Combination of whole body cryotherapy with static stretching ... reduces fatigue and improves functioning of the [ANS] in CFS, 2022, Kujawski et al

Sample selection

We've seen these extreme losses in screening from Polish research before.
Of the 238 people excluded, 180 did not meet (even) the Fukuda criteria; 30 had a 'psychological/psychiatric impairment'; in 174, another diagnosis or fatigue was not the main complaint.

Edit - The method comes at the end of the paper. It turns out the 250 people self-identified as having fatigue. Perhaps a question could be asked about whether there are doctors who could diagnose people with ME/CFS.
Edit again - The methods section also says that people could only participate in this study if they had been referred by a general practitioner, neurology and psychiatry. So, I don't know, why are the referring doctors getting things so wrong?

That's a big percentage of the people with CFS who had not been ill for very long, suggesting natural improvement is likely to be significant confounder. Edit - if they had assessed people over a long enough time, not just two weeks.

I'm not understanding how 12.5% of the people with CFS would not have fatigue, especially as the paper says that people who did not have fatigue as the main complaint was screened out. 73% had post-exertional fatigue but only 34.4% reported having a long recovery from exertion. There might be questions that could be asked about post-exertional malaise versus post-exertional fatigue.

Edit - from the Method at the end of the paper, participants had to have had

So, 12.5% of the 32 people in the CFS group not having fatigue makes no sense at all.

Effects of WBC + SS on self-reported measures of fatigue and daytime sleepiness in the CFS group

Looks like they use Chalder Fatigue Questionnaire as well as the Fatigue Impact Scale and Fatigue Severity Scale. A question could be asked about whether they understand the shortcomings of the CFQ and if they will continue to use it.

It's not clear how long after the cryotherapy the surveys were done, or what period they applied to. Figure 1 says "Analysed just after WBC". The cryotherapy was undertaken for two weeks - assessment after two weeks isn't long enough in an unblinded trial. Given that uncertainty, the subjective nature of the measured outcomes and the unblinded trial structure, I don't know if the reported results are worth much at all. Which is a shame, as it would be good to know if it helps.


Cardiac and autonomic assessment; cognitive assessment
The same goes for the cardiac and autonomic assessments - it's not clear when the measurements were made. If it's just a fleeting effect, it's not clear that there is anything important. My eyes and brain started to glaze over here, as there are acronyms introduced without explanation. I'm not sure there are any significant differences between the CFS and HC groups. Improvements in the cognitive outcomes could just be a training effect.

 

Discussion

I'm not sure that they can conclude this, because I don't know how long they had the participants report PEM and other symptom effects for after the cryotherapy and stretches.

I found the whole thing rather vague, unconvincing and frustrating.

It's possible it could work - brief exposure to extreme cold could somehow allow people with ME/CFS to stretch without PEM. But this study doesn't really tell us whether it does or not.

I think there could be a question to the authors about how the study could be better designed to get around the problem of subjective outcomes with a blinded treatment.

 

Thinking about this overnight, this study makes me a bit angry. We are all so desperate; if anyone made cryotherapy easy to access and affordable to people with ME/CFS, I'm sure there would be a long queue of people ready to try it. I might even be among them. There doesn't need to be any good studies, or any clear understanding of possible harms for people to turn up, and possibly pay a lot of money to try anything that is suggested as possibly useful.

In that context, we need well-conducted, well-described studies that cut through the hype. This study certainly doesn't do that. It doesn't even show that having the treatment (including the frequent visits each week for the treatment) is safe for people with ME/CFS, let alone provide evidence of benefits.

The IACFSME journal club event will have to be managed very well, to avoid it just being a promotion for cryotherapy and to instead help the researchers and the participants learn about how research can be better. I do hope some of our members will join the journal club event.

 

I think the healthy controls were there to provide a baseline for the cardio and cognitive measures. But yes, it does make for a muddle - it sort of makes it sound like it was a proper trial with controls, when there was no treatment control.

 

A reminder that this webinar is coming up. In the registration process, there is a field to record questions to the researchers. Unfortunately, it only has a character allowance long enough for one sentence. Questions can be sent to kg180@nova.edu. Or, if you prefer to note questions here, I can forward them on. I'm a bit surprised the Journal Club organisers chose this paper, it's pretty much terrible across the board, which won't make for a fun experience for anyone.

My questions are:

1. Why is the Fukuda criteria used? How can you be sure that this trial has any relevance to people with ME/CFS (where PEM is a core symptom)?

2. It isn't clear from the paper how the 250 patients came to be screened. The paper says 238 patients were excluded, and that 32 patients were given the treatment. But 250-238 is 12 patients. Did another 20 patients come from somewhere else? Why are doctors sending patients that they think are suffering from CFS, when almost all of them don't even meet the Fukuda criteria?

3. The paper suffers from a lot of English language problems - these make it hard to understand what is meant in places and decrease the paper's credibility a lot. What happened there? Was Julia Newton not available to proofread the paper and why didn't the Journal help? Do you want someone with English as a first language who knows about ME/CFS to proofread future papers? The international forum Science for ME could probably find you someone.

4. The paper is not clear on whether all of the 32 patients had fatigue or not. It says 'the vast majority of those with CFS described fatigue (87.5%). But it also says that people who did not have fatigue as the main complaint were screened out. The Methods section says that patients had to score more than 36 on the Fatigue Severity Scale. Did all of the patients have fatigue at baseline or not?

5. Are you aware of the problems with the Chalder Fatigue Questionnaire? Why did you use it?

6. Why didn't you have patient controls i.e. patients who didn't receive the treatment?

7. When were the surveys filled out and the assessments done? Was it immediately after the end of the last session?

8. How can you be sure that the cardiovascular effects, almost all of which did not differ significantly between controls and patients, were not just short-term effects? It isn't clear if there was a significant increase in the heart rate of patients from the beginning of the treatment to the end - was that the case? If so, is that of concern?

9. Is it not likely that the cognitive improvements (seen in both the patients and controls) were just the result of a training effect? How can you rule that out without any patient controls who did not do the treatment?

10. Subjective outcomes with unblinded treatments are notoriously unreliable - trials with this structure don't tell us anything about whether a treatment works. Given that, on what basis do you make the claim that the preliminary data show a beneficial effect of the cryotherapy + stretching? How could you trial this treatment using a more effective trial structure?

11. What do you understand about the term 'Post-exertional fatigue'? How does it differ from the more usually used 'Post-exertional malaise'? How was the trial structured to ensure that any PEM arising from the cumulative effect of the regime of three sessions a week would be measured?

12. Did any of the patients choose to continue the cryotherapy + stretching treatment?

 

I made it to the webinar, I woke up nearly in time although missed the first five minutes. Most of the webinar was filled up with a presentation by the researcher.

The host, Rochelle Joslyn, asked some questions, but little information came out in response. Other than Rochelle, I was the only person who asked a question. So, it wasn't really a discussion.

I asked about the numbers in the trial - the 250 participants, with 238 screened out, and yet 32 participants started the trial. I think the answer was that the 32 participants was correct, but I'm still not sure whether it was the 250 or the 238 or both which were incorrect. The researcher apologised for the error.

From the presentation, only 22 of the 32 participants made it to followup. I asked about this too. Of the missing 10, there was a loss of contact with 3, and the remaining 7 didn't want to continue the study. It sounds as though the charts in the paper apply to just the 22 participants for which there was full data - it was noted that the missing 10 tended to be those who had the most severe fatigue at baseline, so if their data had been included at baseline it would have biased things. I asked if it was possible that the 10 who dropped out did so because of the effects of the exertion of the study; the researcher didn't think so, as they asked the 7 why they were dropping out, and they didn't say that.

So, it sounds as though nearly a third of the participants who started the trial, tending to be those with the most severe fatigue at baseline, chose not to participate in the study to the end.

The researcher commented several times that more funding was required to progress the team's research.

Rochelle closed with comments along the line of 'good to see an unbiased approach to dissecting the heterogeneity of ME/CFS' - I'm not entirely sure what that comment applied to - and, finally to the researcher, 'sounds like you have the expertise to explore [ME/CFS]'.

I'm going to get a bit more sleep now, but, well, if this particular paper can be the subject of the journal club and the main conclusion is praise for the research. ... I'm struggling to find the right words. I don't understand why everyone doesn't see what we see; why people think research like this is not only ok, but praiseworthy.

I have more notes, I'll go through them later. If anyone else made it to the webinar, I'd really like to hear what you took away from it.

 

Here are notes on other things:
A power point slide on the premise for testing cryotherapy included a reference to Kulis et al 2017 which found that cryotherapy induced a decrease in the elasticity of erythrocytes. But, I thought, if anything we had a problem with the rigidity of our red blood cells, so a treatment that decreases the elasticity of them doesn't sound very useful.

The cold exposure time is very short; it is less extreme than cold water immersion that goes on for much longer.

A lot of what was said was off-topic of questions asked and didn't fully make sense to me.

Q. Length of benefit?
The researcher thought that two weeks should be a long enough intervention to produce a benefit. He note that participants with CFS reported improvements in energy after 3 to 4 hours, although not dramatic.

Q. Static stretching
Rochelle noted that Rowe induced PEM by have people with ME/CFS do stretching, so what did the static stretching in the intervention involve and did it cause PEM?
The reply was that the stretching didn't cause PEM. The stretches were held for only 15 to 30 seconds whereas Rowe had people holding stretches for much longer. It was very gentle exercise. He said that it might be that the cryotherapy allows people to undertake this stretching without ill-effects.

Q. Post-exertional malaise
Rochelle noted that Fukuda doesn't require PEM. She said that there was a question about whether the protocol can cause PEM, but noted that the fact that even within hours you are seeing a benefit, so that would suggest otherwise. (I'm not sure that Rochelle understands how PEM works - how it can have a delayed onset of 24 hours.) The researcher replied that some patients suffered PEM for just a few hours, so the question is, is that PEM or not? (Yes, it is.)

He note that multiple stressors cause an increase in heart rate, so that might be the commonality. I think he was suggesting that there might be a reaction to activation of the sympathetic nervous system. (That's interesting to think about - if you always keep your heart rate under a certain level, do you always avoid PEM? Or is it more related to energy expenditure?).

The researcher commented that is very difficult to objectively characterise PEM. Rochelle noted that Lenny Jason has developed an instrument to identify PEM.

Q. Plans for a controlled trial?
Rochelle talked about the concept of having a sham group, and how difficult that would be in this case, but perhaps there could be a variation in the temperature used. The researcher replied that he's not sure what the optimum temperature. -130 degrees C may not be the best temperature; there had been some research, I think with athletes, suggesting that -60 degrees C might be good enough. Even cold showers might be good enough.

The researcher noted feeling jealous of the amount of RCTs that have been able to be done for Long Covid. He is very skeptical of many of the ideas that have been put forward. It is much harder to do RCTs in Poland, the administration is complicated, the bioethics approval are demanding. (I'm not sure if that then makes it ok to do studies that people will think prove cryotherapy is useful that aren't RCTs.)

The researcher noted that it's likely that any treatment won't be working in all patients.

Q. Sleep?
I missed the detail of this question. I just have a note that the researcher again noted that he was jealous about the funding other fields get.

Q. POTS?
Rochelle noted that POTS is common in ME/CFS, and asked if the researcher thought that the benefit of cryotherapy might be due to vasoconstriction or due to an effect on inflammatory processes.

The researcher replied that during cold exposure, there is constriction of peripheral vessels and a decrease in heart rate. (There might have been something interesting said there, something about these being unusual or paradoxical about cardiovascular impacts specifically during cold exposure, but I missed it.) After the exposure there is a dilation of blood vessels. He thinks CFS might involve a problem in the control of blood vessel tone.

It was not possible to see other people on the call; I don't know how many people were on the call. I was the only caller who spoke. The chat function was disabled.

So, yeah, I found it disappointing. I don't know why it is so hard to see the problems with this research, and why there wasn't more engagement from other callers. I don't know why Rochelle wasn't more critical and insightful in her questioning. I do feel bad being so critical of this research. I think the researcher did want to try to find a genuinely useful treatment.

I feel a bit annoyed that I'm probably seen as ungrateful for the efforts of the IACFSME and researchers who bother to research this illness. I don't think my involvement in the call, in terms of providing questions ahead of time and asking the questions I did made any difference. I'm not sure how I feel about trying to participate in future Journal Club events; probably it's just a waste of time.

 

Thank you Hutan for the effort you have put into this. I agree it's very disappointing that there doesn't seem to be a useful level of discussion and critique in these sessions.