The Lyndonville Journal:

Evaluating Blood Volume Studies - Some Thoughts

David S. Bell, MD, FAAP

Published in Lyndonville News, March 2000

For the past three years, I have been studying issues concerning the decreased circulating blood volume in patients with CFS. For those who come to the office regularly, you know that while these studies have been lots of fun, they have not been terribly productive, and most of you are just as miserable now as you were three years ago. But the subject is of great interest and importance, and I remain convinced that hidden here is an important key to understanding and treating the illness. I want to try to summarize the past three years of work and thinking, breaking it down into discrete segments. Finally, I will describe where I am stuck, spinning my wheels in the Lyndonville snow. It is possible that someone out there will have a tow truck and be able to come to the rescue. It is also possible that the whole idea should just be buried where it lies.

I. Blood Volume Data. So far in our office we have measured the circulating blood volume in nearly fifty patients using the Chromium 51 method. It is essential that this method be employed (done in the nuclear medicine department of large University hospitals) as it is the only reliable method of assessing blood volume. There are two components of blood: the red blood cells and the plasma (fluid); everything else doesn't contribute much to the volume. The results are expressed as a function of body weight. Normal red blood cell mass should be between 23 and 28 ml/Kg, and the plasma volume should be between 40 and 52 ml/Kg. The total circulating blood volume is the sum of the two parts, and should lie between 60 and 80 ml/K.

Overall, about eighty percent of our patients with CFS have had either a low red blood cell mass, plasma volume, or both. Some patients have been extremely low, less than 50% of normal blood volume. To put this in perspective, if a healthy person were to bleed 40% of their volume out in a car accident it would likely be fatal. The loss in CFS is presumably gradual. The finding of decreased blood volume in CFS first came from Dr. David Streeten, and I am convinced it is accurate and will serve as a marker for the illness in some regard.

II. So What? If the body does not have enough blood, the blood flow to the tissues will be compromised or decreased. With a decreased blood volume, the area to be affected most prominently would be the brain, particularly when standing up. In the standing position, gravity usually holds almost a quart of blood in the lower extremities, thus making it even less able to get to the brain. Without adequate blood flow, the brain tissues will not get adequate oxygen, and this, presumably, is the cause of the symptoms in CFS.

This assumption further assumes that the decreased blood flow to the brain messes up the neurotransmitters (serotonin, norepinephrine, and the like), the pituitary hormones (CRH, ADH, sex and thyroid hormone regulation), physiology of pain perception and special sensory senses leading to sensitivities. It can also be argued that the abnormal immune response of CFS is due to decreased blood flow. If this basic assumption is wrong, everything that follows is totally irrelevant. While this makes an attractive hypothesis, it is important to remember that it has not been proven.

III. Cause or Effect? If the low circulating blood volume causes decreased blood flow to the brain, it could not be the original cause of the illness; it must be the result or effect of the illness. That is, it would not matter if CFS were caused by a viral infection, head injury, or even stress, the result would be the same. Presumably, some common mechanism would lead to the decreased circulating blood volume, most likely in the autonomic nervous system.

IV. Evidence supporting the concept of blood volume/brain blood flow causing symptoms:

a) Orthostatic nature of the symptoms. CFS is not about tiredness, it is about orthostatic intolerance. If you take someone with CFS and lie them down for a while, they feel not so bad. Unfortunately, nearly everything we do in life is either standing or sitting up.

b) Global neurologic dysfunction. In severe CFS, some patients will have neurologic episodes that resemble strokes or the damage of MS. There does not appear to be permanent damage in CFS, and the numbness, weakness, even seizure-like episodes come and go.

c) Fixing the low volume makes CFS patients feel pretty good for a while. IV saline is a great pick-me-upper, but lasts only a few hours to a day, but not everyone even has this response. I am told that adding albumen to expand the blood volume may make it work a little better. Anecdotal reports of CFS patients with a blood transfusion indicate that they may feel pretty good for up to six weeks. Increasing the volume by these methods helps, but the effect is very short lived.

Florinef has been the single best treatment for CFS I know of when it works. Unfortunately it only works 20% to 30% of the time. I think it is clinically possible to predict which patients will respond. I don't think it is because of neurally mediated hypotension, but rather from simple volume expansion, as some responders do not demonstrate hypotension. The problem with florinef is that most patients cannot tolerate the volume expansion: they get the "florinef headache" also known as the "headache from hell." Here's where it starts getting really interesting. The circulating blood volume is low, but the body with CFS doesn't want more volume.

V. Problems with the low blood volume theory: There are several problems with this theory

a) Roughly 20% of the patients we have tested are in the normal range. They may be in the low normal range, but normal is normal and if it were simply an issue of low volume, these patients shouldn't be sick.

b) Clinically, some of the sickest patients I have seen are in the normal range. If the symptoms were a function of the degree of volume restriction, the sickest would always have the worst volumes.

c) The volume can be expanded over time with dDAVP, a synthetic form of vasopressin, or ADH. By expanding the volume with dDAVP, we have been able to show volume expansion as well as a decrease in blood osmolality, but, alas, there was no obvious clinical benefit.

VI. Mechanisms to increase circulating blood volume in CFS:

If a healthy person were dehydrated they would have a low plasma volume. But most patients with CFS drink lots of fluid; the problem is that they cannot retain it, it is passed in the urine right away. Same thing when you give someone a bag of saline, they pee it out, sometimes before they even leave the office. Interestingly, some patients may recall the acute onset of CFS and state that they remember being very thirsty or urinating a lot.

If you look at the mechanisms that control blood volume, they all seem to be turned off. ADH (vasopressin) is shut down. Renin may be shut down. For some reason the body does not want to accept a normal volume. You replace volume and symptoms improve but the body does not want that. It goes back to the symptoms by reducing the volume. I have not found anyone with CFS who can keep their volume up with just about any of the methods to increase volume. So this creates a paradox that I think is central to CFS, low circulating blood volume but absent corrective mechanisms.

VII. Possible alternative explanation - vasoconstriction

For the past three years I have assumed that the low volume was abnormal in CFS. Maybe the abnormal low volume is normal in CFS. There are two aspects to the volume in any given container, the fluid and the size of the pipes. Imagine a room with a heating system with one-inch diameter water pipes. If you drain all the pipes, you get five quarts of water. Now suppose you replace the one-inch wide pipes with new pipes only 1/2 inch diameter and drain the fluid. The volume would be only half as much. This may be the reason for the low circulating blood volume in patients with CFS: the diameter of the blood vessels is narrow, they are vasoconstricted. If this is true, the body mechanisms to increase volume would be turned off because it now assumes that the smaller pipes are normal. Unfortunately, the smaller pipes are not able to get enough oxygen to the brain, just as the smaller pipes would not heat the room adequately.

This seems to fit with the lack of sustained response to volume increases with dDAVP. If the main problem were the small blood vessels in the brain (vasoconstricted blood vessels) even if you increase the volume it doesn't get to the brain. In this sense, CFS is like total body migraine. Constricted blood vessels causing all sorts of symptoms. Like migraine, CFS is a generic term. There may be as many as thirty different types of migraine according to some headache specialists. Classic migraine, abdominal migraine, ophthalmic migraine, and so on...

Here is why this is an important concept. If the symptoms of CFS are due to decreased brain oxygen and the decrease is due to excessive constriction of the blood vessels in the brain, symptom reversal could be accomplished by dilating the vessels and adding fluid. Because of the potential of promising treatments, this theory needs to be explored. And here is where it starts to get even more interesting. In the next issue, I will try to explore the studies being conducted in "orthostatic Intolerance," and the role of the adrenergic system on blood vessels.

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