TL;DR: Hyperbaric oxygen therapy (HBOT) for necrotizing soft tissue infections (NSTIs) remains a debated adjunct, but recent 2024-2026 cohort and registry evidence consistently associates the addition of HBOT to early surgical debridement and broad-spectrum antibiotics with lower mortality and amputation rates. The largest 2024 National Inpatient Sample analysis reported a 78% relative reduction in mortality risk (adjusted OR 0.22). A 2025 University of Maryland cohort confirmed mortality benefit, especially in patients with large wounds and high APACHE II scores. The major 2024 JAMA Surgery review still rates routine HBOT use as “insufficient evidence” given the absence of high-quality randomised controlled trial (RCT) data, leaving the evidence base classified as low-certainty but mortality-favourable.
What is a necrotizing soft tissue infection?
A necrotizing soft tissue infection is a rapidly progressive, life-threatening bacterial infection that invades the skin, subcutaneous tissue, fascia, and sometimes muscle, producing tissue death faster than the immune system or antibiotics can contain it. NSTI is the umbrella term that includes necrotizing fasciitis, necrotizing cellulitis, gas gangrene (clostridial myonecrosis), and Fournier gangrene. Annual incidence ranges from 0.86 to 32.64 cases per 100,000 person-years depending on climate, season, and population, with mortality between 20% and 30% even at high-volume centres.
Standard care rests on three pillars: immediate surgical debridement within six hours of presentation, broad-spectrum intravenous antibiotics, and intensive care support. Adjunctive therapies, including hyperbaric oxygen therapy and intravenous immunoglobulin, sit outside the consensus core but are used at many specialised centres in Canada and internationally.
Why is hyperbaric oxygen therapy used as an adjunct in NSTI?
HBOT delivers 100% oxygen at pressures of 2.0 to 3.0 atmospheres absolute (ATA), elevating tissue oxygen tension to levels unreachable by surface breathing. In NSTI, this hyperoxia is thought to act through several converging mechanisms documented in a 2025 Journal of Clinical Medicine review by Gregory and Sethuraman at the University of Maryland trauma centre in Baltimore (JCM 2025 review (PubMed)):
- Direct bacteriostasis against anaerobes, particularly Clostridium species responsible for gas gangrene
- Suppression of bacterial exotoxin production, including alpha-toxin from C. perfringens
- Restoration of neutrophil oxidative burst, which fails in hypoxic tissue and impairs bacterial killing
- Potentiation of selected antibiotics, notably aminoglycosides and fluoroquinolones, which require oxygen-dependent transport
- Improved demarcation of viable tissue, helping surgeons limit the extent of subsequent debridements
- Attenuation of the systemic inflammatory response, reducing organ dysfunction during the critical first 72 hours
These mechanisms explain why HBOT is positioned as an adjunct, never a replacement, for source control and antimicrobial therapy.
What does the 2024-2026 evidence show on mortality and amputation?
Four large studies published in the last 24 months provide the most current evidence base for HBOT in NSTI. None are randomised, but several use rigorous propensity-matched or multivariable approaches that significantly improve on earlier work.
| Study | Design | Patients (HBOT vs no HBOT) | Mortality finding | Amputation finding |
|---|---|---|---|---|
| Toppen et al. 2024 (PLoS One) | National Inpatient Sample 2012-2020, multivariable adjustment | 600 vs 59,881 | Adjusted OR 0.22 (95% CI 0.09-0.53), p<0.001 | Adjusted OR 0.73 (95% CI 0.55-0.96), p=0.03 |
| Shishido et al. 2025 (Surg Infect) | Single-centre cohort, COVID-era natural experiment | 143 vs 110 | 5.8% vs 15.4% 90-day mortality, p=0.015 | OR 0.12 in large wounds and high APACHE II (95% CI 0.02-0.72) |
| Chiang et al. 2024 (Surg Infect) | Retrospective cohort, time-to-HBOT analysis | 98 (all received HBOT) | Survivors received HBOT sooner after diagnosis (p=0.031) | Limb-preserved patients received HBOT sooner (p=0.031) |
| Kariksiz et al. 2025 (Eur J Trauma Emerg Surg) | Single-centre lower-extremity NSTI cohort | 50 (mixed HBOT use) | Overall 20% mortality; HBOT not significantly associated with amputation in this small sample | 60% amputation rate; comorbidity burden dominated outcome |
The Toppen 2024 NIS analysis
The most cited recent paper is Toppen and colleagues analysis of the 2012-2020 National Inpatient Sample, published in PLoS One (Toppen 2024 (PubMed)). Of 60,481 surgical NSTI admissions, 600 received HBOT. After multivariable adjustment for age, comorbidities, and disease severity proxies, HBOT was associated with an adjusted odds ratio for in-hospital death of 0.22 (95% CI 0.09-0.53) and an adjusted odds ratio for amputation of 0.73 (95% CI 0.55-0.96). Length of stay rose by 1.6 days and hospital costs by approximately 7,800 USD, but rates of non-home discharge fell.
The authors acknowledge the residual confounding inherent in administrative data: NSTI severity is incompletely captured by ICD codes, and centres offering HBOT may differ systematically in surgical and critical-care quality. Even so, the direction and magnitude of the mortality signal in 60,000+ patients is difficult to dismiss.
The Shishido 2025 Maryland cohort
Shishido and colleagues at the University of Maryland exploited an unusual natural experiment: COVID-19 disrupted HBOT availability at their centre, producing a comparator group of NSTI patients who would normally have received HBOT but did not (Shishido 2025 (PubMed)). Of 253 patients, 143 received HBOT and 110 did not. Ninety-day mortality was 5.8% in the HBOT group versus 15.4% in the non-HBOT group (p=0.015). The mortality benefit was concentrated in the sickest patients: those with wound surface area at or above 450 square centimetres and APACHE II scores at or above 18 had an odds ratio for death of 0.12 (95% CI 0.02-0.72) when treated with HBOT.
This study is the closest the literature comes to a quasi-randomised comparison. The COVID disruption was not a true randomisation, but it removed the strongest source of indication bias (centres choosing to treat sicker patients with HBOT) and produced groups with similar baseline characteristics.
The Chiang 2024 time-to-HBOT analysis
Chiang and colleagues took a different angle, examining whether timing of HBOT after diagnosis affected outcomes (Chiang 2024 (PubMed)). In their 98-patient retrospective cohort, the mean interval from NSTI diagnosis to first HBOT session was significantly longer in patients who died (p=0.031) and in patients who underwent amputation (p=0.031). The interval from initial surgery to first HBOT session showed the same pattern. This dose-response finding strengthens biological plausibility: HBOT acts through time-sensitive mechanisms (toxin suppression, immune restoration), and delay reduces benefit.
How does the 2024 JAMA Surgery review interpret the same evidence?
The most authoritative 2024 review of NSTI management, published in JAMA Surgery by McDermott and colleagues from Stanford, McGovern, and Harbor-UCLA, reaches a more cautious conclusion (McDermott 2024 (PubMed)). After surveying the same observational literature, the authors write that “there are insufficient data to support the routine use of adjunct treatments such as hyperbaric oxygen therapy and intravenous immunoglobulin.” Their reasoning rests on three points familiar to evidence methodologists:
- No completed multicentre RCT compares HBOT plus standard care against standard care alone in NSTI
- Selection bias is unavoidable in observational data: HBOT-eligible patients are typically transferred to specialised centres with better surgical and critical-care infrastructure, confounding the apparent benefit
- Logistical constraints limit generalisability: only a minority of Canadian and US hospitals operate hyperbaric chambers capable of treating critically ill ventilated patients
This tension between strong observational signal and absent RCT evidence is the defining feature of the current HBOT-NSTI literature. Researchers should treat the field as low-certainty but mortality-favourable, with the strongest evidence supporting use in monomicrobial clostridial infections, large wounds, and high-severity cases as outlined in the 2024 update by Allaw and colleagues (Allaw 2024).
What does this mean for Canadian research priorities?
Canada is well positioned to contribute high-quality evidence in this area. The country has a small but well-distributed network of hospital-based hyperbaric chambers capable of treating critically ill patients, including units in Toronto, Vancouver, Halifax, and Montreal that serve as referral centres for NSTI. A pragmatic multicentre trial nesting HBOT randomisation inside an existing NSTI registry is technically feasible and would address the most pressing gap identified by the JAMA Surgery review.
Three concrete research questions deserve priority attention:
- Does HBOT timing modify outcome? Chiang time-to-HBOT signal needs prospective replication. A trial randomising eligible patients to HBOT within 6 hours of diagnosis versus standard care would directly test the mechanistic prediction.
- Which subgroups benefit most? Shishido wound-size and APACHE II interaction suggests benefit concentrates in the sickest patients. A pre-specified subgroup analysis in any future trial should test this hypothesis.
- What is the cost-effectiveness? Toppen 7,800 USD per-patient excess cost translates to a defensible incremental cost-effectiveness ratio if mortality benefits hold prospectively. A formal Canadian health-economic model would inform provincial funding decisions.
Canada Hyperbarics maintains an indexed database of more than 14,000 HBOT studies, including a continuously updated NSTI subset, available for researchers building grant proposals or systematic reviews. The full research database is freely searchable, and the lower-extremity-focused 2025 cohort by Kariksiz and colleagues highlights how comorbidity-rich populations need careful subgroup analysis (Kariksiz 2025 (PubMed)).
Frequently Asked Questions
Is HBOT a Health Canada-recognised indication for necrotizing soft tissue infections?
NSTI, including gas gangrene (clostridial myonecrosis) and necrotizing fasciitis, sits within the established Undersea and Hyperbaric Medical Society (UHMS) recognised indication list and is recognised by Canadian hyperbaric medicine programs. Health Canada regulates the chamber as a Class III medical device but does not maintain a separate condition-by-condition approval list. Use is guided by UHMS and CUHMA standards.
Why has no large RCT been completed in NSTI?
NSTI is rare, time-critical, and geographically clustered around tertiary centres with hyperbaric capability. Equipoise is also limited at experienced centres where clinicians believe HBOT confers benefit. These factors have stalled multicentre RCT enrolment for over two decades.
Does HBOT delay surgery?
No. Every contemporary review reinforces that surgical debridement must occur first and must not be delayed for HBOT. HBOT is initiated after the first debridement and continued between subsequent operative trips.
What HBOT protocol is typically used in NSTI?
Most centres use 2.4 to 3.0 ATA for 90 minutes, with two to three sessions in the first 24 hours, followed by twice-daily sessions until clinical stabilisation. Total course length varies by extent of infection, typically 5 to 15 sessions.
What outcome measures should future NSTI trials prioritise?
The current literature reports a mix of in-hospital mortality, 30-day mortality, 90-day mortality, amputation, length of stay, and discharge disposition. A core outcome set, ideally co-developed with patient and surgeon stakeholders, would improve comparability across trials.
Where can researchers access NSTI study summaries?
The Canada Hyperbarics research database indexes more than 14,000 HBOT studies with structured AI-generated summaries covering background, methods, findings, limitations, and Canadian relevance. Filter by condition or year to extract the NSTI subset.
Where to refer patients in Canada
Suspected NSTI requires immediate transfer to a tertiary centre with both emergency general surgery capability and access to a hospital-based hyperbaric chamber. The list of Canadian hospitals and regulated facilities offering hyperbaric medicine is maintained on our facilities page, with provincial coverage rules summarised under regulatory guidance.
This content is for informational purposes only and does not constitute medical advice. Clinical decisions in necrotizing soft tissue infection require multidisciplinary specialist input, including surgery, infectious diseases, critical care, and hyperbaric medicine. Consult your institutional protocol and the most recent UHMS and CUHMA guidance before applying any treatment recommendation discussed here.