Ascorbic acid or vitamin C is a known antioxidant. Clinicians have conducted numerous studies to discover its role and effectiveness on life-threatening diseases such as sepsis, acute respiratory distress syndrome (ARDS), cancer and COVID-19.
Dr Alpha 'Berry' Fowler joins us in this episode to share his work on vitamin C and its role in improving the survival of critically ill patients. He also talks about ongoing trials on vitamin C and its possible benefits on COVID patients.
If you want to know more about the research backing up the success of vitamin C in disease treatment, then this episode is for you.
Here are three reasons why you should listen to the full episode: Learn the mechanism of sepsis in lung disease. Discover the role of vitamin C in treating patients with sepsis and ARDS. Find out more about past and ongoing trials on vitamin C.
Resources Learn about Dr Fowler's Phase 1 safety trial of IV vitamin C in patients with severe sepsis. Explanation lecture of the CITRIS-ALI study by Dr Fowler JAMA publication on CITRIS-ALI Article on the sequential organ failure assessment (SOFA) scores and mortality of patients involved in the CITRIS-ALI trials Dr Paul Marik's protocol for sepsis using vitamin C and steroids
Episode Highlights [04:02] How Dr Fowler's Research on Bacterial Sepsis Began Dr Fowler started working on mouse models to investigate sepsis. A solution made from mouse pellets was injected into ten mice, five of which received a treatment of vitamin C. The septic mice in the control group all died while those treated with vitamin C were crawling around, drinking water and eating. Dr Fowler then started using animal models to determine how vitamin C treats sepsis. [09:05] How Sepsis Damages the Lungs In sepsis, the lung barrier is injured. The progression of sepsis traps activated neutrophils in the capillary space of the lungs. Activated neutrophils release their DNA and enzymes, damaging the capillaries. Plasma then fills the air spaces, causing the patient to drown in their fluid. [09:34] The Role of Vitamin C in a Septic Lung In vitamin C-treated mice, the lung’s barrier function is preserved. Vitamin C stops neutrophils from disgorging their DNA into the extracellular space. Free DNA has become a marker to predict mortality. Blood reanalysis showed vitamin C lowered free DNA circulation as a result. Vitamin C completely inhibits the expression and appearance of inflammatory proteins. [16:15] Phase 1 Safety Trial Outcomes In a randomised, blinded trial, 24 patients were enrolled to determine the safety of vitamin C. Organ failure score was tracked in all patients. The higher the score, the higher the incidence of mortality. Patients treated with vitamin C saw a dramatic and significant reduction in their organ failure score. Vitamin C also improved their chance of survival. Intermittent infusion of vitamin C every 6 hours could get the plasma level up to 3000 times the normal level. [25:47] Phase 2 Proof-of-Concept Trial Outcomes Patients enrolled in the study had septic ARDS. The vitamin C treatment resulted in no adverse event. After 96 hours, 19 of 83 placebo patients died while only 4 of 84 patients with vitamin C died. Upon follow-up after 28 days, 46% of placebo patients died while only 30% of treatment patients died. This was the first blinded trial to show vitamin C’s impact on the mortality of patients with ARDS. [28:17] Explaining the Inconsistency of the SOFA Score Jean-Louis Vincent created the SOFA score. Jean-Louis Vincent sent a letter to the editors of Dr Fowler's work that the data was incorrectly analysed. Reanalysis showed the patients who died had the top SOFA score. Vitamin C significantly impacted organ failure scores. Vitamin C treatment resulted in a significant number of ICU-free days, improved mortality and more hospital-free days at day 60. [36:05] Is There Another Trial Underway? The NIH tasked the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network to turn towards COVID treatment. Dr Fowler started a trial on vitamin C as a treatment for patients with early COVID pneumonia, and the results are dramatic. There is another trial for sepsis and vitamin C planned by the PETAL Network involving 1000 patients across 69 medical centres. [39:48] Why Larger Doses of Vitamin C Are Not Administered The primary concern for higher doses of vitamin C is the formation of renal stones. A safety trial is first recommended before vitamin C treatment for COVID pneumonia can begin.
7 Powerful Quotes from This Episode
‘The cage that the mice got the sepsis and the vitamin C, they were all crawling around, drinking water and eating. And I knew at that point that we had stumbled on something pretty significant’.
‘One of the first things we found was that the lungs of the treated mice that were septic, they weren’t injured’.
‘Most people understand sepsis as being a bacterial infection, but they don't understand that it's actually taking all the organs and causing oxidative damage to multiple organs, not just the lungs’.
‘We had kind of a basic grasp on the immune system and how vitamin C could alter the septic immune response and how vitamin C could protect the lung’.
‘Vitamin C was actually improving the possibility of survival’.
‘The amount of vitamin C that you administer is critical. Dose matters’.
‘You’re going to save not only thousands and eventually more — hundreds and thousands of lives. You’re going to reduce hospital bills enormously’.
About Dr Fowler
In his 35 years of service at VCU, Alpha A. ‘Berry’ Fowler, M.D., Professor of Medicine and Director, VCU Johnson Center for Critical Care and Pulmonary Research, has had a profound influence at VCU and beyond. Considering his robust grant support and over 300 publications and abstracts in clinical areas including adult respiratory distress syndrome (ARDS) and sepsis, he might well be lauded for that alone.
Likewise, with over 16 years as Pulmonary Disease and Critical Care Medicine (PDCCM) Division Chair, with numerous ‘Top Doc’ awards and other honours, his pursuit of excellence in clinical care, impacting thousands of patients and their families, might well be the highlight of most careers.
To learn more about Dr Fowler’s research on vitamin C, you may contact him at 804-828-9071 or send a message to alpha.fowler@vcuhealth.org.
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To pushing the limits,
Lisa
Welcome to Pushing the Limits, the show that helps you reach your full potential with your host Lisa Tamati, brought to you by lisatamati.com.
Lisa Tamati: Hi everyone and welcome to Pushing the Limits. This week I have an exciting interview with intensive care medicine doctor, Dr Berry Fowler, who is an intensivist from the Virginia Commonwealth University. The director of the VCU unit via 35 years of service at the VCU Johnson Center for Critical Care and Pulmonary Research. And he's also the author of a number of studies around vitamin C.
So today we're continuing that conversation that we've been having in the last few weeks around the importance of vitamin C. Last week, we had Professor Margreet Vissers on, from Otago University, talking about—who worked with vitamin C in cancer. She's been studying this for 20 years. And Dr Berry Fowler has been studying vitamin C in regards to sepsis and pneumonia and how to use it in COVID. And he's been researching in this area with vitamin C for over 15 years. So some really amazing insights into this incredible vitamin and how it can help with all of these things. So please don't miss this episode.
If you enjoy the content, please share it with your family and friends. You know, there’s some important messages that we're wanting to get out in this vitamin C thing that I've been doing, because I lost my father recently and this would have been a major player and I was desperate to get him help with intravenous vitamin C, and I was unable to until way too late. And so I'm desperately wanting to get out the information about this research about the clinical studies that have been done, the research that's been done, to share this really important information.
As always, I really appreciate a rating or review for the show. If you can do that, that'd be so so appreciated. And if you've got any questions, please email me at support@lisa tamati.com, if you want to discuss anything that was brought up in these topics, in this podcast. I'm also doing some one on one consultations. I have a limited number of spaces available for people who are wanting to work with me one on one. If you are facing difficulties in areas from whether it be around some of your health aspects like head injuries, obviously I've spent five years researching head injuries. I have a lot of knowledge around vitamin C. I have a lot of knowledge around biohacking, around epigenetics trained as an epigenetics coach, gene testing, and so on. And I work with a very small number of people who are needing help with these areas. As well as of course run coaching and mindset in high performance. So if you're wanting to get some one on one support with me, please reach out to me it's lisa@lisatamati.com. And I can send you the information there.
Right over to the show now with Dr Barry fellow who is sitting in Virginia in the USA. Well welcome everybody to Pushing the Limits. This week. I have a very special interview continuing our series around intravenous vitamin C or vitamin C in general. I have Dr Barry Fowler with me, who is sitting in Virginia and Dr Fowler has agreed to come and have a little chat today about his work in this area. Dr Fowler, I've done a wonderful extra introduction. So we won't go into all your amazing credentials and your achievements, of which there have been many. But Dr Fowler, can you just give us a little bit of background? You are the director of the VCU Virginia University over in the States. Can you tell us a little bit about your work and your background?
Dr Berry Fowler: Okay, well, I am professor of medicine in the Division of Pulmonary Disease and Critical Care Medicine and I'm one of the ancient doctors in the division, just turning 71 last week. I trained at the Medical College of Georgia in the US, then went to the Medical College of Virginia in the US, then went to the University of Colorado for pulmonary and critical care disease training, and then came back and joined the faculty at Virginia Commonwealth University which used to be the Medical College of Virginia, it's now VCU, in 1982 and I've been here ever since.
Lisa: Wow.
Dr Berry: I rose slowly through the ranks. I led the pulmonary division for a number of years, for approximately 17 years, and then stepped aside in 2016. And all during this time, at least for 13 years now, we've had this interest in vitamin C. And it's interesting how our interest in vitamin C developed. It first started at a very molecular level where we were studying cardiac ischemia, but some of the heart attendings. And then slowly began to get back to what we have been doing for years which was bacterial sepsis. And we had some molecular reasons that drove us towards vitamin C.
And so first thing we did was we created an animal model of sepsis. And let me explain that. It was pretty straightforward to create. We had 30 gram mice and we went to the mouse cage and collected mouse pellets. Then took them to the laboratory and sonicated them really hard until it became a solution.
Lisa: So this is the fecal matter. Yes.
Dr Berry: And we would take that solution and centrifuge it really hard so that all the solid matter went to the bottom of the tube and we just took off the liquid from the top, which contained multiple different kinds of organisms.
Lisa: So all the bacteria. Yes.
Dr Berry: Yes. And so we took that, put it in the refrigerator overnight and then came in the next morning. And we had 10 mice. We had 5 control mice and then 5 treatment mice. So all the mice first were injected into their peritoneal space, you mentioned that earlier, with a tenth of an mL of this solution containing all this bacteria. And so all 10 mice. And then in the mice that were going to receive the vitamin C, we injected a tenth of an mL, which was 200 micrograms per gram of bodyweight of the mice and then closed off the light. By that point, it was about 4:00 in the afternoon. And just let the mice sit in the laboratory where we had left them and I always get to work at 6:00 in the morning and I was thinking, ‘Holy cow, I got to see what's going on.’ And so I went into the lab where we had the mice and the cage that was the control mice that were septic. They were all dead. In the cage that the mice got the sepsis and the vitamin C, they were all crawling around drinking water and eating.
Lisa: Wow.
Dr Berry: And I knew at that point that we had stumbled on something pretty significant. This take us back to around 2010. Maybe 2009. My laboratory has had this intense interest in sepsis ever since I finished my training at the University of Colorado. And so what we decided is that we would begin to use the treatment animals and some control animals to determine exactly how vitamin C was working.
Lisa: To look at the molecular, the mechanism of action. Why is this happening? Why are they surviving better?
Dr Berry: So what we did was—in these studies, we were always comparing the control mice to the treated mice. And one of the first things we found was that the lungs of the treated mice that were septic, they weren't injured.
Lisa: Wow.
Dr Berry: And we have a number of ways to determine the way a lung is injured. One of the things that happens in sepsis, and this might have been what you and I were talking about earlier, is the lungs barrier function, which is the ability to keep the blood in the blood and keep the air in the air.
Lisa: Yes.
Dr Berry: It gets injured. And so the bloodstream floods into the airspaces of the lung.
Lisa: And fills it.
Dr Berry: Yes. And one of the things we discovered was lung barrier function was preserved and the vitamin C treated septic mice.
Lisa: Wow. So you're perceiving that it’s stopping the plasma and the neutrophils getting into the alveolar space.
Dr Berry: Exactly.
Lisa: And the NET— of one of your lectures, you talk about neutrophil extracellular traps (NET). Is that a part of the barrier function?
Dr: Berry: Very nice. When are you starting medical school?
Lisa: Thank you, Dr Fowler.
Dr Berry: So what happens as sepsis progresses is that there are a bunch of molecules that live in the capillaries of the lung that begin to get expressed. And what they do is they trap neutrophils that are activated in the capillary space of the lung. And one of the things that happens in a highly activated neutrophil is they disgorge their DNA and all of the enzyme systems inside a neutrophil begin to damage the capillaries. And then what happens as the capillaries get injured, the plasma from the lung, just a vein from the bloodstream, just flows into the lungs.
Lisa: So you’re basically lost—it's like your skin barrier, if you like, between the ear and your insides is disintegrating.
Dr Berry: Well, one injury from sepsis is like drowning.
Lisa: Wow, so you fill it with your own fluid.
Dr Berry: The airspaces of the lung fill up with your own plasma.
Lisa: So when you have, cause sepsis—I don't think most people are not aware of the progression of sepsis to acute respiratory distress syndrome. That this is a sort of a linear progression that happens, isn't it? That you actually get lung—because most people understand sepsis as being a bacterial infection but they don't understand that it's actually taking all the organs and causing oxidative damage to multiple organs, not just the lungs, but particularly the lungs. And so this is a very important finding that what you've had here because this means that if you can stop the vitamin C, if the vitamin C can stop the neutrophils from disgorging their own DNA into the extracellular space, which is then, that's in a marker, isn't it? That cell-free DNA, when you take a plasma drawn and you see that cell-free DNA floating around at a certain level, that's a predictor of mortality, isn't it?
Dr Berry: Listen, you've done some fabulous reading. But let me just tell you, it's been known for several years that in septic individuals, one of the unfortunate things that will predict mortality is how high the cell-free DNA arises in the circulation. And I don't want to jump too far here, but I will tell you and the vitamin C trial that we reported one year ago this month, that when we reanalyzed the blood from those individuals, we found that vitamin C dramatically lowered the cell-free DNA in the treated patients.
Lisa: Wow. That was in the CITRIS-ALI study?
Dr Berry: Exactly.
Lisa: Oh, okay. That's a new finding from that study because, yes, we will go through that progression of how you got to do that study. So let's bookmark that for a moment and backtrack because that is a very important finding for that study. So let’s backtrack a little bit.
So we are talking about vitamin C being able to protect the lungs if we put it very simply and protect the barrier function of the lungs, stop the neutrophils from disgorging the DNA and causing these traps, which is a predictor of mortality. What are other things is vitamin C doing? And why is a septic patient, without fail, going to be very low in vitamin C? So you’re using that for Vitamin C.
Dr Berry: I'll get to that in a minute. But what we demonstrated in a huge number of murine mouse studies is that the septic lung in a control animal, the septic lung began to express many inflammatory proteins. And that's just your endogenous immune system trying to protect itself. But we showed in the next cage, in the septic mice that we had treated with Vitamin C, that the expression and the appearance of those inflammatory proteins was totally inhibited completely.
Lisa: Wow.
Dr Berry: Yes. The idea of leaping from preclinical animal studies into humans was that we had kind of a basic grasp on the immune system and how Vitamin C could alter the septic immune response and how Vitamin C could protect the lung. Well, protecting the lung in terms of septic critical illness is very, very important.
Lisa: Absolutely. And so then you went to a phase one safety trial, which was really to look at some basic markers. Is this going to be damaging for people if they get vitamin C and look at hypertension? And is it going to affect the kidneys and so on. I think some of those safety mechanisms. Can you tell us a little bit about that phase one safety trial and then the outcomes of that trial?
Dr Berry: Well, I can tell you, I had this really close colleague. His office sat right next to mine. He's a molecular biologist, basic scientist. And after we'd done all these murine studies, one day he walked in, he looked at me, said, ‘Fowler, this needs to go into the hospital. We've developed all this data. You've got to make it happen to get it into the hospital’. We designed this little safety trial, enrolled 24 patients. The safety trial was randomized and it was blinded. And so half the trial was just controlled sepsis. The other half was septic patients treated with Vitamin C and we had no idea who the hell was giving vitamin C to people who were critically ill.
Lisa: Yes.
Dr Berry: And we found it had no impact. But one of the things we were shocked at, and we were just trying to define, was vitamin C safe?
Lisa: Yes.
Dr Berry: One of the things we tracked was what is called an Organ Failure Score. And we found that all of the patients treated with Vitamin C, their Organ Failure Score reduced dramatically and significantly.
Lisa: Wow.
Dr Berry: And the way Organ Failure Scores, basically you're counting numbers. A higher number is a higher incidence of mortality. Lower numbers are improved and that vitamin C was actually improving the possibility of survival.
Lisa: So this is like, in my father's case, is the sepsis progressed and I was unable to get him Vitamin C as we discussed earlier, Dr Fowler, early enough for him to get to survive. But as I watched his sepsis progress, more and more organs started to fail. So his liver started to fail. His kidneys started to fail. His heart started to fail. And so this is the Organ Failure Score. If this person's Organ Failure Score is going up, that is a very strong predictor of mortality.
Dr Berry: Yes.
Lisa: Okay, so this was reduced with the people who received the Vitamin C in the small trial.
Dr Berry: So what we did, we took the data, we combined it with our preclinical data, and applied to the National Heart Lung and Blood Institute. They had just published an announcement where they were asking for anybody who could think of some clever trial. And we said, ‘Well’. And so we submitted an application. What the NIH wanted, they wanted the proposal for a phase two, proof of concept trial.
Lisa: Right.
Dr Berry: And so what we proposed was a trial that had seven medical centers. I have friends in seven medical centers around the US. And with this application in and that was I guess you guys don't remember Hurricane Sandy.
Lisa: Yes, I do.
Dr Berry: Hurricane Sandy was just—it killed the Atlantic Coast of the US. And the National Heart Lung and Blood Institute happens to sit on the Atlantic Coast in Washington, D.C. And it was a year and a half before we found out that we had received the highest priority score because of the application that we had submitted. And the NIH gave us 3.2 million dollars to do a multicenter, randomized, double blind, placebo-controlled trial, proposing to administer 50 milligrams per kilogram of intravenous Vitamin C every six hours for ninety six hours. Patients were continuously receiving vitamin C.
Lisa: Can you explain why that continuous topping up that level is important every six hours?
Dr Berry: That's a great question. So from the safety trial that we had performed, we analyzed the plasma Vitamin C levels that we had achieved by infusing. So basically someone your size, for example, would probably get maybe 3 1/2 grams intravenously every six hours for ninety six hours. And what we showed was, we could get the plasma level up to basically three thousand times the normal plasma level. So from a normal diet, human plasma levels of vitamin C are about 70 to 80 micromolar. When you give the protocol that we had settled with, we got the Vitamin C levels up to five millimolar.
Lisa: Wow.
Dr Berry: Yes. And so that's what we were shooting for in this NIH trial. And that's what we did. We charged into it, the trial. What we had proposed again, was the Organ Failure Score as well as the two biomarkers. We also proposed in the secondary outcomes, days on mechanical ventilation.
Lisa: Yes, which is hugely important.
Dr Berry: And what we were studying specifically, was patients who were septic, who had gone on to develop acute lung injury called Acute Respiratory Distress Syndrome, ARDS. And so when a patient was septic, like your father, we would become a fly on the wall and visit the patient every day until a lung injury developed. And that's when they would get randomized.
Lisa: This was a critical—from my analysis of the data, that was a critical thing in the phase. So you had to wait until I basically had developed ARDS before you were able to put them. So this wasn't really a sepsis trial, but more of an ARDS trial. So the progression of the sickness comes into play here, doesn't it? If you’ve gone through day one, like in the phase...
Dr Berry: In the safety trial...
Lisa: Yes.
Dr Berry: The second aseptic individual walked in the door, that's when they got random.
Lisa: Which is a much better, more effective with the timing.
Dr Berry: We had a couple of patients who got Vitamin C in the emergency room.
Lisa: Yes, wow.
Dr Berry: You know you have to get informed consent. You have to get the pharmacy on board and get the patient enthused.
Lisa: I wish I'd had you tending to my father. We could have had that from the moment he got to the emergency. That would have been, I think we would have had a different outcome. But so this was a key point that you had to wait until I had developed ARDS. So in this CITRIS-ALI trial, so here you have, I think it was 47 patients in the control and 47 in the intervention group, was it right?
Dr Berry: 83. And 84 in the Vitamin C treatment.
Lisa: Oh, 83. I'm sorry. Sorry. So 167. One of the big questions I had in my— why was mortality not one of the primary objectives of the study?
Dr Berry: That has been the most frequent question. When we answered the NIH, they had put out a program called, UM1, and we applied to the UM1 program and they were not interested in mortality as a primary outcome. Part of it was this. There had been hundreds of sepsis trials and nobody had ever shown any impact on a treatment for sepsis. And so NIH didn't want to get burned again so they said that they wanted a physiological outcome. That was the Organ Failure Score. And they wanted a biochemical outcome. Those were the biomarkers.
Lisa: It's the C-reactive protein, procalcitonin and thrombomodulin. And yes. So the reasoning was that we don't want to shoot for the stars here and automatically hope for a decrease in mortality and a decrease of days in hospital. We're going to go for something else just to see if this has legs, so to speak, if this treatment is possible, possibly going to work. And that's why they went for the safer scores, rather than the mortality. Looking back, do you think...
Dr Berry: By the way, we haven't talked about this yet, but SOFA stand for Sequential Organ Failure Assessment Score.
Lisa: Thank you. Yes, it's amazing the jargon that you pick up and then forget that you haven't explained yourself. So what actually was the outcome? This was a seven multicenter trial. You did a double blinded. This was incredibly important because I know Dr Paul Marik had also done a study with intravenous Vitamin C, thiamine, and hydrocortisone. And one of the criticisms that was thrown at him was that it wasn’t a double blind, randomized controlled trial, so it didn't have any meaning, which is absolutely tragic. So this was—what was the outcomes of this phase two trial?
Dr Berry: So we enrolled 170 patients. One of the placebo patients we had to take out because that patient did not have septic ARDS. They had Acute Eosinophilic Pneumonia. That's something else to discuss later. And then in the Vitamin C arm, we had two patients with Acute Leukemia who had no coagulation in their bloodstream and they were hemorrhaging into their lung and that was not sepsis. So as I mentioned, we had 83 in the control placebo and 84 in the vitamin C-treated group. First of all, we saw no, and I emphasize capital N-O, adverse events. There was not a single adverse event.
Lisa: Exactly.
Dr Berry: All right. And so what we showed was in 96 hours, placebo patients in the trial, 19 of 83 died within 96 hours.
Lisa: Wow.
Dr Berry: In the Vitamin C group, 4 of 84 patients died. And if you look at the statistics and the analysis of that, the difference is P=0.0007. We then followed the patients out because in sepsis trials, there's always this demand to see what is happening to a patient at 28 days.
Lisa: Yes.
Dr Berry: And what we showed was 46% of placebo patients died and only 30% of the Vitamin C treated septic patients with ARDS died.
Lisa: Wow, that's a huge result in my mind.
Dr Berry: And that was the first trial. I'm not slapping myself on the back, but I will just tell you, that was the first trial to ever show in a blinded fashion, an impact on ARDS.
Lisa: Yes. On mortality of ARDS.
Dr Berry: Yes.
Lisa: And this was extremely sick people. Now, unfortunately, the SOFA scores didn't show any difference and the C-reactive protein markers didn't show any difference.
Dr Berry: So let me explain.
Lisa: Is it because... Yes, is it because of the mortality.
Dr Berry: So we thought publishing the results of the trial in probably one of the most important journals on the planet, JAMA, which as it turns out, is a very, very conservative journal. And they had their ideas about what we could and we couldn't say. So we published, and this is very important for you to listen to and all of your listeners, we published that there was no difference in the SOFA scores at 96 hours. And immediately, letters to the editor started coming in and one of the most important letters to the editor was the person who created the SOFA score. His name is Jean-Louis Vincent in Brussels, Belgium. He told us that we had analyzed the data incorrectly and that what we were reporting was a survivorship bias.
Lisa: What does that mean?
Dr Berry: And what he said we needed to do, and he provided five publications where he had important statisticians tell him that analyzing the data, like we reported, as a worst rank, best rank scenario, that we had to reanalyze it so that the patients who died, what we were reporting was the SOFA scores on the people who had survived.
Lisa: Not the ones who died.
Dr Berry: We had not considered the SOFA score on the patients who died.
Lisa: And because they died so quickly.
Dr Berry: So what we did was we went back and the people who died along the way, those 19 patients, they got the top SOFA score. The patients who survived and left the unit, they got a low SOFA score. And so when we reanalyzed the data, according to the way these letters that had come in from Dr Vincent and two or three other colleagues, it turns out that Vitamin C significantly impacted the Organ Failure Score.
Lisa: Wow.
Dr Berry: And then we—here's the important thing, we reported that February 25th of 2020. So you can go to JAMA, you can look it up and you can see our response to the SOFA score reanalysis.
Lisa: Because this was a key factor in my father's case. They threw the CITRIS-ALI trial at me and the original data from JAMA, which said negative result, which when I analyzed...
Dr Berry: That lets you know that the doctors were not reading JAMA.
Lisa: Exactly. And they weren't on the up to date and they did not look at secondary outcomes and they did not look at the parameters of the score and I was not able to present the case. They had just read it briefly.
Dr Berry: Let me go on. We had a strong trend to ventilator-free days and the people who got the Vitamin C, but it just missed statistical significance.
Lisa: Yes.
Dr Berry: But we had a strong significance for the people who got Vitamin C in Intensive Care Unit-free days.
Lisa: Which is huge.
Dr Berry: So the people who got Vitamin C had a significantly higher number of ICU-free days. There was an improved mortality. The other thing is patients who got Vitamin C had significantly more hospital-free days at day 60.
Lisa: Wow. So they were actually out of the system altogether. Do you think—now this is controversial, I'm playing devil's advocate here. But do you think the fact that it costs so much for someone to be in ICU when they have sepsis—I think in America it's something like, to the order of 60,000 dollars US a day—and the medications that they are typically on are costing around 20,000 dollars a day, do you think that if you come along with Vitamin C and you start dropping the mortality rate, you start dropping the days? Is that part of the resistance to accept and acknowledge these findings, that the pharmaceutical companies are going to lose out on profit?
Dr Berry: Oh no no no. No, no, no. At VCU, Virginia Commonwealth University—that Anitra knows well—the average care cost per day is about 46,000 per day because that accounts for medical care, nursing care, radiology, all laboratory data, respiratory care, caring for the ventilator. All of that is somewhere in the neighborhood of about 45 to 50,000 dollars per day. And so, if you have a treatment, first of all, that gets people out of the ICU earlier and keeps them out of the hospital, think about the impact on the cost of care.
Lisa: Yes, it’d be huge.
Dr Berry: But here's the other thing. There's not going to be any drug company out there who would argue with that. They are all trying to do the best they can with their different antibiotics, but the common antibiotics that are administered in an ICU when patients are septic levofloxacin, meropenem, vancomycin. Just one day of meropenem is 1500 per day.
Lisa: Exactly. It's a lot of money.
Dr Berry: Yes.
Lisa: So you don't think that...
Dr Berry: And listen to this. That's the cost of the drug. That's not the cost of pharmacy preparing the drug, cost of nursing administering the drug and so on and so on and so on.
Lisa: Okay, so all right. So if you can work this problem out and if you can get this in all ICUs around the world, we're going to save not only thousands and eventually more hundreds of thousands of lives, you're going to reduce the hospital bills enormously. So this is incredibly important work. And you've proven—so the statisticians proved in that phase two trial that the way that you are measuring it was incorrect because a lot of people, as you said, 19 died in those first four days in the control group and only four, so that skewed—if you like—the statistics to initially look like we hadn't had a win here. Now, that's been rescinded and you've managed to get JAMA to publish it in a different light, that the SOFA score was impacted. What has been the effect now? Have you got another trial underway or have you got one in sight? Because this work’s too important, obviously, not to be taken further into a phase three.
Dr Berry: All right, so you are in New Zealand where there's not much COVID.
Lisa: No.
Dr Berry: We are in the United States, where it's a pandemic, where we are close to 220,000 people who have died from the virus. We are at 50,000 new cases per day.
Lisa: Oh my God. It's so...
Dr Berry: And there are somewhere in the neighborhood of 1,800 to 2,000 patients dying per day of COVID. And so because of that, the network that I'm part of, that unfortunately—I'm going to have to jump off and listen to it, because it's been going on since 2:00, the annual meeting of the Prevention and Early Treatment of Acute Lung Injury Network, abbreviated P-E-T-A-L, the PETAL Network. The PETAL Network was tasked by the NIH to turn sharply towards COVID treatments.
Lisa: Yes. That makes sense.
Dr Berry: And so we were thinking, ‘Well, maybe vitamin C to treat patients with early COVID pneumonia’. And so what we did was we started a trial. We have studied 20 patients now and that trial is complete, where patients who develop COVID infection and develop early COVID pneumonia, so it's just at the start of an oxygen requirement, are treated with Vitamin C and the results have been pretty dramatic. We are in the midst of writing that up. But again, it's a—open label trial. It's not blinded. Everybody in the world knows that an open label trial does not have the power like we did with CITRIS-ALI.
Lisa: Yes.
Dr Berry: And so what is happening at a world level is that all of the health organizations around the world have come to bear to try to design treatments for COVID pneumonia.
Lisa: Yes.
Dr Berry: And that is ongoing right now. And there are like 9 or 10 major networks in, across the world. Probably, I'm not sure if New Zealand is included in that, but Europe, the US, possibly Australia. I don't know if they commit to participating in what is called the network of networks formation.
Lisa: Yes.
Dr Berry: So right now, the next trial for patients with sepsis that's not COVID is going to be conducted by the PETAL Network where we will be probably next April, starting a trial with a thousand patients.
Lisa: Wow.
Dr Berry: Using vitamin C conducted by the PETAL Network.
Lisa: Gotcha.
Dr Berry: And the PETAL Network has 69 medical centers. So doing a trial that would get a thousand patients can be done within a year.
Lisa: Wow. So this is exciting stuff because this is hopefully you'll be able to reproduce and show a strong correlation between intravenous vitamin C and I'd like to see the decrease in the mortality rate. That would be a key factor. Some centers are already using vitamin C because as you mentioned before, there were no adverse reactions. And this is like in all of the studies that I've seen there has never— this is a low risk intervention and my argument when fighting for my father was that, ‘He's dying. There is no other options. Why can't I throw the bus in? Why can't I put intravenous Vitamin C’? And they were like, ‘You still have to go through all the ethics committees’. I had to sign off from every single doctor and every single nurse in the ICU unit of which there are many.
Dr Berry: Well, let me make another statement. So Paul Marik, who was using 1.5 grams of Vitamin C, 200 milligrams of thiamine and 50 milligrams of hydrocortisone, administered every six hours. That meant that the patients were only getting 7 grams.
Lisa: Very small amount.
Dr Berry: In the CITRIS-ALI, I mean, some patients got 16 to 18 or 20 grams.
Lisa: Yes.
Dr Berry: According to body weights, 50 milligrams per kilogram. In the aftermath of that article that you mentioned that Marik published, there have been efforts to repeat that trial. The vitamins trial came out in January, using that and it failed. Then another trial, the ACTS trial using the Marik protocol failed. And then a trial that I just participated in called the VICTAS trial completely failed. And so the Marik protocol is not an effective treatment for sepsis. And well, look. As I think Anitra Carr mentioned to me a couple of years back, the amount of vitamin C that you administer is critical.
Lisa: Absolutely.
Dr Berry: So dose matters. And the adult, again, of your size, you probably weigh 120 pounds or something would probably get somewhere in the neighborhood of about 12 and a half to 13 grams, spread out over a 24-hour period. And then you would get it for four days.
Lisa: Yes. And that is still a relatively low dose.
Dr Berry: It is.
Lisa: When I'm doing intravenous vitamin C with my mum, I did it with my dad prior and unfortunately, months prior to his aneurysm. Too little, too late. We were getting 30 grams. We get 30 grams a week. When I take my mum and niece today for an intravenous Vitamin C is a prophylactic as I try to keep her, as a 79 year old healthy, 30 grams. So why—I had this question certainly with Dr Marik’s protocol. It seemed to me to be very low, although the six hourly is obviously a very important point as well. Why not do the bigger dosages? Like in Japan, I know they did a study with up to a hundred grams of Vitamin C in a burns case, a burns trial, where they had some markers of sepsis there. Why are you not trying higher levels?
Dr Berry: Let me come in here quick? Because I'm going to have to jump off in about 8 minutes. But listen to this. The major concern for those high doses of vitamin C, and if you talk to the oncologists who have been using it for years, they will give, like you said, they will give massive doses. And I'm talking massive, like in somebody with pancreatic cancer, they will get 60 to 80 grams intravenously, Monday, Wednesday and Friday for seven weeks.
Lisa: Yes.
Dr Berry: But the major concern, in somebody who's septic, who's hypotensive, in shock, that you're giving vitamin C, one of the major concerns is that it causes a significant rise in oxalate crystals formatiion in the kidneys. Now, I will mention here in the CITRIS trial, we had no evidence of renal stone formation.
Lisa: No. And I mean, that was one of the arguments that the doctors had at me, ‘You could have damaged his kidneys’. And I said, ‘Well, the last time I looked, being dead damages your kidneys too’. To me, that wasn't even a consideration. And he had—after the very first vitamin C, and for my dad, his kidney function went from 27 percent to 33 percent. He's actually improved his kidney function overnight. And I know that's just one anecdotal case, but kidney stones are not going to kill you either. So surely that's not the most important consideration here when you've got a septic patient who is on death's doorstep.
Dr Berry: With vitamin C struggling in the United States after the CITRIS trial, the Federal Food and Drug Administration, they always have to be concerned about adverse events. And we have put together a trial randomized and double blind using Vitamin C in patients with COVID-pneumonia. That's about to start.
Lisa: Wonderful.
Dr Berry: And we had, I unfortunately let my IND, Investigational New Drug lapse after CITRIS. And so I've had to claw our way back into the good graces of the FDA. And one of their major, major, major complaints was, ‘You're going to be forming renal stones’. And we're using the same protocol that we used in CITRIS. So FDA got their nephrologists involved and finally gave us the IND. But for us to begin treatment of COVID pneumonia, they have demanded that we first do a small safety trial to show that we are not causing any renal stone formation. We can get that done. We currently have somewhere in the neighborhood of 60 to 70 COVID patients in the MCV hospitals right now.
Lisa: Wow. Well, Dr Fowler, look, I know I'd love to spend another five hours with you discussing all this because I think it's incredibly important, both for COVID and for the sepsis and for pneumonia and for obviously, for cancer. I just want to thank you for your dedication to this. I mean, you could be in retirement and sunning yourself somewhere, relaxing, but, you know...
Dr Berry: That's right.
Lisa: You know that this work is critically important. And I heard one of your lectures is the equivalent of two 747 planes going down every day filled with people.
Dr Berry: Every day in the United States.
Lisa: In the United States alone.
Dr Berry: That’s just in the U.S.
Lisa: Yes. And these people, thousands of families being destroyed with losing loved ones. I'm one of those, unfortunately, sitting here all the way in New Zealand. And so this work is incredibly important. So please keep going. And I'm desperate to hear what comes from this COVID clinical trials and the other sepsis trials, obviously. So thank you so much for your work, Dr Fowler, and I really appreciate you.
Dr Berry: It's been wonderful meeting you and speaking with you, and your and your audience. And when you have Anitra on a couple of weeks, give her my regards.
Lisa: I will definitely do that, Dr Fowler. That's been awesome. Thank you, Dr Fowler. And all the very best there in Virginia.
Dr Berry: Take care. Bye.
That’s it this week for Pushing the Limits. Be sure to rate, review and share with your friends, and head over and visit Lisa and her team at lisatamati.com.
The information contained in this show is not medical advice it is for educational purposes only and the opinions of guests are not the views of the show. Please seed your own medical advice from a registered medical professional
