Hyperbaric Oxygenation in the Treatment of Fournier’s Gangrene: A Systematic Review

Fournier’s gangrene (FG) is a sporadic, life-threatening, necrotizing infection affecting the perineum, perineal region, and genitals [1-3]. As the incidence is low, most of the limited knowledge about FG arises from retrospective single-institutional studies with very small patient cohorts [1, 4-16]. Unfortunately, FG also has a poor prognosis. Early studies of FG reported a 20–88% mortality rate [1, 2, 17-19], but 2 studies from 2017 calculated a mortality rate of 25–26% [3, 12], which is still worrisome. Furthermore, Kranz et al. [1] reported in 2018 that the situation of FG patients is alarming since outcome of this disease failed to improve over the last 10 years despite more intensive critical care therapy.

Key points for the successful treatment of FG are immediate surgical debridement, accompanied by forced antibiotic therapy and, usually, intensive medical management [20]. However, hyperbaric oxygenation (HBO) was first used by Boerema, who was a Dutch cardiovascular surgeon. He observed that when surgery was performed in an environment filled with pressure, vessels could be contracted for a longer time, resulting in cardiac repair [21, 22]. Additionally, HBO improves tissue perfusion, promotes angiogenesis and collagen synthesis, increases oxygen levels in tissues, and inhibits the production of toxins. Therefore, HBO therapy is widely used to treat mixed infections [20, 23, 24]. Despite these positive effects of HBO, the indication and the effects on outcome as adjunct therapy in FG remain controversial [21].

Consequently, we decided to perform a systematic review to compare the treatment of FG with or without the use of HBO as an adjunct therapy. To enunciate our question we used the PICO scheme (Patient Intervention Comparison and Outcome), illustrated in Figure 1. The primary aim of this review was to summarize the current evidence for HBO use in patients with FG and thereof knowledge for planning further clinical studies, especially prospective evaluations, which are warranted [1].

We followed the recommendations provided in the Cochrane Handbook of systematic Reviews [25] and the PRISMA reporting guidelines [26].

Due to the paucity of data and a suspected lack of randomized controlled trials (RCTs) in this disease, we considered all the available information for this systematic review. Thus, all types of study designs were included: randomized and quasi-randomized studies (if available), comparative studies (e.g., cohorts, case and control), and non-comparative studies (e.g., case series or case reports); the only exclusion were made for narrative reviews. Full-text articles and abstracts were considered. No exclusions were made by publication date. We only included German and English publications.

All patients diagnosed with FG were included in this systematic review.

Measurement of outcomes assessed in this review will not be used as an eligibility criterion. The primary outcomes were mortality rate or overall survival. Secondary outcomes were accepted reporting of duration of inpatient treatment, duration of intensive care treatment, number of surgical debridements, and quality of life.

A combination of electronic and manual searches for the identification of studies was conducted.

We searched the following databases: MEDLINE via PubMed from 1946 to 2020 (search strategy: “fournier gangrene”[MeSH Terms] OR (“fournier”[All Fields] AND “gangrene”[All Fields]) OR “fournier gangrene”[All Fields] OR (“fournier’s”[All Fields] AND “gangrene”[All Fields]) OR “fournier’s gangrene”[All Fields]) AND (“hyperbaric oxygenation”[MeSH Terms] OR (“hyperbaric”[All Fields] AND “oxygenation”[All Fields]) OR “hyperbaric oxygenation”[All Fields]). Last search was conducted on April 2020. The electronic searches were complemented by searching the World Health Organization International Clinical Trials Registry Platform Search Portal (WHO ICTRP) and ClinicalTrials.gov by using the term “Fournier’s gangrene” (MeSH) to identify possible completed or ongoing trials.

The reference lists of included studies were hand-searched for additional references. Conference proceedings of 8 journals (European Urology, European Urology Supplements, European Urology Focus, The Journal of Urology, British Journal of Urology International, World Journal of Urology, Urologia Internationalis, Central European Journal of Urology) were hand-searched as well from the year 2010 onwards.

Citavi 6.0 (Swiss Academic Software, Wädenswil, Switzerland) was used to manage the bibliographic references. Two review authors (L.S. and J.K.) independently screened title and abstracts to determine which studies should be assessed further. Two review authors (L.S. and J.K.) have assessed all potentially relevant records as full texts, mapped records to studies, and classified studies as included studies, excluded studies, studies awaiting classification, or ongoing studies in accordance with the criteria for each provided in the Cochrane Handbook for Systematic Reviews of Interventions [25]. Discrepancies will be resolved through consensus or consultation of a third review author (P.A.).

For studies that fulfilled the inclusion criteria, 2 review authors (L.S. and J.K.) have independently extracted the following information: Study dates and settings, participant details, grade of evidence SIGN (Scottish Intercollegiate Guideline Network), definitions of relevant outcomes, method and timing of outcome measurement, and any relevant subgroups (Table 1).

We extracted outcomes data relevant to this systematic review as needed for calculation of summary statistics and measures of variance. For dichotomous outcomes, we attempted to obtain numbers of events and totals for population of a 2 × 2 table, as well as summary statistics with corresponding measures of variance. For continuous outcomes, we attempted to obtain means and standard deviations or data necessary to calculate this information. For time-to-event outcomes, we attempted to obtain hazard ratios with corresponding measures of variance or data necessary to calculate this information.

We resolved any disagreements by discussion, or, if required, by consultation with a third review author (P.A.). We attempted to contact authors of included studies to obtain key missing data as needed.

We have attempted to assess the risk of bias by using the Cochrane risk of bias tool for RCTs and quasi-RCTs [25], the SIGN tool for cohort studies, case-control studies, and case series [27].

Due to the different study designs of included studies and their different end points, we could finally not perform a synthesis of results, and therefore no meta-analysis was performed.

The literature search for primary studies yielded 79 results. Finally, 13 studies were considered, which included a total of 376 patients with FG, of whom 202 (53.7%) received HBO therapy (Fig. 2) [20, 21, 28-38]. We could only identify retrospective studies for this review. At the time of this review, 1 prospective study was registered at WHO ICTRP or ClinicalTrials.gov, named “Prognosis and treatment of Necrotizing Soft Tissue Infections: A Prospective Cohort Study” from Copenhagen University Hospital (Denmark). This study is completed but not yet published. Table 1 shows the main characteristics, interventions, end points, and main results of the 13 included studies.

The included studies are very heterogeneous, especially in terms of the administration of the HBO therapy. However, Table 2 gives a specification of administration of HBO in the included studies. Due to this heterogeneity, we were not able to perform a meta-analysis of the data.

On the whole, 12 of the included studies concluded that adjunct HBO to standard treatment of FG has positive effects, especially in terms of mortality rate, and further investigations are reasonable. In contrast, Mindrup et al. [31] reported that the data do not support routine HBO in the treatment of FG. There was a trend towards higher baseline morbidity in the HBO group, suggesting that more severely ill patients were selected for HBO treatment.

Furthermore, 5 of the 13 included studies had a retrospective case-control design [20, 21, 28, 31, 33]. Mortality rate in these studies ranged from 0 to 26.9% in the HBO groups. All authors reported a significant lower mortality rate in the HBO group except Mindrup et al. [31] (12.5% non-HBO vs. 26.9% HBO). Interestingly, Creta et al. [28] identified surgical debridement and HBO as independent predictors for lower mortality in multivariate analysis. Additionally, Li et al. [21] indicated that the difference in the number of surgical debridements, indwelling drainage tube time, and curative time were significantly lower in the HBO group. However, these 5 case-control studies included a total of 319 patients; 145 of these patients were treated with adjunct HBO therapy. Overall, this is leading to a mortality rate of 16.6% in the HBO group and 25.9% in the non-HBO group [20, 21, 28, 31, 33].

Reporting of methodological quality parameters was incomplete in all of the 13 studies. Overall, risk of bias was assessed as moderate to high and the quality of evidence was rated rather low. Table 3 shows the summary of risk of bias assessment using SIGN methodology checklist for each included study.

We conducted a systematic review to compare the treatment of FG with or without the use of HBO as an adjunct therapy. This is a crucial topic since FG is a rare but severe disease with a high mortality rate, and final outcome of FG failed to improve over the last 10 years despite more intensive critical-care therapy [1]. On the whole, we were able to identify 13 retrospective studies for our review. Furthermore, 5 of the included studies had a case control design with a total of 319 patients; 145 of these patients were treated with adjunct HBO [20, 21, 28, 31, 33].

To our knowledge, this is the first systematic review on HBO therapy in FG. Interestingly, a narrative review about this topic was published early in 1986 by Eltorai et al. [39]. The authors concluded that in the exceedingly early stage, HBO may avert gangrene or reduce it. It is important to have a high index of awareness of this disease amongst the medical profession. More work is needed for the more precise definition, classification, and management of the complex syndrome of FG [39]. However, systematic reviews have been published about different entities of necrotizing soft tissue infections, also including FG. The newest 1, published in 2019, by Fauno and Ovesen [40], included 21 studies, of which 19 were case series with a control group. The authors stated that the evidence of HBO therapy in necrotizing soft tissue infection is weak and biased. There is a strong need for RCTs.

Furthermore, we were not able to include 1 study which met our inclusion criteria since there was only an English abstract available, while the full-text article is in Portuguese. Rosa and Guerreiro [41] reported a retrospective case series of 34 patients over the last 25 years in 2015. In the abstract, the following conclusion was stated: Although FG is a rare condition, it is nevertheless a fatal illness, namely, in patients with comorbidities. HBO therapy is recommended as an adjunct to conventional treatment and should be considered whenever available. To further assess the role of HBO therapy in the treatment of this condition, additional studies should be carried out [41]. Still, we identified another interesting study, with a full text only available in Spanish, which included FG patients receiving HBO therapy, but the study focused on the benefit as well as use of FG severity index (FGSI). The author concluded that FGSI score did not predict disease severity and the patient’s survival. Metabolic aberrations and extent of disease seemed to be significant risk factors for predicting FG severity and patient’s survival [42].

The data of the included studies for this systematic review were very heterogeneous; thus, we were not able to perform a meta-analysis. Most notable are the differences in administering HBO therapy. Several of the included studies did not describe how HBO was administered. This makes the results difficult to compare, even in a descriptive manner, and raises questions, as follows: When is the right time point to start HBO therapy? Which absolute atmospheric pressure should be used? At the moment, there is no established therapy protocol for HBO in FG patients available. Therefore, further studies are urgently warranted to address these questions. Furthermore, the study populations are very heterogeneous in terms of mortality rate. Interestingly, only 2 studies give a detailed information of how severe the disease has presented prior to inclusion and treatment with HBO including FGSI [21, 28]. Furthermore, there is a moderate to high risk of bias in all included studies, mostly due to the retrospective study design.

The most important result of this systematic review arises from the 5 case-control studies. Overall, this is leading to a mortality rate of 16.6% in the HBO group and 25.9% in the non-HBO group [20, 21, 28, 31, 33]. All authors of these studies reported a significant lower mortality rate in the HBO group except Mindrup et al. [31]. They discussed their results critically and stated that there was a trend toward higher baseline morbidity in the HBO group, suggesting that treatment may have been given to patients who were more severely ill [31]. Interestingly, Anheuser et al. [20] described that despite the fact that the HBO treated group was better in terms of mortality, the wound debridement frequency and length of hospitalization were significantly higher in the HBO group. On the whole, these facts suggest that some patients might benefit from adjunct HBO therapy especially in terms of mortality rate, but FG is still a very complex disease, which is sometimes difficult to predict [42]. So, a defined patient group who will benefit from HBO in FG must be identified in further investigations. It is also noteworthy that the results for HBO therapy in FG in this systematic review are slightly better than the results from the review of HBO in other necrotizing soft tissue infections [40]. This might be due to multiple underlying conditions, such as pathogen spectrum and pathogenicity or different wound healing conditions in the various body areas. This might be a hint that necrotizing soft tissue infections are actually a group of diseases and each group should precisely be defined. This will also be problematic with the unpublished registered prospective trial on HBO from Copenhagen University Hospital since all entities of necrotizing soft tissue infections are included.

Even if HBO has potential in FG therapy, not every hospital has fast access to an HBO chamber. Furthermore, there is no established therapy protocol for HBO. Finally, we must assume that this systematic review has limitations, we only included English and German publications, which is a selection bias.

We conclude that, despite the risk of bias, HBO has the potential as an adjunct in FG treatment, but it is challenging to carry out further studies or even RCTs due to the rareness of this disease, restricted availability of HBO and the complex character of FG. We, therefore, suggest a prospective register trial first to answer some of the primary open questions and then plan a proper RCT to precisely define the role of HBO in FG treatment.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, a formal consent was not required.

All authors declare that they have no conflict of interest regarding this manuscript.

This project received no external funding.

L.S., P.A., S.S., F.M.E.W., and J.K. participated in the design of the review and critical revision of the article. L.S., P.A., and J.K. participated in data acquisition, data analysis, and drafting of the article.