To our knowledge, this is the first study to compare mortality outcomes in patients with COVID-19 respiratory failure treated with HBOT among a cohort of patients all of whom received dexamethasone, which to date, has been the only clearly effective treatment for COVID-19.10 Previous reports have shown preliminary efficacy of HBOT in COVID-19 but many of these studies were performed earlier when steroids were not standard-of-care and early intubation was preferred. Our results showed that among hospitalized patients with COVID-19 respiratory failure, the addition of HBOT to standard-of-care therapy was associated with a decrease in rate of intubation and mortality.
One explanation for the benefits of HBOT on the improved outcome of COVID-19 patients is its beneficial effects on the respiratory system as well as on the inflammatory cascade. The SARS-CoV-2 virus induces a dysregulated immune response in the host involving a massive release of cytokines and chemokines, inflammatory cell infiltration particularly in the lung, resulting in acute lung injury and acute respiratory distress syndrome (ARDS).3,23 Ventilation-perfusion mismatch due to blood perfusing lung tissue with impaired or no ventilation is thought to be a major mechanism of hypoxemia in COVID-19 respiratory failure.24 Coagulopathic mechanisms leading to microemboli and hemoglobin poisoning affecting its oxygen-carrying capacity may also play a role.25–27 HBOT is thought to reduce inflammatory cytokines and tissue inflammation, as seen in the treatment of radiation injuries, soft tissue wounds, infections,16–18 and therefore, it may also reduce inflammatory cytokines and tissue inflammation seen in COVID-19. The ability to increase the amount of dissolved oxygen in plasma at hyperbaric pressures would allow for enhanced hemoglobin-independent tissue oxygen delivery in COVID-19 hypoxemia.28 In patients requiring high rates of supplemental oxygen or fraction of inspired oxygen (FiO2), HBOT received at the earliest possible juncture could improve tachypnea, reduce work of breathing, and ward off the inflammatory cascade progressing into multiple organ dysfunction syndrome.29
Our data showed a lower mortality in the HBOT treatment group, across all age strata. After adjusting for differences in age and baseline oxygen requirements in the survival analysis between the two groups, the difference in mortality was not statistically significant. The treatment group included younger patients with likely fewer comorbidities at the time of treatment. The baseline oxygen requirements were also lower in the treatment group. The extent of COVID-19 disease at the time of hospitalization was likely more advanced in the non-treatment group, relegating this group to higher mortality regardless of HBOT.3
We noted a higher rate of tocilizumab administration in the non-treatment group. This may have been correlated with worsening clinical course of COVID-19 hypoxia in this group requiring escalation of care with an anti-inflammatory agent that was not part of the standard-of-care treatment regimen.
Practice patterns at our institution with respect to invasive mechanical ventilation (IMV) for COVID-19 hypoxia were fairly consistent during the duration of the study, and early intubation was avoided. While our analysis showed a statistically significant correlation (P = 0.03) between treatment with HBOT and lower rates of progression to IMV, shifts in intubation criteria, changing attitudes in patients and families towards intubation during the pandemic may have confounded this correlation. As seen in other studies conducted during the earlier months of the pandemic,3,4 we did note significantly higher mortality in intubated patients, irrespective of treatment with HBOT.
It is worth noting that a number of patients with higher oxygen supplementation requirements were unable to be offered HBOT treatment due to being too unstable for transport to the HBOT suite. These patients were not included in our analysis, however, this highlights the need for early identification and evaluation of patients eligible for HBOT in addition to receiving standard-of-care therapies such as steroids and antivirals.
Our study also showed that HBOT is a safe intervention similar to other reports that have been published in this realm.13–15, 30 Our cohort had a small number of minor adverse events from HBOT, with a single instance of ear barotrauma, confirming the safety profile that has been established over the years for HBOT in general, as well as in the case series which specifically evaluated HBOT in COVID-19 respiratory failure.13–15, 31
Our study had several limitations inherent to a retrospective analysis with a small study cohort. Due to the size and non-randomized nature of the cohort, there were differences in the baseline characteristics of the compared groups limiting the statistical significance of our results. With a larger cohort, we could potentially control for the effects of other treatments (e.g., remdesivir, tocilizumab), age, and comorbidities, all of which are potential effect modifiers. In addition, this study occurred prior to the deployment of COVID-19 vaccines, therefore, mortality may decrease in general as older and high-risk patients are vaccinated.19,20,32 We acknowledge that several non-randomized studies for COVID-19 treatments (convalescent plasma, antiviral and immune-modulating agents) initially showed great potential for therapeutic benefit but failed to reveal definitive results in randomized trials.12,33,34 HBOT may meet with the same fate but given the effect size observed in our study, further investigation is warranted.