In the United States, approximately 50,000 patients with carbon monoxide (CO) poisoning are admitted to the emergency departments (EDs) of hospitals annually, with 1,500 deaths reported annually (1–3). Neurocognitive sequelae develop in 25–50% of acute CO poisoning survivors (4). Neurocognitive sequelae, including gait and motor disturbances, cognitive dysfunction, hearing loss and vestibular abnormalities, dementia, depression, and psychosis, are variable and can be permanent (5).

Of the six published randomized controlled trials (RCTs) that evaluated the effect of hyperbaric oxygen therapy (HBO₂) in acute CO poisoning (4, 6–10), the most well-designed double-blind RCT by Weaver et al. satisfied all the elements of the Consolidated Standards of Reporting Trials (CONSORT) (4), and compared normobaric oxygen therapy (NBO₂) with three sessions of HBO₂ that were implemented within 24 h after arrival at the hospital. They reported that in patients arriving at the hospital within 24 h after CO poisoning, the intervention significantly reduced the incidence of cognitive sequelae at 6 weeks and 12 months post-treatment. In another RCT, Thom et al. (8) observed patients with mild to moderate CO poisoning and compared a group that received one session of HBO₂ within 6 h with a group that received atmospheric oxygen. They found that HBO₂ reduced the frequency of delayed neuropsychological sequelae (DNS). Therefore, one or three sessions of HBO₂ performed within 24 h of CO poisoning may be a reasonable recommendation for patients with symptomatic CO poisoning.

Although there is no current consensus on the number of HBO₂ sessions within 24 h, three sessions are recommended, according to the best-performing RCT study by Weaver et al. (4), by the Undersea and Hyperbaric Medical Society (1). Although Weaver et al. (4) performed three HBO₂ sessions within 24 h after hospital arrival, they did not compare the number of HBO₂ sessions implemented within 24 h. Additionally, Thom et al. (8) showed that one HBO₂ session alone might be effective in acute CO poisoning. Therefore, we do not know how many sessions of HBO₂ treatment within 24 h after ED arrival are most effective in preventing neurocognitive outcomes in acute CO poisoning. Therefore, we evaluated the difference in therapeutic effect according to the number of HBO₂ sessions [one vs. multiple (two or three)] in patients who received HBO₂ therapy within 24 h after ED arrival in CO poisoning.

In this study, there was no significant difference in the neurocognitive sequelae at 1 month according to the number of HBO₂ sessions performed within 24 h. In the 2018 annual scientific meeting of the Undersea and Hyperbaric Medical Society, Weaver et al. presented (unpublished) the results of a randomized trial comparing one and three HBO₂ sessions for acute CO poisoning (16). They included English-speaking patients with accidental CO poisoning who arrived at the hospital within 24 h of exposure and were not intubated. There was no difference in the rate of neuropsychological sequelae in those who received 3 HBO₂ sessions and those who received 1 HBO₂ session and two sham sessions (6 weeks and 6 months after CO poisoning). For patients meeting the inclusion criteria stipulated in this study, one HBO₂ treatment may be sufficient. However, they did not publish this study and included neither intentional poisoning nor severe CO poisoning (i.e., invasive mechanical ventilation patients). In our subgroup analysis according to severity, there was no significant difference in terms of neurocognitive sequelae at 1 month between the number of HBO₂ sessions. This implies that regardless of severity, one session of HBO₂ may be reasonable. Fujita et al. concluded that multiple HBO₂ sessions were associated with the incidence of DNS (17). Although they conducted a prospective multicenter study, they used different HBO₂ treatment protocols for each institution. In addition, among the 165 patients treated with HBO₂ within the first 24 h, only 79 patients (47.9%) received the first HBO₂ session with more than 2.8 ATA that could develop the therapeutic effect of HBO₂ (18, 19) (see Tables 3, 4).

In previous RCTs, HBO₂ with 2.8 or 3.0 ATA was more effective than NBO₂ in patients with symptomatic CO poisoning, (4, 7, 8) particularly in patients treated within 6 h after CO exposure. In an RCT by Ducassé et al. (7), one session of HBO₂ treatment was performed in patients with GCS >12 with an elapsed time between discovery and hospitalization of less than 2 h. In an RCT by Thom et al. (8), one HBO₂ session was performed within 6 h in patients with no loss of consciousness or cardiac instability. Two RCTs (7, 8) showed that HBO₂ was superior to NBO₂ in reducing neurocognitive sequelae. In addition, in an RCT by Weaver et al. (4), HBO₂ was given in three sessions in all patients, regardless of severity, and this treatment (mean exposure-to-treatment interval: 5.8 h) reduced neurocognitive sequelae incidence by half at 6 weeks, and from 25 to 18% at the 1 year evaluation, compared with no HBO₂ treatment. It means that in existing RCTs, both one and three HBO₂ sessions performed within 6 h worked more effectively than NBO₂ in patients with acute CO poisoning. Our results, combined with the previous RCTs (4, 7, 8) suggest that the first HBO₂ (2.8 or 3.0 ATA) session administered rapidly after CO exposure is the most important and effective. Meanwhile, some RCTs did not exhibit the therapeutic effect of HBO₂ (6, 9, 10). However, in a study by Raphael et al. (6), an insufficient dose of HBO₂ was used at 2.0 ATA, and nearly half of the study group was treated after more than 6 h post-exposure. Annane et al. (10) also used an insufficient dose of HBO₂ (2.0 ATA). For the optimal effect of HBO₂, adequate pressure is necessarily required (1). Although 2.8 ATA was used in the study by Scheinkestel et al. (9), the 1 month cognitive outcomes were not evaluated. Instead, the only cognitive outcomes provided were reported a few days after poisoning. In addition, three RCTs that showed no beneficial effects of HBO₂ did not meet the CONSORT guidelines, unlike the RCT conducted by Weaver et al. (4).

The findings of this study can be understood in terms of the time frame of pathophysiology by CO poisoning and the HBO₂ mechanism of action. Acute CO poisoning causes neutrophil degranulation by activating intravascular neutrophils through platelet–neutrophil aggregates (20). This process leads to oxidative stress, transformation of xanthine dehydrogenase to xanthine oxidase in endothelial cells, lipid peroxidation, and apoptosis by causing the release of myeloperoxidase, proteases, and reactive oxygen species (20, 21). Finally, these reactions develop an adaptive immunological response causing CO-mediated neurocognitive sequelae by the formation of chemically modified myelin basic protein (22). These CO-mediated inflammatory reactions proceed rapidly after CO exposure. The leukocyte adherence in the vascular endothelial cells that triggers these changes occurs early. In the first 90 min after CO poisoning in an animal model, xanthine dehydrogenase is converted to xanthine oxidase, and reactive oxygen species produced by xanthine oxidase result in lipid peroxidation, which is temporary, dissipating within 16 h (23).

In terms of the time frame of the HBO₂ mechanism of action, exposure to 2.8 or 3.0 ATA HBO₂ can inhibit leukocyte ß₂-integrin function by S-nitrosylation and cell adherence to the cerebral microvasculature, inhibiting the sequential immunological reaction, as shown in both animal and human studies (18, 19). HBO₂ temporarily inhibits adherence within 2 h after treatment (19). Additionally, HBO₂ efficiently protects from neuronal apoptosis 3–5 h after CO poisoning (24). In rats treated with HBO₂ 45 min after CO exposure, HBO₂ prevented immune-mediated neurological damage through partial prevention of chemically modified myelin basic protein formation (25). Therefore, early HBO₂ administration at 2.8 or 3.0 ATA is the most important because it may stop the process early, in turn preventing brain injury related to an adaptive immunological response.

There are a few limitations to this study. First, this was an observational, non-randomized study. From an analytical perspective, PSM was used to minimize bias due to the study design (26). Nevertheless, hidden bias may remain due to the effects of unmeasured confounding variables. However, this is the first study with a large sample size (>500 patients). Second, the number of patients who received three sessions of HBO₂ in this study was small. Weaver et al. chose to provide three HBO₂ sessions because a retrospective report suggested that the use of more than two treatments resulted in better outcomes than that of a single treatment (27). In addition, they provided the three sessions within a 24 h period because they anticipated that patients’ compliance would be better during a shorter period than a longer one. However, it is practically very difficult to perform three sessions at intervals of 6–12 h, all within 24 h at the clinical site. Third, we did not evaluate the effects of additional HBO₂ after 24 h. To date, no study has evaluated additional HBO₂ after 24 h. Therefore, we excluded patients with additional HBO₂ sessions after 24 h. Fourth, although few RCTs have conducted more than 6 neurocognitive tests, usually equivalent to CO batteries (4, 8), we only evaluated outcomes with the GDS combined with neurological impairment. Our institute uses the GDS stage to evaluate neurocognitive prognosis in patients with CO poisoning because it has the advantage of recognizing neurocognitive functions, such as memory and concentration, as well as activities of daily living, through interviews. We have previously reported the GDS stage for the measurement of neurocognitive outcomes in a study related to CO poisoning (11, 13, 28). Fifth, a few patients were lost to follow-up due to their condition, distance from the hospital, or poor compliance. Sixth, charcoal was the most common CO source in this study. Gas and oil combustion, which are the main sources of CO poisoning in Western countries, were the CO sources in 93 patients of the total cohort. In the gas and oil combustion-exposed subpopulation, there was no significant difference according to the number of HBO₂ sessions (p = 0.632) (Supplementary Table 3).

There were no differences in terms of the reduction in poor neurocognitive outcomes according to the number of HBO2 sessions administered within 24 h after CO poisoning. In addition, there was no difference according to severity in terms of neurocognitive outcomes. Therefore, one HBO2 treatment within 24 h may be reasonable.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Wonju Severance Christian Hospital’s institutional review board. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

YC conceived the study and designed the trial, obtained research funding, supervised the conduct of the study and data collection, and takes responsibility for the paper as a whole. JL provided statistical advice on study design and analyzed the data. JSL and YC drafted the manuscript, and all authors contributed substantially to its revision. All authors contributed to the article and approved the submitted version.

This work was supported by the National Research Foundation of Korea, which is funded by the Korean government (Ministry of Science and Information and Communications Technology, grant no. NRF-2021R1A2C200492211).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2023.1127978/full#supplementary-material