Hyperbaric oxygen therapy improves neurocognitive functions & symptoms of post-COVID condition: randomized controlled trial, 2022, Zilberman-Itskovich

[Sly Saint]

Abstract


Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms after SARS-CoV-2 infection. The mechanism can be related to brain tissue pathology caused by virus invasion or indirectly by neuroinflammation and hypercoagulability. This randomized, sham-control, double blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT or HBO2 therapy) on post-COVID-19 patients with ongoing symptoms for at least 3 months after confirmed infection.

Seventy-three patients were randomized to receive daily 40 session of HBOT (n = 37) or sham (n = 36). Follow-up assessments were performed at baseline and 1–3 weeks after the last treatment session. Following HBOT, there was a significant group-by-time interaction in global cognitive function, attention and executive function (d = 0.495, p = 0.038; d = 0.477, p = 0.04 and d = 0.463, p = 0.05 respectively). Significant improvement was also demonstrated in the energy domain (d = 0.522, p = 0.029), sleep (d = − 0.48, p = 0.042), psychiatric symptoms (d = 0.636, p = 0.008), and pain interference (d = 0.737, p = 0.001).

Clinical outcomes were associated with significant improvement in brain MRI perfusion and microstructural changes in the supramarginal gyrus, left supplementary motor area, right insula, left frontal precentral gyrus, right middle frontal gyrus, and superior corona radiate. These results indicate that HBOT can induce neuroplasticity and improve cognitive, psychiatric, fatigue, sleep and pain symptoms of patients suffering from post-COVID-19 condition. HBOT’s beneficial effect may be attributed to increased brain perfusion and neuroplasticity in regions associated with cognitive and emotional roles.

https://www.nature.com/articles/s41598-022-15565-0

 

[cassava7]

From Dr Herbert Renz-Polster (member of the scientific advisory board of the Deutsche Gesellschaft fur ME/CFS):

“First RCT on HBOT in #LongCovid

I am unimpressed. If you do 40 HBOT sessions you want to have larger effects. If you deduct the improvements also seen in the sham group , the HBOT patients rarely improved by > 10 points in the (100 point) SF-36 domains.”

 

[cassava7]

A question on statistics. The authors wrote:

To evaluate HBOT’s effect, a mixed-model repeated-measure ANOVA model was used to compare post-treatment and pre-treatment data. The 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 significant.

Considering that the primary outcome was an evalution of 6 neurocognitive domains, shouldn’t it rather be 0.05 / 6 = 0.0083?

As for the secondary outcomes, considering that 22 domains were compared (across 4 questionnaires), shouldn’t it be 0.05 / 22 = 0.0023?

Or should it be the sum of all comparisons across both primary and secondary outcomes, i.e. 0.05 / (6 + 22) = 0.0018?

Edit: the authors seem to have applied Bonferroni correction to within-group pre-post intervention (HBOT or sham) comparisons of subdomain scores, but not to their ANOVA model. Should they have?

 

[Hutan]

Conflicts of interest? Yep

Declared conflicts of interest:

Amir Hadanny and Efrat Sasson work for AVIV Scientific LTD. Shai Efrati is a shareholder at AVIV Scientific LTD.

Undeclared conflicts of interest:
Sagol Center for Hyperbaric Medicine and Research employees

Shani Zilberman-Itskovich
Merav Cataglona
Efrat Sasson
Karin Elman-Shina
Amir Hadanny
Erez Lang
Shachar Finci
Nir Polack
Gregory Fishlev
Calanit Korin
Ran Shorer
Yoav Parag
Marina Sova
Shai Efrati​

(Oh, that's all the authors.)

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 first draft of the manuscript.
All authors revised and finalized the manuscript.

Aviv Scientific is a leader in research on age-related cognitive and functional decline and novel applications of hyperbaric medicine to maximize human performance. Aviv focuses on improving the aging process by increasing cognitive and physical performance in healthy aging adults. Based on an exclusive global partnership with the world’s largest Hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Israel, Aviv Scientific is rolling out a global network of medical clinics focused on the enhancement of cognitive and physical performance with hyperbaric medicine and related technologies at its core.

 

[Milo]

So...

What is a sham HBOT treatment? You simply sit in the chamber and it doesn't get pressurized, for 40 sessions on end? yes. 90 minutes per treatment, 5 days a week.

Intervention
Both HBOT and sham protocols were administrated in a multi-place Starmed-2700 chamber (HAUX, Germany). The protocol comprised of 40 daily sessions, five sessions per week within a two-month period. The HBOT protocol included breathing 100% oxygen by mask at 2ATA for 90 min with five-minute air breaks every 20 min. Compression/decompression rates were 1.0 m/min. The sham protocol included breathing 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 first five minutes of the session along with circulating air noise followed by decompression (0.4 m/min) to 1.03 ATA during the next five minutes.

These are big claims:

In recent years, evidence has been accumulated about the neuroplasticity effects of hyperbaric oxygen therapy (HBOT)11,12,13,14,15,16,17,18,19. It is now realized, that the combined action of hyperoxia and hyperbaric pressure, leads to significant improvement in tissue oxygenation while targeting both oxygen and pressure sensitive genes11. Preclinical and clinical studies have demonstrated several neuroplasticity effects including anti-inflammatory, mitochondrial function restoration, increased perfusion via angiogenesis and induction of proliferation and migration of stem cells11,12,13,20,21. Robbins et al. suggested a possible benefit with HBOT in a recent case series of ten post-COVID-19 condition patients22.

Lastly this caught my attention:

This article discusses cognitive and behavioral aspects of post-COVID-19 condition. Additional secondary outcomes including neuro-physical evaluation, cardiopulmonary exercise test, echocardiography, and functional brain imaging will be presented in future manuscripts.

 

[rvallee]

In recent years, evidence has been accumulated about the neuroplasticity effects of hyperbaric oxygen therapy

Lost me there. This is so much like in a cult where the doctrine always has to be injected into any discussion.

The obsession with neuroplasticity is destroying more brain function than literally all the alcohol in the world. It's like concentrated Humours, except all the other organs have been eliminated from the list so every unknown is attributed to some magical brain function somewhere. What a dumb era in medicine, even worse by comparison to the Humours because of how late it's happening.

 

[cassava7]

Leonid Schneider (data sleuth & scientific integrity journalist) has flagged this study because the authors have previously been involved in scientific fraud. The owner of the company, Dr Schai Efrati, has previously made claims that HBOT is an effective treatment for many conditions.

Importantly, Schneider spotted that 11% of the patients in the intervention group had been hospitalized for Covid while that number rose to 22% in the control group.

The study has also been retweeted by Peter McCullough, a notable anti-vax cardiologist.

https://forbetterscience.com/2022/07/15/schneider-shorts-15-07-2022-how-to-swear-in-french/#hbot

 

[5vforest]

Just to play devil's advocate... do we expect any doctors or scientists who *aren't* already interested or invested in Hyperbaric to spend the time and money to study it?

Anyway, valid critiques aside, it's kinda cool that they successfully blinded this trial. Almost like this listened to this guy from last year: https://www.s4me.info/threads/hyper...vention-2021-robbins-et-al.23750/#post-396804

 

[Wyva]

There is a doctor here, owner of a private clinic for HBOT, who has been popping up in the media recently, promoting HBOT as a treatment for long covid. (Interestingly, she is a psychiatrist originally.) To prove her point, she says there have been double-blinded placebo controlled studies that show this works for LC, so I guess this study is what she meant. Not very convincing then.

 

[SNT Gatchaman]

Followed up with Long term outcomes of hyperbaric oxygen therapy in post covid condition: longitudinal follow-up of a randomized controlled trial (2024, Nature Scientific Reports)

 

[Hutan]

Patients’ baseline characteristics demographics, and high-risk comorbidities, are detailed in Table 1. No statisti- cally significant differences in baseline characteristics were observed between the original study’s HBOT group and the current cohort with long term evaluation.

Patients were excluded if they did not complete either short or long term evaluations.

Out of 91 eligible patients, 79 were randomized to either HBOT or control/SHAM in the original study. Out of the 40 patients allocated to the HBOT arm, 37 patients completed the intervention and performed the short term evaluation. Of those, six declined their participation in long term evaluation. Accordingly, a total of 31 patients received HBOT, had both short term and long-term post treatment evaluations and were included in the current study analysis.

Third, in the original RCT, patients who received sham intervention were not evaluated long term. Since the original sham group, after completing the study protocol, were offered to be treated with HBOT, and most of them received it (27/39, 69%) they could not serve as a proper control group for the current study.

Fairly small sample size, which is not reported in the abstract.

Quite a lot of loss of patients from the intention to treat - so they are only getting data from a select group. And no controls.

 

[Hutan]

Why would a trial like this report the numbers of people with each sort of marital status (single, married, divorced, widowed)? Or number of children?
Can you imagine them saying 'our treatment works for married people only'? No - there's no conceivable mechanism for that. So why not only collect that data, but clutter up their tables telling us about it?

There's a lot of questionable statements that make the discussion sound all very sciencey.

At the subcellular level, HBOT restores mitochondria function (in both neurons and glia cells) and metabolism37, attenuated by long COVID.

That one for example has a reference 37: Mechanisms of hyperbaric oxygen and neuroprotection in stroke, 2005
That paper has a paywall, but it says

In addition, the mechanisms of HBO on neuroprotection remain elusive.....
Two obstacles that hamper the extensive use of HBO in stroke treatment are the lack of controlled clinical trials and limited knowledge of established mechanisms.

So, I think it's very unlikely that the cited paper unequivocally states that HBOT restores mitochondria function in neurons and glia cells. The 'attenuated by Long Covid' in that sentence is actually a bit ambiguous, but I expect that they were trying to suggest that mitochondrial function in neuron and glial cells is reduced in Long Covid. I don't think we can yet say that with confidence.

 

[Fizzlou]

Straight in at 2ATM? MS HBOT centres ease people in at 1.5ATM (equivalent to 16 feet depth) for 20 sessions minimum. Then you can choose to go to 24ft, then 33ft which is 2ATM. I tolerated 1.5ATM well but 1.75ATM set me back. Possible oxidative stress? I would be very worried if LC patients started on 2ATM HBOT if they had developed ME in the meantime.
In MS there is little evidence for HBOT being effective. MS patients cannot even access home surface oxygen.

 

[SNT Gatchaman]

So, I think it's very unlikely that the cited paper unequivocally states that HBOT restores mitochondria function in neurons and glia cells.

The paper spends half its time discussing hypoxic-ischaemic encephalopathy in neonates, with experiments in 7-day old rats. Then goes on to focal and global cerebral ischaemia.

In summary figure 6 is —

Fig. 6. Mechanisms of HBO neuroprotection. Cerebral hypoxia–ischemia disables energy metabolism, reduces ATP production, releases glutamate, and causes calcium overload and depolarization. Mitochondrial damage follows, with oxygen radical generation and inflammatory reactions. All these pathological events not only lead to apoptotic neuron death, but also result in brain infarction, brain edema and the dysfunction of blood–brain barrier. The final outcome is the death or disability of patients. HBO either improves oxygen delivery or oxygen extraction to enhance neuronal viability. HBO protects the blood–brain barrier and reduces cerebral edema. Cerebral metabolism is improved by HBO and levels of glutamate, glucose, and pyruvate are stabilized. The inhibitory effect of HBO on inflammatory agents and on apoptosis may be mediated by the re-regulation of superoxide dismutase and by enhancing the expression of pro-survival Bcl-2 genes. Finally, HBO decreases the deformability of the red blood cells to improve microcirculation and reduce hypoxia–ischemia.​

The legend says HBO decreases the deformability of the red blood cells, but they mean increases, as in the graphic. Blood and oxygen needs to get to the brain but also blood flow needs to clear neurotoxic waste-products of metabolism. RBC deformability will help the microcirculation but is probably not fully compensating.