Back in April of this year I wrote a blog on the discovery by Dr. Paul Marik, a critical care physician at East Virginia Medical School, that a cocktail of vitamin C, hydrocortisone and thiamine was remarkably effective at treating patients with severe sepsis and septic shock. Results with use of Marik’s cocktail were so astonishing (87% reduction in mortality) that the story received wide coverage in the medical and mainstream press.

Marik’s early experience with his vitamin C cocktail was published in the June issue of Chest as a retrospective observational before-after study that has generated considerable controversy in the field. Details of the study and its results were described in my previous blog and can also be found in the Chest paper here. While many received the study with enthusiasm, others have been quite skeptical, to put it mildly. Marik’s study seems to have divided the medical community into those who think this is a miracle cure for sepsis and those who think this is another example of vitamin C snake oil.

Needless to say, I’ve been following this story very closely because if truly effective, this vitamin C cocktail could be an enormous breakthrough. The Marik cocktail, as it has become known, not only presumably works wonders, but is also very safe and inexpensive. With sepsis being not only extremely deadly, but also extremely costly (ranked #1 in US hospital costs at $24 billion per year)[1], this could truly be the miracle cure patients, doctors and hospital CFOs have been waiting for. And since most of the people who die of sepsis every year (6 million by WHO estimates) [2] do so in poor and underdeveloped countries, having an inexpensive and readily available treatment such as vitamin C could literally save millions of lives in countries where high-tech expensive treatments are out of reach. Lastly, if the Marik cocktail truly works, it greatly emphasizes the importance of vitamins in the body’s ability to fight off severe illness, something that perhaps the medical establishment has underestimated (I myself am a skeptic of most vitamin claims). So, this is a very BIG deal, perhaps one of the biggest seen in medicine in a long time.

After the initial storm of press coverage the story seemed to die down, and over the past couple of months, I could find few updates on Marik and his work with vitamin C in sepsis. Curious to know what was happening, whether the results are still holding up, whether more trials are in the works, especially the randomized trials that everyone is demanding, I decided to go straight to the source and reach out to Marik directly.

Dr. Marik was gracious enough to grant an interview to provide an update on the state of affairs.

Daniel: Hello Dr. Marik and thank you for granting me this interview. I’ve been following your work closely since the story of your remarkable results with vitamin C broke earlier this year, and I wanted to get an update on your progress. First, I must say, your study has been quite controversial and the response of the medical community has not been uniformly enthusiastic. Can you comment on that?

Marik: So, you know, overwhelmingly, the response has been very positive. It’s been very bi-modal, either you think this is the greatest thing on earth or you think it’s BS. There’s no question that the BS category is shrinking in size as people kind of move to the other camp, but there are some vocal, it’s a small minority, but they have been very vocal, and it’s usually the sepsis experts that have been very vocal. The response has been interesting from the sepsis community, they do not like it one little bit and I have taken some big hits. They can be skeptical about the science, but they have attacked me personally. There are lots of reasons – it’s very threatening to them and it’s very threatening to industry because if this is what I think it is, it puts half of the clinical care researchers out of business and puts a lot of industry research out of business. This is a very cheap intervention and no one is going to make money. So that’s very anti-capitalistic and people don’t like that.

As you know there are some very expensive technologies that are looking to treat sepsis, very expensive. So there’s plasma filtration and cytoabsorption, and there are new kinds of vasopressor agents coming out, and immune-modulating drugs, monoclonal antibodies, there are very expensive technologies in the pipeline. Somebody just spoke to me about some kind of recombinant interleukin molecule, so you know, these are really expensive interventions. What’s somewhat disappointing to me is that some of the biggest societies haven’t embraced this more aggressively. Because, you know, [the cocktail] reduces organ failure, it improves quality of life, and it’s cheap and hospitals can save enormous amounts of money, enormous amounts.

Daniel: Some level of skepticism can be expected and is healthy, but it is very unfortunate that some responses have gotten personal. Ultimately, however, the results will speak for themselves. So how many people have you treated with the vitamin C cocktail so far and are the initial results still holding up?

Marik: We have treated over 300 patients and the results are exactly the same. It’s predictable like gravity. I know it works, I see it everyday. Obviously, people are somewhat skeptical when I say that, but I’ve got emails from people across the world who observed the same kind of response from every corner of the earth. Unfortunately, you know, we’re in the mindset that with anything that’s new you need a randomized study. People are unwilling to accept anything less than that. They’re just unwilling. It’s kind of a pity because you take a drug like penicillin, no one’s ever done a randomized trial of penicillin vs. placebo in infection, or patients with asthma, giving steroids or no steroids. There are many therapies that are standard of care that really have never been put to a randomized trial. But it seems like nowadays just because we have the ability to do these massive randomized trials, that’s what people want. I suppose the other reason is that the stakes are so high. Just because if this works the way we think it works, it basically puts a halt in every other pursuit because this is the cure. And all these hundreds and thousands of studies and millions of dollars that are being spent will basically end because there’s no reason to pursue them. So obviously there’s a lot at stake.

Daniel: Your finding could certainly have major ramifications indeed, and no doubt you are rocking a few boats. A lot of the naysayers are demanding results from randomized clinical trials before they buy this, and we’ll get to that in a bit, but first, let me ask you, given these great results, is this now the standard of care at your institution?

Marik: So, it’s interesting, we have multiple ICUs and we don’t run all the ICUs. In our medical ICU, it is the standard of care.

Daniel: But in other ICUs, it is not?

Marik: Physicians have the option to do it if they want to do it. Obviously, some people even within our institution are somewhat skeptical. You know, obviously, our nurses that see it would find it unacceptable not to do it. In our unit, because our nurses have seen how it works, the natural history of sepsis has completely changed and the concept of refractory septic shock we just don’t see. It’s a disease we just don’t see. And maybe sepsis is a disease in medical ICU patients. The other ICUs are cardiac, cardiothoracic, burn, trauma in which they don’t see as much sepsis.

Daniel: What about the surgical ICU, I imagine they see some sepsis there?

Marik: Yeah, the surgeons are somewhat skeptical. They do see some sepsis, but the surgical sepsis is somewhat of a different animal because the treatment is surgical source control. But without question, [the cocktail] has a role. Our surgeons are somewhat skeptical although some of the patients they will treat. But you know, surgeons are a different kind of animal, so we can’t force them to do it. I think once more data is available, [they will]. One of the concerns surgeons have, and this is a world-wide thing, is that you can’t give steroids to a surgical patient. They have this mistaken [belief], it’s a myth, that steroids interfere with wound healing and will cause infection. And in fact that’s completely false. But it’s interesting, it’s like a myth, but it’s a worldwide myth.

I’ve had two patients who failed, and they contacted me and they wandered what I thought. And both of them were surgical patients in whom they didn’t give the steroid piece. So you know, it’s like making cake, it’s a recipe, you can’t leave out one of the ingredients, it’s not going to work. For whatever reason we came across this elixir, and all three [ingredients] have to be given, and people have tried to microdissect it out, but you can’t do that.

Daniel: Yes, it seems that most studies to date have studied these ingredients separately, and that people are still calling for their separate study to identify the precise contribution of each one. What do you think of that?

Marik: This is a concoction that works together. It’s like when you have cancer. No cancer therapy is one agent, it doesn’t work. Everything in cancer chemotherapeutic protocols has multiple drugs that act on multiple pathways, that’s accepted. It would be absurd to give one drug. When you look at treatment of TB, you don’t give one drug, you give multiple drugs. So to try to dissect which piece works is stupid – they work together!

Daniel: So then, what do you think will be the outcome of Dr. Berry Fowler’s CITRIS-ALI study, given that it is only studying vitamin C alone, do you expect it to fail?

Marik: Dr. Fowler’s study will be interesting, however, I don’t think it was powered for mortality benefit. So I think it may show some physiological benefit, but I would be really surprised if he found a mortality benefit.

Daniel: Yes, Dr. Fowler’s study does not have mortality as a primary endpoint, but rather, a change in SOFA score and levels of biomarkers like CRP and thrombomodulin. Speaking of sepsis biomarkers, I noticed that aside from lactate of course, your study used procalcitonin and not CRP or other markers. Is procalcitonin your preferred biomarker in sepsis?

Marik: Just fortuitously, we measure procalcitonin, and it is a remarkably interesting biomarker. It is without question essential in these patients and the response is quite extraordinary. So if we have a patient in whom say procalcitonin is 100 and it doesn’t follow the exponential decline that we expect, we know within 24 hours why that happens. It’s because you have the wrong antibiotic or you don’t have source control. Because with this concoction, predictably, I mean in every single patient, the procalcitonin falls exponentially. If it doesn’t then you have to look for a reason why. So it is remarkably sensitive to our intervention. Now, why that is, I can’t tell you, it is one of the remarkable observations that needs further study. But it seems that the combination completely switches off procalcitonin, it just switches it off immediately. So I favor procalcitonin as a really important biomarker. The CDC now recommends its use to follow patients because CRP is a non-specific marker, it goes up with trauma and inflammation from whatever cause, whereas procalcitonin only goes up with bacterial infections. So it seems to be a sensitive marker for bacterial infections. And now the CDC actually endorses its use, to follow the course of procalcitonin and use it to stop antibiotic treatment. So it is getting more traction.

Daniel: I noticed in your study the mean lactate levels were below the 4 mmol/L typically used as a cut-off for severe sepsis. What is the role of lactate in sepsis?

Marik: People don’t understand lactate. It is not a sepsis marker, all it is is an index of disease severity, that’s all it is. Obviously, the higher the lactate, the higher the risk of dying, but it’s not specific for sepsis, and lactate clearance is a poor marker of response. We kind of measure it for 4 days because we kind of can and it’s interesting to do, but you can’t titrate therapy to lactate which people have tried – it’s a ridiculous idea. It’s the same as titrating your antibiotics or pressors to a white cell count or BUN, I mean, it’s stupid. Lactate is just a marker of disease severity, that’s all it is, it’s certainly not specific for sepsis.

Daniel: Many people have taken issue with the design of your study – small, single-center, retrospective before-after, etc, and want to see an RCT before applying this therapy. So the big question that everyone I’m sure wants to know is, do you have any plans to conduct a randomized clinical trial?

Marik: We got funding in the US to do a large randomized study. You know, obviously it’s going to take a little bit of time in the design and putting it together because it involves the major medical centers in the US. And whenever you have influential people involved they all have very strong opinions. So to get a consensus has been somewhat difficult, but I think they have, so I would suspect that in the US a study would start in about 4 to 6 months.

There’s a study that already started in China, in Slovenia, and there’s one that’s about to start in Greece. [The Greek researchers] had some difficulty getting intravenous vitamin C in Greece, which wasn’t available, but they’ve now solved that issue. [The researchers] tell me that they have their drug, they have their IRB approval, they plan to start in about two weeks and they are going to send me the protocol. This has created an interest and people will study this. What’s somewhat interesting is that each study will give us a somewhat different inclusion criteria and trial design, so I think it will give us an answer.

[Of note, in a subsequent clarification email, Dr. Marik added that a study will also start in Norway. At the moment, only the Chinese trial is listed on ClinicalTrials.Gov, but the other studies should also be listed in the coming weeks.]

Daniel: That’s really great to hear, I’m sure people will be happy to know things are moving quickly with the randomized studies. Is the US trial NIH funded?

Marik: No, so the NIH (NHLBI) weren’t interested, we made some overtures, they said submit a grant and we’ll have a look. Remarkably, we got a private donor, we actually have 3 donors, so these are philanthropic donors, which is most unusual in the history of medicine. They came to us, we didn’t approach them, they came to us and asked us to do this.

Daniel: So the NIH didn’t want to fund this?

Marik: Well, the NIH didn’t say they wouldn’t fund this, but there wasn’t a lot of excitement, and it would’ve taken a long time because you have to submit a grant and they have to score it and whatever, and there’s limited funding. So we have these philanthropic donors who are willing to support the entire study.

Daniel: What is the target enrollment size?

Marik: The protocol is still in flux and the exact trial design is being [determined]. So provisionally, they’re going to have some interesting stopping rules because obviously you don’t want to continue if there’s a clear benefit or harm, like most studies. So the target, I believe, will be between 1,500 and 2,000 patients, they are still working on the power analysis. We’re aiming for 80 centers, so obviously this is a big enterprise so it will take time. Obviously I wish it could start like tomorrow, but you know, it takes time.

Daniel: Well, everyone is certainly looking forward to seeing the results of these randomized studies. I think I have taken up enough of your time, is there anything else you would like to add?

Marik: Even if I’m wrong, which I doubt, which I am highly skeptical that I am, [the vitamin C cocktail] is completely safe, it’s completely 100% safe. So what have you got to lose? There’s no question it’s effective, I know it’s effective, but you know, assuming that it isn’t as effective as I think [even though] we see it, but for the skeptics you could say, ok maybe it doesn’t have the mortality reduction that we found, but on the other hand, it’s completely safe, completely! There’s not a single side effect, so what do you have to lose? And it’s cheap. So we’re not talking about a really expensive intervention, it’s really cheap! Sepsis is the most expensive hospital diagnosis in the US. Even if you negate that it may save lives, you know what it can do to the amount of healthcare expenditure, it can dramatically slash it. If you were a health economist, you’d say, gee wiz, we gotta look at this.

Daniel: Yes, you definitely can’t beat the price, but I think the bottom line is the results. If you have shown and are continuing to show the same great results, and others are as well, I don’t see how this can stay under wraps for very long, randomized trials or no randomized trials. Obviously these are important to take on, but these continued positive results should speak for themselves. Sooner or later the world will take notice and have no choice but to use this because like you said, the problem is so big.

OK, well, thank you very much for your time Dr. Marik, it’s been a real pleasure.

Marik: Thanks Daniel, bye.

 

Safety considerations of the Marik cocktail

While the world awaits the results of the RCTs, many will be asking if they should be trying this cocktail anyway given its impressive results. Personally, based on what I know about the safety of its ingredients, and the evidence presented by Marik, I would absolutely want to receive the cocktail if I was a sepsis patient. However, let’s quickly cover some of the safety issues people have expressed concern over with these ingredients.

Vitamin C

First, it is important to point out that vitamin C is generally extremely safe, even at very high IV doses. The ascorbic acid solution package insert (Mylan International LLC) specifies that parenteral doses up to 6 g daily have been used in normal adults without evidence of toxicity, part of the reason why Marik used this dose. Furthermore, IV vitamin C in doses as high as 100-150 g have been administered to cancer and burn patients, as Marik states in his paper, without any adverse events. Lastly, in the study by Berry Fowler et al of high-dose IV vitamin C in sepsis, a study which partially served as the basis of Marik’s work, the high-dose test group received 200 mg/kg/day of IV vitamin C, or 14 g/day for an average 70 kg patient (more than twice Marik’s dose), with no adverse events noted. Incidentally, the treatment response in the Fowler study was nearly identical to that seen by Marik – markedly reduced SOFA and procalcitonin, as well as CRP and thrombomodulin – and was actually dose-dependent. Another group that received only 50 mg/kg/day also had a very positive, but lesser, treatment effect than the 200 mg group.

That said, there are a few safety issues to keep in mind with vitamin C use. High-dose vitamin C should be avoided in patients with G6PD deficiency as it can cause hemolysis. High-dose vitamin C also has not been tested in pregnant women. Renal oxalate crystal deposition can occur, but typically at much higher doses than the 6 g per day used in Marik’s cocktail, and the thiamine component of the cocktail serves to lower this risk, according to Marik.

It should also be noted that vitamin C may falsely elevate glucose readings with some testing systems, as pointed out by Flannery et al in a response to Marik’s study. Flannery’s tests indicated that high-dose vitamin C falsely elevated glucose readings by >30% using Accu-Chek (Roche Diagnostic) and Optium (Abbott Diabetes Care) POC systems, but not with the StatStrip (Nova Biomedical) system. However, such false glucose elevations were not observed in this study at the 6 g daily dose of vitamin C used, according to Marik. Nonetheless, care should be exercised so insulin is not accidentally administered for falsely elevated glucose readings. Keep in mind that sepsis can itself cause glucose elevation, but the target glucose level should be 180 mg/dl if insulin is used, according to SSC guidelines.

Thiamine (vitamin B1)

As for the thiamine component of the cocktail, its safety is well established and it is commonly administered to hospital patients, especially alcohol abusers, who are often deficient in it. Donnino et al found that in patients with sepsis who are thiamine deficient, 200 mg every 12 hours of thiamine (the dose used by Marik) improves survival. Its role in improving sepsis outcomes in potentially deficient patients is the reason thiamine was added to the cocktail. The other reason, as previously discussed, is that it is a cofactor to an enzyme that metabolizes oxalate thus reducing the risk of oxalate crystal deposition in the kidney.

Corticosteroids

With regard to corticosteroids, although their usefulness in sepsis continues to be debated, they are in fact recommended for refractory septic shock by the 2012 SSC guidelines at the 200 mg/day dose used by Marik. This is the reason why some of the control patients in Marik’s group were also given hydrocortisone, because it is standard of care. Some have pointed to this as a potential confounder, and while it may be, it actually should have lessened the treatment effect in Marik’s study. If hydrocortisone on its own had a clear benefit, the bias would’ve been in the direction of benefit for the control group, and thus a lower relative benefit for the treatment group. The use of corticosteroids in septic shock continues to be studied in studies such as the ADRENAL trial.

Some are also concerned about corticosteroid interference with wound healing, especially in surgical patients as Marik pointed out. Long-term chronic corticosteroid use may have this effect, but a 1-week course of acute steroids should not. In a large meta-analysis, Wang et al found that while patients taking chronic corticosteroids for at least 30 days prior to surgery did have impaired wound-healing (x2-5 risk of wound complications), acute high-dose administration of corticosteroids for <10 days had no clinically significant impact on wound healing. Interestingly, vitamin A has been found to reduce the negative effect of corticosteroids on wound healing.

Final thoughts

The bottom line is that this cocktail is extremely safe in most people. The risk of dying from severe sepsis and septic shock is far greater than the risk of complications from any of the ingredients in the Marik cocktail. So even if one were to take a purely risk-benefit approach, the cocktail wins by a mile. As Dr. Marik says, what have you got to lose? Nothing, except perhaps the patient’s life.