Insights from Invasive Cardiopulmonary Exercise Testing of Patients with ME/CFS (Joseph et al., 2021)

Pyrrhus

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A new publication by the team of Phillip Joseph, Anne Oaklander, and David Systrom, which I personally find exciting.

Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Joseph et al., 2021)
https://journal.chestnet.org/article/S0012-3692(21)00256-7/fulltext

Main points:
  • 160 ME patients were subjected to both an exercise test (iCPET) and a skin biopsy of the lower leg.
  • Results were compared to 36 healthy people.
  • As some other studies have found, the ME patients could not reach the same level of oxygen consumption during exercise that healthy people could. (lower peak VO2) Whereas most other studies that showed this difference did not achieve statistical significance for the finding, this study found the difference clearly statistically significant.
  • During exercise, ME patients had lower blood pressure in the veins transporting blood from the legs to the heart. (lower right atrial pressure)
  • 31% of ME patients showed Small Fiber Neuropathy (SFN) in the lower leg.
  • The authors interpret the findings as possible clinical evidence for dysautonomia of the small nerves that control constriction of the small veins in the legs, which means that:
    1. The small veins in the legs remain abnormally dilated while standing,
    2. which means insufficient blood pressure to return the blood from the legs to the heart,
    3. which means the muscles in the legs have impaired circulation (blood pooling) and possibly insufficient oxygen,
    4. which may mean that the insufficient oxygen in the legs leads to death of the small nerve fibers in the legs. (Small Fiber Neuropathy)
    5. ...Which is exactly what many people have suspected for a while, and is the same mechanism behind dysautonomic orthostatic intolerance!
Excerpt:
Joseph et al 2021 said:
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in ∼50% of POTS and fibromyalgia patients.

Research Question
Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?

Study Design and Methods
We analyzed 1516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mmHg, results from 160 patients meeting ME/CFS criteria who had skin-biopsy test results were compared to 36 controls. Rest-to-peak changes in cardiac output (Qc) were compared to oxygen uptake (Qc/VO 2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO 2 tertiles.

Results
During exercise, the 160 ME/CFS patients averaged lower RAP (1.9±2 vs. 8.3±1.5; P<0.0001) and peak VO 2 (80%±21 vs. 101.4%±17; P<0.0001) than controls. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4±19% vs. 99.5±23.8% vs. 99.9±19.5% predicted; P<0.01). In contrast, systemic oxygen extraction was impaired in high-flow versus low and normal-flow participants (0.74±0.1% vs. 0.88±0.11 vs. 0.86±0.1; P<0.0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% was consistent with SFN (epidermal innervation ≤5.0% of predicted; P < 0.0001). Denervation severity did not correlate with exertional measures.

Interpretation
These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance–depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.

EDIT:
There's one important distinction here that needs to be addressed:
Most exercise studies in ME use a 2-day non-invasive CPET, whereas this study used a one-day invasive CPET. An invasive CPET (iCPET) is like a non-invasive CPET, except that the investigators insert catheters directly into your arteries and heart, allowing them to measure more cardiovascular parameters directly, and collect more relevant data.
 
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sometexan84

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31% of ME patients showed Small Fiber Neuropathy (SFN) in the lower leg.
I'd like to point out that the 31% number, could actually be way higher. If they would have done the high thigh and lower thigh, in addition to lower leg (which I'm guessing is referring to calf area), they would have found more SFN positives.

Here's a screenshot from the linked video showing how the calf biopsy could be normal, while the thigh biopsies are abnormal.


1613016431272.png
 

sometexan84

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I also want to make sure people understand how important it is to test all three areas of the leg. Some people w/ SFN have tested neg because it was just in one spot (like calf), only to later realize they did in fact have SFN.
 

bread.

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The SFNP is a secondary downstream issue.

Diabetics have SFNP, like MANY other patients with a very wide variety of ailments do. I do not see the average SFNP patient even moderately incapacitated. They even mention in this study that SFNP severity does not correlate with ecxertional intolerance.

The oxygen extraction is the issue and it is NOT correlated to SFNP or only partly correlated or causal.

It is very likely a mitochondrial issue.
 
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mitoMAN

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This is where I would see high dose ITPP fit the picture.
https://www.newscientist.com/article/dn16564-chemical-drink-breathes-life-into-damaged-hearts/

Designed to make haemoglobin release more of its oxygen than normal, the drug, myo-inositol trispyrophosphate (ITPP) boosted exercise levels in the ailing mice by 35% when given dissolved in water. When given by injection into the abdomen, exercise levels rose a massive 60%.
“ITPP doesn’t deliver oxygen itself, but makes haemoglobin able to release a larger amount of oxygen to tissues,”
 

bread.

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This is where I would see high dose ITPP fit the picture.
https://www.newscientist.com/article/dn16564-chemical-drink-breathes-life-into-damaged-hearts/

Designed to make haemoglobin release more of its oxygen than normal, the drug, myo-inositol trispyrophosphate (ITPP) boosted exercise levels in the ailing mice by 35% when given dissolved in water. When given by injection into the abdomen, exercise levels rose a massive 60%.
“ITPP doesn’t deliver oxygen itself, but makes haemoglobin able to release a larger amount of oxygen to tissues,”
I believe it works (enhancing capacities) to 100%, but at what longterm costs might be the question to ask?

Will it push cells in overdrive that have been put to „sleep“ for a reason? Will it further increase oxidative stress in a system with limited anti oxidative stress capacities and push them therfor further down the pathology by literally spitting out mtDNA?
 

ChookityPop

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Fascinating for sure.

"160 ME patients were subjected to both an exercise test (iCPET) and a skin biopsy of the lower leg."
"31% of ME patients showed Small Fiber Neuropathy (SFN) in the lower leg."

The percentage can indeed be higher as a negative skin biopsy doesnt necessarily rule out SFN. Some people have negative biopsy and positiv sweat test for example. And later on they have a positive skin biopsy.
 

Pyrrhus

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I'd like to point out that the 31% number, could actually be way higher. If they would have done the high thigh and lower thigh, in addition to lower leg (which I'm guessing is referring to calf area), they would have found more SFN positives.
The percentage can indeed be higher as a negative skin biopsy doesnt necessarily rule out SFN. Some people have negative biopsy and positiv sweat test for example. And later on they have a positive skin biopsy.
Yes, you can have SFN in one part of the body, but not another part of the body. The lower leg (calf) is usually used because that is the most common place to find SFN, if your SFN is caused by poor circulation.

Perhaps more relevant to this study, you can have SFN of the small nerves that control the small veins in your lower leg, but without any SFN in the small nerves near the skin in your lower leg.

The oxygen extraction is the issue and it is NOT correlated to SFNP or only partly correlated or causal.

It is very likely a mitochondrial issue.
They even mention in this study that SFNP severity does not correlate with ecxertional intolerance.
Yes, this study's abstract does not imply that the poor oxygen use of the muscles is only due to poor circulation. It also allows for the possibility of poor oxygen use of the muscles because of impaired mitochondria in the muscles.

Would this have any interaction with the drug Propranolol ?
Perhaps. Propanolol is a drug that blocks β-adrenergic receptors in autonomic nerves. Some of these receptors are used by the autonomic nerves that control exertion-related dilation of arteries. So, in theory, taking propanolol might cause a sort of exertion intolerance.

It is also important to note that many people with ME or POTS have auto-antibodies directed at the β-adrenergic receptors in autonomic nerves. Thus, auto-immunity is one explanation for why there is dysautonomia of the small nerves that control blood vessels during exercise.
 
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Pyrrhus

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Someone has pointed out that, during exercise, there can also be local (paracrine) effects whereby the cellular lining (endothelial cells) of the small arteries closest to exercising muscles release signaling molecules (primarily nitric oxide) which relax the small muscles surrounding the arteries, resulting in dilation of those arteries, providing more oxygen to the exercising muscles.

(As a reminder, arteries carry oxygenated blood from the heart to the muscles, while veins carry de-oxygenated blood from the muscles back to the heart.)

Although a failure of this effect might be a contributor to the poor oxygen use of exercising muscles, this effect is not terribly relevant to the observed low blood pressure in the veins returning blood from the legs to the heart. (low right atrial pressure)

Anyone interested in this type of "endothelial dysfunction" can learn more in this discussion:

Endothelial Dysfunction in ME
https://forums.phoenixrising.me/threads/endothelial-dysfunction-in-me.83521/
 
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sometexan84

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The SFNP is a secondary downstream issue.

The oxygen extraction is the issue and it is NOT correlated to SFNP or only partly correlated or causal.

It is very likely a mitochondrial issue.
Autonomic nerve damage interferes with blood pressure, dysregulation of the heart and blood vessels. And certainly is well-documented in its association w/ exercise intolerance (including studies demonstrating how this works).


Diabetics have SFNP, like MANY other patients with a very wide variety of ailments do. I do not see the average SFNP patient even moderately incapacitated. They even mention in this study that SFNP severity does not correlate with ecxertional intolerance.
maybe of them have textbook "post exertional malaise" AND chronic fatigue. But when I talk to them, they have never heard of PEM, and know little to nothing about ME/CFS. You find a lot more of this group w/ pain. I believe this is because the pain symptoms helped them quickly get to a SFN diagnosis. Whereas someone (like me) w/ just fatigue, well, the docs just don't know what to do w/ you.

We are the same. But if you have predominantly fatigue symptoms, you're prob more likely to end up in a forum like this. If predominantly pain, you're prob more likely to end up elsewhere (and likely to have a quicker diagnosis).

Though, they don't all have PEM, it all depends on where the damage is, which nerves. Also, not everyone even in this forum has PEM, and some don't have fatigue symptoms.

Also, the nerve damage can lead to orthostatic hypotension, blood pressure, heart, and blood vessel dysregulation. After a while, your RBC count starts getting lower. So of course there's going to be reduced oxygen delivery.

In fact, here's Systrom showing he believes the nerve damage is in fact the cause of it all.
https://batemanhornecenter.org/systrom_cpetresearch/

"Systrom believes that ME/CFS, preload failure syndrome, and oxygen extraction failure may all be mediated by imbalance between the sympathetic and parasympathetic nerves of the autonomic nervous system"

Btw, this actually fits w/ my personal condition perfectly.
 
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sometexan84

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Yes, you can have SFN in one part of the body, but not another part of the body. The lower leg (calf) is usually used because that is the most common place to find SFN, if your SFN is caused by poor circulation.
I've not seen poor circulation as a common cause of SFN. What I have seen is that there are not only a ton of different reported causes, but they are still discovering new causes. And that a large percentage still remains idiopathic (cause unknown).

Referring to that screenshot... If it's immune-mediated, you're more likely to find abnormal results in the thigh area. Important due to the high frequency of immune dysfunction and autoimmunity seen in these parts.

It is also important to note that many people with ME or POTS have auto-antibodies directed at the β-adrenergic receptors in autonomic nerves. Thus, auto-immunity is one explanation for why there is dysautonomia of the small nerves that control constriction of the small veins in the legs.
After documenting mentioned auto-antibodies in this forum (and elsewhere), I actually haven't seen β-adrenergic receptors to be nearly as common as previous studies led us to believe. It's a very small handful.

From what I've been seeing, it seems there are many autoantibodies targeting peripheral nerve cells that have yet to be discovered (or named). Lots of complex carbohydrate antibodies, expressed on the surface or nerve cells. You could call them anti-glycan antibodies, though they're not just gangliosides.
 

bread.

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Autonomic nerve damage interferes with blood pressure, dysregulation of the heart and blood vessels. And certainly is well-documented in its association w/ exercise intolerance (including studies demonstrating how this works).



maybe of them have textbook "post exertional malaise" AND chronic fatigue. But when I talk to them, they have never heard of PEM, and know little to nothing about ME/CFS. You find a lot more of this group w/ pain. I believe this is because the pain symptoms helped them quickly get to a SFN diagnosis. Whereas someone (like me) w/ just fatigue, well, the docs just don't know what to do w/ you.

We are the same. But if you have predominantly fatigue symptoms, you're prob more likely to end up in a forum like this. If predominantly pain, you're prob more likely to end up elsewhere (and likely to have a quicker diagnosis).

Though, they don't all have PEM, it all depends on where the damage is, which nerves. Also, not everyone even in this forum has PEM, and some don't have fatigue symptoms.

Also, the nerve damage can lead to orthostatic hypotension, blood pressure, heart, and blood vessel dysregulation. After a while, your RBC count starts getting lower. So of course there's going to be reduced oxygen delivery.

In fact, here's Systrom showing he believes the nerve damage is in fact the cause of it all.
https://batemanhornecenter.org/systrom_cpetresearch/

"Systrom believes that ME/CFS, preload failure syndrome, and oxygen extraction failure may all be mediated by imbalance between the sympathetic and parasympathetic nerves of the autonomic nervous system"

Btw, this actually fits w/ my personal condition perfectly.
I am not a doctor but know many people with diabetic neuropathies, to compare their „fatigue“ to me/cfs is ridiculous by all means, this has nothing to do with their pain and that their struggle is real, it only is NOT very relevant to me/cfs and its cardinal symptom PEM.

Apart from that I have severe SFNP and have been in contact with specialists around the world for it: they all say the same thing: It is at very best contributing factor for PEM and even „fatigue“ - one you want to treat if you can obviously, it will definitely make you feel better in many aspects, it will not get your muscle out of a deficient glucose and oxygen utilisation state though, there is even some evidence for this (re cultured musclecells of me/cfs patients show this defiency - without any nervous system derived blood circulatory constraints).
 
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pattismith

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A new publication by the team of Phillip Joseph, Anne Oaklander, and David Systrom, which I personally find exciting.

Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Joseph et al., 2021)
https://journal.chestnet.org/article/S0012-3692(21)00256-7/fulltext

(Although I haven't been able to read the full paper, I find it exciting that David Systrom has evolved from talking about "preload failure" to talking about dysautonomia as the driving force behind cardiovascular preload failure.)

Main points:
  • 160 ME patients were subjected to both an exercise test (iCPET) and a skin biopsy of the lower leg.
  • Results were compared to 36 healthy people.
  • As many other studies have shown, the ME patients could not reach the same level of oxygen consumption during exercise that healthy people could. (lower peak VO2)
  • During exercise, ME patients had lower blood pressure in the veins transporting blood from the legs to the heart. (lower right atrial pressure)
  • 31% of ME patients showed Small Fiber Neuropathy (SFN) in the lower leg.
  • The authors interpret the findings as possible clinical evidence for dysautonomia of the small nerves that control constriction of the small veins in the legs, which means that the small veins in the legs remain abnormally dilated, which means insufficient blood pressure to return the blood to the heart, which means the muscles in the legs have impaired circulation and possibly insufficient oxygen, which may mean that the insufficient oxygen in the legs leads to death of the small nerve fibers in the legs. Which is exactly what many people have suspected for a while, and is perfectly consistent with dysautonomic orthostatic intolerance.
Excerpt:
insufficient O2 to the muscle would increase Lactate and activate the ASICs.

Do you think it could explain the muscle pain? and PEM?

This muscle vascular hypothesis is very interesting, because it fits with the erythromelalgia-like symptoms in feet and hands that is often observed in ME/CFS (erythomelalgia is a skin vascular disorder)

However, I recently did a trial with spices seeds of Sinapis Alba + Cuminum Cyminum and had a great result for both muscle pain and PEM (it fix them all!!), and this is unexpected in this theory because spices are known triggers for erythromelalgia and may increase vasodilation....

How to reconcile this?
 

Learner1

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In fact, here's Systrom showing he believes the nerve damage is in fact the cause of it all.
https://batemanhornecenter.org/systrom_cpetresearch/

"Systrom believes that ME/CFS, preload failure syndrome, and oxygen extraction failure may all be mediated by imbalance between the sympathetic and parasympathetic nerves of the autonomic nervous system"
But what damaged the nerves to begin with?
I've not seen poor circulation as a common cause of SFN. What I have seen is that there are not only a ton of different reported causes, but they are still discovering new causes. And that a large percentage still remains idiopathic (cause unknown).

Referring to that screenshot... If it's immune-mediated, you're more likely to find abnormal results in the thigh area. Important due to the high frequency of immune dysfunction and autoimmunity seen in these parts.
Or not. I recently had a bout with searing pain, with excruciating nerve zaps in my thighs. After a week of it,

I thought about what I'd done differently, and realized it started a few days after trying a different form of thiamine than the one I've been taking for the past 3 years - Life Extension Mega Benfotiamine. I took the new one after repeatedly running into a camp of people that maintain only TTFD is useful and all other forms of thiamine don't cross the BBB and are inadequate. Ive never felt this to be the case, or maybe like so many, I have a leaky gut which can increase BBB permeability, so it hasn't been an issue. At any rate, if always done fine on the benfotiamine, but after repeatedly hearing the TTFD dogma, I decided to try it.

Within 4 days, searing nerve pain and nerve zaps in my thighs and tingling in my fingertips fort the next 3 weeks. I switched back to benfotiamine after the first week and it took a couple of weeks for the nerve pain and tingling to go away.

B12 deficiency and too little or too much B6, particularly too much Pyridoxine HCl can also cause nerve issues and neuropathy.

The chemotherapy drugs I had also cause neuropathy due to severe oxidative stress. When I began to get it in my hands and feet, my naturopath put me on NAC which reversed the neuropathy.

The oxidative stress and nitrosative stress, which is a known feature of ME/CFS, creates peroxynitrites, which impair mito complex 1 and damage mitochondrial membranes. Nerves

https://pubmed.ncbi.nlm.nih.gov/15823672/

https://pubmed.ncbi.nlm.nih.gov/24687457/

https://www.jneurosci.org/content/32/18/6149

It is very likely a mitochondrial issue
Indeed it is.
However, I recently did a trial with spices seeds of Sinapis Alba + Cuminum Cyminum and had a great result for both muscle pain and PEM (it fix them all!!), and this is unexpected in this theory because spices are known triggers for erythromelalgia and may increase vasodilation.
Cuminum is an antioxidant. You might want to discuss it with @Wishful in another location and it seems to have helped his PEM. The sinapis sounds potentially problematic, especially for mucus membranes, and ??

https://practicalplants.org/wiki/Sinapis_alba
 

Pyrrhus

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insufficient O2 to the muscle would increase Lactate and activate the ASICs.

Do you think it could explain the muscle pain? and PEM?
It could certainly explain sore muscles right after exercise.

If the muscles are damaged by insufficient oxygen during exercise, then it might also lead to delayed-onset muscle soreness (DOMS). DOMS usually occurs 1-2 days after the muscle damage, so it might be a contributing factor to PEM.

However, I recently did a trial with spices seeds of Sinapis Alba + Cuminum Cyminum and had a great result for both muscle pain and PEM (it fix them all!!), and this is unexpected in this theory because spices are known triggers for erythromelalgia and may increase vasodilation....

How to reconcile this?
I don't know the pharmacology of any spices, except that spices containing large amounts of curcumin can have anti-inflammatory effects.

If there is inflammation of the small nerves controlling constriction of the small veins in the legs, and this inflammation is the cause of the dysautonomia, then anti-inflammatory supplements might reduce this inflammation and eliminate the dysautonomia that leads to poor circulation.
 

sometexan84

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@bread. Once I've treated my peripheral nerve damage, I'll be sure to let you know if my PEM and fatigue have gone or remained. I will be honest. I will reluctantly admit I was wrong, or gladly share that I was right. I have been wrong before.
 

sometexan84

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But what damaged the nerves to begin with?
I only started researching this stuff like a month and a half ago, since I got the TS-HDS AB results. But from the little I do know at this point... there are multiple causes of this type of nerve damage, and it seems there are glycan-type or carbohydrate-type antibodies, many of which have yet to be discovered/labeled.

There's fluid buildup that can cause nerve damage, puts pressure on nerves, can come from things like hypothyroidism.

There's amyloid protein deposits that can cause nerve damage.

Autoantibodies that attack either peripheral or central nervous system. Seems like the peripheral nervous system autoimmunity has a lot less documentation. They know very little about this. These complex carbohydrate antibodies that can potentially damage nerve cells are just now being looked into. I believe they are still trying to confirm whether or not they're actually pathogenic. Which means they are very far away from determining their origin.

I happen to think it's a form of molecular mimicry. And that glucose and lipid metabolism are involved. Also, complement activation.

Of course, there are a bunch of other ways nerves could be damaged.
 

bertiedog

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f the muscles are damaged by insufficient oxygen during exercise, then it might also lead to delayed-onset muscle soreness (DOMS). DOMS usually occurs 1-2 days after the muscle damage, so it might be a contributing factor to PEM.
My muscle pain comes on during and after an exercise like walking. It's happening to me now and it started 3/4 way through my walk. I know my oxygen is affected because I had my autonomic nervous system tested at the Breakspear and was told I had 50% less oxygen uptake in my cells when my body was stressed by just taking 6 deep breaths in a minute! I was advised to buy an oxygen concentrator and have been using one, 3 times daily for around 7 years now. It does help to replenish some of the oxygen as long as I have a prolonged rest laying horizontally.

On the morning of the autonomic test I had gone for a short swim which exhausted me and I suspect I had PEM before the test had even started but know that in my case a lack of oxygen happens every time I exercise and also my blood sugar gets used up way too quickly and my body isn't able to replenish this unless I eat which will give me back a little more energy for a short time.

Pam