Vitamins C/E in Criticially Ill improve odds 40%

This forum will focus on analyzing recent clinical studies of vitamin C.

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ofonorow
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Vitamins C/E in Criticially Ill improve odds 40%

Post Number:#1  Post by ofonorow » Sun Mar 29, 2009 6:52 am

Randomized, Prospective Trial of Antioxidant Supplementation in Critically Ill Surgical Patients

Pubmed: http://www.ncbi.nlm.nih.gov/pubmed/1245 ... d_RVDocSum
[quote]
Nathens, Avery B. MD, MPH*; Neff, Margaret J. MD, MSc†; Jurkovich, Gregory J. MD*; Klotz, Patricia RN, BSN*; Farver, Katherine RD, CNSD*; Ruzinski, John T.†; Radella, Frank†; Garcia, Iris*; Maier, Ronald V. MD*
Issue:
Volume 236(6), December 2002, pp 814-822
Publication Type:
[Original Articles]
Publisher:
© 2002 Lippincott Williams & Wilkins, Inc.
Institution(s):
From the *Division of Trauma and General Surgery, Harborview Medical Center and the Department of Surgery, University of Washington,
and the †Division of Pulmonary Medicine and Critical Care, Harborview Medical Center, Seattle, Washington
Supported by grant R49/CCR002570 from the Centers for Disease Control and Prevention and a Surgical Infection Society Fellowship in Evaluative Sciences, supported by Wyeth-Ayerst Laboratories. Presented in part at the Annual Meeting of the Surgical Infection Society, Snowbird, Utah, May 2001.
Correspondence: Avery B. Nathens, MD, MPH, Harborview Medical Center, Box 359796, 325 9th Ave., Seattle, WA 98104-2499.
E-mail: anathens@u.washington.edu
Accepted for publication June 24, 2002.

Results: Five hundred ninety-five patients were enrolled and analyzed, 91% of whom were victims of trauma. The relative risk of pulmonary morbidity was 0.81 (95% confidence interval 0.60–1.1) in patients receiving antioxidant supplementation. Multiple organ failure was significantly less likely to occur in patients receiving antioxidants than in patients receiving standard care, with a relative risk of 0.43 (95% confidence interval 0.19–0.96). Patients randomized to antioxidant supplementation also had a shorter duration of mechanical ventilation and length of ICU stay.

Conclusions: The early administration of antioxidant supplementation using [alpha]-tocopherol and ascorbic acid reduces the incidence of organ failure and shortens ICU length of stay in this cohort of critically ill surgical patients
.
Owen R. Fonorow
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godsilove

Re: Vitamins C/E in Criticially Ill improve odds 40%

Post Number:#2  Post by godsilove » Sun Mar 29, 2009 7:40 am

There is an ongoing Canadian study (the REDOXS study) that is also looking at antioxidant and glutamine supplementation in clinically ill patients. Vitamin C will be given enterally at a 1500mg dose, rather than intravenously. The study is looking to enroll 2000 patients, and results are expected sometime this year, and if it replicates the findings of the 2002 study, it should prompt a change in the management of critically ill patients. The larger sample size allows the use of mortality as a primary endpoint.

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Re: Vitamins C/E in Criticially Ill improve odds 40%

Post Number:#3  Post by ofonorow » Mon Mar 30, 2009 4:14 am

Thank you for this update/report. I understand medical inertia to some extent, but what I find hard to understand is why medicine doesn't immediately begin giving ICU patients these antioxidants? What is the downside? The upside seems to be the chance of preserving organs in half the patients who would otherwise experience organ failure. I can understand the hesitancy w/r to prescription drugs, which are usually highly toxic, but antioxidants are at the other end of the spectrum. If it was a member of your family, wouldn't you want them to be getting the antioxidants?
Owen R. Fonorow
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American Scientist's Invention Could Prevent 350,000 Heart Bypass Operations a year

godsilove

Re: Vitamins C/E in Criticially Ill improve odds 40%

Post Number:#4  Post by godsilove » Mon Mar 30, 2009 1:04 pm

ofonorow wrote:Thank you for this update/report. I understand medical inertia to some extent, but what I find hard to understand is why medicine doesn't immediately begin giving ICU patients these antioxidants? What is the downside? The upside seems to be the chance of preserving organs in half the patients who would otherwise experience organ failure. I can understand the hesitancy w/r to prescription drugs, which are usually highly toxic, but antioxidants are at the other end of the spectrum. If it was a member of your family, wouldn't you want them to be getting the antioxidants?


It's a fair question, but do we really know for certain that the combination of antioxidants is safe in all ICU patients? Based on what we know from healthy patients, it probably is - but it doesn't hurt to have a larger trial to corroborate both the efficacy and safety findings. Sometimes an intervention that appears perfectly safe in a few hundred patients ends up having some rare side effects in a much larger trial.

Let's keep in mind that the incidence of myocardial infarctions for Vioxx in the controversial VIGOR study was 0.4% vs. 0.1% in placebo. The study had thousands of patients, but let's say a study was done on just 100 patients. The drug could have appeared to have no adverse effect on the incidence of MIs. I'm not saying this to imply that micronutrients are anything like rofecoxib in terms of safety - however, I don't think we can definitively extrapolate information for usage in healthy populations and say that it is perfectly safe to give them to patients who have undergone trauma.

That said, the practice of supplementing with antioxidants may already be in place - it may just be a question of how widespread it is. Certainly, a larger, positive study would make it more widely used than it currently is. I'm not sure if that data can be found anywhere - perhaps a survey would need to be done to see what is commonly being practised by ICU doctors. I looked at some guidelines for critical nutrition (link) and it appears that supplementing with antioxidants is already recommended. These guidelines are usually created by committees of experts that review and synthesize the relevant clinical literature and then give each recommendation a score based on the strength of the available evidence. The document relevant to antioxidants is here: http://www.criticalcarenutrition.com/do ... _FINAL.pdf

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Re: Vitamins C/E in Criticially Ill improve odds 40%

Post Number:#5  Post by ofonorow » Fri Apr 03, 2009 5:44 am

It's a fair question, but do we really know for certain that the combination of antioxidants is safe in all ICU patients? Based on what we know from healthy patients, it probably is - but it doesn't hurt to have a larger trial to corroborate both the efficacy and safety findings. Sometimes an intervention that appears perfectly safe in a few hundred patients ends up having some rare side effects in a much larger trial.


This is always the excuse given, that "larger" trials are necessary, when in fact larger trials are less scientific, primarily because they are harder (impossible) to replicate by other objective scientists.

In this case, the conditions are controlled better than any human study we might invent. ICU patients diets (lives for that matter) are under 24 hour observation and tightly controlled. (In my case, when I was having abdominal surgery, my wife sneaked me vitamin C which I added to my water, and I subsequently became my surgeon's poster boy for fast recovery. I tried to tell him later, but he was uninterested, to say the least. It is unlikely for the same thing to happen in the ICU.)
Owen R. Fonorow
HeartCURE.Info
American Scientist's Invention Could Prevent 350,000 Heart Bypass Operations a year

godsilove

Re: Vitamins C/E in Criticially Ill improve odds 40%

Post Number:#6  Post by godsilove » Fri Apr 03, 2009 1:19 pm

ofonorow wrote:
It's a fair question, but do we really know for certain that the combination of antioxidants is safe in all ICU patients? Based on what we know from healthy patients, it probably is - but it doesn't hurt to have a larger trial to corroborate both the efficacy and safety findings. Sometimes an intervention that appears perfectly safe in a few hundred patients ends up having some rare side effects in a much larger trial.


This is always the excuse given, that "larger" trials are necessary, when in fact larger trials are less scientific, primarily because they are harder (impossible) to replicate by other objective scientists.


A poorly designed, large trial may be less valid than a very well run small trial; nonetheless, larger trials that are well designed help to mitigate sampling error, effects due to chance, poor randomization, etc. They are also essential for finding small but clinically important differences that would not reach statistical significance in a smaller trial.

In this case, the conditions are controlled better than any human study we might invent. ICU patients diets (lives for that matter) are under 24 hour observation and tightly controlled. (In my case, when I was having abdominal surgery, my wife sneaked me vitamin C which I added to my water, and I subsequently became my surgeon's poster boy for fast recovery. I tried to tell him later, but he was uninterested, to say the least. It is unlikely for the same thing to happen in the ICU.)


Sure, you might be able to control what an ICU patient receives in the form of food or treatment. But then you're assuming that everyone in the trial will receive the same treatments; that's not true, and if you look at the study in the OP, patients with a wide variety of conditions were recruited for the study. The two groups in the study are quite homogenous in terms of baseline characteristics that were recorded, but you always run the risk of unaccounted for differences for the treatment groups when the study is small. For instance, I do not see things like smoking status/history being accounted for in the baseline characteristics of the two groups - chances are that the incidence should be the same in both groups due to randomization, but that is not always the case. Such differences could potential confound the results.

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Re: Vitamins C/E in Criticially Ill improve odds 40%

Post Number:#7  Post by ofonorow » Sat Apr 04, 2009 2:37 am

A poorly designed, large trial may be less valid than a very well run small trial; nonetheless, larger trials that are well designed help to mitigate sampling error, effects due to chance, poor randomization, etc. They are also essential for finding small but clinically important differences that would not reach statistical significance in a smaller trial.

This is the general argument used to justify larger trials, and in the case of prescription pharmaceuticals (i.e., highly toxic (toximolecular) substances) there may be some justification, but in general the argument is fallacious. At some value of N the statistical confidence reaches a high enough level that adding more subjects does not provide that much more useful information. But increasing the study size/cost does makes it harder to replicate and increases the chances for error and bias.

The following is, I believe, a profound quote on this very issue that I happen to agree with from Professor Hickey and Robert's book ASCORBATE: The Science of Vitamin C (lulu.com/ascorbate) After reviewing the basics of the scientific method, they write on page 34:

Large-scale double-blind mega-studies are the current fashion in medicine. The assumption is made that by increasing the number of subjects, the work somehow becomes more valid. Regrettably, these studies are borderline science, as a large scale study is difficult to repeat and replication is at the core of the scientific method. Of particular concern are those studies that are so expensive that only pharmaceutical companies are ever likely to perform them. The way studies are financed and the potential source of any experimental bias or error become more important with larger studies, as they are more difficult to replicate. Replication reduces the possibility of bias. A large-scale study giving positive results is less convincing than, say, three smaller, equally positive studies by independent researchers, in different institutions, separately funded and using dissimilar methods.


Sure, you might be able to control what an ICU patient receives in the form of food or treatment. But then you're assuming that everyone in the trial will receive the same treatments; that's not true, and if you look at the study in the OP, patients with a wide variety of conditions were recruited for the study. The two groups in the study are quite homogenous in terms of baseline characteristics that were recorded, but you always run the risk of unaccounted for differences for the treatment groups when the study is small. For instance, I do not see things like smoking status/history being accounted for in the baseline characteristics of the two groups - chances are that the incidence should be the same in both groups due to randomization, but that is not always the case. Such differences could potential confound the results.

The logical extension of this argument is that you should only study male smokers, age 50 who weight 150 to 190 lbs, etc. However, then you only know what affects 50-year-old males of medium weight, which means you don't really know anything. We are all biologically unique, and of course people in intensive care will vary across the board in almost all factors. Yes, they may be getting different drugs, so I suppose that creating subgroups on the basis of medications might be useful, but the test is whether innocuous antioxidants added to the normal ICU regimen helped, or hurt patients. The answer in at least 2 studies was yes - vitamin C and E reduced the average length of stay and reduced organ failure by almost half.

You sound like you don't trust these researchers, that you fear they would have somehow put all the smokers in the group that experienced organ failure.

I know the feeling about not trusting researchers. When science is conducted in accordance with the scientific method - is replicated as Hickey/Roberts discuss - the requirement to trust researchers is greatly diminished.
Owen R. Fonorow
HeartCURE.Info
American Scientist's Invention Could Prevent 350,000 Heart Bypass Operations a year

godsilove

Re: Vitamins C/E in Criticially Ill improve odds 40%

Post Number:#8  Post by godsilove » Sat Apr 04, 2009 10:38 am

ofonorow wrote:
A poorly designed, large trial may be less valid than a very well run small trial; nonetheless, larger trials that are well designed help to mitigate sampling error, effects due to chance, poor randomization, etc. They are also essential for finding small but clinically important differences that would not reach statistical significance in a smaller trial.

This is the general argument used to justify larger trials, and in the case of prescription pharmaceuticals (i.e., highly toxic (toximolecular) substances) there may be some justification, but in general the argument is fallacious. At some value of N the statistical confidence reaches a high enough level that adding more subjects does not provide that much more useful information. But increasing the study size/cost does makes it harder to replicate and increases the chances for error and bias.

The following is, I believe, a profound quote on this very issue that I happen to agree with from Professor Hickey and Robert's book ASCORBATE: The Science of Vitamin C (lulu.com/ascorbate) After reviewing the basics of the scientific method, they write on page 34:

Large-scale double-blind mega-studies are the current fashion in medicine. The assumption is made that by increasing the number of subjects, the work somehow becomes more valid. Regrettably, these studies are borderline science, as a large scale study is difficult to repeat and replication is at the core of the scientific method. Of particular concern are those studies that are so expensive that only pharmaceutical companies are ever likely to perform them. The way studies are financed and the potential source of any experimental bias or error become more important with larger studies, as they are more difficult to replicate. Replication reduces the possibility of bias. A large-scale study giving positive results is less convincing than, say, three smaller, equally positive studies by independent researchers, in different institutions, separately funded and using dissimilar methods.



I'm not sure how this applies in this case. A second trial is being run precisely in order to replicate the findings of the earlier trial. It just so happens that they have opted to enrol more patients - I do not see how this is undesirable, except in terms of cost. An added benefit is that it allows subgroup analyses to be performed that might not be possible with a smaller trial.

I'm not disagreeing that poorly-designed trials can be counterproductive - I'm just not seeing how this undermines the value of large trials that are well-designed. And I certainly don't see your point in this context, as the trial in question is looking to replicate the results of an earlier trial.

Sure, you might be able to control what an ICU patient receives in the form of food or treatment. But then you're assuming that everyone in the trial will receive the same treatments; that's not true, and if you look at the study in the OP, patients with a wide variety of conditions were recruited for the study. The two groups in the study are quite homogenous in terms of baseline characteristics that were recorded, but you always run the risk of unaccounted for differences for the treatment groups when the study is small. For instance, I do not see things like smoking status/history being accounted for in the baseline characteristics of the two groups - chances are that the incidence should be the same in both groups due to randomization, but that is not always the case. Such differences could potential confound the results.

The logical extension of this argument is that you should only study male smokers, age 50 who weight 150 to 190 lbs, etc. However, then you only know what affects 50-year-old males of medium weight, which means you don't really know anything. We are all biologically unique, and of course people in intensive care will vary across the board in almost all factors. Yes, they may be getting different drugs, so I suppose that creating subgroups on the basis of medications might be useful, but the test is whether innocuous antioxidants added to the normal ICU regimen helped, or hurt patients. The answer in at least 2 studies was yes - vitamin C and E reduced the average length of stay and reduced organ failure by almost half.


Well - that's precisely the conundrum. You could have a small trial where any effect could be down to differences in the two treatment groups, rather than the experimental intervention. So you could try to control these factors by enrolling patients of only specific characteristics - but that would then minimize the utility of the findings. The other option is to have a larger trial, where due to randomization any differences between the two treatment groups would be minimal. The larger the trial, the better the randomization - based on probability. It also allows the inclusion of more groups e.g. women that are often under-represented in smaller trials.

You sound like you don't trust these researchers, that you fear they would have somehow put all the smokers in the group that experienced organ failure.


I in no way am trying to undermine the integrity of the researchers or the validity of their findings. Based on what I've seen, I think the evidence does support supplementation with antioxidants at the doses studied. I'm just pointing out that a trial that confirms these findings is a good thing - a positive finding would increase the strength of the recommendation in guidelines, and could make their use more widespread (as I pointed out earlier, I have no way of knowing how widespread the use currently is).

Smoking status is just an example - it could be one of many factors that are unaccounted for. I'm not implying that the researchers did anything shady; smokers could be more abundant in one group than another simply by chance - small as it may be. When you flip a coin ten times, the probability of there being more heads than tails is still fairly high. When you do it a hundred times the probability is lower. When you do it a thousand times, the probability is even lower.

Likewise, if you take 100 people and randomly allocate them to two different groups, it is likely that you will have roughly equal proportions of men, people over 50, smokers, people whose favourite color is blue, etc in both groups. But differences between the two groups will exist simply by chance. For instance, the number of people who supplement with Vitamin C or who can wiggle their ears might be different in both groups. The larger the number of people, the lower the chance of finding differences between the two groups.

I know the feeling about not trusting researchers. When science is conducted in accordance with the scientific method - is replicated as Hickey/Roberts discuss - the requirement to trust researchers is greatly diminished.


Again, this has nothing to do with a lack of trust in the researchers. To the contrary, I'm simply pointing out that a second study will be in concordance with the scientific method, by presumably validating the findings of the earlier study.

As I said before, I do not see the downside here - except in terms of the cost of running the trial, which presumably my tax dollars have gone towards. (i) A positive finding would strengthen the validity of the earlier study. (ii) A larger amount of data would allow us to identify groups of patients that might have an increased or decreased benefit from antioxidant supplementation. (iii) The practice of antioxidant supplementation already appears to be a part of critical care nutrition guidelines - a positive finding would simply increase the strength of the recommendation. (iv) the study is also going to look at the effect of glutamine supplementation.

I just don't understand why you seem to be against this second study. The protocol has already been published - so perhaps you're anticipating a negative outcome due to the design of the study. I have not looked into in detail, but I don't see any red flags.

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Re: Vitamins C/E in Criticially Ill improve odds 40%

Post Number:#9  Post by ofonorow » Sun Apr 05, 2009 10:34 am

I am not against the second (or other) studies to confirm the work, in fact, this should be the norm, not the exception. I just think you are making this far too complicated. My initial comment regarding how tightly controlled (and thus useful) an ICU study is had to do with knowing that the patients in the control group weren't getting vitamin C. This is a problem with most non-prescription (nutritional) studies because people can purchase vitamin C and E on their own, and they have to be on their honor not to, especially when studies are of low dosages of vitamins.

The study size is necessary to provide confidence that what was observed was not a fluke, due to chance. Make the study larger, fine, and please, have them provide even more antioxidants to the study group!

In the non-ICU studies, when two groups - vitamins and placebo - appear to be responding the same, (or placebo better!) it may be because the placebo group is obtaining the nutrient. Again, in the case of the ICU, we are as confident as you can be in human studies that the control group was not receiving antioxidants, and again, the difference between the two groups was important. (I remember one study in JAMA that was published because "Chelation Therapy showed no improvement over Placebo". However, the researchers had used vitamin C/magnesium IV in the placebo group, and BOTH groups had increased their treadmill time by important amounts, more than I could find for any drug. It makes interesting reading, especially if you study the data and ignore the author's conclusions:

JAMA STUDY: [color=#400040] JAMA Jan 23/30 2002 RANDOMIZED, DOUBLE-BLIND CONTROLLED TRIAL IN HUMANS FOUND STATISTICALLY SIGNIFICANT 60-SECOND TREADMILL EXERCISE IMPROVEMENTS IN 5000 MG VITAMIN C GROUPS [Chelation Therapy for Ischemic Heart Disease: A Randomized Controlled Trial, Knudtson, et. al. JAMA, Jan 23/30, 2002 - Vol 287, No 4. Pp 481-486]

)

You say you are in Canada, and I am happy to hear that you believe adding antioxidants are approved/becoming more common, but they are definitely not in the USA, with rare exceptions. I hope this is changing, but I have at least 3 experiences of relatives going into ICU during the past 3 years - no additional antioxidants were given.

As far as the second study, again considering the safety, why not double the dosages of the antioxidants/vitamins and see whether even better results are obtained.[/color]
Owen R. Fonorow
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American Scientist's Invention Could Prevent 350,000 Heart Bypass Operations a year


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