review.

Table 3.

Summary of outcomes from included studies

Additionally, only three of the eight studies mentioned blinding in their methodologies, enhancing their validity. A broader assessment that compares HBOT’s efficacy against other alternative therapies is needed. For example, one of the included studies did a comparison between HBOT and extracorporeal shockwave therapy, revealing a slightly lower efficacy for HBOT in that context. Thus, a comprehensive evaluation of HBOT’s efficacy against a wider range of therapeutic methods should be considered.

Appraisal result

Table 4 presents the appraisal results conducted on each of the included studies using the 2020 JBI Checklist for Randomized Controlled Trials [8]. All the included studies implemented randomization and showed appropriate study designs and statistical analyses. However, two studies were open-label, and thus no blinding was done [10,11]. Additionally, three studies did not explicitly state whether blinding was performed [12-14]. The absence of blinding in these studies may have affected the overall findings by introducing bias, which could decrease the validity of the conclusions extracted from said studies. Blinding is a critical aspect of RCTs, as it reduces bias and enhances the strength and validity of the final conclusions. Without blinding, misleading results and erroneous conclusions may arise due to influenced decision-making [15]. Therefore, conclusions drawn by these studies regarding the benefits of HBOT for DFU may be skewed towards a more favorable outcome. Among all the included studies, three studies successfully fulfilled all the criteria provided by the checklist [16-18].

Table 4.

Summary of appraisal results

Pathogenesis of DFU

Wound healing represents a complex physiological process within the human body in response to tissue injury, involving a series of sequential events. However, in diabetic patients, this intricate process is often disrupted, resulting in delayed or non-healing wounds [17]. This disruption can arise from various factors such as ischemia, edema, inadequate glycemic control, neuropathy, abnormal hemodynamics, or infection [3,17]. Such impairments in healing are culminated in the chronic wounds known as DFUs. DFUs are characterized by the slow or poor healing of either partial or full-thickness wounds typically in diabetic patients. While these ulcers may initially present as superficial wounds, opportunistic microbes can spread to the underlying subcutaneous tissues, exacerbating the condition further [14].

The pathogenesis of DFU typically initiates with the development of callus, a process influenced by neuropathy involving three distinct mechanisms: motoric neuropathy leading to foot deformities and biomechanical impairments, sensory neuropathy resulting in the loss of protective sensation, and autonomic neuropathy that diminishes sweating and causes skin dryness [3,19]. Callus formation primarily occurs in high-pressure zones on the plantar surface of the foot, notably at the metatarsal region [19]. Subsequent repetitive or minor trauma, often due to walking, can lead to the progression of the affected area into a subcutaneous hemorrhage. Peripheral artery disease, such as arterial insufficiency, or repeated trauma can further contribute to the development of a foot ulcer [3,19]. Once a DFU forms, appropriate and prompt treatment is needed to prevent further complications. Various procedures, including surgical debridement, pressure off-loading, eradication of infections, and vascular reconstruction, are performed to facilitate DFU healing, a process that typically spans approximately 12 months. Unfortunately, despite recovery, DFU recurrence is exceedingly common [3]. While standard therapy usually necessitates an average of 12 months for healing, several studies have reported that HBOT may shorten the healing process. For instance, a trial conducted by Abidia et al. [17] indicated that some DFUs healed within 6 weeks of therapy. Additionally, Wang et al. [11] revealed that after completing the first course of HBOT for DFU, 25% of their patients experienced complete wound closure. HBOT appears to address the time-consuming issue of standard DFU therapy, potentially promoting faster wound healing.

Mechanism of HBOT

HBOT has served as an adjuvant treatment in various medical conditions for over 50 years, employing diverse protocols and regimens [6]. As of 2021, approved indications for HBOT include a range of conditions such as air or gas embolism, acute thermal burn injuries, osteoradionecrosis, carbon monoxide poisoning, decompression sickness, intracranial abscess, central retinal artery occlusion, and necrotizing soft tissue infections [5,6]. Notably, DFU has yet to be officially included in the list of approved indications, as ongoing investigations are still underway [5].

The therapeutic mechanisms of HBOT generally rely on partial pressure elevation and hydrostatic pressure in accordance with Boyle’s Law. This makes it particularly effective in treating conditions where gaseous bubbles are present in the body [20]. In the context of wound healing, the increased oxygen gradient between the center and periphery of the wound generates a strong angiogenic stimulus, resulting in fibroblastic proliferation and ultimately leading to increased neovascularization [21].

HBOT promotes angiogenesis through a multifaceted mechanism. Fibroblast proliferation and collagen synthesis, both essential for wound healing, are oxygen-dependent, and collagen serves as the foundational matrix for angiogenesis. Moreover, HBOT likely stimulates the production of growth factors, particularly vascular endothelial growth factor, which plays a key role in angiogenesis and the broader wound healing process [22]. It should be noted that angiogenesis plays an important role in wound healing, especially in diabetic wounds, as these wounds often result from poor circulation [17]. Additionally, HBOT has both direct and indirect antimicrobial properties, notably enhancing intracellular leukocyte activity and the killing of pathogens. HBOT also serves as a reducer of edema by causing systemic vasoconstriction, improving oxygen and nutrient diffusion throughout tissues while alleviating pressure on nearby vessels and structures [22].

In DFUs, HBOT has demonstrated the ability to enhance healing rates, as strongly indicated in the studies conducted by Nik Hisamuddin et al. [14] and Abidia et al. [17]. As mentioned previously, one of the mechanisms of action for HBOT involves increasing neovascularization [21]. This could potentially be the underlying mechanism by which HBOT treats DFUs, as it is theorized that the promotion of vascularization may lead to an increase in cell regeneration and prevention of bacterial growth in DFU patients [23]. Other suggested mechanisms for how HBOT contributes to the healing of DFUs include enhancing fibroblast activities and collagen synthesis, as well as increasing the phagocytosis activity of neutrophils [16].

Complications and amputations in DFU

If left unmanaged, DFU can progress further into various complications including cellulitis or deep infection, commonly caused by Staphylococcus aureus, Streptococcus species, and Escherichia coli. Other complications include gangrene and foot deformities [24]. While cellulitis and gangrene can be treated using antibiotics and surgical debridement, in more severe cases, the infections are often polymicrobial, involving more than one species of pathogens [2]. In these advanced cases, addressing the complication may necessitate amputation of the affected region. Approximately 14% of DFU patients ultimately require major amputation, and 24% will undergo minor amputations [24]. This relatively high rate of amputation, coupled with the costly treatment of diabetes in general, significantly diminishes the quality of life for patients with DM, especially those with DFU [25].

Some of the studies included in this review display a decrease in the amputation rate for patients treated with HBOT in comparison to standard therapy. A slight reduction in amputation rate was observed in the trials conducted by Abidia et al. [17], Londahl et al. [16], and Chen et al. [10]. Meanwhile, Duzgun et al. [13] revealed an even higher decrease in the amputation rate with HBOT compared to standard therapy. These improvements in amputation rates can be attributed to accelerated DFU healing brought on by HBOT. This quickening of the healing process may lower the risk of infection or disease progression, factors that normally lead to amputation. Furthermore, reduction in amputation rates has been associated with improved quality of life for patients with DFU. This improvement is evidently seen in a study conducted by Londahl et al. [26], showing an overall enhancement in mean physical and mental health conditions.

Contradicting evidence

Despite most of the included studies indicating HBOT increases healing rates and decreases incidences of amputation, Fedorko et al. [18] stated that HBOT does not confer an advantage in reducing the need for amputation or aiding wound healing in patients with chronic DFUs. Their study presented similar amputation rates in a HBOT group and placebo group, with a 51% amputation rate for the HBOT group and 48.1% in the placebo group. Despite the difference not being statistically significant, it remains a noteworthy observation. This results align with a cohort study conducted in 1966 by Margolis et al. Their research similarly showed that HBOT did not improve wound healing or prevent amputation. Margolis et al. [27] compared 793 patients receiving HBOT to 5,466 patients under standard therapy, with no improved likelihood of wound healing or amputation prevention.

One possible reason for these conflicting results is the variation in the populations studied, including differences in sex, race, and ethnicity. Most studies included more males than females, and some studies were conducted in European populations while others in Asian populations. Moreover, slight differences in intervention methods, such as pressure levels and treatment durations, could influence outcomes. Studies by Feldman-Idov et al. [28] and Fife et al. [29] investigating factors that impact HBOT outcomes have supported this hypothesis. Their studies further stated that pre-existing comorbidities should also be considered, as they may have a significant impact on HBOT outcomes. As conflicting evidence continues to emerge, the role of HBOT in treating DFUs and other conditions must be further evaluated, and only an abundance of high quality, positive evidence can definitively determine its applicability in these contexts [27,30].

Potential clinical applications of HBOT

HBOT has demonstrated its effectiveness in improving wound healing time compared to standard therapy. As seen in Table 3, six of the eight included studies suggest that HBOT aids the healing course of DFUs, with significant acceleration seen in studies by Abidia et al. [17], Duzgun et al. [13], and Londahl et al. [16]. However, Wang et al. [11] suggested that extracorporeal shockwave therapy is more effective than HBOT as an alternative for DFU therapy. Another positive impact observed in the majority of the studies is the reduction in amputation rates, which, if applied clinically, would undeniably be beneficial towards DFU patients. This was distinctly shown in the trial conducted by Duzgun et al. [13], revealing a rate reduction as high as 66%. Despite these positive outcomes, as discussed previously, the study by Fedorko et al. [18] revealed no significant improvements in healing or amputation rates when using HBOT compared to a placebo, thereby necessitating reevaluation and further investigation.

While this review provides more evidence supporting HBOT for patients with DFUs, there are various other aspects should be considered. Further research is necessary to fortify the potential of HBOT in becoming a standard treatment for DFUs. Safety concerns associated with HBOT treatment should be extensively explored to precisely weigh its associated risks and benefits. Particularly, the review results show variations in HBOT doses administered to patients between studies. This indicates inconsistency and necessitates a standardization of protocols to equalize doses, thereby reducing the risk of under- or overdosing.

Contraindications and adverse effects of HBOT

In general, HBOT is considered a safe procedure, employing noninvasive techniques [5]. However, when considering the use of HBOT in treating DFU patients, there are specific predisposing conditions that contraindicate its application. HBOT is absolutely contraindicated in untreated pneumothorax and highly contraindicated in chronic obstructive pulmonary disease [5,30]. Additional relative contraindications encompass claustrophobia, hereditary spherocytosis, pregnancy, heart failure, asthma, retinopathy, upper respiratory infections, and other underlying respiratory pathologies [5].

These contraindications are also seen in one of the included studies by Kessler et al. wherein DFU patients with predisposing factors such as emphysema, proliferative retinopathy, and claustrophobia were excluded from the study [12]. One crucial effect of HBOT that requires careful observation, especially in diabetic patients, is hypoglycemia, as fluctuations in blood glucose levels may interfere with diabetic medications [30]. Patients undergoing HBOT may also experience various adverse effects, including but not limited to headache, middle ear barotrauma, pulmonary barotrauma, fatigue, vomiting, reversible myopia, and thrombocytopenia [5,30]. Exposure to excess oxygen during HBOT may additionally lead to oxygen toxicity [5].

Limitations

The restriction of this review to English articles may have contributed to a language bias, a common issue in systematic reviews. An editorial letter by Stern and Kleijnen [31] suggests that this limitation can be mitigated by recruiting individuals proficient in other languages to help identify and extract relevant information from non-English studies. Expanding the search to include more databases, thereby increasing the breadth of evidence gathered, could further increase the quality of review results. Future systematic reviews encompassing the comparison of efficacy of HBOT in DFU healing with other alternative therapeutic methods could also contribute to the strength of evidence supporting the application of HBOT in clinical settings.

Conclusion

Some of the included studies have reached the consensus that HBOT indeed plays a role in facilitating the healing process of DFUs, resulting in reduced instances of amputation and worsening of DFU conditions. While these findings suggest that HBOT holds potential as an effective alternative method for treating DFUs, additional investigations, such as analyzing data from histopathological evaluations to uncover the types of cells involved in the healing process of DFU, are imperative. Furthermore, it is crucial to compare HBOT with other alternative therapies, such as extracorporeal shockwave therapy, before considering its integration into clinical guidelines and standardization in clinical practices.