Dr Paul Marik's Sepsis/SIRS Protocol for ME/CFS? (Vit C / Hydrocortisone / Thiamine)

[dannybex]

Very interesting, do you recall how long it took you to see improvement from the thiamine and what dose you were taking?

Well, I should say I did find benefit from methylb-12 injections along with nebulized glutathione starting at the end of 2002 (I became ill in 1998, and 2002 was just hell on wheels). I did the b12 shots and glutathione for about 2 months -- and found improvement -- say 50-60% within about 2-3 weeks. Continued on with the B12, but started to become more and more agitated, anxious and 'wired', considerably so, by May of 2003.

So I stopped the B12 and started trying different probiotics for what I assumed was a fungal/candida infection. Started with the cheap ones, then ended up with a high-dose formula from Custom Probiotics, so it's possible that played a role, but was still restless and had a very difficult time relaxing, let alone sleeping.

Since I had been diagnosed with a thiamine deficiency a couple years before, he decided to try thiamine injections -- I believe they were 100mgs. And I swear, within maybe a week or so, I was so relaxed, so 'not-wired', that I felt I could quit my clonazepam cold turkey. It really was remarkable.

 

[Jesse2233]

@dannybex thanks for sharing that, did you find the thiamine gave you more energy as well? and have you tried it again since?

 

[dannybex]

@dannybex thanks for sharing that, did you find the thiamine gave you more energy as well? and have you tried it again since?

Yes it did. It also helped with brain fog -- I suppose because it calmed me down so I could think more clearly.

As noted above, I completely forgot I had ever been prescribed the thiamine -- until I found the receipt in a file folder in late 2013. Started balling like a baby, both from relief and of course regret that so many years had passed since that 'miracle'. Anyway, I was able to get it a few more times, and definitely found benefit, but could not convince my family that it was helping (even though my sister noticed the improvement), so since I couldn't afford it, I haven't been able to take it since early 2015.

I do take benfotiamine, which helps with neuropathy, but doesn't do much more. I should try high-dose regular thiamine for a few weeks...see if it makes a difference.

Edit: This time the benefit was maybe 25%...but that's after many, many years of illness, almost becoming bedridden a couple years ago.

 

[Jesse2233]

From an excellent MEAction article by Robert Steven

Could ME/CFS be Sepsis?

The sepsis illness concept is predicated on infection as its trigger and ME/CFS has not yet revealed an identifiable pathogen. However, in 1992 the sepsis definition (named ‘sepsis-1’) accommodated the patient’s systemic inflammation response and no definable bacterial infection was required. Another revision in 2001 (‘sepsis-2’) shifted focus to mortality risk, then in 2016 the current revision (‘sepsis-3’) is focused more on organ dysfunction proposing sepsis as “life threatening organ dysfunction due to a dysregulated host response to infection”. This latest revision is surrounded in controversy and has not been universally adopted. It seems no-one can agree on exactly what sepsis is, so it is unlikely ME/CFS will include the name sepsis any time soon. Nevertheless, researchers revealed that ME/CFS is identical to SIRS, a precondition to sepsis and formerly the criteria for sepsis. Furthermore, the paths of research for both ME/CFS and sepsis are converging, or have converged.

So, it seems with some certainty that ME/CFS, SIRS and Sepsis are all manifestations of systemic inflammation of varying severity and risk of MODS, separated perhaps only by the presence of an infection, sharing a common pathophysiology.

http://www.meaction.net/2017/02/20/is-sirs-cars-mars-and-now-pics-causing-the-chaos-in-mecfs/

The article continues in great detail to compare the molecular and symptom similarities of both diseases.

For me the million dollar question is, can a curative treatment for acute SIRS benefit (or even put into remission) "chronic SIRS"

 

[Hip]

Sepsis is one of the key things that interferes with the pyruvate dehydrogenase enzyme

That's very interesting dannybex, I did not know that.

It says here that sepsis promotes an increase in pyruvate dehydrogenase kinase, which in turn reduces inhibits pyruvate dehydrogenase, a crucial enzyme in aerobic glycolysis (pyruvate dehydrogenase kinase acts as an inhibitor of pyruvate dehydrogenase).

Fluge and Mella of course found an increased expression of pyruvate dehydrogenase kinases in ME/CFS patients, which they think might explain the low energy state of ME/CFS.

That makes me wonder whether the mechanism which down-regulates pyruvate dehydrogenase kinase in sepsis might be the same fundamental mechanism causing ME/CFS.


Dr Bell posited that ME/CFS may be a sort of "slow sepsis":

Dr. David Bell proposed that patients with ME/CFS have what he called "slow sepsis." In his monograph, Cellular Hypoxia and Neuro-Immune Fatigue, he suggests that ME/CFS is a slow, chronic form of septic shock.

The sequence of events in septic shock is: 1) a serious infection, 2) production of cytokines, 3) increased nitric oxide, and 4) interference with the production of cellular energy. In severe cases of septic shock, the loss of cellular energy is so profound that it can be fatal.

Source: here

We know of course that ME/CFS is associated with chronic low-level "smoldering" enterovirus infections in the tissues, thus the idea of ME/CFS being a slow sepsis is not unreasonable.

So if ME/CFS is a slow sepsis, and since sepsis increases pyruvate dehydrogenase kinase and inhibits pyruvate dehydrogenase, this slow sepsis theory could explain Fluge and Mella's findings, and could be the core pathophysiology of ME/CFS.



I can't seem to find at the moment the mechanism by which sepsis down-regulates pyruvate dehydrogenase, and the cytokines or other messenger molecules that might be involved in this down-regulation; but that mechanism could conceivably be the key to understanding ME/CFS.

However, this paper says that the cytokine IL-6 is a marker of the severity of sepsis, so IL-6 might be an important player in sepsis. And interestingly enough, this paper finds that in mice, IL-6 inhibits pyruvate dehydrogenase in skeletal muscle. So possibly IL-6 might be involved in the pyruvate dehydrogenase inhibition Fluge and Mella found in ME/CFS (some studies have found IL-6 raised in ME/CFS, and huge quantities of IL-6 are released by the muscles during exercise, since IL-6 is also a myokine, which might perhaps explain PEM).




Some Notes on Terminology

Bacteremia = the presence of bacteria in the bloodstream (which can temporarily occur in a non-dangerous way when you brush your teeth).

Septicemia = the presence and multiplication of bacteria in the blood (which is more dangerous than bacteremia). Septicemia is also known as blood poisoning.

Systemic inflammatory response syndrome (SIRS) = a dysregulated inflammatory state affecting the whole body, usually (but not always) in response to infection. SIRS is a type of cytokine storm, in which there is abnormal regulation of cytokines.

Sepsis = SIRS caused by septicemia or by another infection in the body, resulting in injury to body tissues and organs. Usually the infection is bacterial, but it may also be fungal, viral or parasitic.

Septic shock = the dangerously low blood pressure that can occur during sepsis.

 

[Hip]

I just found this paper which suggests TNF-alpha might be responsible for the pyruvate dehydrogenase down-regulation during sepsis:

Several cytokines have been implicated in the pathogenesis of sepsis, most notably tumour necrosis factor-α (TNF-α), and it has been shown that sequestering TNF-α with a TNF binding protein (TNFbp) normalized muscle and blood lactate concentrations in sepsis, and prevented the inhibition of PDC and increased PDK activity (Vary et al. 1998).

 

[Jesse2233]

thanks @Hip, as usual very illuminating

Given all this what do you make of Dr Marik's protocol for ME?

 

[pattismith]

also, as a result, Thiamine helps recovering from hyperlactetemia/lactic acidosis found in sepsis patients

 

[Hip]

thanks @Hip, as usually very illuminating!

Given all this what do you make of Dr Marik's protocol for ME?

Well we know that corticosteroids temporarily can make significant improvements to ME/CFS symptoms (and some ME/CFS patients have used one-off, one-day-only dosing of corticosteroids in order to be more fit and able to attend important engagements). So in that respect, the corticosteroid component of Marik's protocol does work for ME/CFS.

However, long term use of corticosteroids for several months usually eventually makes ME/CFS patients worse, likely as a result of down-regulating the immune response, and thereby allowing the underlying viral or bacterial infections to grow and multiply. Some patients find low dose corticosteroids helpful though, and seem to be able take this for long periods without problem.

The vitamin C and thiamine components of the protocol may just be addressing specific problems found in sepsis, so I am not sure if they would offer any benefits to ME/CFS (though it is interesting to read earlier of @dannybex's major improvements from thiamine injections).

 

[Jonathan Edwards]

It may be worth remembering that after Hench discovered cortisone corticosteroids were used very widely indeed both in intensive care and in chronic disease. By 1970 their use had almost completely stopped because so many people died of complications - of which sepsis was one. In general terms the use of steroids such as hydrocortisone makes the outcome from sepsis worse. It is strange to me that the doctors concerned were not aware of this but maybe they are young.

As far as I can see there is no trial here - just a retrospective review of patients treated with a new protocol compared to standard treatment a year before. That is not a good way to obtain reliable evidence. This does not look like good science to me.

I also see no way to extrapolate this to ME since it is not acute sepsis, or even chronic sepsis as far as we know. There isn't even a slight rise in CRP. Seems like microbabble to me to be honest.

 

[Jesse2233]

@Jonathan Edwards thanks for your viewpoint

what do you make of the genetic expression similarities between ME and sepsis?

and what do you think of the claimed synergy between Vitamin C, thiamine, and hydrocortisone?

 

[A.B.]

I also see no way to extrapolate this to ME since it is not acute sepsis, or even chronic sepsis as far as we know. There isn't even a slight rise in CRP. Seems like microbabble to me to be honest.

I'm not trying to defend this treatment but there are now two different research groups (Montoya and Davis) that have reported that in ME/CFS the gene expression profile is a close or exact match of SIRS.

Medscape says this of SIRS

In 1992, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) introduced definitions for systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS). [1] The idea behind defining SIRS was to define a clinical response to a nonspecific insult of either infectious or noninfectious origin. SIRS is defined as 2 or more of the following variables (see Presentation and Workup):

• Fever of more than 38°C (100.4°F) or less than 36°C (96.8°F)
• Heart rate of more than 90 beats per minute
• Respiratory rate of more than 20 breaths per minute or arterial carbon dioxide tension (PaCO 2) of less than 32 mm Hg
• Abnormal white blood cell count (>12,000/µL or < 4,000/µL or >10% immature [band] forms)

SIRS is nonspecific and can be caused by ischemia, inflammation, trauma, infection, or several insults combined. Thus, SIRS is not always related to infection. (See Pathophysiology and Etiology.)

http://emedicine.medscape.com/article/168943-overview

I can't see how it makes sense but if two groups report the same finding it becomes harder to just dismiss these reports on the basis of it not making sense.

 

[Jonathan Edwards]

@Jonathan Edwards thanks for your viewpoint

what do you make of the genetic expression similarities between ME and sepsis?

and what do you think of the claimed synergy between Vitamin C, thiamine, and hydrocortisone?

What do you mean by genetic expression similarities? I think you may mean RNA levels for specific gene products in white blood cells. I doubt one can make anything much of that and as far as i know we do not have any clear evidence for ME being different from normal. There are a few preliminary studies but that is not enough to want to theorise about. If the CRP is normal I cannot see that ME is anything like significant sepsis.

I cannot see how synergy can be claimed if the authors have not tried the agents individually and in combination in a parallel prospective study. The work has not been done. There is no basis for a claim. Ten years ago nobody would take this sort of publication seriously. I am not sure quite what has changed but it seems now you can publish almost anything and nobody cares if it is done properly. (Note that at least the authors indicate that their findings are preliminary and need confirmation.)

It is a bit like saying that petrol makes cars go faster and both cars and bicycles have wheels so we should put petrol in our bicycles. It is that level of disconnect. Airline pilots are not allowed to play around with what they do like doctors are, because they have people's lives at stake. Why doctors are allowed to play around like this without proper methodology when people's lives are at stake I have no idea but it goes back a long way. Doctors have always been allowed to play around with people's lives like that.

 

[Jonathan Edwards]

I'm not trying to defend this treatment but there are now two different research groups (Montoya and Davis) that have reported that in ME/CFS the gene expression profile is a close or exact match of SIRS.

I think they must mean a slight whiff of something similar, not a match. If the gene expression was the same then the proteins produced would be the same - like IL-6, TNF, CRP, all the acute phase proteins, and so on, none of which are found in ME. The only cytokine that seems to come up regularly in ME is an 'anti-inflammatory' one, TGFbeta. It is a bit like saying 'gosh this is like rush hour' when there are no cars in sight but you can faintly hear a horn sounding round the corner. The horn may turn out to belong to a drunk football supporter.

 

[Jesse2233]

@Jonathan Edwards Dr Marik has said doing a non-retrospective trial would be unethical because it would deny a life saving treatment to the control group.

 

[Hip]

If the gene expression was the same then the proteins produced would be the same - like IL-6, TNF, CRP, all the acute phase proteins, and so on, none of which are found in ME.

One question I would to ask is about the interepretation of blood tests for cytokines like TNF-alpha, which I understand is a paracrine (ie, has a very short range in the body, and only affects nearby cells).

Could there be high tissue levels of paracrines like TNF-alpha in certain localities in the body (in say chronically infected muscle tissues), yet because paracrines have such a short range, you would find negligible TNF-alpha elevations in a blood sample?

If this were the case, then ME/CFS studies showing that TNF-alpha was not significantly raised in the blood would not rule out raised TNF-alpha locally in certain tissues. This would also apply to other cytokines, as I believe most are paracrines (with the exception of IL-6, which is an endocrine).

 

[Jesse2233]

@Hip cytokines may also be elevated post exertion and that may not have been picked up in Montoya's study

Or perhaps a low chronic grade sepsis might affect the body in a similar way but without the high cytokine serum levels

 

[Jesse2233]

A further parallel between ME/CFS and SIRS/sepsis is Post-sepsis syndrome (PSS). Might PSS and ME/CFS in fact be the same condition?

Post-sepsis syndrome is a condition that affects up to 50% of sepsis survivors. They are left with physical and/or psychological long-term effects, such as:

• Insomnia, difficulty getting to sleep or staying asleep
• Nightmares, vivid hallucinations and panic attacks
• Disabling muscle and joint pains
• Extreme fatigue
• Poor concentration
• Decreased mental (cognitive) functioning
• Loss of self-esteem and self-belief

The risk of having PSS is higher among people who were admitted to an intensive care unit (ICU) and for those who have been in the hospital for extended periods of time. PSS can affect people of any age, but a study from the University of Michigan Health System, published in 2010 the medical journal JAMA, found that older severe sepsis survivors were at higher risk for long-term cognitive impairment and physical problems than others their age who were treated for other illnesses. Their problems ranged from not being able to walk, even though they could before they became ill, to not being able to do everyday activities, such as bathing, toileting, or preparing meals. Changes in mental status can range from no longer being able to perform complicated tasks to not being able to remember everyday things.

 

[Hip]

This earlier thread discussed whether or not ME/CFS might be a form of sepsis, or a post-sepsis syndrome.

 

[Jesse2233]

I reached out to Dr Marik via email asking if his protocol might benefit CFS/ME. He said he has been asked this question before, and that he does not know.