Outcome of necrotizing fasciitis and Fournier's gangrene with and without hyperbaric oxygen therapy: a retrospective analysis over 10 years

Mortality rates in NSTI

Our retrospective single-center study includes a relatively large, well-characterized cohort of patients with NF and FG with an in-hospital mortality rate of 27.6%. This rate is rather high compared to the recent literature. The largest systemic review and meta-analysis on adjunctive HBOT in NSTI, which comprised 48,744 patients, showed an in-hospital mortality rate of 9.8% [11]. A recent large prospective, multicenter study reported a 30-day mortality of 19.4% and a septic shock rate of 30% [12]. In our cohort, sepsis at admission was more common (68.8%). Treatment of NSTI in centers with a high annual caseload of these entities generally enhances the chances of favorable outcome, but on the other hand, these centers are prone to receive patients with higher disease severity due to higher expertise and availability of adjunct treatment options [13, 14]. These factors may have contributed to worse outcome in our cohort.

A recent systematic review of 109 studies with 6,051 patients revealed a significant reduction in mortality after the year 2000 [15], while this tendency was not found in subsequent study periods [14]. Improvement in intensive care with decreasing sepsis-related mortality [16] and progress in antibiotic treatment [17] are regarded as main factors contributing to better survival.

Impact of surgical treatment on mortality

Delayed surgery is known to be associated with increased mortality due to NSTI [18], and debridement within 12 h after admission is explicitly recommended [15, 19]. Our HBOT patients and the subgroup ineligible for HBOT had timely debridements significantly more often than the group without need of HBOT. Altogether, only 47.9% of our patients received their first debridement within 12 h after admission to our hospital. However, one third had already obtained a debridement prior to transfer to our center. Outcome of transferred and directly admitted patients was similar, supporting early transport of patients with NSTI to specialized centers as recommended in prior work [13, 20].

VAC therapy and defect reconstruction were associated with a higher chance of survival. These observations should rather be interpreted as correlation than as causality, as defect conditioning and reconstruction require vital wounds and hemodynamic stability. The benefit of defect coverage is nevertheless evident, as it reduces the risk of complications related to large wounds and promotes mobilization, which is essential for convalescence. A larger number of debridements, including minor interventions for wound conditioning, and a longer hospital stay were both significantly associated with survival, which should be interpreted within this line of argumentation.

Impact of HBOT

To our knowledge, this study is the first to stratify patients with NSTI into three groups according to indication and practicability of HBOT. The subgroup treated with HBOT had significantly worse initial conditions and greater disease dissemination and required more arduous treatment compared to patients without indication for HBOT. Nevertheless, rates of survival, defect coverage and hospital discharge without severe disability were similar in both groups, which points to a benefit from HBOT.

Even if HBOT is routinely used for treatment of NSTI in specialized centers worldwide, unequivocal scientific evidence for its benefits has not been provided yet. Many studies investigating its impact on outcome of NSTI demonstrated positive effects [21,22,23,24,25,26,27,28,29], whereas others did not show significant benefit [30,31,32,33,34]. Past systematic reviews provided only limited evidence on the clinical advantages of HBOT and had difficulties performing reliable meta-analyses due to shortcomings in the design and limited cohort sizes of included studies, high risk of confounding, substantial study heterogeneity and poor concordance of inclusion criteria [4, 5, 35, 36]. According to the latest meta-analysis, HBOT improves the odds for survival of NSTI [11].

In our study, ineligibility for HBOT was associated with increased mortality and significantly worse outcome despite early and frequent surgical debridements, extensive antibiotic therapy and intense supportive care, corresponding to results from a large multicenter database study [31]. The most common reason for withholding HBOT despite available infrastructure and highly experienced staff even after introduction of an in-house hyperbaric chamber was severe hemodynamic instability, e.g., due to septic shock. By contrast morbid obesity prevented HBOT only before the in-house chamber was established. Morbidly obese patients were younger, had less comorbidities and also survived more frequently, albeit commonly with severe physical impairment. As HBOT contributes to better oxygenation of insufficiently perfused fatty tissue, it could be speculated that obese patients benefit particularly from HBOT, although respective clinical evidence is lacking so far.

Diabetes mellitus is known to be one of the main risk factors for NSTI. Concordant with the literature [37, 38], almost half of our participants suffered from this comorbidity. Compared to nondiabetics, patients with diabetes were reported to have a higher risk of a severe disease course [39] and of limp loss due to their NSTI [37, 38]. Therefore, and due to diabetes-associated comorbidities potentiating the risk of adverse outcome, patients with diabetes and NF or FG may be preferentially considered for HBOT. The same applies to immunocompromised patients and patients with concomitant cardiovascular and metabolic diseases that may contribute to particularly severe and complicated disease courses and unfavorable outcome.

HBOT was shown to significantly reduce the risk of amputation in patients with NSTI in earlier studies [11, 24, 40], which encourages its use in patients with limb localization. In our cohort a major amputation of the lower limb was performed in 44 patients. These patients did not differ significantly from others with regard to HBOT, but the percentage of patients with limb loss appeared particularly high in the subgroup ineligible for HBOT.

Another subgroup expected to benefit particularly from HBOT according to the literature are patients with FG. A recent systematic review demonstrated overall mortality rates of 16.6% and 25.9% in patients with FG with and without HBOT [29]. We did no detect accordant differences in our cohort, possibly because of the limited number of patients with FG.

During the whole study period, only one complication possibly related to HBOT was recorded, i.e., a ruptured pulmonal cavern after the first HBOT session. This low rate of complications indicates high safety and good tolerability of HBOT. Therefore, this adjunctive treatment should be offered to patients with severe NF or FG whenever possible, in particular if they suffer from comorbidities which increase the risk of adverse outcome or if they are threatened by limb loss.

Limitations

Due to the single-center design and the limited cohort size, generalizability of our findings may be restricted. However, characteristics of our study population and prognostic factors identified are well compatible with the literature [14, 41]. Although the cohort size is relatively large compared to other single-center studies, the study may be underpowered for assessment of certain impact factors on mortality and outcome. Some subgroups including the one ineligible for HBOT were small. Therefore, relevant risk factors for mortality may have been missed.

Owing to the retrospective study design, some clinical and laboratory parameters were not consistently available and data quality might be inferior to that of prospective studies. Comorbidities were documented in categories without assessing their severity. Use of a classification system for comorbid conditions like the weighted Charlson Comorbidity Index [14, 42] should be considered in future studies. Smoking habits were not consistently documented in the patient records, because many patients were too critically ill to take a detailed smoking history at admission and required long-term ventilation in the further course.

The fact that a large proportion of patients were transferred to our center implicates the possibility of confounding factors originating from transferring hospitals and the risk of selection bias towards patients who were fit enough for transport.

The use of different hyperbaric chambers during the study period could be another source of selection bias. The old HBOT chamber was not suitable for morbidly obese and severely unstable patients. After implementation of the new chamber in October 2017, morbid obesity ceased to pose a restriction and hemodynamically unstable patients could be treated with higher safety. Indeed, the number of patients treated with HBOT increased noticeably after implementation of the new chamber, and the percentage of patients with NF or FG who received HBOT raised from 43% before 2018 to 58% between 2018 and 2020.

Strengths

We present a relatively large retrospective study which provides insight into mortality and outcome of patients with NF and FG treated in a large HBOT center under routine clinical conditions. Our study was performed in a Department of Plastic and Reconstructive Surgery with a certified Center of Wound Medicine and a highly specialized national HBOT center with long-time focus on NSTI and long-standing experience in their treatment. Diagnostic criteria of NF and FG as well as inclusion and exclusion criteria of the study were precisely defined, which is not always the case in retrospective studies on treatment of NSTI. The indication of HBOT was made according to standardized criteria independent of individual preferences of the surgeon or other team members. Clinical and laboratory parameters as well as details on the HBOT sessions, surgical procedures, antibiotic and supportive treatment and complications were documented accurately and comprehensively. Information on defect reconstruction, which is lacking in many other studies, was captured in detail and integrated into the analysis. The impact of various patient-, disease- and treatment-related factors on morbidity and outcome of NF and FG was assessed in multivariate regression models controlling for the key confounding factors.

Patients were stratified according to the indication, but also according to practicability of HBOT, which has not been done in other studies so far but reflects real medical care situations well and allows for a comparison of mortality and outcome close to clinical reality.

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