Wednesday, May 6, 2020

Vitamin C: too little too late?

There is always a low enough dose given late enough to show no effect whatsoever.

Dr. Fowler research group finished their phase II trial of intravenous vitamin C for sepsis (CITRIS-ALI) last year. Since they hadn't preselected mortality as main outcome the reduction in mortality cannot be asserted as proven in the statu quo mind. It seems there could have been bureaucracy reasons behind not including it as main measure as pointed out by Dr. Farkas. Let's make clear two things:
So, proof shouldn't be used at all in most of medicine literature. Instead we should be talking about enough clues to suspect an overall benefit, that is, we should be talking about benefit/risk analysis and certainly 5% is no magical number at all in that conversation. I have to point out that I side with Fisher's interpretation of the p-value as a measure of how strong the evidence favoring the hypothesis is, and not with Neyman's one (the prevalent one) where it doesn't matter how much lower than 5% a computed p-value is and where a p-value of 5.01% is deemed statistically insignificant. I will dig deeper on this at the following section.

At the other hand, just some months after Dr. Fowler's group results, those of the VITAMINS trial were published. Instead of focusing on Dr. Fowler's approach it studied Dr. Marik's miscellaneous approach. Dr. Marik studied the efficacy of a mixed treatment including vitamin C, hydrocortisone and thiamine (vitamin B1) on sepsis with a historical control group instead of a concurrent randomized one. VITAMINS trial was a randomized trial instead that studied the combined treatment against hydrocortisone alone. There are some people saying that it falsifies vitamin C efficacy and any tentative hypothesis from CITRIS-ALI. This is false.


Mortality as THE objective main measure


Should we discard mortality results as THE most important measure conceivable within a clinical trial where deaths are expected? Certainly it is my opinion that it must not be, as I have focused always on it alone beforehand and I have clearly stated that focusing on soft outcomes is NOT a good idea even when it came from Linus Pauling.

Mortality being the main objective measure of any clinical trial with expected deaths means that we should evaluate the strength of a trial results on it using Fisher's approach. It REALLY matters where that p-value stands by itself without no comparison whatsoever with any α-value (Neyman's approach, usually with α=5%) and without requiring taking any look at any other measure at all. Not so strongly worded there are those expressing similar preoccupation:
'there is something disquieting to me about this business, that whether a result for an important endpoint like mortality is considered “significant” or “not significant” based partly on how many other outcomes the authors decided to consider.'
In my view mortality should come first and alone and anything else is just methodolatry where secondary measures are given bureaucratic importance that they don't deserve at all. Just ask a patient if after a treatment they prefer either to still be alive or just in the case of still being alive to have arrived to a better whatever score. I am not alone on this either:
"As a patient, I probably don’t care that much if my SOFA score improved, I care whether I walked out of the hospital alive."
That's the difference between aseptic mathematics where Neyman's approach gives rise to very consistent and clear hypothesis testing even in the presence of multiple comparisons and the dirty reality where mortality objectively rules over anything else to be measured and Fisher's approach (while not as amenable to a multiple comparison adjustment) gives us a reasonable measure of strength of the evidence favoring effectiveness of treatment on THE objective main measure through its p-value and corresponding conditional posterior probability type I error α(p).

Paradoxically the statu quo actually uses the mortality as main objective measure as such in any posterior meta-analysis focused on mortality without any multiple comparison adjustment whatsoever.


Mortality in CITRIS-ALI


As I have stated beforehand I think it is not defensible at all to study an intravenous vitamin C intervention lower than 3g/day for less than 5 days. Of course even this dose timing and duration given too late is not going to do a thing.

Vitamin C plasma level in CITRIS-ALI patients (Figure 2A from Fowler et alter 2019)

We see how something like 16 g of vitamin C each day (dose for a 80 kg person, approximate average weight in the VITAMINS trial) doesn't get all of the patients over the marginally deficient level of 28 μM pointed out by Fowler et alter at day 4. By day 7 we see how three quarters of those receiving treatment are below the kidneys reabsorption level (70 μM) and more than a quarter are already marginally deficient. Ideally treatment should be given for as many days as needed until the patient is cured. Not what we see in actual randomized control trials. Of course at the current state of things, we should take a closer look at mortality at treatment end point. Of course we can take a look at mortality in following days in order to discard a possible delayed toxic effect from vitamin C.

In the case of CITRIS-ALI vitamin C was given intravenously for 4 days in the intervention arm. They measured mortality for the 28 first days after beginning the trial. So I am going to point out mortality from enrollment in the trial until the 4th day was completed and from this point forward until the last of the 28 days.


Mortality in CITRIS-ALI both during treatment and afterwards
Days 1–4 Days 5–28
Vitamin C Placebo Vitamin C Placebo
Initial patients 84 83 80 64
Deaths 4 19 21 19
Mortality 4.8% 23% 26% 30%
p value 0.068% 65%
α(p)≥ 1.3% 43%

We see how mortality is clearly different in the vitamin C group during treatment duration with the posterior conditional probability of sheer chance giving rise to these results being 1.3% or greater. Even a more classical interpretation à la Neyman with multiple comparison with Bonferroni correction (dividing α by the number of measures, 49 specified in the CITRIS-ALI trial plus the two pinpointed out by Dr. Fowler at LIVES 2019 conference) give rise to a statistically significant result:
0.068% < 5%/51 = 0.098%.
Since these two measures have been added after trial completion, perhaps it could be more correct (not that any post hoc selection of α agrees with Neyman's view) to say that it is statistically significant at the 5%•(1+1/50+1/51)=5.2% level.

We also can see how mortality is not clearly different after treatment completion (days 5 to 28) but without any sign of worst outcome due to delayed vitamin C toxicity.

In the face of these results any critical mind would apply the intravenous vitamin C treatment for 4 days at least to any septic patient with a low enough probability of side effects while awaiting for other randomized trials to settle the lingering doubts due to researches not including mortality as main outcome in CITRIS-ALI trial.


CITRIS-ALI versus VITAMINS versus Zabet et al. (2016)


First I will point out the main characteristics of these three randomized trials on critical ill septic patients, where treatment is not applied until severe complication of sepsis such as either acute respiratory failure or septic shock is ascertained:

CITRIS-ALI VITAMINS Zabet et al.
Blinding double-blind open label double-blind
Patients selection acute respiratory failure in sepsis ICU (70% septic shock) septic shock septic shock after gastrointestinal surgery
Number of patients 84+83 105+101 14+14
Treatment vitamin C vitamin C, hydrocortisone plus thiamine vitamin C



Control group placebo hydrocortisone placebo
Corticosteroid use 66% 100% 0% (exclusion criteria)
Vitamin C dose 50 mg/kg every 6 hours 1.5 g every 6 hours 25 mg/kg every 6 hours
16 g/day for 80 kg person 6 g/day 8 g/day for 80 kg person
Treatment duration specified 4 days max. 10 days 3 days
Actual treatment duration ~4 days 3.4±2.1 days (average ± standard deviation) ~3 days
Total vitamin C dose ~64 g for 80 kg person 23.8±14.7 g ~32 g for 80 kg person
Mortality at end point 29.8% vs 46.3%, p=0.03 22.6% vs 20.4%, p=0.69 14.28% vs 64.28%, p=0.009

Why treatment in VITAMINS was applied in average only half the time prespecified? The treatment was interrupted for three reasons:
  • Cessation of vasopressor administration, that is, septic shock resolution "of the initial septic shock" (was there any relapse?).
  • Discharge from the ICU,
  • 10 days of treatment.
These and the number of patients being given vasopressors (treatment of septic shock) in VITAMINS let us know more or less how many patients received treatment each day.


By day 3 only half of them. By day 4 only a third. It is not clear to me how many of the deaths happened after treatment was withdrawn.

Although in CITRIS-ALI corticosteroids weren't included in the protocol, something like 66% of all the patients received them during the study in an unspecified dose. These all being said I think it should be cristal clear that CITRIS-ALI used a superior study design (double blind instead of open-label) that was followed more thoroughly (until ICU discharge instead of initial septic shock resolution) and with a clear intervention to judge vitamin C effectiveness. VITAMINS could only conclude that vitamin C and hydrocortisone effects are not synergistic at most (as pointed out by Dr. Carr too). Although being smaller, Zabet et alter double-blind study supports either this conclusion (it used no corticosteroids) or that time to intervention really matters.

We don't know how much time was wasted in Zabet et alter until beginning intervention but we can speculate that it must have been lower than the median value of 12.1 hours with interquartile range of 5.7–19.0 hours in VITAMINS, that is, almost three quarters of patients in VITAMINS awaited more than 6 hours for the first dose of vitamin C after eligibility criteria were met. As pointed out by several Dr. Marik's colleagues at Critical Care Reviews 2020 this time in the rest of interventions presented on the conference seems to have been limited to 6 hours. Neither Dr. Marik's paper on his non randomized study nor Dr. Fowler's one on his randomized one specifies the distribution of this time to first dose either. Nevertheless we have very interesting  results on 28 day mortality of the study by Ping et alter (2020), a partially single-blind (placebo used only on 12 of 40 patients in the control group) randomized study replicating Dr. Marik's 4 days intervention on septic patients:
  • "there was no difference in mortality between the treatment and control groups [relative risk (RR), 0.79; 95% confidence interval (CI), 0.41 to 1.52; p = 0.47]", but
  • "the subgroup diagnosed with sepsis within 48 h at ICU admission showed an improvement in mortality in the treatment group (13.6% vs.47.6%; RR,
    0.29; 95% CI, 0.09 to 0.90; p = 0.02)".
Either way it seems to me that delaying treatment until the patient is severely ill and then applying a meager dose is NOT justified at all. The meager dose is certainly Dr. Marik's fault.


Conclusion: too much too soon?


Let's remember the dose of vitamin C used by Dr. Klenner on a severe case of sepsis:
"In another case, using 1200 mg. per Kg. of body weight the first 12 hours, in divided doses, and 600 mg. per Kg. body weight in subsequent 24-hour periods, in divided doses, a patient with advanced puerperal sepsis following a criminal abortion was returned to normal in 9 hours. Penicillin, sulfadiazine and I.V. Achromycin were also employed. The rapidity in which the pathology was reversed can hardly be attributed to these other antibiotics alone. This patient entered the hospital with 105.4° F. and in 9 hours it was 98.6° F. and remained so throughout the uneventful hospital stay."
That would be 72 g for a 60 kg woman in the first 12  hours, 36 g/day from there on.

Let's remember de higher dose of vitamin C used by Dr. Mao at Ruijing Hospital in a patient of COVID-19 "deteriorating rapidly":
"He gave a bolus of 50,000 mg Vit C IV over a period of 4 hours. They watched the patient’s pulmonary (oxygenation index) status stabilizing and improving in real-time. "
Let's remember the dose used in Allan Smith just to make his family at ease before disconnecting life support: 50 g in about 12 hours.

Let's remember the oral dose taken by those following Dr. Cathcart's titrating to bowel tolerance method for a severe flu: ~140 g/day.

Let those who have eyes see.


If your kidney function is correct, you don't have a big oxalate intake and you don't have fat malabsorption (Spanish blog post with links discussing oxalate nephropathy associated with vitamin C consumption), what will happen if you take generous doses of vitamin C by yourself at first symptoms of a suspected viral infection including  SARS-CoV-2?:
  1. If the vitamin C efficacy is finally just noise, you would have spent a little money for nothing.
  2. If the intravenous vitamin C efficacy is real perhaps generous dose of oral vitamin C taken early will have had a positive effect.
What happens if instead you don't take vitamin C?:
  1. You have saved some money.
  2. Perhaps you will fare worse than if you would have taken it.
Your choice. Good luck anyway.

Saturday, March 21, 2020

COVID-19: vitamina C; hyperinsulinemia; others.

Simply for collecting interesting things, in my opinion, about COVID-19, for those who don't mind wasting their time reading unreliable misinformation.

Of course chloroquine seems to be a good hospital treatment at least, but I am not going to deal with any xenobiotic substance here.


Vitamin C



I have already commented on the work of Dr. Fowler's group on its effect in the case of sepsis:
  • Main mechanism of action identified with in vitro and mice study in 2013: high dose of vitamin C prevents the last desperate kamikaze broadside of neutrophils, the formation of the extracellular trap, causing the lung damage that led to the death of all mice in the control group (0 survivors out of 7) by 3 deaths of those treated with vitamin C (4 survivors out of 7); the probability of obtaining this result or more extreme (more survivors in the treated group, that is, one-sided test) by pure chance is 0.17%. This extracellular neutrophil trap is observed in the lungs of patients with acute respiratory distress syndrome.
    Figure 7 from Fowler et alter (2013) showing in vitro inhibition by vitamin C (C and F) of the extracellular neutrophil trap (B and E)
  • Phase I randomized trial in severe sepsis patients, with a placebo group of 8 patients and two intervention groups for 4 days, one with 8 patients and a dose of 50 mg/kg/24 h, and another with 8 patients and a dose of 200 mg/kg/24 h. Mortality at 28 days (yes, 24 days after finishing the treatment), was 62.5% in the placebo group and 44.4% in the treatment groups: the probability of giving the same or more favourable result for the randomised treatment groups is 14.6%.
There I commented on the phase II multicenter trial that had been initiated... for which we already have results:
  • A dose of 50mg/kg/6 h (about 3.5g every 6 hours for a 70kg patient) of vitamin C for 4 days.
  • The main measures of the trial (the truly important ones) did not improve with respect to the placebo: neither at 4 days the evaluation score of organ failure related to sepsis (improvement of 3 points in the group under vitamin C, 3.5 in the group under placebo, p=0.9 (all of the p-values from two-sided tests if not stated otherwise), on the one hand, nor at 7 days the levels of C-reactive protein (54.1 vs 46.1 μg/mL, p=0.33) and thrombomodulin (14.5 vs 13.8 ng/mL, p=0.7), on the other.
There was a slight improvement when measured in terms of total fillers, such as mortality after 24 days of treatment, of 29.8% in the group with vitamin C compared to 46.3% in the group with placebo (p=0.03).
Figure 3 from Fowler et alter (2019)

The incredible p-value drop. Source: Jiajia et alter0 (2020) (via George Henderson)

What about mortality after 4 days (duration of treatment)?: although some innocent minds might think that the initial benefit of vitamin C —dropping to a mortality of about 4% (4?/84) from about 27% (22? /83) from the placebo (p=0'0001)— should persist if the treatment would be continued beyond 4 days, the high toxicity of vitamin C (🙄) makes it totally unadvisable to prolong it, so it is a spurious result that is totally ignorable and dispensable. That the main measures have not improved (because fewer severe patients died on the treatment group) clearly supports such a result.

[BEGIN added section on 4/22/2020]

Dr. Fowler's presentation on his CITRIS-ALI trial (on sepsis patients who have developed acute respiratory failure) commenting upon mortality results:
 

CITRIS-ALI mortality and ICU graduadion at treatment end point
Dr. Fowler reports on some out-of-protocol measures:
  • Deaths at 4 days (treatment end point): 19/83 in those under placebo, 4/84 in those under treatment, p=0.00068=0.068%.
  • ICU graduates at 4 days (treatment end point): 1/83 in those under placebo, 9/84 in those under treatment, p=0.0096.

Bonferroni multiple comparison correction with these two measures added to the 49 measures stated at the paper (3 main outcome measures and 46 secondary ones): 5%/51=0.05/51=0.00098=0.098%. Even disregarding mortality at treatment end point as an objective main measure by itself, it is still statistically significant* (0.068%<0.098% —it still would have been statistically significant with 73 total measures) except when you think that selecting mortality at treatment end point is fishing within an unlimited set of irrelevant outcomes (without reporting doing it) to get a "statistically significant" one by pure chance alone.

It is important to point out that p-hacking consists of checking as much measures as needed to get a "statistically significant" one with p<0.05: you don't make any multiple comparison correction or even further if you don't report that all those measures have been checked at all. Adding a given number of measures and checking for statistically significant ones with p<0.05/n is NOT p-hacking at all: the family-wise error rate is still 0.05 at most*. Moreover, it must be my medical ignorance but I cannot think of any other important measure to a potential patient than mortality at treatment end point. I think disregarding this result is simple cult of methodolatry. My opinion.

Taking a look at Table 2 of Fowler et alter  (2019), it boggles the mind why mortality at 96 hours wasn't included too. Perhaps the reason is related to Dr. Farkas perception:
This is pure speculation, but my guess is that the CRP and thrombomodulin endpoints were added primarily to obtain the NIH grant (they’re unusual primary endpoints to choose in a multi-center clinical trial).

[END added section]

[Added on 4/24/2020 and edited on 4/25/2020] *Actually, adding them after Bonferroni correction of 49 previous on-protocol measures it still would be statistically significant at the 5'2% level at most —5%•(1+1/50+1/51)—, that is, adding two measures more would imply a slightly larger family-wise error rate.

Some will not wait for the results (expected date 9/30/2020), including medical staff who follow the Shanghai protocol. Moreover, three days ago Dr. Cheng summarized for us (video) the preliminary results of Dr. Mao treating at Ruijing Hospital in Shanghai approximately 50 moderate (10g per day) to severe (20g) cases for 7–10 days: all recovered. In one severe case the patient was injected 50g in 4 hours, with clear improvement in that time.

However, it is interesting to look at some of the previous (inconclusive) evidence that was available before Fowler's group's multicenter phase II randomized trial to appreciate the speed with which unpatentable substances are studied (other technical factors were presumably at play too):
  • First anecdotal case of respiratory complication in pneumonia (cyanotic) treated by Dr. Klenner with intramuscular vitamin C, at home, with improvement at half an hour: 1943 (a simple count, from the year of publication of Klenner's and Fowler's results: 2019-1953=66 years).
  • Dr. Cathcart's clinical experience with oral vitamin C, published in 1981.
  • In 2009 Allan Smith was going to be disconnected from life support after his swine flu complications: a doctor, at the insistence of the relatives and for leaving them at ease before disconnecting him, agreed to give him intravenous vitamin C, 50g twice. He got better (actually because a bus passed by). They lowered the dose. The relatives ended up giving him vitamin C encapsulated in liposomes as soon as he was able to swallow.

If you are considering joining the group of those of us who saturate in vitamin C in the face of colds, flus and other suspected viruses, as in the case of COVID-19, remember that the serious complication of ingesting vitamin C in high doses (apart from genetic deficiency of the enzyme G6PD, where even at the Riordan clinic they have put intravenous treatment with 25g of vitamin C), oxalate nephropathy, is only documented to occur in situations such as dehydration, previous kidney transplant, fat malabsorption (by medication or after bariatric surgery, among others) or kidney failure (Spanish blog with all the links).


If you are encouraged to try, how do you proceed with sodium ascorbate powder?
  • At least let 2 hours pass from last food intake, in order to take advantage of it.
  • Mix one level tea spoon (something like 4000mg of vitamin C) in a glass of water.
  • After 1/2 hour to 1 hour, if you have not saturated go to point 2.
  • Space out doses when you return to take vitamin C after a few hours.

Don't forget drinking plenty of liquids.

If you proceed with vitamin C tablets, and if the symptoms are acute, take 1 every 5 minutes with plenty of water.

How will we know that we have saturated: sodium ascorbate no longer absorbed → retains water in the intestines → roar of guts or mild diarrhea (no cramps). The necessary dose will depend on the disease, as already checked by Dr. Cathcart.


Where can you buy vitamin C? Here are some of the shops on the Internet selling sodium ascorbate:
I would ask at your bakery too if the need arises.

If you get better, when will you know if vitamin C is likely to have contributed to it and not simply because you were going to get better anyway?: hopefully in October this year. Why bother then and take it now: just in case it is going to be effective as the injectable one is in the case of sepsis. Yes, you have to make a decision in the face of incomplete information: there is no certainty that you will make the right one. Personally, the risk-benefit analysis supports saturating yourself with vitamin C at the first signs of a suspected viral infection. By now it's a question of credibility (no, I'm not talking about Linus Pauling), and for the moment the late doctors Klenner and Cathcart have it for me as long as their hypotheses are not falsified: the effectiveness of high-dose intravenous vitamin C on the one hand and oral vitamin C to saturation on the other, in keeping you alive and speeding up your healing from a viral infection. Dr Levy (a cardiologist) also has it with respect to vitamin C encapsulated in liposomes for the above-mentioned viral infections.


In case someone goes the route of vitamin C encapsulated in liposomes, it could be that taking 4–6g two or three times a day (half an hour before meals) is enough. Stores and brands, e.g. Altrient, California Gold Nutrition or Aurora.


Hyperinsulinemia



In the Chinese report published a few days ago on COVID-19 (via Henry Lahore), the higher than average mortality (2.6%) was noted in those patients with some previous diseases, all associated with insulin resistance and its hyperinsulinemia (high blood insulin):

However, it could also be that the comparison with the average mortality rate does not take into account age (higher mortality in older people who are more likely to have one of these chronic diseases): we will have to wait for a future paper.


If it is ultimately true that COVID-19 is more severe in hyperinsulinaemia (according to Petro's hypothesis because the virus would take advantage of the higher amount of insulin to replicate more quickly) then it would have made sense to try to reduce this state of excess insulin:

Risk/benefit analysis of the three: no risk, possible benefit.



Others



Any further action to consider, even if it is more speculative (or not) than the previous ones.



Fever



Dr. Chan Kan Ping's hypothesis is that the 2002 coronavirus, SARS-CoV, may be sensitive to high body temperature. It simply doesn't make sense to reduce fever with antipyretics, and more so if it does not even rise above 40°C. As George Henderson points out, it is not wise to take paracetamol for viral infection when the available data, in animals infected with flu, indicate higher mortality. The widespread use of antipyretics, shielded by the stupid "treat the discomfort", is only understundable in mild disease, by inertia and by giving satisfaction to the impulse to act and do something... if it leads you to the use of antipyretics during COVID-19 be aware that you will be making an even potentially worse decision than the use of homeopathy.


Vitamin D


I personally see vitamin D more as a background treatment, not as an acute measure. Even so, if you haven't worried about maintaining good levels during the fall/winter, you can supplement, perhaps first days with higher dose.

As a matter of fact, good levels of vitamin D could reduce the likelihood of the serious complication (via Ana), acute respiratory distress syndrome.



Selenium



This connection, pointed out by George Henderson, is not really workable, but I put it in here for completeness. It seems that, like the flu virus, SARS-CoV-2 would mutate more rapidly in the face of selenium deficiency. Unworkable because we would have to guarantee selenium sufficiency for everyone.


I have used www.DeepL.com/Translator but edited it afterwards. So, anything wrong is my fault.