Saline infusions

I wouldn't rule it out. I just don't think we know enough as to why saline is beneficial.

I mean it directly improves the functioning of the vascular system. Repeatedly pumping up the system may be enough for some people to get to a better level of functioning.

This is too speculative though, point is that it's worth studying to characterise its impact.

 

I am 100% certain that I lose water during PEM. I am bedridden, my caregivers measure every single ml of input and output. They have been doing it for years, so we know it is absolutely certain.

I have 1500 pages of documentation to back that up. most of the loss of water/volume loss happens relatively quickly ater the overexertion.

 

Similarly, I used a urinal bottle for a couple of years and can testify that, in PEM, the quantity of my output jumps massively (we're talking from 500mL to 1500mL per go). The urge also comes on very strongly and quickly, and I feel constant dehydration symptoms (dry mouth, pounding headache) despite throwing back more than 3L of water a day.

I also don't have POTS (my tachycardia isn't triggered by upright posture, it's triggered by crashing) but reacted very similarly to epinephrine as the others have described here. I also experience a mast cell flare when surprised by something suddenly (itchy skin, thousands of little red dots, sometimes hives, all of which can dissipate in about a minute), which may potentially be related?

 

I posted a couple of studies and we had a discussion here and here

 

Hi @MelbME. Is saline beneficial?

Standard physiology would suggest that the chances of saline infusions being more use than drinking a pint of gazpacho soup fairly quickly is close to zero, and that any continued benefit after a couple of hours for either is almost as near to zero.

I haven't seen any convincing data on saline being more than a placebo, have you?

 

Not convincing data in ME yet we hope to provide the answers to this question by testing sham, saline, hypotonic saline and hypertonic saline.

Some evidence in POTS though and it may very well be that those with POTS are who we see improve.

Generally though saline is the most commonly improving treatment (a long with Pacing) that ME patients and ME clinicians report in our experience.

We do expect it to be temporary as you point out and are interested in the basic physiological understanding this would produce. We try all treatments in each individual and are interested to see if we could subtype based off which treatment (sham, saline, hypertonic and hypotonic) has outsized improvement on the other 3.

If we do find it is helpful based on our study then we will certainly test ORS and Gazpacho as cheaper alternatives

 

I would be very happy to have health insurance reimbursed Gazpacho prescriptions.

 

Is the effect purely related to volume expansion (correcting pre-load failure / reduced pre-load reserve) or is there a secondary more beneficial effect on the microcirculation, including the microcirculation of the blood vessels themselves?

 

If it is effective then it could be doing many things. We will have a better understanding after the study based on the design. If we wanted to just test saline then it would be saline vs placebo. But we want to test whether the variations in salts makes a difference and if repeated volume delivery 3 times in a 6 week period has a more enduring effect.

It's part observational and part treatment trial, which they all should be IMO.

 

Hi @MelbME

I can see the value in doing a well-designed trial of saline infusion, if only to show that it doesn't work, which I think is the 95% probability.

With my ethical committee hat on I would have to say that I would not approve infusion of hypertonic or hypotonic saline. There is no rationale for changing tonicity as far as I can see and these would introduce additional hazards, however small the risk, such as hemolysis or epileptic fits.

I don't think reports of benefit are of any use to us because saline infusion is the perfect placebo format - apparent scientific rationale and an injection nd impressive equipment. If homeopathy convinces people saline infusions will certainly do so.

I am interested to know how you think that saline infusion can possibly do more than oral water and salt. Both will tend to expand circulating water and sodium pools over a period of minutes. Both will be followed by an appropriate diuresis to return pools to normal within an hour, unless of course the person is in renal failure, where the treatment would be dangerous.

Why would altering the tonicity make a difference? The input will mix immediately in the right atrium. I appreciate that all things are possible but they do tend to turn out to fit with what we know of physiology.

 

I just want to add that the only oral rehydration fluids that help for me are the ones that contain both salts and glucose. Specifically the Swedish brand Resorb. None of the other oral rehydration solutions I've tried over the years (shop-bought or home made) has worked for me. This doesn't seem to be uncommon, juding by posts in Swedish discussion forums for various forms of dysautonomia.

Because of this, I'd love to see glucose added as a factor in this kind of studies, in addition to variations in salts.

(I have severe/very severe orthostatic intolerance, but not POTS or OH according to the active standing test I did at home recently. Pre-syncope, fainting + some kind of weird orthostatic/PEM oedema that also makes the skin/flesh/? on my legs collapse when I'm standing...)

 

Hi, @MelbME! Just wanted to know if you have read this recent research about low vasopressin in ME-patients and the suggestion of diabetes insipidus being part of the ME picture? I’m one of those with a pathological low U-osm and during severe crashes it’s like my body empties itself of fluid. I am curious if your research will look into this in any way?

https://www.neurology.org/doi/10.1212/WNL.0000000000205761

https://www.researchgate.net/public...phalomyelitisChronic_Fatigue_Syndrome_P4-4006

 

While some of your study details cannot be shared, I'd like to comment that it could be hard to have a sham infusion when the liquid infused is usually cold and can be felt entering the vein. Also there is a percentage of the population that can taste the saline when it is initially infused, I am one of them. That means that when I have an IV started and saline infused, I have a salty taste in the back of my mouth. I would not know whether a Dextrose 5% would do the same but normal saline (0.9%) does that to me each and every time, so I'd know.

Of course it may not matter according to your study endpoints- but if as usual the endpoints are subjective, some patients would know whether they received saline or nothing at all.

 

There are very real problems here but I think the obvious solution is a dose ranging study. If you think 500ml of saline is likely to be a realistic dose then compare 50ml, 200ml, 500ml and 1litre. Maybe run them all in at the same rate for the first minute then slow the smaller doses down invisibly with a programmed pump. If there is no difference between doses then it doesn't work. (If you think it credible that 50ml might have an effect go down to 10ml - you just choose a dose you don't think could work and stick to that.) If you still believe it works then 50ml works and you have to do a further dose response study of 1ml, 5ml, 20ml and 50ml anyway, to find the lowest effective dose.

Dose response studies are great because:

1. For any licensed medication you are expected to have identified the minimum effective dose.
2. Ethical use of a treatment requires that you know that.
3. Getting a dose response curve is ten times more convincing than just getting a result in a drug study because the statistical chances of getting a smooth curve out of randomly scattered results is effectively zero. Nobody has ever developed a statistical analysis of this but it is way more powerful than a single result that could have been by chance or more likely some systematic bias.
4. Dose response studies get over the dummy problem by using a very small dose as the dummy. Even if blinding is increasingly lost at high dose because of side effects it is relatively unlikely that the loss of blinding will have the same steep section as efficacy on the curve so it will corrupt the curve and you can see that.

 

So the infusions are all used in patients already they aren't hypotonic or hypertonic tona degree that would be abnormal. It's dextrose, saline and Hartmann's.

It could be an impressive placebo and this is why we want to test it once and for all. The placebo in the Rituximab trial was saline and it was significant.

Not saying saline is more useful than salt and water but it's more exact and there's potential that salt and water provides a more a stressor through the guy and by entering the bloodstream as too much salt or too little. Just much easier to control for experimental design.

A lot of patients that have tried saline suggest improvement lasts a few days, not hours. So we want to understand that. We have measures the patients provide for the following few days.

Different tonicity will tell us about whether it's expansion of vascular space or tissues/cells themselves that is more beneficial.

 

Yes the sham part is difficult, we will be providing some saline. We are also providing 4 different interactions per individual and expect all will feel a little different. But I agree it's something to consider as a limitation when we publish

 

OK, that would be fine, dextrose is hypotonic, Hartmann's a bit of a mix but maybe functionally a bit hypotonic too.

The main reason for preferring drinking the salt and water is that you wouldn't need to go to hospital or pay £1000 dollars for the privilege of an infusion. When I developed rituximab for RA a leading academic physician said that US physicians would not be interested because it needed so few infusion - less money.

It will be interesting to see the results.

Do you have a sham without the volume? Presumably the other solutions are similar volume to the saline? The difficulty might be that patients could tell they had not diuresis.

The placebo problem for me is not that it is likely that a saline infusion produces a six month benefit that fits exactly with what the doctor predicted (the kinetic data form the open Bergen phase II extension) because it was saline but simply because of the idea of having an treatment by infusion. The placebo response is likely to be just as good without anything in the bag.

 

Sham will be a reduced volume infusion yes. It's not perfect I agree but by giving each patient 4 infusions we expect that each may feel a little different.

If it is shown that saline is useful we would absolutely do long-term trials on salt and water and other forms of ORS.

What do you think happened with the Rituximab trial? Went from 67% responding in Fukuda patients to 26% responding in CCC patients. Was it just the definition difference? Why do you think placebo (35%) was better than Rituximab in the phase 3?

 

@MelbME I wonder if the septic shock microcirculation literature might be helpful, specifically what's happening in early septic shock.

Eg Microcirculatory dysfunction in sepsis: pathophysiology, clinical monitoring, and potential therapies (2016, Am J Physiol Heart Circ Physiol)

Others —

Microcirculatory dysfunction and resuscitation: why, when, and how (2015, British Journal of Anaesthesia)

Microcirculatory dysfunction in cardiogenic shock (2023, Annals of Intensive Care)

Endothelial Damage and the Microcirculation in Critical Illness (2022, Biomedicines)

Microcirculatory alterations: potential mechanisms and implications for therapy (2011, Annals of Intensive Care)

Recruiting the microcirculation in septic shock (2019, Annals of Intensive Care)

 

I think some of the same physiology described here is used to try understand the vascular abnormalities.