To me it seems like a poor study design to have the placebo be a glucose infusion rather than a matched quantity of sodium chloride. They cannot say that the beneficial effects were not just due to sodium. Figure 3[1] shows that sodium concentrations indeed rose compared to placebo. They acknowledge this in their limitations, but this is a flaw of study design that could have been foreseen from the beginning.
Glucose is a common carrier fluid, and in this particular case is given at a very low concentration (D5%). You need to infuse glucose as part of your parental nutrition regimen. This is standard practice across intensive care units, and they probably wouldn't have gotten approval for the protocol without it.
As an aside, my company [1] is working on solving this and other problems by focusing on glucose control. When you keep the blood sugar under control, sepsis develops at much lower rates and mortality decreases across the board by 20-30%.
D5W is common, sure. My post makes no complaint about D5W being uncommon.
The problem here, again, is that this choice led to both sodium and ascorbate administration being different between the two arms. They think they are testing the ascorbate, but they can’t exclude the possibility that they are getting results due to sodium.
Since you used this as an opportunity to plug your company, I will say that the company’s claims about reducing mortality from glucose management seem very poorly supported. Your site only lists retrospective studies, but you will need multicenter prospective RCTs to have any credibility with such claims. Saying that “mortality decreases” is easily read as causal language, but there is no data supporting such language. If the effect size is anywhere near as large as you claim, these trials will be very easy to run and won’t need a large sample size.
There are several multicenter RCTs showing the efficacy of glucose control, but none as yet that do it well in a fully automated way. We don't have these studies listed on the website, and that's one thing we could definitely change, but they're pretty easy to find in the literature.
You're correct though, that the number of patients needed to demonstrate efficacy in a pivotal trial will be somewhere in the 100-300 range, which is something we're working up to! As with all things in medicine, these things take lots time and lots of capital, but the need is clear and for people who understand that need, there are very few who wouldn't want to incorporate a fully automated glucose control system into their unit.
Regarding mortality reduction claims, I'd encourage you to read the work of Van DeBerghe, Krinsley, Kovatchev, Hovorka, Chase, and Umpierrez, to name but a few of the academics who have run larger studies
Van DeBerghe is cited in the editorial discussing the pivotal practice-changing RCT that showed increased mortality from tight glucose control in the ICU (Finfer NEJM 2009). I think a lot of us intuitively believe that there is a mechanism of glucose control that should be helpful, but like I said, an RCT (of the specific device) will be necessary.
Absolutely! Yeah, NICE-SUGAR definitely has its flaws, the main one being that it has a lot more hypoglycemia than it should - a combination of the open loop protocol, infrequent sample time, no patient model, and static dosing protocol with only rescue bolusing. We did a series of simulation studies a few years ago comparing various state of the art ICU controllers, and while NICE-SUGAR has excellent time in range, it has poor performance in the hypo range, which has been linked to increased mortality.
The key is to get low variability and lots of time in range, but absolutely no hypoglycemia of any kind. That's what it's going to take to crack this problem. We hope our second human trial will continue to show those characteristics, and in a few years, an RCT pivotal trial.
Considering that saline drips a the norm for IV hydration, it might be that a saline infusion added to a saline IV line would be superfluous. Interested to get a medically qualified person's take on this.
Would they need to have 2 placebo arms to make this an optimal study design then? One for glucose (as sodium ascorbate was diluted using a glucose solution), and another placebo group for sodium chloride?
Honestly if they had balanced the sodium via almost any mechanism, I wouldn't have had much to say about it. The difficulty with 2 placebo arms is that you have to expand your study population which I think poses an ethical issue, but otherwise yes.
Not really relevant. Let’s say the authors modify the study as you suggest and use sodium chloride as the active ingredient. Now let’s say no difference is observed between the placebo group and the test group. Does that mean sodium is effective or ineffective? You can’t say without having a true control group to compare against. You’re basically saying “I would be more ok with this study if it was totally useless.”
> Does that mean sodium is effective or ineffective?
This comment misidentifies what the authors see as the active ingredient. They are not trying to study sodium. They are trying to study ascorbate. If you want to study ascorbate, then also giving sodium to one group and not the other will confound your interpretation of the results, as it does here.
> Let’s say the authors modify the study as you suggest and use sodium chloride as the active ingredient
That is not, at all, my suggestion. The authors have identified the active ingredient they want to test. Their test, however, was imbalanced in other ways. I am pointing out that imbalance.
In a placebo trial, it’s very important that the placebo be statistically independent from the treatment group. You’re basically saying you would change the study so the placebo and control were not independent distributions. That would make the study worthless. I don’t know what else to say other than that you have no idea what you’re talking about. No where did the authors say they’re only studying ascorbate. They explicitly say they’re studying a treatment regime of sodium ascorbate. If you want to study only sodium, then run a RCT with only sodium chloride. Comparing sodium chloride to sodium ascorbate is not the way to study the effect of sodium.
> In a placebo trial, it’s very important that the placebo be statistically independent from the treatment group.
Statistical independence has nothing to do with our conversation, which is about designing an appropriate set of comparator groups to enable valid inference about the hypothesis.
I’m afraid I don’t have time to continue a discussion where we have to pretend that the authors - who have identified sodium as a confounder for their hypothesis - actually wanted to study sodium.
Statistic independence has everything to do with it. If your control and treatment groups are not independent, you can’t differentiate a case where both groups experience an effect vs. both groups experiencing no effect. Please explain how that would work in your experiment.
This has been beaten to death in high quality randomized controlled trials in sepsis. Don’t believe a university press release lol. HN is a pretty poor source of health information overall.
The study says: "Randomized controlled trials, however, have shown variable results or even possible harm [10,11,12]. Moreover, current guidelines and a Bayesian re-analysis of a previous trial have led to recommendations not to use intravenous vitamin C in patients with sepsis because of possible harm [13, 14]. Regrettably, these studies used ascorbic acid, a compound associated with the induction of metabolic acidosis and acidemia [15]. This makes it uncertain whether the unclear effects in human sepsis were due to the administration of a suboptimal preparation of the study medication. In contrast, sodium ascorbate (NaAscorbate) has a physiological pH, does not contribute to acidosis, can be given at a much greater dose, and may carry a different efficacy profile [16]."
i would love if years later it turned out he didn't just have "nobelitis" and was right in some respects. but this is one small pilot study and the larger body of literature around it shows mixed results. not saying it should be disregarded, but there are several reasons why it's not exciting and it shouldn't be mistaken for a anything more than a pilot trial to evaluate safety.
i'm sure there's a lot more to criticize than i can see, but:
1) study's primary outcome of increased urine output is not necessarily clinically meaningful---urine output (UOP) is selected because in septic shock (sepsis + low blood pressure), organs slowly shut down with the kidneys typically being the first to go. thus, UOP can be informative as a measure of renal perfusion and ultimately end-organ damage. however, the control arm received D5 fluids [water? saline?] alone, whereas intervention group received D5 fluids + NaAscorbate, thus ultimately receiving more solute. you would expect when given a more osmolar solution, you would see increased diuresis (solute will draw in water in the kidney's tubules, thus more urine output). additionally, vitamin c itself is renally excreted, thus if the kidneys are working to excrete high doses of NaAscorbate, the tubular cells could alter their usual reabsorption and secretion patterns, potentially affecting overall fluid balance.
2) as above this is a small pilot study; however, the authors (laudably) include their power calculations in which they used an effect size of 900cc UOP. the difference in mean UOP between the groups was 891cc's, so it's dubiously powered (even if we ignore consideration (1)). accordingly, their 95% confidence interval itself crosses 0 meaning no difference in effect was detected in urine output (thus their p values was >0.05). you have to wonder what statistical games might have been played to p-hack when results come so close.
ultimately why this isn't news is that the 'next phase of human trials' have already been conducted on vitamin c in sepsis.
there's a few other things: mean baseline CRP was notably much higher in the intervention group, and it makes me wonder if this affects the effect size considering that anyone in sepsis might benefit from fluids (though they received so little overall).
I've looked a little at the literature and I doubt Linus Pauling was right.
His ideas remind me of a saying from a favoriteprofessor: "I am the primitive of my way."
I am all for using nutrition to heal people but I think his ideas were half baked. He was maybe kind of "on to something" but in a general ballpark kind of way, I suspect.
that’s not what the comment said tho, he just stated that death by septic shock made up about 50% of hospital fatalities, as in if you are able to even somewhat help that large of a pt group, that’s a pretty big step forward.
I understand. I meant "bit different" in the nuanced context of this study. As the authors note in their introduction of the paper [1]: "Regrettably, these studies used ascorbic acid, a compound associated with the induction of metabolic acidosis and acidemia [15]. This makes it uncertain whether the unclear effects in human sepsis were due to the administration of a suboptimal preparation of the study medication. In contrast, sodium ascorbate (NaAscorbate) has a physiological pH, does not contribute to acidosis, can be given at a much greater dose, and may carry a different efficacy profile."
Yeah to try to maybe draw an analogy, NaAscorbate vs Ascorbic Acid is a bit like CSV vs JSON encoding - you might be sending the exact same data but if the serialisation format isn't what the API expects, then you could get errors but that doesn't necessarily mean that you sent the wrong data.
The body can react differently to salt vs pure form for the same active ingredient - eg crack vs cocaine
I used to be in the camp that supplements/vitamins are bs in general and unless you are deficient they won’t do a thing for you.
However, I am now learning that serum levels don’t often tell the whole truth.
For example, many suffers of neurological disorders benefit greatly from using B1 even if their levels are not below “good” threshold. There is a physician who has done a lot of work on this. You can technically megadose b1 without any negative side effects.
I am now seeing neurologists even recommending things like ALA to patients along with meds to stop symptoms.
I welcome the open mindedness because the online groups of suffers often discover pretty interesting things.
Years ago I talked to a chemist who cured his neuropathy with pirenzepine(drug used for ulcers with good safety profile), there is a startup now with a cream that uses pirenzepine as main ingredient to treat neuropathy. They are in stage 3 trials and have seen success.
B vitamins are water soluble, so they are generally relatively safe to take in large amounts because they don't accumulate in the body, so you can't poison yourself like you can with some things. Some water soluble vitamins are associated with kidney stones if taken in high doses, so "unlikely to poison yourself" does not mean zero side effects.
I am seeing conflicting reports on B1 aka thiamine. If you don't have a compelling reason to try megadoses, I wouldn't do it. There's a lot we don't know.
But for many things, it's completely reasonable to increase your consumption of B vitamins. There's a lot of space between do nothing and megadoses that is safer to play in than skipping straight to megadoses.
Megadosing B6 can lead to B6 toxicity/syndrome as a result of its longer half life and ability to accumulate in the system. Between multivitamins, energy drinks, preworkouts and food, it's very easy to go well above the recommended amount. I'm currently recovering from B6 induced peripheral neuropathy (tingling in my feet) caused by 20-50mg/day over several years.
This is a simplification. For example niacin (vitamin B3) excesses cause cholesterol to become more atherogenic. And supplementation in patients without deficiency is ultimately harmful.
> However, I am now learning that serum levels don’t often tell the whole truth.
> For example, many suffers of neurological disorders benefit greatly from using B1 even if their levels are not below “good” threshold. There is a physician who has done a lot of work on this. You can technically megadose b1 without any negative side effects.
Megadosing vitamins despite normal serum levels is a favorite of alternative medicine practitioners. The story has played out for nearly every vitamin you can name that doesn't have immediate toxicity upon overdose: Vitamin C, Vitamin D, various B vitamins, etc.
It's never a good sign when there's "a physician who has done a lot of work on this" is the primary source, the claim is that all of medical knowledge to this point has missed it, the range of conditions/symptoms covered is so broad that nearly anyone could be considered impacted, and they preemptively try to claim that blood tests can't diagnose it or must be ignored. It's textbook alternative medicine pseudoscience and it's playing out for every vitamin, mineral, and supplement out there.
One might be the MTHFR mutation. I forget the percentage, but a dizzying amount of westerners suffer from it - and it basically always gets misdiagnosed as depression.
Supplementing with B12 helps, to a degree (you're providing more input to a broken machine), but you can supplement 5-MTHF (methylfolate) to get what the mutation inhibits your body from producing.
> One might be the MTHFR mutation. I forget the percentage, but a dizzying amount of westerners suffer from it - and it basically always gets misdiagnosed as depression.
MTHFR has been hijacked by alternative medicine and exaggerated into an "explains everything" diagnosis.
The first red flag is that MTHFR pushers use it to explain ever vague disorder under the sun: Depression, anxiety, stomach issues, being tired, being unhappy, inflammation, etc. If you name it, chances are someone on an alternative health board will spring up and suggest MTHFR as a narrative, or other variations on the theme ("methylation", etc.)
The second red flag is when they moved to diagnosis anyone with any mutation, including heterozygous people, as "having it". This isn't backed by evidence and was purely an attempt to stretch the diagnosis to cover more people,
Internet MTHFR and "methylation" advice is generally terrible. Don't buy into it.
You can actually test for high homocysteine levels in the blood, but most MTHFR proponents skip that step and just assume they "have it" and that B12 and Methylfolate will solve all of their problems (they don't). Alternative medicine has stepped in to provide endless articles, podcasts, and paid advice about supplements to add to deal with MTHFR, which of course never work because MTFHR isn't the root cause of all of their symptoms. It's terrible.
Some links to get you started. B1 deficiency can be caused by things like alcoholism. He also thinks we don’t get enough of b1 in our diet and the current scale is not sufficient.
Symptoms can vary and can involve different nervous systems. Things like tingling, insomnia, fatigue.
A lot of people talk about getting paradoxical reaction or refeeeding syndrome, meaning once they start taking b1 they get massive flare up of symptoms.
Can we get enough B1 by just diet alone? It seems a lot of foods either have in naturally or are fortified with it. Why the need for extra supplements?
Back in the day when we were all doing enough work (men, women, children) to need over twice our base-metabolic-rate number of calories per day, and eating whole foods, particularly red and white offal and leafy greens like collard and beet greens, steamed and roasted, we got enough of these mesonutrients and micronutrients.
Twice your BMR is about 5000 Cal/day for an adult male. You need to do eight hours' physical work (shoveling, threshing, chopping, sawing, lifting, doing the laundry by hand, etc.) to burn off the extra.
Now, the hypothesis says, we are deficient in many of these nutrients because we simply do not eat enough food, only 2500 Cal/day and a lot of that is from vegetable oils and low-nutrient animal fats.
I have no investment in the hypothesis. Just reporting it.
Edit: Vegemite and Marmite are high in vitamin B1. Possibly Bovril also. Spread it thinly on your toast and grill it.
That is an interesting point. What we also know is that soils are being depleted of minerals, and farmers are selecting for crops with higher shelf life over higher nutrition.
e.g. tomatoes have lost most flavor and nutrition over past few decades, some efforts are underway to hybridize them with older variants to get the best of both worlds.
> e.g. tomatoes have lost most flavor and nutrition over past few decades
can't speak for nutrition (nor do you provide support for that claim) but as to flavour, you clearly haven't been round long! Old fashioned tomatoes were shite I can testify (at least those available in the UK).
I grow heirloom tomatoes in the United States, and they are spectacular. The tomatoes available in the grocery store pale in comparison to anything grown in your own garden.
This probably has more to do with the fact that supermarket tomatoes are picked before they fully ripen on the vine (often green). I also enjoy growing my own (Brandywine is a favorite), and letting it ripen on-vine to the point where it's probably hours away from falling off or starting to rot results in a much better tasting tomato than jumping the gun.
My grandmother said the ones from the 20s in the us tasted way better, but they didn't keep any time at all, which was fine because they grew or raised all their own food.
same story here. she also said that it was commonplace for people to have plants that originated from seeds from 'the old world' and brought over; maybe they were at that point closer to some genetic cousin.
Thanks for that, very interesting. There used to be some fruitarian who said his bloodwork was all perfect eating primarily some ridiculous number of bananas each day. And his conclusion everyone should just eat fruit. Well he was burning over 10000 calories a day bicycling, I think he was a delivery rider and it was his hobby. That diet doesn't scale down to 2000 calories for the reasons you mention. I also wonder about all that potassium...
Do you have a source for the amount of calories we used to consume historically? Twice the calories means twice the food which means twice the bulk, twice the time to eat etc. My perception is that we were actually quite underfed historically.
What I heard was that some people have mutations that impair digestion (absorption requires some cellular machinery) or in other cases the utilization of B1.
Apparently the mechanisms for absorbing it depend on having sufficient B1, and can get "stuck" in a deficient mode if you went through a period of deficiency, which can then be "unblocked" (kickstarted) with a megadose.
Take this with a grain of salt, it's supposedly based in research, but I didn't check any papers about it yet.
Usually they're fortified with a low enough amount of vitamins that it prevents pellagra, beriberi, etc. Not necessarily enough to address other problems.
And if you aren't eating a lot of enriched flour you might not be consuming it in fortified foods at all.
I’ve said technically because most physicians would probably not recommend doing such a thing. However there are many case studies of its benefits using even 1800mg/day even though the RDA is 1.1mg.
I've had patients with sepsis standing up and talking to me, complaining about being tired and feeling woozy. And in the middle of a sentence they fall to the floor dead and we start CPR. Put the pads on them but never got a shockable rhythm after 45 minutes of high quality CPR.
> One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention.
Just in case people see "vitamin c", and think it's safe to use IV or high dose medicine for day to day supplementation.
These are septic people whose organs are shutting down. Don’t draw conclusions between what affects someone with profound organ damage and a healthy person.
> Promising results from an initial clinical trial at the Austin Hospital in Melbourne, published today in Critical Care, show that sodium ascorbate – a pH-balanced formulation of vitamin C – is effective in treating sepsis
> “In our trial at Austin Hospital, patients were given sodium ascorbate into their bloodstream, resulting in promising improvements to multiple organs.”
Oh boy, vitamin C is having a very strange year. First cancer, now sepsis.
It's the delivery method that is the difference, not just the dose. Vitamin C IV is pro-oxidant (promotes damage to mitochondria (cancers have famously messed up mitochondria already), etc) whereas Vitamin C that passes through the gut is anti-oxidant.
Sugar (like from a glucose infusion) can raise your blood pressure and low blood pressure is one metric for concluding it is sepsis. A quick search brings up one source that says antibiotics and other drugs are used, another that indicates IV fluid is also routinely used.
I don't understand the study, why they concluded this might help, what they think is going on with sepsis nor do I see any indication of how one would make a differential diagnosis of this sepsis patient might benefit from this, this other one might not.
I am happy to see that medicine is finally acknowledging that vitamin C in large doses is a thing with virtually 0 side effects. No wonder all living creatures make it in huge doses. Orthomolecular researches claimed this "discovery" decades ago. At least we didn't have to wait hundreds of years.
1 = https://ccforum.biomedcentral.com/articles/10.1186/s13054-02...