Discussion

This systematic review and meta-analysis aim to provide important insights into the efficacy and safety of HBOT for RAO. Our analysis included nine studies with a total of 499 patients (286 HBOT, 213 non-HBOT). The results show that HBOT might be associated with better BCVA in patients with RAO when heterogeneity is accounted for, although no significant differences were found in uncorrected VA between HBOT and non-HBOT. Serious AEs reported with HBOT were rare and included seizures, ear barotrauma and epistaxis. Interestingly, HBOT was notably associated with lower rates of neovascular glaucoma and stroke. Our results highlight the need for high-quality comparative prospective studies with standardized outcome measures to better guide RAO clinical management.

This meta-analysis provides nuanced insights into the potential role of HBOT in managing RAO in the acute setting. While our analysis showed a significant improvement in BCVA after removing one heterogeneous study, the overall evidence remains controversial. The heterogeneity observed in our analysis underscores the complexity of RAO management. Factors such as time from symptom onset, patient age and underlying comorbidities likely influence treatment outcomes. The varied baseline VA measurements across studies further complicate direct comparisons.

HBOT functions through a unique mechanism of action, primarily by increasing tissue oxygenation, which might ultimately mitigate ischemic damage to the retinal tissue.^{Reference Hadanny, Maliar and Fishlev17} It increases tissue oxygenation by delivering 100% oxygen under elevated atmospheric pressure, substantially raising the partial pressure of oxygen in the blood. In RAO, perfusion to the inner retinal layers is compromised due to obstruction of the central or branch retinal artery. However, the outer retina remains perfused through the choroidal circulation, which is supplied by the posterior ciliary arteries. HBOT facilitates enhanced diffusion of oxygen from the well-perfused outer retina toward the ischemic inner retina. This compensatory oxygen delivery may help sustain retinal metabolism, delay irreversible cellular damage and preserve visual function while awaiting spontaneous or therapeutic reperfusion.^{Reference Beiran, Goldenberg, Adir, Tamir, Shupak and Miller18–Reference Celebi20} Ultimately, by saturating tissues with high-concentration oxygen, HBOT aims to reduce hypoxia, support cellular metabolism and potentially limit the irreversible damage associated with RAO.^{Reference Celebi20} Therefore, HBOT has a distinctive mechanism of action from thrombolytic interventions considered for RAO patients, including systemic intravenous thrombolysis (IVT)^{Reference Huang, Wang and Zhang21} and intra-arterial fibrinolysis.^{Reference Page, Khattar and White22} One of the main limitations of HBOT in the treatment of RAO is the limited availability of hyperbaric chambers in the hyperacute setting. HBOT requires specialized equipment and trained personnel and is often located in tertiary centers or facilities with limited hours of operation, making timely access challenging for many patients. This logistical barrier limits the widespread implementation of HBOT as a first-line treatment despite its physiologic rationale and potential benefit when administered early.^{Reference Butler and Moon23}

It is crucial to understand the current evidence in the literature regarding the available acute treatment modalities for RAO other than HBOT. Systemic IVT, primarily using tissue plasminogen activator, presents another potential treatment strategy for RAO.^{Reference Mac Grory, Schrag and Biousse24} Several studies have shown that while systemic IVT might theoretically restore retinal blood flow, the permanent visual damage often occurs within the first few hours of occlusion, rendering late interventions largely ineffective.^{Reference Kozner, Eichenmann, Ceska Burdova, Pavlikova, Hlozanek and Dotrelova25,Reference Schultheiss, Hartig and Spitzer26} However, its application remains highly debated due to significant limitations.^{Reference Stretz, Paddock and Burton27} The narrow therapeutic window – typically less than 4.5 hours from symptom onset – severely restricts its clinical utility. Moreover, the risk of systemic complications, particularly hemorrhagic transformation, makes clinicians hesitant to routinely employ this approach.^{Reference Huang, Wang and Zhang21}

On the other hand, the EAGLE trial provided valuable insights into the use of local intra-arterial thrombolysis (IAT) for central RAO (CRAO). This approach directly targets the occlusive thrombus through localized intervention, offering a mechanistic approach to addressing the underlying pathophysiology of CRAO. Although the trial was terminated early after the first interim analysis due to similar efficacy between IAT and conservative management and a higher rate of AEs in the intervention group, it underscored critical safety considerations and the challenges of translating promising interventional approaches into clinical benefit. Rather than representing a therapeutic advancement per se, the EAGLE trial highlights the necessity of well-designed, adequately powered trials to evaluate interventions for CRAO.^{Reference Schumacher, Schmidt and Jurklies28}

To summarize, while our primary analysis focused on the efficacy and safety of HBOT, it is essential to contextualize its potential role among other acute interventions for RAO. IVT, typically administered within 4.5 hours of symptom onset, has demonstrated modest visual recovery rates ranging from 20% to 35% in observational studies but carries a risk of systemic bleeding and is often underutilized due to delayed presentation.^{Reference Mac Grory, Lavin, Kirshner and Schrag29,Reference Schrag, Youn, Schindler, Kirshner and Greer30} IAT, explored in the EAGLE trial, showed no superiority to conservative therapy and was associated with higher complication rates, leading to early termination of the study.^{Reference Schumacher, Schmidt and Jurklies28} In contrast, HBOT may offer visual improvement in 30%–45% of treated patients when initiated within 12–24 hours. In one of the largest retrospective studies, minor and reversible AEs occurred in approximately 5.5% of patients.^{Reference Hadanny, Maliar and Fishlev17} However, access to HBOT is often restricted by the limited availability of hyperbaric chambers, which constrains timely intervention.^{Reference Butler and Moon23} The current guidelines from the American Heart Association suggest that while IVT may be considered in select CRAO patients, evidence remains limited, and HBOT is not yet formally endorsed as standard of care.^{Reference Mac Grory, Schrag and Biousse24} Therefore, the optimal management strategy continues to evolve, and head-to-head comparative trials are needed to guide treatment selection.