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HYPERBARIC OXYGEN THERAPY HBOT VS COVID

HYPERBARIC OXYGEN THERAPY HBOT BENEFITS



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HYPERBARIC OXYGEN THERAPY HYPERBARICS HELPS BY INCREASING BLOOD FLOW

HYPERBARIC OXYGEN THERAPY HYPERBARICS HELPS BY INCREASING BLOOD FLOW

HYPERBARIC OXYGEN THERAPY HYPERBARICS HELPS BY INCREASING OXYGEN REACH

HYPERBARIC OXYGEN THERAPY HYPERBARIC THERAPY STIMULATES STEM CELLS

HYPERBARIC OXYGEN THERAPY HYPERBARIC THERAPY IMPROVES THESE AREAS

© Royal College of Physicians 2021. All rights reserved. e629Clinical Medicine 2021 Vol 21, No 6: e629–32 ORIGINAL RESEARCHHyperbaric oxygen therapy for the treatment of long COVID: early evaluation of a highly promising interventionAuthors: Tim Robbins,A Michael Gonevski,B Cain Clark,C Sudhanshu Baitule,D Kavi Sharma,E Angel Magar,F Kiran Patel,G Sailesh Sankar,H Ioannis Kyrou,I Asad AliJ and Harpal S RandevaKBackgroundLong COVID is a common occurrence following COVID-19 infection. The most common symptom reported is fatigue. Limited interventional treatment options exist. We report the first evaluation of hyperbaric oxygen therapy (HBOT) for long COVID treatment.MethodsA total of 10 consecutive patients received 10 sessions of HBOT to 2.4 atmospheres over 12 days. Each treatment session lasted 105 minutes, consisting of three 30-minute exposures to 100% oxygen, interspersed with 5-minute air breaks. Validated fatigue and cognitive scoring assessments were performed at day 1 and 10. Statistical analysis was with Wilcoxon signed-rank testing reported alongside effect sizes.ResultsHBOT yielded a statistically significant improvement in the Chalder fatigue scale (p=0.0059; d=1.75 (very large)), global Authors: ANIHR clinical lecturer, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK, Warwick Medical School, Coventry, UK and Coventry University, Coventry, UK; Bhyperbaric doctor, Midlands Diving Chamber, Rugby, UK; Cassistant professor, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK and Coventry University, Coventry, UK; Dclinical fellow, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK; Etrial manager, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK; Fresearch grant coordinator, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK; Gchief medical officer, deputy chief executive officer and consultant cardiologist, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK and Warwick Medical School, Coventry, UK; Hassociate medical director, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK and Warwick Medical School, Coventry, UK; Iassociate professor, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK, Warwick Medical School, Coventry, UK and Coventry University, Coventry, UK; Jconsultant sleep and respiratory physician, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK and Warwick Medical School, Coventry, UK; Kdirector of research and development, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK and Warwick Medical School, Coventry, UKcognition (p=0.0137; d=–1.07 (large)), executive function (p=0.0039; d=–1.06 (large)), attention (p=0.0020; d=–1.2 (very large)), information processing (p=0.0059; d=–1.25 (very large)) and verbal function (p=0.0098; d=–0.92 (large)).ConclusionLong COVID-related fatigue can be debilitating, and may affect young people who were previously in economic employment. The results presented here suggest potential benefits of HBOT, with statistically significant results following 10 sessions.KEYWORDS: long COVID, hyperbaric oxygen therapy, fatigueDOI: 10.7861/clinmed.2021-0462IntroductionThe COVID-19 pandemic has resulted in the need to support large cohorts of patients suffering from long COVID after recovery from acute infection.1 Long COVID is a term ‘used to describe presence of various symptoms, even weeks or months after acquiring SARS-CoV-2 infection irrespective of the viral status’.2 Long COVID is a common condition, with estimates identifying that between 10% and 20% of people initially diagnosed with acute COVID-19 will go on to develop symptoms of long COVID.3 There remains some debate about the terminology used in long COVID, with the UK National Institute for Health and Care Excellence (NICE) also using the terminology ‘post-COVID-19 syndrome’ for signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis, and ‘ongoing symptomatic COVID-19’ for signs and symptoms of COVID-19 from 4 to 12 weeks.3 However, NICE also recognises the umbrella term ‘long COVID’.Long COVID now poses an emerging public health emergency with multiple challenges for the management of these patients in clinical practice.4–6 The symptoms associated with long COVID are diverse, including breathlessness, cough, fatigue, ‘brain fog’, anxiety and depression.7 One of the most commonly reported symptoms is fatigue, present in up to 65% of long COVID patients, this is accompanied by a substantial proportion also reporting cognitive and affective deficits (described in the literature as ‘brain fog’).8–11 The fatigue experienced by these patients can be particularly severe, preventing them from performing their usual ABSTRACT

e630 © Royal College of Physicians 2021. All rights reserved.Tim Robbins, Michael Gonevski, Cain Clark et alwork and activities, while the age group most affected by long COVID tends to be economically active adults.12Currently specific treatment options for long COVID are limited, with even fewer treatment options available for those suffering from fatigue.13,14 Thus, there is a growing need to identify effective treatments for these patients.15 Despite distinct differences, there are important similarities between long COVID fatigue and chronic fatigue syndrome.9,16Hyperbaric oxygen therapy (HBOT) is ‘an intervention where an individual breathes near 100% oxygen intermittently while inside a hyperbaric chamber that is pressurized to greater than sea level pressure (1 atmosphere absolute, or ATA)’.17,18 HBOT is used for both elective (eg soft tissue radiation complications and non-healing chronic wounds) and emergency medical conditions (eg carbon monoxide poisoning, decompression illness and gas embolism).17 In particular, HBOT has been shown to be safe and effective in the treatment of chronic fatigue syndrome.19,20 At University Hospitals Coventry and Warwickshire NHS Trust, working in direct partnership with the Midlands Diving Chamber at the Rugby Hospital of St Cross, we proposed that HBOT may be of benefit to people suffering from symptoms of long COVID. The first patient to receive HBOT for long COVID received this on the 11 January 2021. Currently, there is no study to our knowledge which explored the effects of HBOT on long COVID-related fatigue. Here we present the first evaluation of a HBOT service for the treatment of long COVID symptoms internationally.MethodsWe retrospectively evaluated the response of fatigue symptoms of patients with long COVID-related fatigue receiving HBOT at the Midlands Diving Chamber medical facility, Hospital of St Cross, Rugby. This retrospective evaluation was approved by the University Hospitals Coventry and Warwickshire NHS Trust COVID-19 Research Ethics Committee through the GAFREC Process (ID: 10026).We evaluated 10 consecutive patients undergoing HBOT for long COVID-related fatigue at the Midlands Diving Chamber. All patients were suffering from new fatigue that developed during or after an infection consistent with COVID-19 and continuing for more than 12 weeks. The clinical inclusion and exclusion criteria for these patients are listed in Table 1.All patients received 10 HBOT sessions, once daily at 2.4 atmospheres for 1 hour and 45 minutes over 12 days (with a 2-day break in the middle for the weekend).The responses of these 10 consecutive patients receiving HBOT therapy were evaluated with the primary outcome measure being the change in Chalder fatigue scale between days 1 and 10 of treatment.21 The secondary measure evaluated was the change in the cognitive profile scores of day 1 and day 10, as reported through the NeuroTrax evaluation.22 This scoring included global cognitive score, memory, executive function, attention, information processing speed, visual-spatial, verbal function and motor skills.Statistical analysisIn order investigate differences between day 1 and day 10 undergoing HBOT, Wilcoxon signed-rank testing was conducted, and reported alongside corresponding effect sizes (Cohen’s d; classified as small (0.2), medium (0.5), large (0.8) or very large (1.2), and 95% confidence intervals (CIs)).23 In addition, Bayes factors were also calculated to express the probability of a difference given H10 (alternate hypothesis) relative to H01 (null hypothesis), that is, values larger than 1 are in favour of H10 assuming that H01 and H10 are equally likely and using a default prior.24 Bayes factors were reported as the probability of the data given the alternative relative to the null hypothesis or vice-versa (classified as anecdotal (BF1–3), moderate (BF3–10), strong (BF10–30), very strong (BF30–100) or extreme (BF>100)).25–27 Bayesian analysis was concurrently utilised because it permits the amalgamation of discipline-specific knowledge, facilitates direct probability statements to be made pertaining to included parameters (ie population level effects), allows zero effects to be determined, provides estimates of uncertainty around parameter values that are more intuitively interpretable than those from null hypothesis testing alone, and supports in the interpretation of p values.28,29 All analyses were conducted using R software.30ResultsIn the present cohort, 60% of the patients were women. The mean average age of participants was 47.5 years (range 24–74). All patients had been suffering from long COVID symptoms for over 3 months.Participant level and overall group data for all collected validated scores between day 1 and day 10 of HBOT are presented in Table 2.Wilcoxon signed-rank tests indicated that once daily HBOT for 10 days yielded a statistically significant improvement in Chalder fatigue scale (p=0.0059; d=1.75 (very large)), global cognition (p=0.0137; d=–1.07 (large)), executive function (p=0.0039; Tabl e 1 . I nc lu si on an d exc lu si on cr it er ia fo r hyperbaric oxygen therapyInclusion criteria Exclusion criteria > Age above 18 years > Previous confirmed COVID-19 infection diagnosed with swab PCR test or positive antibody test > Subject willing and able to read, understand and sign an informed consent to have hyperbaric oxygen therapy > Patient suffering severe, longstand-ing post-COVID-19 syndrome > History of traumatic brain injury or any other non-COVID brain pathology > Active malignancy (current solid organ or blood cancer either under active treatment, observation or palliative care). > Substance use at baseline (alcohol use in excess of current government guidelines) > Severe or unstable physical disorders or major cognitive deficits at baseline > HBOT for any reason prior to study enrolment > Chest pathology incompatible with pressure changes (including moderate to severe asthma, COPD and history of pneumothorax) > Epilepsy > Ear or sinus pathology incompatible with pressure changes > ClaustrophobiaCOPD = chronic obstructive pulmonary disease; HBOT = hyperbaric oxygen therapy.

© Royal College of Physicians 2021. All rights reserved. e631Hyperbaric oxygen for the treatment of long COVIDd=–1.06 (large)), attention (p=0.0020; d=–1.2 (very large)), information processing speed (p=0.0059; d=–1.25 (very large)) and verbal function (p=0.0098; d=–0.92 (large)). Concomitantly, Bayes factors indicated that the evidence favouring the alternative vs the null hypothesis was moderate for global cognition (BF7.63), executive function (BF7.33) and verbal function (BF4.13); strong for attention (BF12.51) and information processing speed (BF15.32), and very strong for Chalder fatigue index (BF98.13).All pairwise comparisons including p values, mean differences (95% CIs), Cohen’s d effect sizes and Bayes Factors are presented in Table 2 and Fig 1. Finally, participant level and overall group data for days 1 and 10 are presented in the supplementary material S1.No adverse events were reported in any of these patients receiving HBOT during this treatment or in the immediate post-treatment phase.DiscussionAt University Hospitals Coventry and Warwickshire NHS Trust, we have established a dedicated clinician-led clinic for patients presenting with long COVID-related fatigue. The severity of symptoms seen and the impact on quality of life is profound. Many patients are unable to work (either in manual or office-based roles), drive, participate in their usual physical activity or, at times, engage with their family in the manner they would wish. The treatment options available for such people with severe symptoms of long COVID are limited, with very few interventional options.Here, to our knowledge, we describe the first evaluated use of HBOT to manage long COVID in the UK or internationally. We report statistically and clinically significant improvements to both the overall fatigue score and a range of cognitive domains using validated scales. The effect size measures calculated are large, suggesting a substantial improvement and, thus, there is a small likelihood these results are due to chance despite the small initial sample size. These are important findings suggesting a possible positive effect of HBOT on the common long COVID-related symptoms of fatigue and ‘brain fog’. These results match with the clinical and qualitative observations of patients receiving the therapy, many of whom report their lives have been transformed.The mechanism of long COVID is still uncertain.1 One possible hypothesis is that the wide variety of changes that characterise long COVID are a result of prolonged tissue hypoxia.6 This is frequently the common denominator for many diseases that are responsive to HBOT.31 Further research is needed to understand the underlying mechanisms of long COVID and positive responses seen in relation to HBOT.1While these results are important, they represent only an initial evaluation. Indeed, the sample size consists of only 10 patients. Furthermore, these patients have not been followed up for a prolonged period to assess whether the noted improvements of these long COVID-related symptoms were sustained. Based on initial informal feedback, patients do excellently in the longer term. Thus, there is a need to assess these effects of HBOT in the context of a randomised placebo-controlled prospective study. However, these initial results suggest that HBOT merits further study as a treatment option for patients presenting with long COVID symptoms (such as fatigue). Given the scale of the emerging long COVID public health emergency globally, and the still ongoing COVID-19 pandemic, there is an urgent need for larger-scale randomised placebo-controlled trials to evaluate the potential impact of HBOT in the context of long COVID. In addition, creation of a registry of patients receiving HBOT for long COVID symptoms (such as fatigue) in order to obtain follow-up data over time is also suggested. These are both elements Tabl e 2 . D ay 1 v s day 10 of hy pe rb ar ic oxyg en th era pyp value Mean difference (95% CI) Cohen’s d BFGlobal cognition 0.0137a–8.4 (–14.55 – –2.9) –1.07 7.626Memory 0.8457 0.9 (–10.6–7) –0.01 0.3091Executive function 0.0039a–7.3 (–12.65 – –2.2) –1.06 7.3286Attention 0.0020a–7 (–12.45 – –2.05) –1.2 12.5093IPS 0.0059a–15.3 (–29.8 – –8.2) –1.25 15.3199Visual-spatial 0.1056 –5.5 (–11.3–0.65) –0.76 2.12Verbal function 0.0098a–21.95 (–44.85 – –6.15) –0.92 4.1335Motor skills 0.0827 –3.9 (–7.55–2.2) –0.52 0.85Chalder fatigue scale 0.0059a18 (9.5–26) 1.75 98.13asignificant difference between time points; BF = Bayes factor; CI = confidence interval; IPS = information processing speed.Fig 1. Scores between day 1 (before) and day 10 (after) of hyperbaric oxygen therapy. *significant difference; arbitrary units are construct specific.******160140120100806040200Arbitrary unitsChader fa!gue scaleGlobal cogni!onMemoryExecu!ve func!onA"en!onInforma!on processing speedVisual-spa!alVerbal func!onMotor skillsBefore A#er

e632 © Royal College of Physicians 2021. All rights reserved.Tim Robbins, Michael Gonevski, Cain Clark et alof work currently being developed collaboratively between the Midlands Diving Chamber and University Hospitals Coventry and Warwickshire NHS Trust. Supplementary materialAdditional supplementary material may be found in the online version of this article at www.rcpjournals.org/clinmedicine:S1 – Descriptive participant level and overall group data, day 1 vs day 10.References1 Marshall M. The four most urgent questions about long COVID. Nature 2021;594:168–70.2 Raveendran A, Jayadevan R, Sashidharan S. Long COVID: an over-view. Diabetes Metab Syndr 2021;15:869–75.3 Venkatesan P. NICE guideline on long COVID. Lancet Respir Med 2021;9:129.4 Rando HM, Bennett TD, Byrd JB et al. Challenges in defining Long COVID: Striking differences across literature, Electronic Health Records, and patient-reported information. medRxiv 2021;2021.03.20.21253896.5 Alwan NA, Johnson L. Defining long COVID: Going back to the start. Med (N Y) 2021;2:501–4.6 Nabavi N. Long covid: How to define it and how to manage it. BMJ 2020;370:m3489.7 Mandal S, Barnett J, Brill SE et al. ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormali-ties following hospitalisation for COVID-19. Thorax 2021;76:396–8.8 Cabrera Martimbianco AL, Pacheco RL, Bagattini ÂM, Riera R. Frequency, signs and symptoms, and criteria adopted for long COVID: a systematic review. Int J Clin Pract 2021;75:e14357.9 Wostyn P. COVID-19 and chronic fatigue syndrome: Is the worst yet to come? Med Hypotheses 2021;146:110469.10 Morley JE. COVID-19 — the long road to recovery. J Nutr Health Aging 2020;24:917–9.11 Boldrini M, Canoll PD, Klein RS. How COVID-19 Affects the Brain. JAMA Psychiatry 2021;78:682–3.12 Maxwell E. Living with Covid19. National Institute for Health Research, 2020.13 Shah W, Hillman T, Playford ED, Hishmeh L. Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ 2021;372:n136.14 Gaber T. Assessment and management of post-COVID fatigue. Progress in Neurology and Psychiatry 2021;25:36–9.15 Palmer SJ. Government funding for research into long COVID. British Journal of Cardiac Nursing 2021;16:1–3.16 Wong TL, Weitzer DJ. Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)—A Systemic Review and Comparison of Clinical Presentation and Symptomatology. Medicina 2021;57:418.17 Kirby JP, Snyder J, Schuerer DJ, Peters JS, Bochicchio GV. Essentials of hyperbaric oxygen therapy: 2019 review. Mo Med 2019;116:176.18 Moon R. Hyperbaric oxygen therapy indications. Best Publishing Company, 2019.19 Akarsu S, Tekin L, Ay H et al. The efficacy of hyperbaric oxygen therapy in the management of chronic fatigue syndrome. Undersea Hyperb Med 2013;40:197–200.20 Hoof EV, Coomans D, Becker PD et al. Hyperbaric therapy in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 2003;11:37–49.21 Jackson C. The Chalder fatigue scale (CFQ 11). Occup Med (Lond) 2015;65:86.22 Doniger GM. NeuroTraxcomputerized cognitive tests: Test descrip-tions. Medina: NeuroTrax, 2013:1–16.23 Robbins T, Keung SNLC, Sankar S, Randeva H, Arvanitis TN. Application of standardised effect sizes to hospital discharge outcomes for people with diabetes. BMC Medical Informatics and Decision Making 2020;20:1–6.24 Eyre EL, Clark CC, Tallis J et al. The effects of combined movement and storytelling intervention on motor skills in South Asian and White children aged 5–6 years living in the United Kingdom. Int J Environ Res Public Health 2020;17:3391.25 Marsman M, Wagenmakers E-J. Bayesian benefits with JASP. European Journal of Developmental Psychology 2017;14:545–55.26 Wagenmakers E-J, Marsman M, Jamil T et al. Bayesian inference for psychology. Part I: Theoretical advantages and practical ramifica-tions. Psychon Bull Rev 2018;25:35–57.27 Wagenmakers E-J, Love J, Marsman M et al. Bayesian inference for psychology. Part II: Example applications with JASP. Psychon Bull Rev 2018;25:58–76.28 Wasserstein RL, Lazar NA. The ASA statement on p-values: context, process, and purpose. The American Statistician 2016;70:129–133.29 Amrhein V, Greenland S, McShane B. Scientists rise up against sta-tistical significance. Nature 2019;567:305–7.30 R Core Team. R: A language and environment for statistical com-puting. R, 2013.31 Choudhury R. Hypoxia and hyperbaric oxygen therapy: a review. Int J Gen Med 2018;11:431–42.Address for correspondence: Dr Timothy Robbins, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK. Email: timothy.robbins@nhs.net

!|!!!!!!!!(2022)!12:11252!!|!www.nature.com/scientificreportsFinci*As of January 2022, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in more than 300 million infected cases. Even though most infected patients recover, 10–30% remain with persistent symptoms that have devastating eects on their quality of life1,2. e World Health Organization has recognized this clinical condition and dened it as post-COVID-19 condition. is condition is conrmed three months from the onset of COVID-19 with having physical, neurocognitive and psychiatric symptoms that persist for more than two months and cannot be explained by an alternative diagnosis1. Neurocognitive and psychiatric symptoms include decreased executive functions, anxiety, depression and posttraumatic stress symptoms3,4. Most common physical symptoms include fatigue, dyspnea, ageusia, anosmia, insomnia, headaches and systemic widespread pain5.e pathogenesis of post-COVID-19 condition is not yet determined. Suggested mechanisms include direct brain invasion of the virus, dysregulated immunologic responses, thrombotic disease, mitochondrial dysfunction and vascular injury with secondary tissue hypoxia6,7. Currently studied treatment options of post-COVID-19             Israel.!        Sagol! School! of! Neuroscience,!          Catalogna.!*email:!efratishai@outlook.com

Vol:.(1234567890)!|!!!!!!!!(2022)!12:11252!!|!www.nature.com/scientificreports/condition are targeted anti-inammatory molecules, specic diets, and cognitive behavioral therapy. However, none have been determined eective8–10.In recent years, evidence has been accumulated about the neuroplasticity eects of hyperbaric oxygen therapy (HBOT)11–19. It is now realized, that the combined action of hyperoxia and hyperbaric pressure, leads to signi-cant improvement in tissue oxygenation while targeting both oxygen and pressure sensitive genes11. Preclinical and clinical studies have demonstrated several neuroplasticity eects including anti-inammatory, mitochondrial function restoration, increased perfusion via angiogenesis and induction of proliferation and migration of stem cells11–13,20,21. Robbins etal. suggested a possible benet with HBOT in a recent case series of ten post-COVID-19 condition patients22.e aim of the current study was to evaluate the eects of HBOT on patients suering from post-COVID-19 condition, with ongoing symptoms for at least 3months aer conrmed infection, in a randomized, sham-control, double blind clinical trial.    Ninety-one patients were eligible to participate in the study. Twelve patients did not complete baseline evaluation. Seventy-nine were randomized to one of the two arms. Two patients from the control group withdrew their consent during treatment, and one patient was excluded due to poor compliance and did not complete the assessments. Two patients from the HBOT group were excluded, one due to intercurrent illness, and one due to a personal event that prevented completion of the protocol. An additional patient from the HBOT group withdrew his consent during treatment. Accordingly, 37 patients from the HBOT group and 36 patients from the control group completed the protocol and were included in the analysis. e patient owchart and study timeline are presented in Supplementary Fig.1. Patient baseline characteristics are detailed in Table1. No statistically signicant dierences between the two groups were observed in baseline characteristics. Post-COVID-19 self-reported symptoms data are provided in Sup-plementary Tables1–2. No signicant dierences were observed in baseline symptoms between the two groups.Participants’ blinding was found to be reliable, where the correct groupallocation perceptionrate was 54.1% and 66.7% (p = 0.271) in the HBOT and control groups respectively (Supplementary Fig.2).  ere were no signicant dierences between the groups in all baseline cognitive domains. ere was a signicant group-by-time interaction in the global cognitive score post-HBOT compared to the control group, with a medium net eect size (d = 0.495, p = 0.038). Both attention and executive func-tion domains had signicant group-by-time interactions (d = 0.477, p = 0.04 and d = 0.463, p = 0.05 respectively) (Table2, and Supplementary Table3).  Questionnaire analysis is summarized in Fig. 1, Table 3, and Supplementary Table4. At baseline, there were no signicant dierences in all domains between the groups. In the SF-36, the HBOT group improved in both physical limitation and energy with group-by-time signicant interactions of (d = 0.544, p = 0.023) and (d = 0.522 p = 0.029). In the PSQI, the HBOT group improved in the global sleep score with a signicant group-by-time interaction (d = −0.48, p = 0.042). Improvements in psychological symptoms were also demonstrated aer HBOT with signicant group-by-time interaction and large eect size in the total BSI-18 score (d = 0.636, p = 0.008). Both somatization (d = 0.588, p = 0.014) and depression (d = 0.491, p = 0.04) scores showed signicant group-by-time interactions. e anxiety score improved signicantly in the HBOT and did not change in the control group. However, the group-by-time interaction did not reach signicance level (p = 0.079). Post-HBOT improvement was also found in the BPI pain interface score with a signicant group-by-time interaction and a large eect size (d = 0.737, p = 0.001).Brain perfusion. One patient was excluded due to excessive head motion. erefore a total of 36 patients from each group were analyzed. Voxel-based analysis revealed signicant gray-matter CBF increases in the HBOT group compared to the controls as shown in Fig.2A, and Supplementary Table5. Signicant group-by-time interactions were demonstrated in the le and right supramarginal gyrus (BA40), le anterior cingulate gyrus (BA10/BA32), right superior parietal lobule (BA7), le supplementary motor area (BA6), le parahippocampal gyrus, and the right insula (BA13).Brain microstructure. Voxel-based DTI analysis of brain gray-matter mean diusivity (MD) maps is shown in Fig.2B and Supplementary Table6. Signicant group-by-time interactions were demonstrated in the le frontal precentral gyrus (BA6), and the right middle frontal gyrus (BA10, BA8).Voxel-b ased DT I an alysis of brai n white -matt er fr action al aniso tropy ( FA) m aps is show n in Fi g.2C, and Supplementary Table7. Signicant group-by-time interactions were demonstrated in both right and le superior corona radiata.ere were signicant correlations between pain interference and energy scores and MD changes in the right middle frontal gyrus (r = 0.465, p < 0.0001, r = −0.309, p = 0.008 respectively). e NeturTrax global score cor-related to increased perfusion in the le supramarginal gyrus (r = 0.285, p = 0.0152) (Fig.2D,E).e results of the smell and taste evaluations are summarized in Supplementary Table8, and Supplementary Figs.3–4. Impairment in odor detection at baseline was found in 27(73%) of the HBOT patients and in 25(69%) of the control. Both groups’ odor detection improved signicantly and there was no signicant group-by-time interaction.Abnormal taste sensation at baseline was found in 18(49%) patients from the HBOT group and in 12(33%) from the control. Compared to baseline, there were signicant improvements in the HBOT group in the total

!"#$%&'()*+,-./012322222222&)'))12()%((),)2232444$56789:$;"<=>;?:57?@?;9:A"97>=taste score, and in sweet and bitter taste domains (p = 0.003, 0.007 and 0.014 respectfully). In the control group, there was a signicant improvement in only the sweet domain (p = 0.034). However, there were no signi cant group-by-time interactions.Baseline blood tests, and pulmonary function tests were within the normal range. No signicant changes were observed post-treatment (Supplementary Tables9–10). e reported side eects are present in Supplementary Table11. ere was no signicant dierence in any of the reported side eect between the groups (35.1% and 38.9%, p = 0.739 in the HBOT and control groups respectively). None of the patients needed to discontinue the treatment because of side eects.is is the rst prospective, randomized sham-controlled trial demonstrating signicant improvement beyond the expected clinical recovery course of post-COVID-19 condition. We found that HBOT improves dysexecu-tive functions, psychiatric symptoms (depression, anxiety and somatization), pain interference symptoms and fatigue. ose changes were associated with increased CBF and brain microstructural changes in frontal, parietal and limbic regions associated with cognitive and psychiatric roles.Tabl e 1. Baseline characteristics. Data presented as n (%); continuous data, mean ± SD; †e body-mass index is the weight in kilograms divided by the square of the height in meters. *During COVID-19 infection. MoCA Montreal Cognitive Assessment.HBOT Control p-valueN 37 36Age (years) 48.4 ± 10.6 47.8 ± 8.5 0.784Males 18 (48.6) 11 (30.6) 0.153Female 19 (51.4) 25 (69.4) 0.153BMI (Kg/m2) 26.9 ± 5.1 26.5 ± 4.7 0.690Years of education 14.6 ± 2.7 15.1 ± 3.6 0.592Marital statusSingle 5 (13.5) 7 (19.4) 0.543Married 27 (73.0) 22 (61.1) 0.326Divorced 3 (8.1) 6 (16.7) 0.308Widowed 2 (5.4) 1 (2.8) 1.000Number of children 2.5 ± 1.4 2.4 ± 1.5 0.839Employment statusFull time 24 (64.9) 22 (61.1) 0.811Part time 9 (24.3) 11 (30.6) 0.607Not employed 4 (10.8) 3 (8.3) 1.000Time from infection (days) 159.1 ± 71.3 171.5 ± 66.4 0.450Hospitalized* 4 (10.8) 8 (22.2) 0.221MoCA—cognitive assessment 25.4 ± 3.6 25.0 ± 3.3 0.601High risk conditionsBMI† > 30 11 (29.7) 9 (25.0) 0.794Age > 60 years 4 (10.8) 4 (11.1) 1.000Cancer 0 (0.0) 0 (0.0) 1.000Diabetes mellitus 1 (2.7) 1 (2.8) 1.000Hypertension 4 (10.8) 2 (5.6) 0.674Heart disease 1 (2.7) 1 (2.8) 1.000Immune deciency 0 (0.0) 0 (0.0) 1.000Asthma 2 (5.4) 1 (2.8) 1.000Other chronic lung diseases 0 (0.0) 0 (0.0) 1.000Chronic liver disease 0 (0.0) 4 (11.1) 0.054Chronic kidney disease 0 (0.0) 0 (0.0) 1.000Hematologic disease\disorder 0 (0.0) 0 (0.0) 1.000Chronic neurological impairment\disease 1 (2.7) 1 (2.8) 1.000SmokingCurrent 0 (0.0) 0 (0.0) 1.000Previous 10 (27.0) 7 (19.4) 0.581

Vol:.(1234567890)!|!!!!!!!!(2022)!12:11252!!|!www.nature.com/scientificreports/Becker etal. show that the main cognitive impairments in post-COVID-19 condition is dysexecutive, or brain fog, with considerable implications for occupational, psychological, and functional outcomes23. In this study, improvements in the memory domain was in both groups, which can be attributed to the natural course of the disease. However, executive function and attention improved only following HBOT. A previous study has demonstrated decreases in CBF in frontal and temporal cortices of post-COVID-19 patients24. Hence, the improvement following HBOT may be attributed to the increases in CBF and MD, demonstrated in the BA10, BA8 and BA6 areas that are associated with executive function and attention25–27.Post-COVID-19 condition is associated with long term psychiatric symptoms including depression, anxiety, and somatization3,4. HBOT improved both depression and somatization symptoms. Benedetti etal. detected robust associations between anxiety and depression in post-COVID-19 patients, and DTI measures of GM and WM microstructure in the superior and posterior corona radiata, superior longitudinal fasciculus and cingulum28. In this study, the psychiatric improvement was also associated microstructure changes in the supe-rior corona radiata area. Furthermore, we previously studied childhood abuse induced bromyalgia patients in whom HBOT induced signicant metabolic improvements in the same brain areas in addition to similar clini-cal improvement in somatization and depression14. e association between improvements in the psychiatric symptoms to the MRI changes gives further strength to the biological nature of this disease and HBOT’s eect.Tabl e 2. Neurocognitive performance changes. Data are presented as mean ± SD; Bold, signicant aer Bonferroni correction; * Cohen’s d net eect size; ** pre-post treatment/ sham P-value. e follow up assessments were performed 1–3weeks aer the last treatment session.HBOT Controlp-value baselineNet eect size*ANOVA (group-by-time) interactionPre Post p-value** Change Pre Post p-value** Change F p-valueN 37 36Score 98.3 ± 11.1 104.1 ± 7.2 0.0001 5.8 ± 7.9 98.9 ± 8.5 101.3 ± 8.9 0.0105 2.4 ± 5.4 0.821 0.495 4.469 0.038Memory 93.7 ± 13.4 102.0 ± 10.9 0.0001 8.3 ± 11.2 94.9 ± 12.2 102.1 ± 8.7 0.0000 7.2 ± 8.5 0.695 0.111 0.226 0.636Executive function103.5 ± 13.1 109.0 ± 8.2 0.0029 5.6 ± 10.6 102.5 ± 10.3 103.8 ± 10.5 0.2526 1.3 ± 6.8 0.725 0.477 4.159 0.045Attention 97.3 ± 16.0 101.9 ± 9.0 0.0292 4.6 ± 12.4 99.6 ± 8.2 99.4 ± 10.1 0.8495 −0.3 ± 8.3 0.434 0.463 3.914 0.052Information processing speed94.8 ± 14.2 102.4 ± 13.0 0.0003 7.6 ± 11.4 94.4 ± 14.2 98.3 ± 17.7 0.0734 3.9 ± 12.7 0.910 0.303 1.673 0.200Motor skills 102.4 ± 12.6 105.3 ± 8.3 0.0827 2.9 ± 10.0 102.9 ± 8.4 102.9 ± 9.0 0.9639 0.1 ± 6.7 0.858 0.338 2.079 0.154Figure1. Questionnaire results analysis shown in violin plots of actual distribution, and in boxplots. Values are normalized to answer scale range: SF-36, Energy [0..100], PSQI, Global [0..21], BSI-18, Total [0..72] and BPI, Pain Interference [0..10]. e red mark indicates the median, and the bottom and top edges of the box indicate the 25th and 75th percentiles, respectively. Black marks indicate mean and standard deviation. †p < 0.0001, N.S. not signicant (see also Table3).

Vol.:(0123456789)!|!!!!!!!!(2022)!12:11252!!|!www.nature.com/scientificreports/HBOT also improved pain interference. Interestingly, the pain interference score was high at baseline in both groups whereas the severity score was not. Diuse muscle and joint pain without local inammation or malformation is one of the common symptoms of post-COVID-19, resembling other central sensitization syn-dromes, such as bromyalgia. A growing number of clinical studies, have demonstrated the ecacy of HBOT in improving pain and quality of life of bromyalgia patients14,15,29–32. Previous studies have shown that bromyalgia is associated with decreased brain perfusion in the insula, hippocampus, putamen, prefrontal and cingulate cortex33–35. In the current study, these regions showed increased perfusion aer HBOT.In post-COVID-19 condition, fatigue is a common symptom, and this symptom was reported in 77% of the study’s patients. HBOT improved both physical limitations and the energy domains. In concordance, Robbins et al. reported a signicant improvement in fatigue following HBOT sessions in post-COVID-19 patients22. e HBOT induced MD changes in the frontal lobe (BA 6,8,10) can be associated with the clinical results, as hypometabolism in the frontal lobe has been implicated with fatigue in COVID-19 patients36. Post-COVID-19 fatigue has many overlaps with chronic fatigue syndrome (CFS). Symptoms common to CFS and post-COVID-19 condition include fatigue, pain, neurocognitive/psychiatric symptoms, reduced daily activity, and post-exertional malaise36. Previous studies have demonstrated the ecacy of HBOT in CFS, in reducing symptom severity and increasing quality of life37,38.e pathogenesis of post-COVID-19 condition in the central nervous system includes direct neuronal injury in the frontal lobes, chronic injury mediated by glial cells, ischemic events mediated by thrombotic events, mitochondrial dysfunction, and chronic in ammation11–19. Growing evidence shows that new HBOT protocols Tabl e 3. Questionnaire results analysis. Data are presented as mean ± SD; Bold, signicant aer Bonferroni correction; *Cohen’s d net eect size; **Pre-post treatment/sham p-value. e follow up assessments were performed 1–3weeks aer the last treatment session.HBOT Controlp-value baselineNet eect size*ANOVA (group-by-time) interactionPre Post p-value** Change Pre Post p-value** Change F p-valueN 37 36SF-36Physical func-tioning60.3 ± 24.7 63.0 ± 29.3 0.439 2.7 ± 21.0 50.7 ± 24.4 58.6 ± 26.9 0.010 7.9 ± 17.5 0.105 −0.269 1.322 0.254Physical limita-tions16.9 ± 26.0 50.7 ± 38.3 0.000 33.8 ± 40.9 29.2 ± 34.1 38.9 ± 38.8 0.224 9.7 ± 47.2 0.092 0.546 5.43 0.023Emotional limitations33.3 ± 33.8 60.4 ± 37.8 0.001 27.0 ± 42.9 32.4 ± 37.3 50.0 ± 43.4 0.024 17.6 ± 44.7 0.913 0.215 0.846 0.361Energy 27.7 ± 17.8 45.9 ± 25.7 0.000 18.2 ± 24.4 28.5 ± 16.5 34.4 ± 21.9 0.121 6.0 ± 22.5 0.851 0.522 4.976 0.029Emotional wellbeing49.9 ± 20.1 64.0 ± 21.5 0.000 14.1 ± 17.8 51.2 ± 18.7 55.3 ± 22.7 0.332 4.1 ± 25.1 0.783 0.459 3.841 0.054Social function 47.6 ± 25.5 67.6 ± 25.7 0.000 19.9 ± 25.6 51.4 ± 26.3 61.5 ± 26.9 0.020 10.1 ± 24.8 0.543 0.391 2.795 0.099Pain domain 39.4 ± 33.6 59.5 ± 33.0 0.000 20.1 ± 28.6 41.1 ± 30.2 54.2 ± 28.4 0.007 13.1 ± 27.1 0.821 0.254 1.179 0.281General health domain51.5 ± 18.3 60.9 ± 20.4 0.003 9.5 ± 18.2 46.5 ± 13.5 49.4 ± 18.6 0.397 2.9 ± 20.4 0.200 0.338 2.088 0.153PSQIGlobal 10.6 ± 4.0 8.1 ± 4.1 0.000 −2.6 ± 3.1 10.3 ± 4.2 9.2 ± 4.3 0.068 −1.0 ± 3.3 0.704 −0.486 4.302 0.042Sleep quality 2.1 ± 0.8 1.5 ± 0.9 0.001 −0.6 ± 1.0 2.1 ± 0.7 1.8 ± 0.8 0.014 −0.3 ± 0.7 0.990 −0.310 1.753 0.19Sleep latency 1.9 ± 1.1 1.3 ± 1.2 0.000 −0.6 ± 0.8 1.9 ± 1.0 1.6 ± 1.1 0.012 −0.3 ± 0.8 0.837 −0.308 1.73 0.193Sleep duration 1.5 ± 1.1 1.4 ± 0.9 0.500 −0.1 ± 1.0 1.3 ± 1.0 1.6 ± 0.9 0.133 0.2 ± 0.9 0.457 −0.360 2.364 0.129Sleep eciency 0.5 ± 0.9 0.4 ± 0.8 0.096 −0.1 ± 0.5 0.5 ± 1.0 0.4 ± 0.6 0.226 −0.2 ± 0.8 0.849 0.047 0.041 0.840Sleep distur-bances1.9 ± 0.6 1.5 ± 0.6 0.001 −0.4 ± 0.6 1.7 ± 0.6 1.6 ± 0.6 0.291 −0.1 ± 0.6 0.224 −0.465 3.94 0.051Sleep medica-tion0.8 ± 1.2 0.5 ± 1.1 0.134 −0.3 ± 1.1 0.7 ± 1.1 0.6 ± 0.9 0.845 −0.0 ± 0.8 0.740 −0.251 1.15 0.287Daytime dysfunction2.0 ± 0.7 1.5 ± 0.9 0.004 −0.5 ± 1.0 2.0 ± 0.8 1.7 ± 0.8 0.039 −0.3 ± 0.9 0.882 −0.221 0.891 0.348BSI-18Tot a l 25.1 ± 13.6 16.2 ± 13.2 0.000 −8.9 ± 10.6 22.3 ± 12.3 20.5 ± 15.8 0.362 −1.8 ± 11.7 0.362 −0.636 7.372 0.008Somatization 9.3 ± 6.0 6.2 ± 5.9 0.000 −3.1 ± 3.8 8.3 ± 4.5 7.7 ± 5.5 0.531 −0.5 ± 5.0 0.397 −0.588 6.312 0.014Depression 7.4 ± 6.1 4.1 ± 4.7 0.001 −3.2 ± 5.4 6.3 ± 5.1 5.6 ± 6.3 0.300 −0.8 ± 4.4 0.446 −0.491 4.395 0.04Anxiety 8.4 ± 4.6 5.9 ± 4.7 0.002 −2.5 ± 4.5 7.7 ± 5.3 7.2 ± 6.3 0.571 −0.5 ± 5.3 0.534 −0.417 3.169 0.079BPIPain severity score1.6 ± 2.3 1.4 ± 2.5 0.520 −0.2 ± 1.8 1.5 ± 1.7 1.3 ± 2.2 0.721 −0.1 ± 2.3 0.701 −0.024 0.011 0.917Pain interfer-ence score4.5 ± 3.0 2.6 ± 2.8 0.000 −1.9 ± 2.3 3.7 ± 2.8 3.6 ± 2.5 0.855 −0.1 ± 2.5 0.223 −0.784 11.204 0.001

Vol:.(1234567890)!|!!!!!!!!(2022)!12:11252!!|!www.nature.com/scientificreports/can induce neuroplasticity and improve brain function even months to years aer the acute injury12,14–18. ese protocols, including the one used in the current study, utilize the so called “hyperoxic-hypoxic paradox”, by which repeated uctuation in both pressure and oxygen concentrations induce gene expression and metabolic pathways that are essential for regeneration without the hazardous hypoxia11. ese pathways can modulate the immune system, promote angiogenesis, restore mitochondrial function and induce neurogenesis in injured brain tissue11–19. Some or all of these eects may explain the benecial eects found in the current study.e primary strength of this study is the sham protocol which was found eective in blinding participants to treatment. Although this study presents advanced imaging methods, and whole brain study approach, which were correlated with clinical ndings, the study has several limitations. e sample size is relatively small. Larger cohort studies may identify patients who can benet the most from the treatment. e HBOT protocol included 40 sessions. However, an optimal number of sessions for maximal therapeutic eect has yet to be determined. Lastly, results were collected 1–3weeks aer the last HBOT session, and long-term results remain to be collected.In conclusion, HBOT can improve dysexecutive functions, psychiatric symptoms (depression, anxiety and somatization), pain interference symptoms and fatigue of patients suering from post-COVID-19 condition. e benecial eect can be attributed to increased brain perfusion and neuroplasticity in regions associated Figure2. Brain regions with signicant post-hyperbaric oxygen therapy changes compared to control. Group-by-time interaction ANOVA model in: (A) cerebral blood ow (CBF) in GM, p < 0.0005, uncorrected, (B) mean diusivity DTI-MD in GM, p < 0.002, uncorrected, (C) fractional anisotropy DTI-FA in WM, p < 0.002, uncorrected. (D) signicant correlation between pain interference score and the right middle formal gyrus MD (BA8). (E) signicant correlation between the energy score and the right middle frontal gyrus MD (BA10). r is Pearson’s correlation coecient. e 95% prediction interval is presented in the shaded area. CBF cerebral blood ow, MD mean diusivity, FA fractional anisotropy, GM gray matter, WM white matter, R right, L le, BA Brodmann area. (A) and (B) brain images were created using BrainNet Viewer soware (http:// www. nitrc. org/ proje cts/ bnv/)43. (C) Brain image was created using ExploreDTI soware (https:// www. explo redti. com/)44.

Vol.:(0123456789)!|!!!!!!!!(2022)!12:11252!!|!www.nature.com/scientificreports/with cognitive and emotional roles. Further studies are needed to optimize patient selection and to evaluate long-term outcomes. Patients were ≥ 18years old with reported post-COVID-19 cognitive symptoms that aected their quality of life and persisted for more than three months following an RT-PCR test conrming a symptomatic SARS-CoV-2 infection. Patients were excluded if they had a history of pathological cognitive decline, traumatic brain injury or any other known non-COVID-19 brain pathology. e inclusion and exclusion criteria are listed Supplementary information. A prospective randomized, double blind, sham-controlled, phase II exploratory study was con-ducted from December 14, 2020, to December 27, 2021, at Shamir Medical Center (SMC), Israel. Aer signing an informed consent, patients were randomized to either HBOT or sham-control groups in a 1:1 ratio according to a computerized randomization table, supervised by a blinded researcher. To evaluate participant masking, patients were questioned aer the rst session on their perception regarding the treatment they received. Evalu-ation procedure was done at baseline and 1–3weeks aer the last HBOT/control session. All evaluators were blinded to the patients’ group allocation. e study was approved by SMC’s Institutional Review Board (IRB) (No. 332-20-ASF) and all participants signed an informed consent prior to their inclusion. All research was per-formed according to the relevant guidelines and regulations. is study was registered with ClinicalTrials.gov, number NCT04647656 on 01/12/2020. Both HBOT and sham protocols were administrated in a multi-place Starmed-2700 chamber (HAUX, Germany). e protocol comprised of 40 daily sessions, ve sessions per week within a two-month period. e HBOT protocol included breathing 100% oxygen by mask at 2ATA for 90min with ve-minute air breaks every 20min. Compression/decompression rates were 1.0m/min. e sham protocol included breath-ing 21% oxygen by mask at 1.03 ATA for 90min. To mask the controls, the chamber pressure was raised up to 1.2 ATA during the rst ve minutes of the session along with circulating air noise followed by decompression (0.4m/min) to 1.03 ATA during the next ve minutes. e primary outcome of the study was the cognitive assessment as evaluated by the Mindstreams computerized cognitive testing battery (NeuroTrax Corporation, Bellaire, TX). is assessment evaluates various cognitive domains including: memory, executive function, attention, informa-tion processing speed, and motor skills. Cognitive scores were normalized for age, gender and educational levels. e tests methods are described in the Supplementary information.e secondary outcomes include the following measures:Brain imaging MRI scans were performed on a MAGNETOM VIDA 3T scanner, congured with 64-chan-nel receiver head coils (Siemens Healthcare, Erlangen, Germany). e MRI protocol included T2-weighted, 3D uid attenuated inversion recovery (FLAIR), susceptibility weighted imaging (SWI), pre- and post-contrast high-resolution MPRAGE 3D T1-weighted, dynamic susceptibility conSupplementary informationtrast (DSC) for calculating whole-brain quantitative perfusion maps, and diusion tensor imaging (DTI) for microstructure changes in grey and white matter determination. A detailed description is found in the . Briey, preprocessing of DSC and DTI images was performed using the SPM soware (version 12, UCL, London, UK) and included motion correction, co-registration with MPRAGE T1 images, spatial normalization, and spatial smoothing with a kernel size of 6mm full width half maximum (FWHM). Whole-brain quantitative perfusion analysis was performed as described in previous studies39,40. MR signal intensity was converted to Gd concentrations, AIF was determined automatically, tted to the gamma variate function and deconvolved on a voxel-by-voxel basis to calculate brain perfusion maps.Diusion brain volumes denoising was performed using Joint Anisotropic LMMSE Filter for Stationary Rician noise removal41 and calculation of DTI-FA (fractional anisotropy) and MD (mean diusivity) maps were performed using an in-house soware written in Matlab R2021b (Mathworks, Natick, MA).Included self-reported questionnaires were the short form-36 (SF-36) to assess quality of life, the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality, the Brief Symptom Inventory (BSI-18) to evaluate psychologi-cal distress, based on three subscales: depression, anxiety, and somatization, and the Brief Pain Inventory (BPI) to measure pain intensity and impact.e sense of smell was evaluated by the Snin’ Sticks Test (Burghardt, Wedel, Germany). e kit is standard-ized for age and gender. Taste was evaluated by a Taste Strip Test (Burghardt, Wedel, Germany), including four tastes: bitter, sour, salt and sweet.Pulmonary function measurements were performed by a KoKo Sx1000 spirometer (Nspire health, USA). Blood samples were collected for complete blood count, chemistry and inammatory markers. Participants were monitored for adverse events including barotraumas (either ear or sinuses), and oxygen toxicity (pulmonary and central nervous system). is article discusses cognitive and behavioral aspects of post-COVID-19 condition. Additional secondary outcomes including neuro-physical evaluation, cardiopulmonary exercise test, echocar-diography, and functional brain imaging will be presented in future manuscripts. Continuous data are expressed as means ± standard deviations (SD). Two-tailed inde-pendent t-tests with were performed to compare variables between groups when a normality assumption held according to a Kolmogorov–Smirnov test. Net eect sizes were evaluated using Cohen’s d method, dened as the improvement from baseline aer sham intervention was subtracted from the improvement aer HBOT, divided

Vol:.(1234567890)!|!!!!!!!!(2022)!12:11252!!|!www.nature.com/scientificreports/by the pooled standard deviation of the composite score. Categorical data were expressed in numbers and per-centages, compared by chi-square/Fisher’s exact tests. To evaluate HBOT’s eect, a mixed-model repeated-meas-ure ANOVA model was used to compare post-treatment and pre-treatment data. e model included time, group and the group-by-time interaction. A Bonferroni correction was used for the multiple comparisons. A value of p < 0.05 was considered signicant. Pearson’s correlations were performed between perfusion and dif-fusion changes and the change in questionnaire scores before and aer HBOT and sham. Imaging data analysis was performed on the normalized CBF, FA and MD maps, using the voxel-based method to generate statistical parametric maps. A gray matter mask was applied on the CBF and MD maps, and a white matter mask on the FA maps (using a threshold of 0.2). A within-subject repeated measure ANOVA model was used to test the main interaction eect between time and group implemented in SPM soware (version 12, UCL, London, UK). A sequential Hochberg correction was used to correct for multiple comparisons (P < 0.05)42. Data analysis was performed using Matlab R2021b (Mathworks, Natick, MA) Statistics Toolbox.e estimated sample size was calculated based on our recent study in healthy adults19. A Mindstreams-NeuroTrax global cognitive score improvement of 5.2 and 0.8 points, with a standard deviation of 6.7 points was found in the HBOT and control groups respectively. Assuming a power of 80%, and 5% two-sided level of signicance, a total of 74 participants would be required, 37 participants in each arm. Considering a dropout rate of 15% the total sample size required is 85.e datasets analyzed during the current study available from the corresponding author on reasonable request.Received:(1(February(2022;(Accepted:(27(June(2022 1. WHO. Post COVID-19 Condition (Long COVID). https:// www. who. int/ srila nka/ news/ detail/ 16- 10- 2021- post- covid- 19- condi tion (2021). 2. Yong, S. J. & Liu, S. Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies. Rev. Med. Virol. 1, e2315 (2021). 3. Stefano, G. B. historical insight into infections and disorders associated with neurological and psychiatric sequelae similar to long COVID. Med. Sci. Monit. 27, e931447. https:// doi. org/ 10. 12659/ MSM. 931447 (2021). 4. Va nd erl in d, W. M . et al. A systematic review of neuropsychological and psychiatric sequalae of COVID-19: Implications for treat-ment. Curr. Opin. 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Leemans, A., Jeurissen, B., Sijbers, J. & Jones, D. K. ExploreDTI: A graphical toolbox for processing, analyzing, and visualizing diusion MR data. Proc. Intl. Soc. Magn. Reson. Med. 1, 3537 (2009).We wou ld li ke to a ck nowl edge Osh ra Mei r Genu th, Hi la G ol dne r Yer us ha lmi , Roy Sagi , E li Mat alo n, Nat aly a Tarasula, Moran Adler, Ron-El Goldman, Eldad Yaakobi, Fanny Atar, Rotem Barti, Yonatan Zemel and Yair Bechor for their dedicated work. We would also like to thank Dr. Mechael Kanovsky for his editing of this manuscript.S.Z.I., M.C., K.E.S., A.H., S.E. conceived and designed the study. S.Z.I., K.E.S., E.L., S.F., N.P., G.F., C.K., S.E. contributed to patients’ recruitment and data acquisition. M.C., A.H., E.S., Y.P., S.E. performed the data analysis. M.C., E.S. and A.H. performed the statistical analysis, M.C., S.Z.I., A.H., S.E. wrote the rst dra of the manu-script. All authors revised and nalized the manuscript.e study was funded by the research fund of Shamir Medical center, Israel. Amir Hadanny and Efrat Sasson work for AVIV Scientic LTD. Shai Efrati is a shareholder at AVIV Scientic LTD. LTD. SZI, MC, KES, EL, SF, NP, GF, CK, RS, YP, MS have no competing interests.Supplementary Information e online version contains supplementary material available at https:// doi. org/ 10. 1038/ s41598- 022- 15565-0.Correspondence and requests for materials should be addressed to S.E.Reprints and permissions information is available at www.nature.com/reprints.Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional aliations.

Citation: Ylikoski, J.; Lehtimäki, J.;Pääkkönen, R.; Mäkitie, A.Prevention and Treatment ofLife-Threatening COVID-19 May BePossible with Oxygen Treatment. Life2022, 12, 754. https://doi.org/10.3390/life12050754Academic Editors: Silvia De Franciaand Sarah AllegraReceived: 19 March 2022Accepted: 12 May 2022Published: 19 May 2022Publisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright: © 2022 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).lifeCommunicationPrevention and Treatment of Life-Threatening COVID-19 MayBe Possible with Oxygen TreatmentJukka Ylikoski1,2,3, Jarmo Lehtimäki2,3, Rauno Pääkkönen1and Antti Mäkitie1,*1Department of Otorhinolaryngology—Head and Neck Surgery, University of Helsinki and HelsinkiUniversity Hospital, 00029 Helsinki, Finland; jukka.ylikoski@fimnet.fi (J.Y.); rauno.paakkonen@ains.fi (R.P.)2Helsinki Ear Institute, 00420 Helsinki, Finland; jarmo.lehtimaki@gmail.com3Salustim Group Inc., 90440 Kempele, Finland* Correspondence: antti.makitie@helsinki.fi; Tel.: +358-50-428-6847Abstract:Most SARS CoV-2 infections probably occur unnoticed or cause only cause a mild commoncold that does not require medical intervention. A significant proportion of more severe cases ischaracterized by early neurological symptoms such as headache, fatigue, and impaired consciousness,including respiratory distress. These symptoms suggest hypoxia, specifically affecting the brain. Thecondition is best explained by primary replication of the virus in the nasal respiratory and/or theolfactory epithelia, followed by an invasion of the virus into the central nervous system, including therespiratory centers, either along a transneural route, through disruption of the blood-brain barrier, orboth. In patients, presenting with early dyspnea, the primary goal of therapy should be the reversal ofbrain hypoxia as efficiently as possible. The first approach should be intermittent treatment with 100%oxygen using a tight oronasal mask or a hood. If this does not help within a few hours, an enclosureis needed to increase the ambient pressure. This management approach is well established in thehypoxia-related diseases in diving and aerospace medicine and preserves the patient’s spontaneousbreathing. Preliminary research evidence indicates that even a small elevation of the ambient pressuremight be lifesaving. Other neurological symptoms, presenting particularly in long COVID-19, suggestimbalance of the autonomous nervous system, i.e., dysautonomia. These patients could benefit fromvagal nerve stimulation.Keywords:SARS CoV-2; hyperbaric oxygen; autonomous nerve system; brain hypoxia; dysautonomia1. IntroductionMany countries are still struggling with COVID-19. The disease has caused manyfatalities because no effective treatment has been available. At the beginning of the COVID-19 pandemic, the causative agent, SARS-CoV-2, was found to show great similarities with2002/3 SARS-CoV and 2012 MERS-CoV. Consequently, severe COVID-19 was primarilyregarded as a pulmonary one-organ disease, with pneumonia and bronchiolitis leadingto dyspnea, and in the most severe cases to acute respiratory distress syndrome (ARDS)and septic shock. The SARS-CoV-2 virus was thought, in severe cases, to affect part of theinnate immune response and to activate an inflammatory cascade stimulating the release ofcytokines and chemokines, particularly within the lungs [1–3]. This would lead to a robustinflammatory response that, if it was not controlled, could result in a “cytokine storm” withdetrimental systemic consequences [3].However, even from the beginning of the pandemic, COVID-19 surprised by somewhatcommonly causing a wide spectrum of clearly extrapulmonary symptoms that do not fitthe aforementioned pulmonary concept. There were several early reports of patients withCOVID-19 seeking medical attention who presented themselves with pure neurologicalmanifestations at onset with nonneurological features first manifesting days later. It wasproposed to term these cases “neuro-COVID syndrome” [4].Life 2022, 12, 754. https://doi.org/10.3390/life12050754 https://www.mdpi.com/journal/life

Life 2022, 12, 754 2 of 20Among these early symptoms were impaired consciousness, fatigue, and headache,which all pointed to impaired oxygenation in the central nervous system (CNS). These usu-ally appeared in combination with respiratory distress as the usual cause for hospitalization.We and others have stated that these symptoms are best explained by early neuroinvasionby SARS-CoV-2 of the CNS, including respiratory centers, leading to brain hypoxia [5–7].In the first report consisting of 214 hospitalized severely affected patients, during January–February 2020 in Wuhan, 36% had neurological manifestations, and in some, these were theonly symptoms. Impaired consciousness was seen in 15% of the cases, and it occurred earlyin the illness, i.e., during the first 1–2 days [5]. It is obvious that in such cases the primarytarget of therapy should be brain hypoxia and not a pulmonary disease. Therefore, theprevailing global principle in anesthesiology concerning oxygenation therapy as distinctfrom oxygen treatment, i.e., “as little oxygen as possible”, might not be accurate for hypoxicCOVID-19 patients. Based on our background experience in diving, aviation, and otherpotentially hypoxia-generating conditions, we have analyzed the reports of the clinicalcourse, including signs and symptoms, of COVID-19. Our analyses have revealed that mostof the early neurological symptoms of COVID-19 resemble those of mild brain hypoxia.Therefore, we propose that it is the oxygen deficiency in tissues, particularly in the brain,that should be the main target of therapies.2. Potential Pathophysiological Mechanisms of COVID-192.1. Early Neurological (Extrapulmonary) SymptomsInitially, COVID-19 was predominantly characterized as a respiratory illness targetingthe upper airways, similar to other human coronaviruses. Clinical findings in peopleinfected with SARS-CoV-2 range from an asymptomatic course to severe pneumoniarequiring mechanical ventilation. The pathophysiology and severity of COVID-19 illnessvary among patients and depend in part on underlying risk factors and chronic diseases. Itspathogenesis follows that of other respiratory viruses typically replicating in the epithelia ofthe nasal cavity or nasopharynx. Even from the early reports from Wuhan, it was clear thatthe great majority of COVID-19 cases show only symptoms of a mild, common cold-typeupper respiratory infection [8] and recover within one or two weeks. However, thesereports also described a significant proportion of hospitalized patients and even about25% of severe cases presenting with neurological symptoms, including anosmia, impairedconsciousness, and dyspnea, but normal pulmonary CT scans [8,9]. It was reported thatmost (up to 89%) of COVID-19 patients admitted to the intensive care unit could notbreathe spontaneously [9]. There were also reports of COVID-19 patients presenting withasymptomatic (silent) hypoxia in whom their early respiratory dysfunction was describedas a “cessation of spontaneous breathing.” These features suggested a central apnea orfailure in the feedback loop from the pulmonary receptors to the respiratory centers,mediated by the vagus nerve [10]. Note that hypoxia may also result from a combinationof these two.So far, several pieces of evidence have clearly shown that SARS-CoV-2 affects not onlythe respiratory tract but also the CNS, resulting in dyspnea and clearly neurological symp-toms such as loss of smell and taste, headache, fatigue, impaired consciousness, nausea, andvomiting in more than one third of individuals with COVID-19 [11,12]. Therefore, it washypothesized, first from Wuhan and later on in many other reports, that SARS-CoV-2 canbe neurotropic, entering the body through the nose and spreading to the CNS, includingthe respiratory centers in the brain stem and medulla. Accordingly, the most dangeroussymptom, the initial respiratory failure, would be neurogenic in origin [4–7,13,14]. Notethat even in the early reports on COVID-19, impaired consciousness, in some patients theonly symptom, was described as occurring in 15–50% of cases [5,6,15,16]. It is particularlynoteworthy that most neurological manifestations could occur very early in the illness.From accumulated human and experimental research data, we have constructed theputative, simplified pathogenetic pathway of SARS-CoV-2 (Figure 1). It seems clear thatthe virus enters the body by first attacking and replicating in the respiratory or olfactory

Life 2022, 12, 754 3 of 20epithelia of the nasal cavity and causing a common cold-like upper respiratory infection,with the highest viral replication occurring in the nose at day four [17]. Olfactory engage-ment seems apparent from the common occurrence of anosmia that has been describedas occurring in more than 90% of cases seeking medical attention [9,18]. The olfactoryepithelium contains, in addition to sustentacular and microvillar cells, olfactory sensoryneurons. Their peripheral olfactory cilia are protected from the external air by only a thinmucous blanket. Therefore, the olfactory nerve has been described as a shortcut into theCNS for several viral diseases [19]. The SARS-CoV-2 spike (S)-protein that binds to itsspecific receptor ACE2, in concert with host proteases—principally TMPRSS2 (promotescellular entry)—is co-expressed in epithelial type II pneumocytes in the lungs and in cili-ated and goblet cells of the nasal epithelium [20]. Olfactory epithelia as the entry site ofSARS-CoV-2 into the CNS were strongly supported by a recent autopsy material study of33 COVID-19 victims. By using immunohistochemistry, in situ hybridization, and electronmicroscopy, it was possible to visualize the presence of intact CoV particles together withSARS-CoV-2 RNA in the olfactory mucosa [21]. That study also revealed viral particlesand RNA in neuroanatomical areas receiving olfactory tract projections that may suggestSARS-CoV-2 neuroinvasion into deeper parts of the brain, including respiratory centersin the thalamus and brain stem, through axonal transport. This is not unexpected, ashuman coronaviruses have been shown to be potentially neurotropic and induce immuneoveractivation [22]. Another possible path for CNS spread is the hematogenous route,which involves early viral crossing of the blood-brain barrier (BBB). In general, the effectof COVID-19 on the brain may take several forms, some via direct infection and othersvia secondary mechanisms, e.g., immune response or respiratory failure-induced hypoxia.Direct presence of SARS-CoV-2 in the brain has been demonstrated through the detectionof SARS-CoV-2 RNA in the cerebrospinal fluid of infected patients [23].                                                                                              Figure 1.Schematic representation showing the putative brain pathway of SARS-CoV2 inCOVID-19.The virus enters the respiratory or olfactory epithelia of the nasal cavity, spreads (by trans-synapticmigration) to the brain through the olfactory or trigeminal tracts, and infects deeper parts of thebrain, including respiratory centers in the thalamus, brain stem, and medulla. This leads to dysfunc-tion of the respiratory centers, including Pre-Bötzinger complex, causing respiratory distress andhypoxaemia/hypoxia and leading to a strong stress response associated with sympathoexcitation.Dysfunction of the ANS triggers upregulation of VEGF and disruption of the BBB, further leading tothe worsening of hypoxia, resulting in both acute and long-standing neurological symptoms.

Life 2022, 12, 754 4 of 20Regarding the extent of SARS-CoV-2 being able to affect the brainstem, it has beenhypothesized that the respiratory breakdown in COVID-19 patients may be caused atleast in part by SARS-CoV-2 infecting and destroying respiratory centers in the medullaoblongata and the pons [14]. Two sets of neuronal networks within the brainstem are crucialto the generation of respiratory rhythm, the Pre-Bötzinger complex (PBC), the pacemakerof the respiratory rhythm generator—also proposed as the kernel of respiration—and theretrotrapezoid nucleus/parafacial respiratory group [24]. When, the PBC was shut downin a mouse model of SARS CoV, it caused lethality due to respiratory failure [25]. It washypothesized that SARS CoV-2 behaves similarly and that the destruction of the respiratorycenter (PBC) in the brainstem could be accountable for respiratory breakdown in COVID-19patients [9,14].It has also been suggested that the virus might enter the lowest region of the brainstem, the dorsal vagal complex (DVC), located in the medulla oblongata, which is involvedin the control of several autonomic activities including breathing, food intake, nausea,and vomiting: these are all frequent extrapulmonary symptoms of COVID-19 [26]. In theDVC, the nucleus of tractus solitarius (NTS) is known, in addition to the hypothalamus,to be involved in food intake. The loss of appetite, sometimes a prominent symptomin COVID-19, means that the crosstalk between the hypothalamus and DVC has beenbroken as in pathological states such as under stress [27]. It is well established that anothercomponent of the DVC, the area postrema lying beneath the fourth cerebral ventricle, playsa crucial role in the elicitation of nausea and vomiting. This structure, together with DVC,NTS, and the dorsal motor nucleus of the vagus (DMNV), forms neurocircuits that havebeen classified as the “emetic chemoreceptor trigger zone” [28]. Interestingly, the eventualinvolvement of the subnucleus of NTS, the gelatinous nucleus, has been documented inthe respiratory failure of sudden infant death syndrome (SIDS). [27]. Taken together, thisneuroinvasive propensity leading to respiratory dysfunction has been demonstrated as acommon feature of CoVs. Furthermore, hypoxemia and subsequent hypoxia are known toinduce a stress reaction with the imbalance of the ANS and in the CNS, particularly of thecentral autonomic network (CAN) [29]. Hypoxia itself, or in combination with ANS/CANimbalance, is a well-known cause of BBB disruption, leading to a multitude of local andsystemic manifestations (Figure 1).2.2. Significance of Virus Genotypes for Virulence Symptoms and NeurotropismA critical initial step of infection is the interaction of the virus with receptors onhost cells. The target tissues for viral infection, i.e., tissue tropism, is determined by theavailability of virus receptors and entry cofactors on the surfaces of host cells. In the case ofSARS-CoV-2 and other coronaviruses, the receptor binding occurs through the spike (S)protein on the virus surface. Both SARS-CoV-2 and the related SARS-CoV bind to ACE2 onhuman cells. ACE2, however, is expressed at low protein levels in respiratory and olfactoryepithelial cells [30]. Although previous analyses have revealed that TMPRSS2, the primaryprotease important for SARS-CoV-2 entry, is highly expressed in different tissues, it waspresumed that additional cofactors are required to facilitate virus-host cell interactions incells with low ACE2 expression. It was shown that the membrane protein neuropilin-1(NRP1) promotes SARS-CoV-2 entry by interacting with the SARS-CoV-2 S-protein andthat NRP1 could thus represent an ACE2 potentiating factor by promoting the interactionof the virus with ACE2 [31,32].It has been presumed that the pathogenic pathways and high transmission potentialsof human coronaviruses are facilitated by an interplay between epigenetics and coronavirusinfection. SARS-CoV-2 utilizes multiple ways for cellular entry (both nonendosomal and en-dosomal) and potentially uses various means of epigenetic control to inhibit the initiation ofthe host innate immune response. During the course of the pandemic, this virus efficientlyhas undergone genomic rearrangements, thereby developing important means for immuno-logical escape. Such mutations have been especially effectively revealed by performinggenome analyses of the SARS-CoV-2 sequences over the course of the COVID-19 pandemic

Life 2022, 12, 754 5 of 20in Costa Rica with a population of five million. Those analyses reveal the detection ofmutations in line with other studies but also point out the local increases, particularly in thedetection of Spike-T1117I variant. These constant genomic rearrangements may offer someexplanation for the variations in transmission rates, symptoms, tropisms, and virulence ofthe SARS-CoV-2 [33–35].2.3. The Role of the Blood-Brain BarrierIt is well-known that the BBB is a dynamic platform, collectively referred to as theneurovascular unit (NVU), responsible for the exchange of substances between the bloodand the brain parenchyma and that it is an essential functional gatekeeper for the CNS. Thepropensity less commonly attributed to the BBB is its responsibility for the exchange ofoxygen, which plays a critical role in the maintenance of brain homeostasis. Dysfunction ofthe BBB/NVU is a characteristic of several neurovascular pathologies. Moreover, physi-ological changes, environmental factors, nutritional habits, and psychological stress canmodulate the tightness of the barrier. Mild inflammation is often associated with reducedBBB integrity, as observed for instance in obesity or psychosocial stress. Among extrinsicinsults known to induce BBB breakdown, hypoxia is probably the most well characterized,but many knowledge gaps remain. Hypoxia can disrupt the BBB and result in increasedpermeability, vasogenic edema, and tissue damage [36]. Of the different types of hypoxia,hypobaric hypoxia (HH) is probably the best characterized because under hypobaric condi-tions, during ascent, it possible to monitor the gradual progression of HH. The proposedmechanisms for NVU damage by HH, and hypoxia in general, include induction of in-creased expression hypoxia-inducible factor-1 (Hif-1), enhanced endothelial transcytosisand oxidative stress [37]. It is well known that increased Hif-1 leads to increased expressionof vascular endothelial growth factor (VEGF) in activated astrocytes, which further leads toNVU damage through changes in its tight junctions. One major mechanism associated withhypoxia-induced BBB opening is enhanced endothelial transcytosis that may be mediatedby factors such as nitric oxide, calcium influx, or the release of inflammatory cytokines [38].This may be a major mechanism because different cellular components of NVU showdistinct differences in sensitivity to oxygen deprivation, so that endothelial cells (ECs) aremarkedly more sensitive than are pericytes or astrocytes. It is currently unclear whetherthe neurological symptoms in COVID-19 are a direct result of neural infection or secondaryto endothelial cell infection, hypoxia, or circulating pro-inflammatory cytokines.Several reports bring up the hypothesis that COVID-19, because it produces proteanmanifestations ranging from head to toe, represents an endothelial disease [39]. A similarpathophysiological mechanism has been proposed for long COVID-19. That hypothesisstates that the initial pathology is due to the virus binding to the ACE-2 protein on ECslining blood vessels and entering these cells in order to replicate, in turn releasing theimmune response and thereby symptoms [40]. It even states that after initiating thisimmunologic cascade, the nascent virus spreads further into the nasopharyngeal tract. Theearly effect on the EC system is particularly attractive because it could explain, throughdysregulation of the BBB and further dysautonomia, the relatively commonly occurringneurological symptoms of long COVID-19. The early EC effect by SARS-CoV-2, however,seems to be a rarity because virus RNA has usually not been found in the blood of patientswith early COVID-19 [17,41–43]. However, several studies have found SARS-CoV-2 viremiaand as such strong support for virus brain entry across the BBB at later stages of severeCOVID-19 [44–47].2.4. Role of Autonomic Dysfunction in Symptoms of COVID-19 and Long COVID-19All our unconscious bodily functions are controlled by the ANS, and particularly bythe CAN [29]. The most common cause for the dysfunction of the CAN is stress, the majorcause of deteriorating health conditions and illnesses. It is well-known that infections,including viral ones, are associated with oxidative stress and subsequent reactive oxygenspecies. Recent research, by investigating small RNAs, powerful stress markers in the

Life 2022, 12, 754 6 of 20blood samples of patients with moderate or severe COVID-19, has revealed that the cells ofCOVID-19 patients undergo tremendous stress [47].The CAN initially reacts to stressor effects with a sympathetic fight/flight response thatis restored to normal by the parasympathetic nervous system’s relax/digest response [48].Many symptoms and illnesses result from the inability of the parasympathetic activityto restore the ANS balance (for review see [49]). These two circuits, the sympathetic andparasympathetic systems, are constantly interacting by heart rate variability (HRV) as aread-out of ANS balance; thus, HRV may consequently serve as a measure of stress [50].The vagal system, with the vagus nerve terminating at the DVC in the brain stem, isknown to be the key factor in most aspects of respiration. It both transmits the sensoryinformation from pulmonary chemoreceptors to the CNS and is responsible for the activitythat provides appropriate stimuli to the nuclei of the respiratory centers of the brain stem.This activity includes stimuli to NTS and nucleus ambiguus to give efferent commandsto the respiratory muscles to function effectively. Interestingly, in some cases, the initialrespiratory failure in COVID-19 can be a weakness or paresis of the diaphragm muscle,which is one of the two pumps necessary for life. Phrenic nerve paralysis has been describedin a COVID-19 patient [51]. The paralysis of the diaphragm muscle was the cause ofrespiratory failure in connection with bulbar polio virus. Notably, the symptoms of “longpolio”, which can occur as long as 15 years after the acute stage, resemble those of longCOVID-19 (fatigue, headache, musculoskeletal pains) [52].Since the COVID-19 pandemic began, there has been a concern that survivors mightbe at an increased risk of neurological disorders. This concern, initially based on findingsfrom infections with other coronaviruses, was rapidly followed by case series studies ofthe current pandemic. Multiple studies reported on the long-term outcomes of SARSsurvivors in Toronto in 2003. Most patients had persistent functional disabilities and wereunable to return to their work. Their persisting debilitating physical symptoms includedmusculoskeletal pains, profound fatigability, shortness of breath, psychological distress,and major sleep problems [53,54]. These neurological long-term sequelae strongly suggestthat they had been caused by an infection or inflammation in the CNS as a causative factor.Following the initial surge of infections by SARS-CoV-2, focus has shifted to managingthe longer-term sequelae of illness survivors. Post-acute COVID-19 syndrome (knowncolloquially as long COVID-19) is emerging as a prevalent syndrome. It encompasses aplethora of debilitating symptoms (including fatigue, breathlessness, pain, palpitations,sleep disturbance, and cognitive impairment (“brain fog”), which can last for weeks ormonths following the acute stage, even after a mild illness [55,56]. These symptoms thusgreatly resemble those seen in follow-up studies of SARS2002/3 survivors [53,54]. Asin the case of SARS-CoV, these neurological long-term sequelae of SARS-CoV-2 stronglysuggest that their cause is an infection or inflammation in the CNS, not only in the lungs.Most patients recover from COVID-19 within a few weeks, but in surprisingly many, the(neurological) symptoms can continue for a long time [55,56]. These symptoms refer toimbalance in the CAN (with sympathetic dominance), “dysautonomia.” This dysautonomiais supposed to be caused by cerebral hypoperfusion that leads to an overactive sympatheticsystem (fight or flight) with correspondingly reduced parasympathetic (relax) activity [57].3. Therapies of COVID-19 and Long COVID-19Most SARS CoV-2 infections probably occur unnoticed or cause only mild commoncold symptoms that need no treatment. Pneumonia is probably the most common compli-cation, but in the same way as ARDS occurs at later stages and thus cannot be responsiblefor early neurological symptoms such as impaired consciousness beginning during the firstdays of the disease, sometimes without any other symptoms.It is well established that COVID-19 currently lacks curative therapy. However, theabove-described mechanisms of the early dyspnea and hypoxia being due to a dysfunctionof the central regulatory mechanisms of respiration shift the main focus of therapeuticefforts to the stage of early brain hypoxia. This pathophysiological concept suggests that

Life 2022, 12, 754 7 of 20therapeutically, the most important step would be to correct the hypoxemia and subsequentbrain hypoxia by optimizing the efficacy of oxygen treatment in preserving the spontaneousbreathing in affected individuals.The role of the ANS, and particularly its CAN partition, in the disease process ofCOVID-19 appears to be crucial from the first symptoms to the final stage. Therefore,returning autonomic imbalance to normal might be important as a part of the therapeuticregimen, particularly in the patient population suffering from long COVID-19.4. Oxygen Treatment4.1. Principles of the Delivery of Oxygen into the Body and Its AdministrationAll of the body’s tissues rely on a continuous oxygen supply at a rate that matches theirchanging metabolic demands. The amount of dissolved oxygen within the tissues and thecells depends crucially on the atmospheric partial pressure of oxygen and how effectivelyrespiration is able to deliver oxygen from air to the blood plasma. Partial pressure ofoxygen (PO2) depends only on the atmosphere’s barometric pressure (BP), and at normalBP conditions the content of inspired oxygen is 20.8%. The oxygen delivery chain beginsin the nose, where the inspired air is warmed, humidified, and delivered by convectionthrough the trachea to the lung alveoli and further to circulation, with the destination beingthe mitochondria (Table 1).Table 1.Atmospheric/ambient pressures under different baric conditions and corresponding oxygentensions in alveoli, arteries, extracellular fluids of tissues, and mitochondria. ATA = atmospheresabsolute; AP = atmospheric pressure; PO2= partial pressure of oxygen; PAO2= partial pressure ofoxygen in alveoli; PaO2= partial pressure of oxygen in arteries; PtO2= partial pressure of oxygen intissues; PmO2= partial pressure of oxygen in mitochondria. * Estimations through extrapolations.Atmospheric/AmbientOxygenTensionof Inspired Air,PO2OxygenTensionin Alvoli,PAO2OxygenTension inArteries, PaO2OxygenTension inTissues, PtO2OxygenTension inMitochondria,PmO2Pressure (AP) mmHgmmHg mmHg mmHg mmHg mmHg2.5 ATA, AP 187515 m diving, 100% O2breathing 1875 1284 * 1274 250–500 [58,59] 80–125 *236 162 * 152 30–60 *5 m diving, 100% O2breathing 1125 771 * 761 (59) 150–304 * 50–76 *1.3 ATA, AP 988 airbreathing207 158 * 148 [60,61] 30–60 * 10–15 *3 m diving, 100% O2breathing 975 668 * 658 130–263 * 45–65 *Sea level (1.0 ATA), AP 760 mmHgAir breathing [62–64] 20–50 y 160 102–110 97–99 20–40 7.5–11>64 y -”- -”- 82–93 16–37 *100% O2breathing [63,64] 760 674 516 207 * 77 *Dead Sea * 457 m AP 802 mmHg 167 114 104 42 15AirAt sea level in normal BP (760 mmHg, 1 ATA, atmospheric absolute), the PO2ofinspired air is 160 mmHg. Along its route down to the alveoli, the PO2is reduced throughvarious resistances, and final reduction takes place in alveoli due to dead space and themixing of inspired and expired gases, resulting in a partial pressure of oxygen in alveoli(PAO2) of about 110 mmHg (Table 1; Figure 2). From the alveoli, oxygen diffuses acrossthe alveolar-capillary membrane to pulmonary circulation with only a small reduction inpartial pressure (PaO2about 100 mmHg). From the pulmonary capillaries and arteries, theoxygen is carried to all parts of the body in two forms—a major fraction (up to 99%) that isbound to hemoglobin (Hb) and a small free fraction that dissolves in the plasma. Therefore,the number of red blood cells will dominantly affect the total capacity of oxygen delivery.However, at an elevated partial pressure of oxygen (such as during hyperbaric conditions),

Life 2022, 12, 754 8 of 20the dissolved amount can become significant. In all cases, the diffusion gradients are theoxygen’s driving force from the plasma to the mitochondria. Thus, the free dissolvedfraction only is transported to mitochondria. While it is transferred to various tissues,the PaO2is evenly reduced so that its level of extracellular tissue fluids (PtO2) at sealevel is20–40 mmHg. From there, PtO2further reduces as oxygen diffuses to cells andmitochondria (partial pressure of oxygen 7.5–11 mmHg) (Table 1; Figure 2).                                                                                                 Figure 2.Oxygen tensions in the body. Reduction of oxygen tensions at different levels of airways,arteries, and tissues after breathing air at sea level and 1.3 ATA and breathing 100% oxygen at sea leveland 2.5 ATA. (ATA = atmospheres absolute; PO2= partial pressure of oxygen; PAO2= partial pressureof oxygen in alveoli; PaO2= partial pressure of oxygen in arteries; PtO2= partial pressure of oxygenin tissues. PmO2= partial pressure of oxygen in mitochondria. * Estimations through extrapolations).Note that the figures above apply to healthy young individuals in normal BP condi-tions. Factors that reduce PaO2include age, humidification, and barometric changes. Ithas been shown that alveolar diffusion capacity decreases with aging, about 0.24 mmHgper year. Consequently, PaO2in pulmonary capillaries in persons < 24 years is 99 mmHg,and 82–93 mmHg in those > 64 years (Table 1; Figure 2)[65]. Humidification in the nosewill add of water vapor to inspired air, and its pressure is constant at 47 mmHg at normalbody temperature (37C) [66]. This leads to a reduction of PAO2by about 10 mmHg- anda corresponding reduction of PaO2.In oxygen therapy planning, it remains important to recognize that the pressure (PO2),and therefore the oxygen concentration, will determine the efficacy of oxygen treatment,i.e., how much oxygen will be transferred from the lung alveoli through the alveolarmembrane to the arterial (capillary) blood. The quantity of dissolved oxygen in bloodplasma, not the hemoglobin saturation, determines how much oxygen is diffused to thetissue. Further, according to Henry’s law, the pressure of oxygen determines the quantityof dissolved oxygen in blood plasma.Currently, most COVID-19 patients who are hospitalized because of respiratory dis-tress are treated according to modifications of guidelines originally published by the BritishThoracic Society (BTS) in 2008 [67] and of the newer modification of these BTS guidelinesconstituting of oxygen delivery through high-flow nasal oxygen (HFNO) with an O2flow

Life 2022, 12, 754 9 of 20of 40–60 L per minute [68]. This HFNO method, in addition to providing more O2, alsonecessitates the use of some elevated pressure, and thereby, lung alveoli are opened moreefficiently. These guidelines stress the importance of the prevention of tissue hypoxia. How-ever, this oxygen treatment strategy is targeted at correcting oxygen deficiency primarilyin one tissue, blood (hypoxemia). Notably, blood is one of the tissues that is extremelyresistant to oxygen deficiency, at least compared with brain tissue.Many patients undoubtedly benefit from the current treatment consisting of respiratoryassistance and supplemental oxygen. However, if the tissue hypoxia is severe enough, thistreatment may remain inadequate. This is because with employed extra-oxygen methods(including HFNO and loose masks), the content of inspired oxygen is only slightly increased.With a nasal cannula set at 2 L/min, oxygen tension of the inspired air ranges anywherebetween 24% and 35%, leading only to a small increase in PaO2[69].This might be sufficient to prevent tissue hypoxia, but it may not be enough tocorrect it. The only means to effectively correct tissue hypoxia is to increase the contentof plasma dissolved oxygen. This is possible by providing the patient’s alveoli with 100%oxygen by using a tight oronasal mask or hood, thereby by practicing conventional oxygentherapy, as for example with severe pulmonary damage [70]. Using this method, theplasma PaO2can be increased about fivefold (from about 100 to 500 mmHg) [71] (Table 1;Figure 2). An appropriate dose could be 40–60 min of 100% oxygen given twice per day.If this does not help within a few hours, an enclosure is needed to increase the ambientpressure. Hypoxemia with COVID-19, as reported, is usually accompanied by an increasedalveolar-to-arterial oxygen gradient, signifying either ventilation–perfusion mismatch orintrapulmonary shunting [72,73]. Preliminary experience from Wuhan suggests that HBOTmay solve this problem [74].Oxygen was first used as a specific treatment by John S. Haldane, often called thefather of oxygen therapy, in Ypres, Belgium, for victims of chlorine gas attack in 1915. Inthe first instance of chemical warfare in history, the German forces bombarded the Britishfront lines with 6000 pressurized bottles containing poisonous chloride gas. Thousandsof young men died, while those who survived suffered from severe pulmonary damage.Haldane designed a tightly fitting oronasal mask, connected an oxygen bottle to it, andrescued a large number of victims with oxygenation therapy using 100% oxygen. Themethod developed by Haldane began to be used in other medical emergencies such as inCO poisoning and also in diving, aviation, and by mountaineers.4.2. Oxygen ToxicityAlready Haldane was already very well aware that long-term 100% oxygen treatmentcan be accompanied by pulmonary damage and other adverse effects. He stressed that alltherapies must be given in appropriated dosages and that the negative effects of hyperoxiamay be avoided if hypoxia is confirmed before oxygen therapy is initiated. It is indisputablethat long-term 100% oxygen breathing can cause pulmonary damage [75]. The mechanismis still uncertain, but the strongest candidate is the so-called absorption collapse theory.The normal maximal lung capacity is 3.5–4.5 L, but at rest we only breathe about 0.5 Land thus use only a small part of our lungs. The peripheral (“resting”) parts containmainly nitrogen (78% of air) that keeps them open. Long-term oxygen breathing slowlyleads to the replacement of nitrogen by oxygen in these pulmonary “resting areas”. Theensuing diffusion of oxygen through alveolar membranes into blood capillaries will leadto decrease in the alveolar gas pressure, and further, to their gas pressure vacuum andcollapse (atelectasis or absorption collapse). This causes local hypoxia and subsequentfurther cellular damage with free radicals that invite inflammatory cells to the scene, andan infection arises. The problem can be easily avoided by taking air breaks in oxygenbreathing, thereby filling the alveoli with nitrogen. Air breaks have been used in hyperbaricoxygenation therapy (HBOT) for decades, and this has diminished the myth of oxygenitself being toxic.

Life 2022, 12, 754 10 of 20When, in 1977, in addition to pulmonary damage theory, a highly recognized bio-chemist named Irwin Fridovich [76] reported that oxygen therapy created free radicals,a general perception of oxygen toxicity arose. Although Fridovich admitted that he waswrong in another article two years later (1979) [77] and that it was not the oxygen but, onthe contrary, hypoxia that creates free radicals, the general perception of oxygen toxicityhas remained the generally accepted “fact.” That concept has continued to live a life of itsown, particularly among anesthesiologists, to this day.4.3. Oxygen Treatment under Increased Ambient PressureFrom the above, it can be concluded that the amount of blood PaO2can be increasedand thereby tissue hypoxia corrected by using 100% oxygen with a tight oronasal mask.However, a much more rapid and efficient method would involve elevating the ambientpressure at which oxygen is administered. A large amount of reliable human experimentalknowledge is available, particularly from aviation and mountain climbing, about theimportance of pressure for brain oxygenation. It was as early as in 1862 when the Britishhydrogen ballooners James Glaisher and Henry Coxwell described their experience inLancet [78]. They climbed to 9000 m, where the content of oxygen remains at about 21% butthe partial pressure falls because the atmospheric pressure is only one third of that at sealevel. Glaisher suddenly lost consciousness, and all of Coxwell’s limbs became paralyzed.However, he was able to open the gas valve by drawing the valve rope with his teeth.Only after a descent of 50 m did their consciousness and bodily functions recover, and theysurvived. That was not the case for many other early ballooners who were supposed tohave died of cold and brain hypoxia.It seems clear that if brain hypoxia plays a role in the early extrapulmonary symptomsof COVID-19, it should be the primary target of treatment. Noninvasive brain oxygen statemonitoring has been relatively reliably used with commercial near-infrared spectroscopy(NIRS) brain oximeters [for review see [79]]. Surprisingly, to the best of our knowledge, theuse of NIRS on COVID-19 patients has not been reported so far.The significance of pressure elevation is easy to understand from the fact that bypressurizing air (20.8% oxygen) to such a low overpressure as 1.3 ATA (correspondingto 3 m diving), the partial pressure of oxygen (PaO2) in blood rises from 95 mmHg to148 mmHgor 50% (Figure 2)[60]. This elevation might be enough for most COVID-19patients for survival, particularly if the oxygen partial pressure of the inspired air is alsoelevated e.g., up to 30–40%. In conventional HBOT, (2.5 ATA, corresponding to a 15 mdive), the amount of blood plasma dissolved oxygen rises 20-fold (i.e., to 6 mL oxygen in100 mL blood).Modern aircrafts resemble pressure chambers as they are usually pressurized to about2400 m above sea level (from about 0.33 ATA/250 mmHg at 10,000 m to 0.76 ATA/577 mmHgat 2400 m) and the cabin pressure is thus elevated by about 0.45 ATA. The proposal to usesome of several hundreds of ground-bound aircrafts in British airports to treat critically illCOVID-19 patients in 1.3–1.5 ATA elevated pressure was made in June 2020 by Dr. PhilipJames [80]. This proposal was made after reports from China, where oxygen treatment usingHBOT when necessary was adopted in Wuhan at the end of March 2020 with dramaticallygood results [74]. In total, 4400 COVID-19-related deaths were reported in China up toMarch 2020; there have only been about 250 more to date.In addition to reports from China, there are already multiple case-control studiesreporting the use of HBOT for patients with COVID-19. All these studies state that HBOTis a safe and promising alternative for the treatment of COVID-19 patients. Some studiesspecifically describe patients reporting the prompt resolution of labored breathing fol-lowing a single HBOT treatment [81–85]. In one very recent study, aimed at becomingRCT-compatible, it was possible to correct severe hypoxemia with mild HBOT (0.45 ATAoverpressure) in three days compared with nine days in the controls [86]. The elevationof the pressure by 0.45 ATA (corresponding to an altitude of 2400 m) is equal to that usedin airplanes prophylactically to correct potentially fatal hypobaria. Another recent study

Life 2022, 12, 754 11 of 20used conventional HBOT, 10 sessions at 2.4 ATA, to treat long COVID-19 patients withdisabling fatigue and found statistically significant beneficial effects [87]. In a recent casereport, HBOT was successfully applied to treat long COVID-19 symptoms, leading toimprovements in cognition and cardiopulmonary function. This effect was proposed tobe due to the ability of HBOT to reverse hypoxia, reduce neuroinflammation, and induceneuroplasticity [88].Additional evidence of the potential usefulness of HBOT in brain hypoxia or ischemiacomes from a large number of clinical studies demonstrating beneficial effects of HBOT.Similar to COVID-19, especially long COVID-19, which is characterized by reduced memoryand cognitive functions in addition to tiredness, brain hypoxia has been proposed to bethe underlying mechanism in such neurological diseases as Alzheimer’s disease, traumaticbrain injury, cerebral palsy, and stroke (see Fisher and Barak 2020 for review) [89].The most convincing evidence comes from management of stroke patients, wherea considerable amount of preclinical research supports the post-stroke use of HBOT fordamaged brain tissue. However, earlier controlled clinical trials of HBOT for stroke patientshave yielded nonconclusive and somewhat contradicting results. This has changed alongwith a more recent breakthrough as prospective, randomized controlled studies havepresented convincing evidence that HBOT can be the coveted neurotherapeutic method forbrain repair [90–93].The authors of COVID-19-HBOT studies conclude in common that well-defined RCT-compatible clinical trials are urgently needed [82–86]. However, designing such a trial maybe difficult. Not only is it challenging to design a placebo treatment, but it might be evenmore difficult to randomize patients for the active vs. placebo treatment when the primaryend point is death. HBOT has been accepted worldwide as the gold standard treatmentfor scuba-diving associated decompression (divers) disease, without any RCT evidence—because there also, the primary endpoint would be death. We propose the correspondingstrategy—an elevated ambient pressure (1.3–1.5 ATA) for the treatment of COVID-19patients with respiratory distress, using the higher pressures used in “conventional” HBOT(2.0–2.5 ATA) if necessary.5. Reversing the ANS/CAN Imbalance in COVID-19 and Long COVID-19Most of the early extrapulmonary symptoms of COVID-19 can be due to sympatheticdominance (and reduced parasympathetic function). Therefore, returning the ANS imbal-ance to normal by improving parasympathetic activity might be an important part of thetherapeutic regimen. In addition, both the severe CNS and pulmonary disease are probablycaused, and the pulmonary infection accentuated, through an inflammatory reflex mecha-nism due to inadequate immunological defense by the neuro-immune axis [94]. Excessiveinflammation plays an important role in the pathogenesis of common and debilitatingdiseases, including septic shock [95].Inflammation and VNSAlthough the common pathways between stress exposure and pathophysiologicalprocesses leading to tissue damage are still debatable, several results indicate that stresscan activate an inflammatory response in the brain and in the periphery [96]. Stress-induced pro-inflammatory factors play an important role in this damaging process. Incommon, over-activated immune systems, increased sympathetic nervous system activity,and reduced glucocorticoid (GC) responsiveness may work in tandem in the activation ofinflammatory responses during stress. As the vagal system with the vagus nerve in frontis responsible for parasympathetic activity, neuromodulation via vagal nerve stimulation(VNS) can serve as a targeted treatment in stressful conditions.When the stimulation patterns and dynamics of functional networks during VNS wereexamined by fMRI, the vagus nerve was found to convey signals to the brain through thepolysynaptic neuronal pathways by projecting to the brainstem nuclei (nucleus tractussolitarius, NTS, locus coeruleus), subcortical areas, and lastly, the cortex [97,98], thus

Life 2022, 12, 754 12 of 20covering the entire CAN. fMRI and a spatially independent component analysis wereutilized in a recent experimental study [99]. That study demonstrated that VNS activated15 out of 20 brain networks and that the activated regions covered >75% of the brain volume.There is strong preclinical scientific evidence for the beneficial role of VNS in the treatmentof immunologic reflex-associated disorders, particularly rheumatoid arthritis (reviewed byTracey, [100].VNS has been conventionally performed for more than two decades to treat severeepilepsy and depression by applying an electrode surgically implanted into the cervicaltrunk of the vagus nerve. More recently, it has been shown by electrophysiological andneuroimaging studies that transcutaneous auricular VNS (taVNS) of the auricular branchof the vagus nerve (ABVN) activates central vagal pathways similar to the VNS with animplanted electrode [101,102].In COVID-19/long COVID-19, taVNS may be especially effective, perhaps due to adual action: it may attenuate the underlying neuroinflammation or inflammatory processin parallel or subsequent to stress response. As a method, taVNS is safer than VNS becausethe ABVN has no efferent neurons. In the pathogenesis of atrial fibrillation (AF), anothercommon medical entity, accumulating evidence indicates that the inflammatory pathwaysplay a significant role [103]. In a recent RCT-compatible clinical trial, chronic, intermittenttaVNS resulted in significant reduction of inflammatory markers [104]. Based on its anti-inflammatory effects, taVNS targeted to the cervical part of the vagus nerve receivedemergency approval by the Federal Drug Administration in July 2020 for the treatment ofasthmatic COVID-19 patients.Earlier studies had failed to convincingly demonstrate that taVNS activates the crucialbrainstem nuclei such as NTS. This has now changed: it was recently demonstratedusing an ultrahigh-field (7T) fMRI that taVNS evokes activation in the ipsilateral NTS andupstream monoaminergic source nuclei of the brainstem [105]. Importantly, NTS activity isknown to be modulated by respiration, both through the bottom-up afferent pathway frompulmonary stretch receptors and aortic baroreceptors and through the top-down effectsfrom respiratory nuclei in the medulla [106]. Thus, taVNS treatment protocols shouldinclude instructions for slow breathing (“respiratory VNS”) [106].The symptoms of “long COVID-19” are best explained by imbalance in the ANS,dysautonomia. This could be reversed by increasing parasympathetic activity, whichcan be done using various behavioral methods such as relaxation and breathing exer-cises (e.g., meditations) but more efficiently by weak electrical stimulation of the vagalsystem/nerve [107,108].6. Brain Hypoxia May Be the Major Cause for COVID-19 and LongCOVID-19 SymptomsThere is strong evidence that the symptomatology of both acute COVID-19 and longCOVID-19 can best be explained by a pathophysiological mechanism in which brain hy-poxia is a crucial component. Lack of oxygen in the brain, including the brain stemand medullary respiration centers, causes symptoms of acute severe COVID-19, andhypoperfusion-induced brain injury also manifests itself as symptoms of longCOVID-19.This mechanism becomes obvious if the symptomatology is compared with the two best-known, most common conditions causing brain hypoxia, the carbon monoxide (CO) poi-soning and hypobaric hypoxia (HH) due to altitude elevation. Small concentrations of COin the inspired air cause headache and fatigue, symptoms that are also the first signal ofbrain hypoxia in mountain climbing as well as in aviation and ballooning. In mountainclimbing, the first symptom of hypobaric hypoxia is headache. If the ascension is continued,the next symptoms will be fatigue and high-altitude pulmonary edema (HAPE). The nextstep is unconsciousness. HAPE is induced by a hypoxic environment [109,110] and ischaracterized by interstitial edema and a large amount of exudation in the pulmonaryalveoli [111]. The frequently described “ground-glass opacity” in chest CTs of hospital-ized COVID-19 patients also, at least if it occurs at the early stage of COVID-19, suggests

Life 2022, 12, 754 13 of 20HAPE-type pathogenesis and thereby may be a sign merely of hypoxia rather than of viralpneumonia. From HAPE and altitude medicine in general, it is known that even a smallincrease in pressure may be life-saving [78]. The symptoms of mild CO poisoning, HH,COVID-19, and long COVID-19 are listed in Table 2. It is obvious that the CNS-relatedsymptoms of COVID-19 match perfectly with those of mild CO poisoning and HH.Table 2.Lists of the most common CNS-related symptoms of mild CO poisoning, hypobaric hypoxia(HH), and COVID-19/long COVID-19. The symptoms of mild CO poisoning were listed in theirorder of prevalence by Haldane (1895). Order of prevalence was also intended by the authors in HHand COVID-19. Symptoms suggest hypoxia, primarily affecting the brain. In mountain climbing, thefirst symptom of HH is headache; the next are fatigue and high-altitude pulmonary edema (HAPE).The next step is unconsciousness. HAPE is induced by a hypoxic environment and is characterizedby interstitial edema, shown as “ground-glass opacity” in chest CT.Mild CO-Poisoning [112,113] Aviation/Ballooning/Mountain Climbing COVID-19/Long Covid(in order of prevalence) (Hypobaric hypoxia) [114–117][55,56,118–123]Fatigue/lethargy Visual disturbances AnosmiaHeadache Headache FatigueNumbness and tingling Fatigue, lethargy Headache“Brain fog” Dizziness, nausea DyspneaDizziness, nausea Impaired fine touch & motor skills “Brain fog”Sleep disturbances Personality & mood changes Impaired consciousnessPalpitations Sensory loss Dizziness, nausea, tinnitusVisual impairments Confusion PalpitationsLoss of consciousness Loss of consciousness Sleep disturbancesNeuropsychological symptomsMild CO poisoning was also described by Haldane (1895) [112] as “the silent killer”,which brings to mind recent reports of “silent hypoxia” (and thereby a potential silent killer)in COVID-19. It is now also known that CO intoxication can cause, in survivors, seriousbrain damage into the midbrain the same as that seen in traumatic brain injuries. Themechanism of this was proposed already decades ago to be injury to the blood-brain-barrier(BBB) [124]. The BBB plays a crucial role in maintaining homeostasis within the CNS, andBBB breakdown is clearly evident in many neurological disorders. It has been shown inmany recent studies. One recentin vitrostudy used a six-cell-type neurovascular unithuman 3D organoid model containing brain microvascular endothelial cells, pericytes,astrocytes, oligodendrocytes, microglia, and neurons that recapitulates characteristics ofBBB dysfunction under hypoxic physiological conditions to show that exposure to hypoxiaresults in BBB breakdown and subsequent its dysfunction [125]. Because the verificationof brain damage usually remains undetected in clinical evaluations, COVID-19 patientswith long-standing CNS-symptoms are often stigmatized as psychosomatic exaggeratorsor even simulants.Thus, we feel strongly that in pathophysiological mechanisms of both acute and longCOVID-19, early neuroinvasion of the virus is involved and that this leads to brain hypoper-fusion and hypoxia. It has now been reported that long COVID-19 (in particular) has taughtus to better understand the putative pathogenic mechanisms of such (for school medicine)“contested diseases” as POTS (postural orthostatic tachycardia syndrome), CFS (chronicfatigue syndrome), neuroborreliosis, and fibromyalgia. All these conditions are best ex-plained by functional disturbances to the CAN [57], dysautonomia, and specifically theassociated sympathetic dominance. Symptoms comparable with those of the present longCOVID-19 were reported in long term follow-up studies of patients of the SARS 2002/3epidemic in Toronto. We propose that the crucial component in the pathophysiologic mech-anism of these “contested diseases” is the injury of BBB [124]. If that is true, it might teachus more about the pathogenetics of other presently enigmatic neurodegenerative diseases.

Life 2022, 12, 754 14 of 207. Significance of Chest CT in COVID-19Diagnosis of COVID-19 infection has largely been based on RT-PCR amplification ofviral nucleic acid from the upper respiratory tract swabs. In addition, the main hallmark ofCOVID-19 pneumonia is the presence of ground-glass opacity (GGO) in lung computertomography (CT). GGO, however, is not only a hallmark of pneumonia-type infection. It ismerely a general sign of interstitial pulmonary edema occurring from diverse causes, ofwhich the best characterized is the aforementioned HAPE from HH. Acute GGO has alsobeen described as a serious complication in conditions such as during forceful swimmingin triathlons and scuba diving and following electroconvulsive therapy (ECT), epilepticseizures, and CNS insults in general [126–131]. A characteristic feature of GGOs occurringin these connections is that they rapidly resolved with appropriate therapy, usually con-sisting of oxygen and diuretics. This may indicate that hypoxia is a component in suchpathophysiologic GGO mechanisms because GGO in HAPE behaves similarly, resolvingrapidly after only a relatively small descent.There are various theories concerning the pathogenetic mechanisms of GGO, againbest studied in HAPE, using animal models. Although the results of animal studies cannotbe directly applied to human, it is interesting that, according to such studies, the brain’sextremely complicated glymphatic systems are presented as playing a primary role, and intreatment aiming to resolve GGO, e.g., in rats, the positioning of animals, i.e., supine vs.sideways, plays an important role. Furthermore, there seem to be hitherto unknown mech-anisms between the brain and the lungs manifesting in patients as GGOs after ECTs andvarious brain insults, named “neurogenic pulmonary edema” [131]. Abdennour et al. [132]even state that the brain and the lungs interact early and rapidly when hit by a diseaseprocess and furthermore that local brain inflammation spreads rapidly to the lung.It is generally held that the diagnosis of COVID-9 is based primarily on a combinationof symptoms and positive results of virus PCR. In addition, chest CT plays a major rolein the diagnostic workup, even if it is not recommended routinely in mild disease and itnot infrequently shows GGO, which finding is interpreted as indicating severe disease.However, several reports suggest that GGO is relatively common in asymptomatic carriersof SARS-CoV-2. One of the first such reports, based on a multicenter study in China,performed chest-CT imaging for 411 symptomatic and 100 asymptomatic individuals, allPCR positive [133]. The surprise finding was GGO in 60% of asymptomatic individuals.About 25% of these later developed symptoms, suggesting GGO as the presymptomaticfinding. Most of asymptomatic carriers with GGOs came from high-altitude areas, whichsupports the idea that (hypobaric) hypoxia might play a role in the development of GGO.Two other studies, consisting of 60 and 64 asymptomatic PCR positive carriers on whomchest CT had been performed, described GGO findings in 47 and 60%, respectively [134,135].This caused De Smet et al. [134] to propose that in a pandemic setting, such incidentalCT-GGO findings should be reported as “compatible with COVID-19 pneumonia” ratherthan as “viral pneumonia” and that non-infectious lung diseases should be excluded fromthe diagnosis. From a therapeutic viewpoint, it would be crucial to know whether earlyGGO in chest CT is a sign of viral pneumonia or of (brain) hypoxia.8. Conclusions and Future ProspectsThe COVID-19 pandemic is beginning to end, and novel therapeutic methods willnot help many patients. For the future, however, it would be extremely important to learnthe pathophysiological mechanisms of the disease and thereby design better treatments.It seems evident that the earliest symptoms of potentially severe COVID-19, includingrespiratory distress, are best explained by primary replication of SARS-CoV-2 in the nasaland/or olfactory epithelia, followed by invasion of the virus into the CNS, including thebrainstem, and that ARDS is a later complication.It seems plausible that SARS-CoV2 is neurotropic, first attacking the mucous mem-branes of the nasal cavity in the same way as the other six coronaviruses. From the nose,there is a short path to the brain, including the respiratory centers where the virus causes a

Life 2022, 12, 754 15 of 20mild infection or perhaps only injures the BBB. These lead to imbalance of the ANS andmalfunction of the CAN with reduced parasympathetic (vagal) tone. The dysfunction ofthe vagal system can lead to inefficient respiration with subsequent hypoxemia and ulti-mately brain hypoxia that further worsens the efficacy of respiration. If the early, centrallytriggered brain hypoxia were recognized, that would automatically lead to a change intherapeutic strategy from providing only supplemental oxygen to real oxygen therapy.Preliminary evidence on the use of elevated ambient pressure for COVID-19-associatedrespiratory failure is very promising.Several recent studies on long COVID-19 offer additional support for the idea thatsympathovagal imbalance plays a crucial role. Therefore, VNS, or in practice taVNS, mightoffer a new, targeted therapeutic tool. Furthermore, taVNS is very patient-friendly andlow-cost. However, as there are currently no appropriate online biomarkers available fortaVNS, there is still a great need for additional research to find the optimal therapeuticregimen as well as better stimulating devices.It will also be important that the medical community change its prevailing opinion andunderstand that oxygen itself is not toxic, that rather, with adequate dosing it has a crucialcurative role. Many illnesses in which hypoxia may play an important pathogenetic rolecould be treated with pure oxygen and, if necessary, with elevated pressure. In the presenceof a proven oxygen deficiency, it is not ethical to withhold additional oxygen, and at thecorrect dosage, which, as the Chinese studies have shown by measurements, may requirethe use of a pressure chamber. Although there is an enormous amount of reliable data onthe importance of ambient pressure for the appropriate oxygenation of tissues, particularlyfor the most sensitive of them, the brain, it appears that the real significance of pressure inrespiratory function is not fully understood even by most competent medical professionals.However, most of us may also not be aware that we have practically all been pressurizedwith 0.4–0.5 ATA and have breathed pressurized air in an airplane “hyperbaric chamber”.Airplane cabin pressurization is necessary (for survival) because atmospheric pressure fallsduring ascent (one millibar per 10 m). Correspondingly, the pressure increases when onedescends from the sea level. The lowest place on earth is the Dead Sea, situated 457 mbelow sea level, which means that the average atmospheric pressure there is 802 mmHg.When a group of hypoxemic (COPD) patients (from Jerusalem, +850 m) stayed there forthree weeks, subjective well-being and all measured functional parameters improvedsignificantly [136]. Similar beneficial effects were also reported in patients with cysticfibrosis [137]. It seems likely that the improvement in tissue oxygen content using evencompressed air at 1.3–1.5 ATA would be valuable judged on the well-established benefitof descent in high altitude pulmonary and cerebral edema. This pressure increase mightbe life-saving for many COVID-19 and other critically ill patients. If this alternative wereincluded in the therapeutic regimen of COVID-19, it might be that this disease could bereduced in severity and become just another “flu”, i.e., influenza.Author Contributions:Conceptualization, J.Y., J.L., R.P. and A.M.; methodology, J.Y. and J.L.;writing—original draft preparation, J.Y. and A.M.; writing—review and editing, J.Y., J.L., R.P. andA.M.; project administration, J.Y. and A.M. All authors have read and agreed to the published versionof the manuscript.Funding:This research was funded by the Research Foundation of the Finnish Otolaryngolog-ical Association.Institutional Review Board Statement:The study was conducted in accordance with the Declarationof Helsinki.Informed Consent Statement: Not applicable.Data Availability Statement: Not applicable.Conflicts of Interest:J.Y. and J.L. are board members of Helsinki Ear Institute Inc. and Salus-tim Group.

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Bhaiyatetal. Journal of Medical Case Reports (2022) 16:80 https://doi.org/10.1186/s13256-022-03287-wCASE REPORTHyperbaric oxygen treatment forlong coronavirus disease-19: acase reportAisha M. Bhaiyat1*, Efrat Sasson2, Zemer Wang1, Sherif Khairy1, Mouzayan Ginzarly1, Umair Qureshi1, Moin Fikree3 and Shai Efrati4* Abstract Background: The coronavirus disease 2019 pandemic has resulted in a growing population of individuals who experience a wide range of persistent symptoms referred to as “long COVID.” Symptoms include neurocognitive impairment and fatigue. Two potential mechanisms could be responsible for these long-term unremitting symptoms: hypercoagulability, which increases the risk of blood vessel occlusion, and an uncontrolled continuous inflammatory response. Currently, no known treatment is available for long COVID. One of the options to reverse hypoxia, reduce neuroinflammation, and induce neuroplasticity is hyperbaric oxygen therapy. In this article, we present the first case report of a previously healthy athletic individual who suffered from long COVID syndrome treated successfully with hyperbaric oxygen therapy.Case presentation: A previously healthy 55-year-old Caucasian man presented 3 months after severe coronavirus disease 2019 infection with long COVID syndrome. His symptoms included a decline in memory, multitasking abilities, energy, breathing, and physical fitness. After evaluation that included brain perfusion magnetic resonance imaging, diffusion tensor imaging, computerized cognitive tests, and cardiopulmonary test, he was treated with hyperbaric oxygen therapy. Each session included exposure to 90 minutes of 100% oxygen at 2 atmosphere absolute pressure with 5-minute air breaks every 20 minutes for 60 sessions, 5 days per week. Evaluation after completing the treat-ment showed significant improvements in brain perfusion and microstructure by magnetic resonance imaging and significant improvement in memory with the most dominant effect being on nonverbal memory, executive functions, attention, information procession speed, cognitive flexibility, and multitasking. The improved cognitive functions correlated with the increased cerebral blood flow in brain regions as measured by perfusion magnetic resonance imaging. With regard to physical capacity, there was a 34% increase in the maximum rate of oxygen consumed during exercise and a 44% improvement in forced vital capacity. The improved physical measurements correlated with the regain of his pre-COVID physical capacity.Conclusions: We report the first case of successfully treated long COVID symptoms with hyperbaric oxygen therapy with improvements in cognition and cardiopulmonary function. The beneficial effects of hyperbaric oxygen shed additional light on the pathophysiology of long COVID. As this is a single case report, further prospective randomized control studies are needed.Keywords: COVID-19, SARS-CoV-2, Case report, Hyperbaric oxygen therapy, HBOT, Long COVID© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Backgrounde coronavirus disease 2019 (COVID-19) pandemic has resulted in a growing population of individuals who experience a wide range of long-lasting symptoms after recovery from the acute illness, referred to by several Open Access*Correspondence: aisha@aviv-clinics.ae; efratishai@outlook.com1 Aviv Clinics, Jumeirah Lake Towers, Dubai, United Arab Emirates4 Sagol Center for Hyperbaric Medicine and Research, Shamir Medical Center, Israel Sackler School of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, IsraelFull list of author information is available at the end of the article

Page 2 of 5Bhaiyatetal. Journal of Medical Case Reports (2022) 16:80 terms, including “post-COVID conditions” and “long COVID.” e five most common symptoms recognized post-COVID are fatigue (58%), headache (44%), cognitive impairment (27%), hair loss (25%), and dyspnea (24%) [1].Two main biological sequelae of COVID-19 play roles in the pathogenesis of long COVID. e first is hyper-coagulability state characterized by increased risk of small- and large-vessel occlusion [2]. e second is an uncontrolled continuous inflammatory response [3]. Microinfarcts and neuroinflammation are important causes of brain hypoxia and can be responsible for the chronic unremitting neurocognitive decline in patients with long COVID [4]. One of the options to reverse hypoxia, reduce neuroinflammation, and induce neu-roplasticity is hyperbaric oxygen therapy (HBOT) [5]. In this article, we present the first case report of previ-ously healthy, athletic individual who suffered from long-standing post-COVID syndrome treated successfully with HBOT.Case presentationA 55-year-old previously healthy Caucasian man suf-fering from persistent unremitting symptoms of long COVID attended our clinic for evaluation. e clinical presentation included memory problems, worsening of multitasking abilities, fatigue, low energy, breathless-ness, and reduced physical fitness, which all started after acute SARS-CoV-2 infection diagnosed 3months before. He initially developed high-grade fever without chest pain, cough, or shortness of breath, on 21 January 2021. He was admitted to hospital because of dehydration on 30 January 2021 and was diagnosed with COVID-19 by reverse-transcription polymerase chain reaction (RT-PCR). During the hospital stay, he developed acute res-piratory syndrome due to pneumonitis and required supportive treatment with high-flow oxygen for 1week. He was discharged from hospital on 16 February 2021. At discharge, he was stable with normal oxygen and no neurological deficiencies were noted on physical exami-nation. In addition, 6weeks after being diagnosed with COVID-19, he developed a pulmonary embolus and was treated with rivaroxaban. Prior to the SARS-CoV-2 infec-tion, he had been a healthy, high-functioning, and ath-letic individual.e baseline evaluation done at our clinic, 3months after the acute infection, included brain magnetic reso-nance imaging (MRI) with perfusion and diffusion tensor imaging (DTI), computerized neurocognitive evaluation, cardiopulmonary exercise test (CPET), and pulmonary function tests.At baseline, the patient complained of shortness of breath with exercise as well as difficulties with memory and multitasking that started after his COVID-19 illness. Physical and neurological examination was normal. Brain MRI evaluation demonstrated reduced perfusion that correlated with the cognitive decline as detailed below. He was referred to hyperbaric oxygen therapy (HBOT) that included 60 sessions, 5 days per week. Each ses-sion included exposure to 90minutes of 100% oxygen at 2 atmosphere absolute with 5-minute air breaks every 20minutes.e patient started his first HBOT on 19 April 2021 and finished on 15 July 2021 without any significant side effects. After the first five sessions, he reported that his breathing had started to improve and that he no longer had muscle aches after exercise. After 15 sessions, he noted less fatigue and an improvement in his previous low energy. After 20 sessions, he noticed that his breath-ing and exercise capacity had returned to his capacity pre-SARS-CoV-2 infection, returning to running moun-tain trails. Additionally, he noted that his memory and multitasking ability returned to his pre-COVID-19 levels.e baseline brain MRI, prior to the HBOT, showed two small foci of signal alterations in the right and left parietal regions suggestive of early small-vessel disease. In addition, there was a global decrease in the brain per-fusion. As detailed in Fig.1 and Table 1, re-evaluation after HBOT (done 4weeks after the last HBOT to avoid any potential intermediate effect) revealed a significant increase in brain perfusion. Tables2 and 3 present the improvements in the brain microstructure as demon-strated by MRI–DTI.Neurocognitive assessment was done using NeuroTrax full computerized testing battery to measure different aspects of brain function, such as memory, information processing speed, attention, and executive function, was done before and after HBOT. e post-HBOT neurocog-nitive testing showed significant improvement in global memory with the most dominant effect being on nonver-bal memory, executive functions, attention, information procession speed, cognitive flexibility, and multitasking. Table4 summarizes the pre- and post-HBOT scores in the different cognitive domains.Physical capacity was evaluated by maximal cardiopul-monary exercise test (CPET) conducted on a COSMED treadmill using the Boston 5 protocol. Table5 presents the pre- and post-HBOT physiological evaluated param-eters. As detailed, there was a 34% increase in the VO2 max from 3083 to 4130mL per minute after HBOT. e forced vital capacity (FVC) improved by 44% from 4.76 to 6.87 L, the forced expiratory volume (FEV) by 23% from 3.87 to 4.76L, and peak flow measurement (PEF) by 20.2% from 10.17 to 12.22L per second.After receiving full information at the end of his post-HBOT evaluation, the patient signed an informed con-sent allowing publication of his medical information.

Page 3 of 5Bhaiyatetal. Journal of Medical Case Reports (2022) 16:80 Discussion andconclusionsHere, we report the first case of a patient with long COVID with cognitive and cardiorespiratory symptoms treated successfully by HBOT. Following treatment, he showed significant improvements in brain perfusion, white matter brain microstructure, and cognitive and cardiopulmonary function. is case report shows that HBOT has potential use for treatment of patients with long COVID who suffer from unremitting cognitive and physical functional decline.Hypoxia plays an important role in the pathophysiol-ogy of long COVID. Systemic hypoxia could result from lung impairment, and organ-related hypoxia can develop because of vascular damage. Persisting lung function Fig. 1 Brain perfusion magnetic resonance imaging before and after hyperbaric oxygen therapy. The upper row represents brain perfusion 3 months after the acute infection, before hyperbaric oxygen therapy. The lower row represents the perfusion magnetic resonance imaging done after completing the hyperbaric oxygen therapy protocolTable 1 Brain blood flow changes before and after hyperbaric oxygen therapyBrain region Pre-HBOT Post-HBOT Change in %White matter right (R) 19.43 22.89 17.80White matter left (L) 19.17 22.23 16Gray matter R 32.34 38.6 19.40Gray matter L 33.3 38.91 16.80Primary gustatory cortex R 34.22 47.43 38.60Lateral postcentral gyrus R 32.08 42.79 33.40Superior temporal gyrus R 38.04 50.65 33.10Supramarginal gyrus R 36.37 46.39 27.60Anterior cingulate cortex L 40.16 50.61 26Inferior frontal gyrus L 39.47 49.6 25.70Inferior frontal gyrus (Broca’s area) R37.55 46.81 24.70Medial frontal gyrus R 29.57 36.67 24Table 2 Magnetic resonance imaging–diffusion tensor imaging fractional anisotropy changes before and after hyperbaric oxygen therapyFractional anisotropy (FA) is a measure used to evaluate white matter ber integrity, directionality, and order. A higher value of FA indicates better ber organization.DTI diusion tensor imagingBrain region Pre-HBOT Post-HBOT Change in %Superior fronto-occipital fasciculus L0.44 0.48 7.52Cingulum (hippocampus) R 0.24 0.26 7.46Superior corona radiata L 0.39 0.42 5.63Body of corpus callosum 0.43 0.45 5.39Cingulum (hippocampus) L 0.23 0.24 4.59Corticospinal tract L 0.37 0.38 3.49External capsule L 0.36 0.38 3.23Superior corona radiata R 0.43 0.44 3.21Table 3 Magnetic resonance imaging–diffusion tensor imaging mean diffusivity changes before and after hyperbaric oxygen therapyMean diusivity (MD) is a measure used to evaluate white matter ber density. A lower value of MD indicates a higher density.DTI diusion tensor imagingBrain region Pre-HBOT Post-HBOT Change in %Medial lemniscus R 1.3 1.24 4.72Superior longitudinal fascicu-lus L0.76 0.73 4.61Medial lemniscus L 1.23 1.18 4.34Superior corona radiata L 0.77 0.74 3.18Superior fronto-occipital fasciculus L0.75 0.72 3.14Sagittal stratum L 0.83 0.81 2.51Pontine crossing tract 0.76 0.75 2.35Fornix L 1.01 0.99 2.06Table 4 Cognitive scores before and after hyperbaric oxygen therapyNeurotrax Pre-HBOT Post-HBOT Change in %Global cognitive score 93.3 99.4 6.5Memory 98.8 105.8 7.1Nonverbal memory 96.2 114 18.5Delayed nonverbal memory 105.6 113.6 7.6Verbal memory 92.1 94.5 2.6Delayed verbal memory 101.3 101.3 0Executive function 101.2 112.6 11.3Information processing speed 74.6 80.8 8.3Attention 87.9 92.1 4.8Motor skills 104 105.6 1.5

Page 4 of 5Bhaiyatetal. Journal of Medical Case Reports (2022) 16:80 impairment has been seen in patients who required sup-plemental oxygen during acute SARS-CoV-2 infection even 6 and 12months after the acute infection [6]. Since brain functionality and regenerative capacity is sensitive to any decline in oxygen supply [7], long-term cognitive deficits correlate with the amount of oxygen needed to overcome the respiratory difficulties [1]. With regard to organ-related ischemia, COVID-19 induced endothelial damage and hypercoagulation, which increases the risk of vascular dysfunction responsible for the high preva-lence of myocardial infarction, ischemic strokes, and pul-monary embolism [8]. In the presented case, the patient required supportive treatment with high-flow oxygen for 1week during the acute illness, meaning he had suffered from systemic hypoxia with its consequent risk for long-term cognitive impairment due to anoxic brain damage. Moreover, 6weeks after the acute infection, he developed a pulmonary embolus, representative of the endothe-lial dysfunction with additional exposure to systemic hypoxia. In addition, as demonstrated by the brain perfu-sion MRI, he had microvascular-related perfusion defects that correlated with his neurocognitive decline.HBOT involves the inhalation of 100% oxygen at pres-sures exceeding 1 atmosphere absolute (ATA), thus enhancing the amount of oxygen dissolved in the body tissues. Even though many of the beneficial effects of HBOT can be explained by improvement of tissue oxy-genation, it is now understood that the combined action of hyperoxia and hyperbaric pressure triggers both oxy-gen- and pressure-sensitive genes, resulting in induction of regenerative processes including stem cell proliferation and mobilization with anti-apoptotic and anti-inflam-matory factors, angiogenesis, and neurogenesis [9–12]. HBOT can induce neuroplasticity and improve cogni-tive function even years after the acute insult [13]. In the case presented of long COVID, HBOT improved cerebral blood flow to the malperfused brain regions (indicative of brain angiogenesis) and improved the integrity of brain microstructure (indicative of neurogenesis). e correla-tion between the significant improvements demonstrated on brain imaging and the neurocognitive improvements indicates that most of the beneficial effects of HBOT are indeed related to its ability to induce neuroplasticity of the brain’s dysfunctional regions.HBOT has been demonstrated to have beneficial effects on mitochondrial function, a crucial element of appropri-ate muscle function [12]. HBOT can also increase the number of proliferating and differentiating satellite cells as well as the number of regenerated muscle fibers, and promote muscle strength [14]. e newly intermittent repeated HBOT protocol was demonstrated to have the potential to improve lung function with respect to peak expiratory flow (PEF) and force vital capacity (FVC) [15]. In the presented patient, performance capacity of the car-diopulmonary system was evaluated using cardiopulmo-nary exercise test (CPET) and pulmonary function tests. HBOT induced a significant improvement of 34% in the maximal oxygen consumption capacity, an improvement of 34.4% in the maximal METs, and an increase of 16.9% in the lactic threshold. With regard to lung function, FVC was improved by 44.3%, and PEF by 20.2%. ese meas-urable improvements correlated with the patient’s ability to regain his previous high athletic performance.In this reported case, HBOT was initiated more than 3 months after the acute SARS-CoV-2 infection. Even though the symptoms persisted till the HBOT was ini-tiated and significant improvement began only after HBOT was initiated, it is possible that at least some of the clinical improvement could have occurred without HBOT. However, the abrupt significant improvement with full recovery after the chronic nature of the symp-toms, our understanding of the physiological effects of HBOT, and the objective measurements done on this patient support the relation between the treatment and the improvements seen. As this is only a case report, fur-ther prospective clinical trials are needed to gain a bet-ter understanding of the potential beneficial effects of HBOOT for patients with long COVID.In summary, this article represents the first case report showing that long COVID can be treated with HBOT. e beneficial effect of HBOT sheds additional light on the pathophysiology of this syndrome. As this is a sin-gle case report, further prospective randomized control Table 5 Physiological parameters before and after hyperbaric oxygen therapyVO2max maximum rate of oxygen consumed during exercise, ml/min milliliter per minute, VO2max/kg maximum rate of oxygen consumed during exercise per kilogram, ml/min/Kg milliliters per minute per kilogram, MET metabolic equivalent of task, bpm heartbeats per minute, VO2/HR rate of oxygen consumed per heart rate, FVC forced vital capacity, L liters, FEV1 forced expiratory volume, PEF peak ow measurement, L/s liters per secondCardiopulmonary exercise testPre-HBOT Post-HBOT Change in %VO2 max (mL/min) 3083 4130 34VO2max/kg (mL/min/kg) 31.5 42.4 34.6Lactic threshold (mL/min) 2941 3439 16.9Respiratory threshold (mL/min) 3103 4076 31.4Metabolic equivalent of task (MET)9 12.1 34.4Maximal heart rate (bpm) 155 164 5.8VO2/HR (mL per beat) 19.9 25.2 26.6Pulmonary function tests FVC (L) 4.76 6.87 44.3 FEV1 (L) 3.87 4.76 23 PEF (L/s) 10.17 12.22 20.2

Page 5 of 5Bhaiyatetal. Journal of Medical Case Reports (2022) 16:80 • fast, convenient online submission • thorough peer review by experienced researchers in your field• rapid publication on acceptance• support for research data, including large and complex data types• gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year • At BMC, research is always in progress.Learn more biomedcentral.com/submissionsReady to submit your researchReady to submit your research ? Choose BMC and benefit from: ? Choose BMC and benefit from: studies are needed for the use of hyperbaric oxygen ther-apy in treating long COVID.AbbreviationsHBOT: Hyperbaric oxygen therapy; MRI: Magnetic resonance imaging; DTI: Dif-fusion tensor imaging; VO2 max: Maximum rate of oxygen consumed during exercise; CPET: Cardiopulmonary exercise test; HR: Heart rate; Bpm: Heart beats per minute; FVC: Forced vital capacity; FEV1: Forced expiratory volume; PEF: Peak flow measurement.AcknowledgementsNot applicable.Authors’ contributionsAMB, ES, SE, and SK analyzed and interpreted the patient data regarding the MRI, perfusion, and DTI. AMB and SE analyzed and interpreted the patient data regarding the cardiopulmonary and pulmonary function tests. All authors read and approved the final manuscript.FundingNo funding was received.Availability of data and materialsAll data generated or analyzed during this study are included in this published article.DeclarationsEthics approval and consent to participateNot applicable.Consent for publicationWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.Competing interestsAMB, ZW, SK, MG, and UQ work for AVIV Clinics. ES works for AVIV Scientific LTD. SE is a co-founder and shareholder at AVIV Scientific LTD.Author details1 Aviv Clinics, Jumeirah Lake Towers, Dubai, United Arab Emirates. 2 Aviv Scientific Ltd, 7 Mezada Street, Bnei Brak, Israel. 3 Rashid Hospital Trauma Center, Dubai, United Arab Emirates. 4 Sagol Center for Hyperbaric Medicine and Research, Shamir Medical Center, Israel Sackler School of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Israel. Received: 11 October 2021 Accepted: 21 January 2022References 1. Lopez-Leon S, et al. More than 50 long-term effects of COVID-19: a sys-tematic review and meta-analysis. Sci Rep. 2021;11(1):16144. 2. Levi M, et al. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020;7(6):e438–40. 3. Mahmudpour M, et al. COVID-19 cytokine storm: the anger of inflamma-tion. Cytokine. 2020;133: 155151. 4. Li B, et al. Brain–immune interactions in perinatal hypoxic-ischemic brain injury. Prog Neurobiol. 2017;159:50–68. 5. Shapira R, et al. Hyperbaric oxygen therapy ameliorates pathophysiology of 3xTg-AD mouse model by attenuating neuroinflammation. Neurobiol Aging. 2018;62:105–19. 6. Huang L, et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet. 2021;398(10302):747–58. 7. Hadanny A, Efrati S. Oxygen—a limiting factor for brain recovery. Crit Care. 2015;19:307. 8. Katsoularis I, et al. Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study. Lancet. 2021;398(10300):599–607. 9. Pena-Villalobos I, et al. Hyperbaric oxygen increases stem cell prolifera-tion, angiogenesis and wound-healing ability of WJ-MSCs in diabetic mice. Front Physiol. 2018;9:995. 10. Cabigas BP, et al. Hyperoxic and hyperbaric-induced cardioprotection: role of nitric oxide synthase 3. Cardiovasc Res. 2006;72(1):143–51. 11. Gregorevic P, Lynch GS, Williams DA. Hyperbaric oxygen modulates antioxidant enzyme activity in rat skeletal muscles. Eur J Appl Physiol. 2001;86(1):24–7. 12. Zhou Z, et al. Protection of mitochondrial function and improvement in cognitive recovery in rats treated with hyperbaric oxygen following lateral fluid-percussion injury. J Neurosurg. 2007;106(4):687–94. 13. Hadanny A, et al. Hyperbaric oxygen therapy improves neurocognitive functions of post-stroke patients—a retrospective analysis. Restor Neurol Neurosci. 2020;38(1):93–107. 14. Horie M, et al. Enhancement of satellite cell differentiation and functional recovery in injured skeletal muscle by hyperbaric oxygen treatment. J Appl Physiol. 2014;116(2):149–55. 15. Hadanny A, et al. Hyperbaric oxygen therapy effects on pulmonary func-tions: a prospective cohort study. BMC Pulm Med. 2019;19(1):148.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in pub-lished maps and institutional affiliations.

Can Hyperbaric OxygenTherapy Improve LongCOVID Symptoms?August 23, 2022Experiencing a bout of COVID-19 is bad enough. But forfar too many people, surviving COVID leads to lingeringneurocognitive, neuropsychological, or physicalsymptoms called long COVID, also known as post-COVID-19 syndrome or COVID-Brain. Of the over 40% ofAmericans who have had COVID-19, an estimated 19% ofthem meet the criteria for long COVID, according to theHousehold Pulse Survey. This means that over 25 millionpeople are still struggling with symptoms related toinfection with SARS-CoV-2. A 2022 brain-imaging studyin Nature Medicine has identified an astounding 62symptoms related to long COVID. These symptoms

include but are not limited to:Brain fogMemory lossAnxietyDepressionFatigueSleep disturbancesPainBut new research shows there is hope for those dealingwith long COVID. Results from a 2022 study in ScientificReports show that hyperbaric oxygen therapy (HBOT), anoninvasive treatment, can produce changes in the brainthat improve long COVID symptoms.Results from a 2022 study in Scientific Reports show thathyperbaric oxygen therapy (HBOT), a noninvasivetreatment, can produce changes in the brain that improvelong COVID symptoms. Click To TweetWHAT IS HBOT?Hyperbaric oxygen therapy is a well-researched treatmentthat involves breathing 100% pure oxygen in a pressurizedchamber. HBOT allows a person to increase the amount ofoxygen taken into the lungs by as much as 3 times what isinhaled with normal air pressure. The blood then carriesthis extra oxygen throughout the body and brain, where itcan accelerate the healing process of any damaged

tissues.HBOT BENEFITS LONG COVID ANDOTHER CONDITIONSHBOT is best-known for treating decompression sicknessin deep-sea divers, but it has solid research showing thatit is also beneficial for a wide range of other conditions,such as carbon monoxide poisoning, burns, woundhealing, and fighting infections. People have reportedbenefits from HBOT treatment for many other issues,such as:Concussions and traumatic brain injuries (TBIs)Memory lossAlzheimer’s diseaseVascular dementiaPosttraumatic stress disorder (PTSD)DepressionAnxietyAttention issuesAutism spectrum disorder (ASD)Lyme diseaseStrokeMigraineThe new research in Nature Medicine shows that longCOVID symptoms can be added to this list. Thisrandomized, double-blind, sham-control trial analyzed theuse of HBOT on people with post-COVID symptoms that

had lingered for at least 3 months after testing positive forthe virus. For this study, 73 people were split into 2 groupswith one group receiving 40 sessions of HBOT and theother group undergoing a sham treatment.The HBOT group experienced significant improvements inattention, executive function (clearing brain fog),psychiatric symptoms, sleep, energy, and pain. Brainimaging scans revealed that the HBOT group experiencedincreased blood flow to multiple regions of the brainassociated with cognitive function and emotions. Thestudy authors suggest that HBOT’s benefits are due tothis increase in blood flow and neuroplasticity.Many brain SPECT imaging studies show that HBOTsignificantly improves cerebral blood flow. SPECTmeasures blood flow and activity in the brain andidentifies areas with healthy activity, too little activity, andtoo much activity. Low blood flow is associated with arange of brain health and mental health issues, includingtraumatic brain injuries, exposure to toxins, ADD/ADHD,some forms of autism, addictions, Alzheimer’s disease,and more.For example, research in BMC Pediatrics shows thattreatment with HBOT improves functioning in people withautism. A 2017 study on military veterans whoexperienced concussions due to explosive blasts foundthat they scored higher on cognitive, psychological, andphysical exams following HBOT treatment. And a

fascinating case study on a 58-year-old woman withAlzheimer’s disease found that after 40 sessions of HBOT,she experienced improvements in mood, energy, and herability to handle daily tasks. Brain imaging scans for thiscase study revealed an increase in brain metabolism,prompting the study authors to suggest HBOT may holdpromise as a therapy for people with Alzheimer’s disease.HOW HYPERBARIC OXYGENTHERAPY WORKSTreatment with HBOT involves lying in a pressurizedchamber for a specified amount of time.HBOT can be delivered in either hard-shell chambers orsoft-sided chambers. The hard-shell chambers can reachhigher air pressures and oxygen levels than soft-walledchambers. Both types of chambers can offer benefitsdepending on a person’s individual needs. The number ofHBOT sessions recommended also depends on yourneeds. A trained technician monitors each session foryour safety and comfort.At Amen Clinics, HBOT may be recommended as part of acomprehensive post-COVID treatment plan. Dependingon your individual needs, this may also include makinglifestyle changes, addressing unhealthy thinking patterns,incorporating stress-reduction techniques, and more.Post-COVID brain fog, anxiety, depression, and other

mental health issues can’t wait. At Amen Clinics, we’rehere for you. We offer in-clinic brain scanning andappointments, as well as mental telehealth, clinicalevaluations, and therapy for adults, teens, children, andcouples. Find out more by speaking to a specialist todayat 855-459-6408 or visit our contact page here.

Long COVID Explained: TheSymptoms and Why TheyStick AroundMillions of individuals who have tested positive for COVID-19 continue to experience ongoing health issues, clinicallyknown as long COVID. If you’re one of these people, theAviv team is here with research-backed information onwhat this means and what you can do.While there is still uncertainty surrounding COVID-19complications and their long-term side effects, there havebeen extensive studies conducted that offer insight into:Post COVID symptomsHow long COVID can impact your body and lifestyleTreatment methods that can help mitigate long-haulCOVID effects

Below, we provide all the details you need to attain aholistic understanding of how long COVID impacts yourbody and promising treatment plans that can help you getback to optimal health. As you’re reading through this,keep in mind:Each person has a unique experience with COVID-19.Therefore, speaking with a doctor is an essential firststep.Several alternative terms are used for long COVID,such as post-COVID, long-haul COVID, post-acuteCOVID, and chronic COVID.How the CDC and WHO Define Long COVIDThe Centers for Disease Control and Prevention(CDC) defines long COVID as a condition whereindividuals experience long-term effects of COVID-19.The World Health Organization (WHO) defines longCOVID as persistent symptoms more than 3 monthsafter the acute infection, that continue, not relapse,that have been reoccurring and there is no otherexplanation for those symptoms.Anyone who has been infected with COVID-19 candevelop long COVID. Approximately 30% of COVID-19 patients report having symptoms of long-haulCOVID.The numbers of people affected long term

are highThe WHO had a definition of long COVID over two yearsago. That means, from nearly the beginning, these healthorganizations studying the virus were seeing long-termside effects and symptoms of impairment from havingCOVID-19.You aren’t alone if you don’t feel like yourself after havingCOVID-19.Approximately 30% of COVID-19 patients reporthaving symptoms of long-haul COVID.20-50% of patients with 1 or more features 3-6months post COVID, receive a long COVID diagnosis.11-20% of children have lingering symptoms at 14weeks post COVID.For a comprehensive understanding of what long-haulCOVID is, let’s flesh out the differences between COVIDand long COVID:Acute COVID:Individuals experience COVID-19 symptoms for up tofour weeks, starting from the onset of illness.Subacute is where COVID-19 symptoms are noticedup to 12 weeks, and the virus can still be found in thebody.Long COVID:

Individuals experience COVID-19 symptoms for anaverage of three months from the onset of illness.Long-haul COVID symptoms may begin after initialrecovery from acute COVID or persist from the initialillness.Long COVID symptoms cannot be explained by analternative diagnosis.Understanding the Symptoms of Long-HaulCOVIDThe Aviv medical staff primarily explores the four keyareas from this long-haul COVID symptoms list todiagnose long COVID.Physical Symptoms:Fatigue

Dyspnea (labored breathing)Chest pain or tightnessCoughDysgeusia (loss of taste)Anosmia (loss of smell)Joint or muscle painCognitive & Psychological Symptoms:Memory declineAttention and concentration difficultiesBrain fogAnxietyDepressionSleep disturbancesHeadachesGeneralized disabling painLung SymptomsShortness of breathChest pain or tightnessCardiac Symptoms:Myocarditis (inflammation of heart muscles)Heart palpitationsShortness of breathElevated blood pressureDrops in oxygen saturationIf you are experiencing long COVID symptoms,contact our team of certified medical professionals

today – click here.The Hard Truth: Long COVID & Brain InjuriesCOVID-19 essentially impacts the brain. This is why themajority of long COVID symptoms are cognitive and maylead to brain injuries, depending on how severely yourbody gets affected by the virus. According to Dr.Mohammed Elamir, MD, FACP, although there are nopatterns between the severity of COVID-19 and thelikelihood of receiving long COVID, there are patternsbetween:Where the virus attacks in the brainHow that location in the brain impacts long COVIDsymptoms

Here are four ways that connection can manifest:1. Direct Brain InvasionThe COVID-19 virus travels through the nose, into theolfactory sensory neurons, and into the frontal lobe ofyour brain called the insula. The olfactory neuronsmanage taste and smell, while the insula overseesmemory and executive function. Depending on where thevirus attacks and the level of damage it creates, anindividual may experience prolonged COVID symptoms.For example, when the virus significantly attacks yourolfactory nerves, this may induce a loss of taste and smell.This is why these symptoms are such a strong indicator ofthe virus.2. Blood Vessel InjuryStudies show COVID-19 can destroy blood vessels thatfeed blood to the brain. As the virus circulates throughoutyour bloodstream, the inner blood vessel lining issusceptible to damage. When the inner lining deteriorates,this allows the virus to: Seep into the tissues, or inhibitblood flow to the brain. Both can cause brain injuries. Anddepending on where those injuries occur, specific brainfunctions (memory, concentration, etc.) may decline morerapidly than normal.3. Dysregulated Immune Response

Damage to the inner blood vessel lining can also inhibitthe growth of cells—the exact opposite of what ourimmune system should be doing. Dysregulated immuneresponses are common in those with severe cases ofCOVID-19.When the body cannot adequately produce a normalimmune response, it either: Underreacts to foreigninvaders, causing viruses to spread quickly; or oerreactsto foreign invaders, causing the immune cells to attackeven healthy cells, tissues, and organs.4. Cellular DysfunctionOn a cellular level, COVID-19 can affect metabolicfunction through the mitochondria. This cell damageslows down the body’s response rate to infection, leadingto high inflammatory conditions.So how long will patients have to deal withCOVID symptoms?According to Dr. Mohammed Elimar, MD, FACP, theanswer isn’t available. But a key guiding factor is theextent of blood vessel damage.Dr. Elimar further explains:“There’s still a lot to learn about how [mitochondrialdysfunction] will last but it will probably be tied to thelevel of microvascular change or blood vessel damage.The more blood vessel damage you have, the more

[long COVID symptoms] you’re likely going to have.Also, the amount of real estate that thosemicrovascular changes are occupying will probablydictate how long [symptoms] will last.”Aviv Clinics’ Treatment for Long COVIDSymptomsLong COVID is a complex disease.Finding a treatment plan that will work for you may takesome time. Because there is no one-size-fits-allapproach, speaking with a medical professional isessential.The right physician will take a holistic approach. Due tothe complexity of long COVID, it’s important to find atreatment program that:Is rooted in data and researchOffers a comprehensive assessment processConnects you with a diverse medical teamAviv Clinic’s team of certified physicians achieves all ofthe above to ensure you’re being provided with a tailoredtreatment plan that works for you. We connect ourpatients with a team of physicians, neuropsychologists,physiotherapists, nurses, and more to provide amultidisciplinary health plan.Our post-COVID symptom treatment plan can be broken

down into three parts:In-depth medical assessment:Leveraging advanced brain imaging, our clinical teamconducts physical, cognitive, and neurological examsto gain a thorough understanding of your health.Tailored treatment program:Based on your assessment, our medical team crafts apersonalized treatment plan tailored to your healthgoals.Post-treatment assessment:Our team initiates another round of tests to assessyour progress and unique findings on any cognitiveand physical improvements.Maximize Your Health and Performance withAvivThough COVID-19 may have brought ongoing healthchallenges, the Aviv team is here to help you and yourloved ones get back to optimal health. Aviv delivers apersonalized protocol to enhance your mind and body andfeel like yourself again.Learn more about our team, contact our clinic toschedule a free phone consultation. Maximizing yourhealth and performance begins with Aviv.

Brain Fog After COVID-19:Why It Happens and WhatYo u Can DoAccording to multiple studies, those with long COVID-19experience a variety of symptoms that may include brainfog.Not only do these reports shed light on how the COVID-19virus can impact our cognition, but they also illuminate thefact that anyone—no matter their COVID-19 history—canexperience persistent brain fog.If you feel you’ve had brain fog after COVID-19, the AvivClinics team is here to help you navigate through that.Stay educated with this essential guide to give yourself

the best chance at getting back to optimal health.As you’re reading through this, keep in mind:Each person has a unique experience with COVID-19.Therefore, speaking with a doctor is a critical firststep to diagnosing long COVID.Per the CDC, several alternative terms are used toreference long COVID, such as post-COVID, long-haul COVID, post-acute COVID, and chronic COVID.What Is Brain Fog?Brain fog is a term that describes slow or sluggishthinking. Someone with brain fog may experienceconfusion, forgetfulness, and/or a lack of mental clarity.We all experience brain fog from time to time. Perhaps youdidn’t get enough sleep the night before, took anantihistamine, or had a cold that made you feel unfocusedor disoriented. In cases like these, you can simply rest andfeel like yourself in no time.But sometimes, individuals experience brain fog thatlingers even beyond six months after having COVID. Thishas been one of the main symptoms of post-COVID.Is Brain Fog a Symptom of Long COVID?Yes, brain fog is a common symptom of long COVID—theCDC lists brain fog under its neurological symptoms. Brain

fog from COVID-19 doesn’t necessarily need to manifeston a substantial level; it can be subtle. One study notesparticipants who didn’t notice their brain fog stillperformed poorly on attention and memory tasks.Why Does COVID-19 Cause Brain Fog?Stanford Medicine researchers note brain fog fromCOVID-19 emulates the same cognitive issues caused bycancer chemotherapy (“chemo brain”). In both cases,excessive inflammation damages the brain cells andprocesses.Aviv physician Dr. Mohammed Elamir, MD, FACP, furtherexplains there is a link between:Where the COVID-19 virus attacks the brainHow that impacted location in the brain affects longCOVID symptomsThere are four main ways COVID-19 can attack the brain:Direct brain invasion: The virus travels through thenose and into the insula—which oversees memoryand executive function through its connection withthe prefrontal cortex.Blood vessel injury: The COVID-19 virus may harmblood vessels that feed blood to the brain.Dysregulated immune response: Damaged bloodvessels caused by COVID-19 can slow down thegrowth of cells, impacting the brain’s immune

response.Cellular dysfunction: COVID-19 can trigger celldamage. This slows down the body’s response rateto infection, leading to high inflammatory conditions.Is My Brain Fog Related to COVID-19?If you notice your cognition has not been the same sinceyour COVID-19 infection, we recommend speaking with aphysician. Your body and health background are entirelyunique from other people’s. Therefore, it’s important todiscuss your lingering symptoms with a healthcareprofessional to assess whether your brain fog is indeeddue to long COVID.The certified physicians at Aviv Clinics assess thefollowing four areas to diagnose long COVID. Walkingthrough these four areas enables your physician toprovide the holistic approach your health deserves.

Physical symptoms: Fatigue, cough, loss of taste orsmell, labored breathing, joint/muscle pain, etc.Cognitive and psychological symptoms: Brain fog,anxiety, depression, sleep disturbances, headaches,etc.Lung symptoms: Shortness of breath, chestpain/tightness, etc.Cardiac symptoms: Heart palpitations, elevatedblood pressure, decline in oxygen saturation, etc.How Can You Minimize Post-COVID BrainFog?Minimizing post-COVID brain fog involves engaging inactivities known to improve memory and thoughtprocesses. These activities may include:ExercisingGetting adequate sleepEating a well-balanced dietAddressing Long COVID SymptomsMultiple studies reveal, as part of a comprehensivetreatment program, hyperbaric oxygen treatment (HBOT)may help in mitigating long COVID symptoms. Fromclinical and qualitative evaluations of HBOT patients,researchers conclude there is hope that HBOT canaddress some of the common symptoms such as fatigueand brain fog.

Aviv Clinics’ team of certified physicians takes a three-step approach to their long COVID treatment:In-depth medical assessment: Conductingcomprehensive testing (physical, cognitive, andneurological) and brain imagingTailored treatment program: Creating a customizedtreatment plan based on your test resultsPost-treatment assessment: Administering secondround of testing to unveil findings/progressLearn more about Aviv’s long COVID approach.How Long Does Post-COVID Brain Fog Last?As everyone’s bodies are different, there is no set timelimit to COVID-19 brain fog. Some research studiesindicate that most patients recover within six to ninemonths, with others experiencing brain fog for two yearsor more.Dr. Mohammed Elamir, MD, FACP, says how long it takesfor brain fog to go away depends on how invasive thevirus is in your body:“[…] the amount of real estate that thosemicrovascular changes are occupying will probablydictate how long [symptoms] will last.”The Bottom Line

Brain fog from COVID-19 can be difficult to live with. If youor a loved one suspects COVID-19 has left lingeringcognitive issues, contact Aviv Clinics. Our team will offerthe resources you need to learn more about how our teamof physicians treats long COVID symptoms. Feeling yourbest cognitively and physically starts with us.

86 KirbyJ. Emerg Med J February 2022 Vol 39 No 2Hyperbaric oxygen therapy for patients withCOVID- 19John KirbyDr Cannellotto and colleagues have published a prospective, multi- centred, open- label randomised controlled study of hyperbaric oxygen (HBO2) as an adjuvant treatment for patients with COVID- 19 who have severe hypoxemia. The study included 40 patients, 20 in the HBO2 treatment arm and 20 in a control (no HBO2) arm who were unable to achieve an oxygen saturation of 90% despite oxygen supplementation. In the current era—both in terms of well conducted research and especially given the COVID- 19 pandemic—this is a decep-tively difficult challenge to overcome. HBO research is often hobbled by precon-ceptions about its utility and the costs of performing it appropriately. I would also point out that this was done in Argentina even though the majority of patients with COVID- 19, if not the majority of HBO2 chambers themselves, lie outside of that country. This group of interested, committed clinicians were trying to improve the care of their patients with COVID- 19 in a time of a pandemic and also managed to write up their work on behalf of all. Bravo.The study by Cannellotto and colleagues1 balanced many factors relating to COVID- 19 so as to be maximally safe for the enroled participants. The authors selected a very low treatment pressure, 1.45 ATA, and by doing so attempted to minimise any haemodynamic risks for the enroled patients. Those less familiar with HBO2 should know that 1.4 ATA is the minimum therapeutic level for clinical HBO2 use in the USA2 and lower thera-peutic pressures have been proposed for other clinical conditions, but such low treatment pressures remain a subject for further study. As the applied pres-sure surrounding the body is increased, higher levels of tissue oxygenation are achieved, but other changes in tissue responses, whole body cardiovascular effects and host inflammatory responses also occur, and some provoke haemody-namic changes that can increase risk for patients.3 Researchers are attempting to determine what might be optimal pres-sures for the treatment of COVID- 19 and other conditions.4The authors also chose a more cost effective, lighter weight model of an HB02 chamber (Revitalair technology), which is not a completely rigid chamber and does not appear to go much above 1.4 ATA. This may have assisted in running the study at three sites. Presumably should HBO2 be found to be more efficacious than previously assumed, lower cost, lighter chambers for HBO2 delivery would allow more patients to access treatments.The study was stopped after a prelimi-nary analysis suggested that HBO2 therapy was safe and those receiving it had faster times to reduced oxygen needs. This meant that the study only included 40 patients where originally it intended to include 80 patients, which potentially prevented observation of significant differences in long- term outcomes. I think it is notable that the authors stopped the study when they felt adequate safety had been demon-strated, even when continuing the study might have contributed to further statisti-cally significant effects.While the authors showed a clear benefit in terms of fewer days to improvement in oxygen requirements, it is important to recognise some aspects of recruitment that could suggest which patients this form of HBO2 therapy might apply to. The authors excluded patients if they could not remain in a seated posi-tion for more than 2 hours, although online depictions of the use of Revitalair chambers seem to demonstrate patients being in semi- recumbent or beach chair positions. In addition, the participants needed to be able to tolerate being off oxygen for 5 min for assessment of their room air saturations. Although this was not stated as an inclusion criterion, the authors do not tell us if patients decom-pensated during this time and thus were not able to be included in the study. Both of these aspects could mean that the patients in the study were not necessarily representative of all patients admitted to hospital with COVID- 19 who remained hypoxic on oxygen therapy. Also none of the patients received antivirals or mono-clonal antibody preparations, which might also suggest less severe infection (unless these treatments were not avail-able in the hospitals). What might have been useful would have been to obtain the clinical parameters of the patients with COVID- 19 who were in hospital at the time of the study to understand the spectrum of illness of the included patients.One enrolment criterion was SpO2 <90% despite oxygen supplemen-tation. A wide variety of oxygen supple-mentation methods have been used due to clinical parameters and patients’ tolerance of these methods. More details about the methods of oxygenation used in these patients would be helpful to interpret the study results. Perhaps with larger numbers, we could determine which oxygen thera-pies (or failure thereof) are associated with improvement with HBO2 therapy.Finally, it would be helpful to under-stand the time frames from presentation of symptoms to diagnosis to need for oxygen or hospitalisation to enrolment? Additionally, if patients receiving HBO2 returned to normal oxygen levels more quickly, did this achieve any cost savings in terms of earlier discharges or conservation of overall oxygen use?Nevertheless, the data from this study are consistent with other recent work involving HBO2 therapy in patients with COVID- 19. These studies have shown that patients begin treatment with very high respiratory rates and raised inflam-matory markers, both of which seem to decrease with HBO2.5 6 during and even after HBO therapy periods. HBO has a direct effect on oxygen absorption and its delivery to the body’s tissues, and therefore increases oxygen saturations. The mechanism by which this treatment decreases inflammation is still being worked out.The study failed to find changes in acute respiratory distress syndrome, mechanical ventilation or death, but this is prob-ably because of the small numbers in the study, and the selection of possibly a less critical cohort of patients. Larger studies must start with smaller studies. Alterna-tive therapies must be considered. Could five to seven 90 min HBO treatments when amortised for each patient’s treat-ment course compete with other advanced therapies, such as antiviral based therapies for costs, logistical feasibility, value and efficacy?As we all look to improve our global capabilities to combat the effects of COVID- 19, this study demonstrates the value of looking to make the most of available resources to properly eval-uate novel treatment modalities such as Correspondence to Dr John Kirby, Washington University in St Louis, St Louis, Missouri, USA; kirbyj@ wustl. eduCommentary on October 6, 2022 by guest. Protected by copyright.http://emj.bmj.com/Emerg Med J: first published as 10.1136/emermed-2021-212015 on 14 December 2021. Downloaded from

87KirbyJ. Emerg Med J February 2022 Vol 39 No 2Commentarya lower cost, portable, lower pressure HBO2 to make a clinical impact on this pandemic.4Funding The author has not declared a specific grant for this research from any funding agency in the public, commercial or not- for- profit sectors.Competing interests None declared.Patient consent for publication Not applicable.Ethics approval This study does not involve human participants.Provenance and peer review Commissioned; internally peer reviewed.This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid- 19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non- commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.© Author(s) (or their employer(s)) 2022. No commercial re- use. See rights and permissions. Published by BMJ.Handling editor Ellen J WeberTo cite KirbyJ. Emerg Med J 2022;39:86–87.Received 22 November 2021Accepted 23 November 2021Published Online First 14December2021  http:// dx. doi. org/ 10. 1136/ emermed- 2021- 211253Emerg Med J 2022;39:86–87.doi:10.1136/emermed-2021-212015REFERENCES 1 Cannellotto M, Duarte M, Keller G. Hyperbaric oxygen as an adjuvant treatment for patients with Covid- 19 severe hypoxaemia: a randomized controlled trial. Emerg Med J 2020 https://clinicaltrials.gov/ct2/show/ NCT04477954 2 Moon R, ed. UHMS Indications Manual. 14th ed. West Palm Beach, FLA: Best Publishing, 2019. 3 Camporesi EM. Side effects of hyperbaric oxygen therapy. Undersea Hyperb Med 2014;41:253–7. 4 UHMS position statement -Hybaric oxygen for Covid19 patients. Available: https://www.uhms.org/images/ Position-Statements/UHMS 5 Thibodeaux K, Speyrer M, Raza A, etal. Hyperbaric oxygen therapy in preventing mechanical ventilation in COVID- 19 patients: a retrospective case series. J Wound Care 2020;29:S4–8. 6 Gorenstein SA, Castellano ML, Slone ES, etal. Hyperbaric oxygen therapy for COVID- 19 patients with respiratory distress: treated cases versus propensity- matched controls. Undersea Hyperb Med 2020;47:405–13. on October 6, 2022 by guest. Protected by copyright.http://emj.bmj.com/Emerg Med J: first published as 10.1136/emermed-2021-212015 on 14 December 2021. Downloaded from

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