Part I: Blood Flow in Sepsis & ME/CFS
Part I: Blood Flow in Sepsis & ME/CFS
A blood flow pattern known as heterogeneous perfusion is found in sepsis. ME/CFS bears a striking resemblance to sepsis. We share peculiar problems with low blood volume, low blood pressure and trouble with pulling oxygen out of the blood to use as energy. Could correcting this pattern of blood flow lead to treatments for ME/CFS patients?
ME/CFS looks like a slow, chronic sepsis, says Dr. David Bell, a longtime ME/CFS physician. He made this observation after decades of treating patients.
At this year’s Open Medicine Foundation symposium for ME/CFS patients, carers and researchers, one of the scientists who spoke held up Dr. Bell’s book and indicated that Dr. Bell was really onto something.
Sepsis is a dangerous illness that occurs after a huge inflammatory response to a bacterial infection. Forty percent of people with sepsis die. We ME/CFS patients don’t often die of our illness, but in other respects, we look strangely similar to sepsis patients.
Like sepsis patients, we tend to have remarkably low blood volume, which means that the total amount of blood we have in circulation is low.1,2 This is a weird symptom not found in very many illnesses. Along with low blood volume, we also tend to have very low blood pressure, just like sepsis patients. My blood pressure often hovers around 84/54, a level of blood pressure you might find in a septic patient.
ME/CFS, like sepsis, often starts with an infection, though this can be bacterial, viral or possibly parasitic.
We used to think that people died of sepsis because of the huge inflammatory response. This is correct, but more specifically, people die of sepsis because this huge inflammatory response causes damage to blood vessels and impairs blood flow. Fundamentally, at its core, sepsis is an illness of blood vessels.
In sepsis, blood flow through our smallest blood vessels, our capillaries, looks like this photo from the research paper “Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock.”
This picture is an image taken from underneath the tongue in sepsis patients where the skin is thin and it’s easier to see the capillaries. The white arrow points to a capillary where blood is flowing normally. The black arrows point to places in capillaries where there is a temporary stoppage in blood flow.
In sepsis, blood flows through certain capillaries just fine, other capillaries too much and still other capillaries extra slow or not at all. This is because the capillaries and blood cells have been damaged by inflammation. The damage to the smallest blood vessels, whose job it is to deliver oxygen to individual cells, prevents cells from getting enough oxygen even there is plenty of oxygenated blood in the body.
In sepsis, when cells are unable to obtain the oxygen they need, they switch to a way of making energy that doesn’t need oxygen called glycolysis. Glycolysis provides fast energy in low oxygen conditions. This mode of energy production increases a substance called lactate and increased lactate is a hallmark of sepsis.
Elevated lactate levels have been found in the muscles and in the brains of ME/CFS patients.
Two ME/CFS researchers, Benjamin Natelson and Ruud Vermeulen have concluded that the most likely cause of low energy production in ME/CFS is that there is something wrong with blood vessels in our illness that prevents oxygen from reaching cells properly. Vermeulen’s research, in particular, found that there is nothing fundamentally wrong with the energy producing cellular machinery itself. Rather, there seems to be something wrong with the delivery of blood flow, and thus oxygen, to muscles.
Perfusion is the flow of blood through parts of the body. We need body parts to be fully and evenly perfused with blood because this means that all cells are getting plenty of oxygen. The kind of blood flow that you find in sepsis is called “heterogeneous perfusion”. Heterogeneous perfusion means that instead of blood flowing at the same rate through capillaries, blood is flowing at different speeds through different capillaries One capillary can have normal blood flow, but its neighbors may have slow blood flow or absent blood flow.
Here is a picture of capillaries with heterogeneous perfusion alongside the same set of capillaries with normal perfusion: link.
Do we look like sepsis patients because we also have heterogeneous perfusion, in which blood travels at very different rates through neighboring blood vessels, in which some blood vessels have normal flow and some have no flow at all?
We know from research that heterogeneous perfusion worsens our ability to pull oxygen out of the blood and use it to make energy, a process called oxygen extraction. The effect of heterogeneous perfusion on oxygen extraction is severe, worse than if blood flow was reduced equally in every blood vessel.
Sepsis patients have trouble with oxygen extraction. In Dr. Vermeulen’s research about ME/CFS patients in exercise, he concludes that we also have trouble with oxygen extraction.
Not being able to pull oxygen out of the blood and make energy with it would provide a good explanation for the crushing fatigue found in ME/CFS. This would also explain the increase in lactate levels found in us.
In addition to sepsis, heterogeneous perfusion is also present in aging and type II diabetes and both of these conditions have a reduced capacity for aerobic exercise, just like ME/CFS patients.
Perhaps we could be treated with agents that help blood vessels stay open and help blood flow more evenly and fully through each one. Nitric oxide is a tiny molecule that is crucial to keeping capillaries open and blood flowing normally.
Øystein Fluge and Olla Mella, Norwegian researchers who study ME/CFS observed that one of their patients had a rapid recovery from ME/CFS symptoms after taking a drug called Imdur for chest pain. Imdur releases nitric oxide in the body, which dilates heart blood vessels, increasing blood flow to the heart and relieving pain there. However, Imdur also releases nitric oxide all over the body and dilates blood vessels all over the body. Fluge and Mella have patented agents that release or otherwise increase nitric oxide for use in ME/CFS after observing improvement in other ME/CFS patients.
I have personally had remarkable effects from taking methylfolate and potassium, both of which visibly increase my blood flow. I can see my skin, my hands and my feet “pinking up.” These treatments give me energy, relieve anxiety, improve my autistic symptoms and allow me to exercise without getting sick, at least on a temporary basis.
Methylfolate supports the levels of a chemical called tetrahydrobiopterin or BH4. BH4 assists in nitric oxide production. Potassium, through some as yet undiscovered mechanism, also increases nitric oxide release from blood vessels.
A patient whose story was featured on Cort Johnsons’ ME/CFS website Health Rising saw great improvement with a drug called Mestinon. This had been sick for 28 years and could not exercise. After taking a low dose of Mestinon, she went for a run, then went cross-country skiing. Now she runs 3 miles twice a week and can work full days.
Mestinon increases a chemical called acetylcholine. Acetylcholine has numerous effects in the body, but one well-known and powerful effect is to dilate blood vessels and increase blood flow through capillaries. Acetylcholine increases blood flow through capillaries by increasing the production of nitric oxide.
Red Blood Cells
Last month, researchers from the Open Medicine Foundation published a paper showing that red blood cells in ME/CFS patients were on average less “squishy” than normal red blood cells.
When this happens, we say that the red blood cells are less deformable. Red blood cells normally deform or change shape so that they can squish through tiny capillaries whose widths are smaller than the width of red blood cells.
When red blood cells cannot deform, they slow blood flow through capillaries and contribute to heterogeneous perfusion.
A loss of red blood cell deformability is an early indication of sepsis and helps to cause the typical blood flow issues in the illness. It is interesting that this looks like it will be a biomarker for ME/CFS as well.
Oxidative stress from damaged and malfunctioning blood vessels is known to cause a loss of red blood deformability in sepsis. In heterogeneous perfusion, stretches of capillaries are not filled with blood or are filled with slow-moving blood. Because red blood cells carry the oxygen and there is less oxygen being delivered in these areas, we would say that these stretches of blood vessels are hypoxic, or low in oxygen. The hypoxic areas generate a lot of oxidative stress and passage through these areas is thought to damage red blood cells and reduce deformability.
For fifty years, ME/CFS has been construed as a psychological disorder. It has been suggested that the real problem with us is that we believe that we are sick when we are not sick.
In his book, Dr. David Bell remarked that ME/CFS is “not an organ-specific illness; it is not localized in a single organ system.” Perhaps this is because it is an illness of blood vessels, a dysfunction that pervades the body nearly invisibly and one that has been slow to come to light because ME/CFS research has historically received such inadequate funding.
If ME/CFS resembles sepsis precisely because our blood vessel function resembles that of sepsis patients, we should be able to shift the conversation from trying to prove our illness exists to trying to find logical treatments.