S. Bell, MD, FAAP Blood volume Study revisited

[Guest guest]

A PS from my post on blood volume.

A lot of people feel better lying down, I do and I attribute it to the

blood in my body being able to circulate without stressing my heart.

The Lyndonville Journal:

Evaluating Blood Volume Studies - Some Thoughts

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. 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.

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.

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.