This post is a work in progress regarding everything you need to know regarding administering high-dose intravenous (IV) Vitamin C (ascorbic acid) to your critically ill patient. I will continue to work on this post regarding IV vitamin c as well as metabolic resuscitation as time allows and data is published.

Glucocorticoids and Septic Shock

The ADRENAL Trial showed us some reasons why we should provide glucocorticoids to our septic shock patients.

Thiamine and Septic Shock

Some background as to why thiamine was injected into the picture.

Vitamin C Deficiency

Here are some things we absolutely know: 88% of patients in septic shock have hypovitaminosis C and 38% of septic shock patients have severe vitamin C deficiency. IV Vitamin C should help.

Vitamin C is necessary for endogenous catecholamine synthesis

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The VITAMINS trial didn’t pan out. It was not a positive study as it was conducted. I’ve already provided my take on that with my main argument being that they took too long to initiate the study drug (median time >25 hours, not including the time to arrive in the ICU). Sepsis management is expedient, you and I see it every day. Waiting over a day is not being expedient. I’m seeing a benefit in my clinical practice, as admittedly worthless as my opinion is on the grand scheme of evidence. But when something doesn’t make sense from a results standpoint, you need to go back to the basics and wonder what happened. Here are some things we absolutely know: 88% of patients in septic shock have hypovitaminosis C and 38% of septic shock patients have severe vitamin C deficiency. What many of you may not know, and I’m here to help you understand why I’m so surprised by the findings of the VITAMINS trial, is that vitamin c is a co-factor to the creation of endogenous catecholamines. That means that without vitamin c, your body isn’t going to produce the appropriate amounts of dopamine, norepinephrine, and epinephrine. It also is necessary for the production of vasopressin. It’s as simple as that. 38% of people will not produce appropriate endogenous catecholamines. The fact that administering exogenous vitamin c did not decrease time that the patients were receiving vasopressors in the study makes me wonder why. I am aware that there was a delay of >24 hours to start the therapies in the study but is there more I’m missing? Hopefully you can take some basic biochem away from this post as to why it should work (although it didn’t in the study). Obtain a copy of the entire free article on my website:eddyjoemd.com A 🎩 tip to the authors. -EJ Carr, A.C.; Shaw, G.M.; Fowler, A.A.; Natarajan, R. Ascorbate-dependent vasopressor synthesis: A rationale for vitamin C administration in severe sepsis and septic shock? Crit. Care 2015, 19, e418. The greatest compliment for my efforts and work to teach you all stuff is when you share with your friends. Thanks for doing so to help me get to 26k and continuing to do so to get the page to 100k by 2021. 💪🏼💪🏼💪🏼

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Why IV and not PO?

Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, Wesley RA, Levine M. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004 Apr 6;140(7):533-7. doi: 10.7326/0003-4819-140-7-200404060-00010. PMID: 15068981.
Link to Article

IV Vitamin C and ARDS

I have covered the CITRIS-ALI in depth here.

Does IV Vitamin C Cause Harm?

I have covered this question in a dedicated post here.

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There are individuals who are quite vocal against providing IV vitamin C in septic shock. They typically have no idea of the multitude of benefits that ascorbic acid has in our critically ill patients. As a quick reminder, we cannot synthesize our own vitamin C. It is a necessary co-factor for endogenous catecholamine production, amongst many other functions. 88% have hypovitaminosis C and 38% have severe deficiency when they present to the ICU. The contrarians yell about “calcium oxalate crystals”, “kidney stones”, and the unknown side effects of IV vitamin C. Well, now there’s data where they’ve looked directly at this. This was published last week. They looked at 74 studies with 2801 patients who were on “high-dose” vitamin C. Marik’s paper in Chest in 2017 used 1.5g IV q6h. The median dose in this paper was 22.5g/d. That’s far more than what I am using in my practice. Heres what they found (out of 2801 patients): – 5 cases of oxalate nephropathy – 5 cases of hypernatremia – 3 cases of hemolysis in patients w/G6PD deficiency – 2 cases of glucometer error – 1 case of kidney stones The authors went on to call the incidence of these events “rare”. I disclosed my bias above but I agree. They described that it is not more harmful than placebo. As an aside, it is postulated that thiamine protects the kidneys by avoiding the conversion of glyoxylate to oxalate via glyoxylate aminotransferase. Hypernatremia could be due to the vitamin c being sold as sodium ascorbate. I personally cannot recall taking care of one single patient with G6PD deficiency due to my geographic location and patient population, but it’s something to keep an eye out for and avoid it. When it comes to the glucometer errors, they mean it reads the blood glucose to read a higher value than what it really is. This only applies to certain glucometers (not all), and does not affect the values provided by our central labs. Please check with the manufacturers of your device to see if it would be affected by vitamin C infusions. Full breakdown on eddyjoemd.com. 🎩 tip to the authors. Does your shop use IV vitamin C? Do they start early or wait until everything else fails?

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Fictitious Hyperglycemia

From burn data and providing high dose vitamin C in that population, and I’m taking about doses >50gm/day, they have noted a cross reactivity in certain point of care blood glucose monitors where the ascorbic acid, due to having to do with glucose having a similar molecular structure to ascorbic acid with six-carbon molecules.

This seems to confuse the POC machine and the readings could be falsely >30%. Ultimately, those designing the studies for 1.5gm IV q6 hours have known this and have been checking to see if there’s a difference between the lab numbers and the POC numbers. As of the time of publication, they found no significant difference. We still need to keep this in mind, though. In the burn population someone died of iatrogenic hypoglycemia 😔.

Flannery AH, Bastin MLT, Magee CA, Bensadoun ES. Vitamin C in sepsis: when it seems too sweet, it might (literally) be. Chest. 2017;152(2):450–1.

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I’m plenty fired up for the VITAMINS trial that’s going to be published on the 17th. That’s the first large RCT looking at Vitamin C, Thiamine, and Hydrocortisone in Septic Shock. If the trial turns out to be positive, which I really hope it does, then we will really need to know about this limitation as our utilization will definitely increase worldwide. From burn data and providing high dose vitamin C in that population, and I’m taking about doses >50gm/day, they have noted a cross reactivity in certain point of care blood glucose monitors where the ascorbic acid, due to having to do with glucose having a similar molecular structure to ascorbic acid with six-carbon molecules. This seems to confuse the POC machine and the readings could be falsely >30%. Ultimately, those designing the studies for 1.5gm IV q6 hours have known this and have been checking to see if there’s a difference between the lab numbers and the POC numbers. As of the time of publication, they found no significant difference. We still need to keep this in mind, though. In the burn population someone died of iatrogenic hypoglycemia 😔. A 🎩 tip to the authors and those who answered the questions. If you enjoy my posts and learn stuff, share it with your friends and colleagues. Let’s help propagate fun evidence based medicine! Flannery AH, Bastin MLT, Magee CA, Bensadoun ES. Vitamin C in sepsis: when it seems too sweet, it might (literally) be. Chest. 2017;152(2):450–1. Addendum: link to the article on eddyjoemd.com 💪🏼

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A poor quality trial looking at IV Vitamin C, thiamine, and hydrocortisone prior to the big RCT’s.

VITAMINS Trial

I have covered this trial in detail here.

Citation:
Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, Deane AM, Shehabi Y, Hajjar LA, Oliveira G, Udy AA, Orford N, Edney SJ, Hunt AL, Judd HL, Bitker L, Cioccari L, Naorungroj T, Yanase F, Bates S, McGain F, Hudson EP, Al-Bassam W, Dwivedi DB, Peppin C, McCracken P, Orosz J, Bailey M, Bellomo R; VITAMINS Trial Investigators. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020 Feb 4;323(5):423-431. doi: 10.1001/jama.2019.22176. PMID: 31950979; PMCID: PMC7029761.
Link to Abstract
Link to FULL FREE Article

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You all know my bias. It shouldn’t be a surprise given my body of work: I wanted this to be a positive study. I wanted patients to benefit from this therapy and SURVIVE. I cannot understand the vitriol I have received in my direct messages when I shared my initial take on the study. I’m prepared to deal with more. Bring it! Ultimately, there’s no difference in the the endpoints, whether primary or secondary. No need to go through them in depth. That’s what the data says, that’s what the study concluded. 🎩 tip to the authors. It is what it is. I can agree with their conclusions based on the study conducted. But clinicians should not take the study as the end of HAT therapy. It would be scientifically irresponsible to do so. The study had a fatal flaw that doomed it from the beginning. Those of us, nurses, RT’s and clinicians who are at the bedside have watched septic shock evolve and know how important being expedient is. My blog post and video on the matter explain in depth how I personally take care of septic shock patients. There are plenty of nurses and physicians who work with me currently and have worked with me in the past following along on IG who can vouch for my style of practicing medicine. What I say on the blog post and video is NOT MEDICAL ADVICE. This post is not all 100% all inclusive for every nuisance. Every pt is different. Ultimately, the first 6 hours of a pt being in septic shock are the most important. Here’s my main problem with the study: – Time for patients to get randomized: I CAN’T FIND THIS DATA – Time from ICU admission to randomization: 13.7 hours (IQR 7.1-19.3 hrs). – Median time for patients to receive study study from randomization: 12.1 hours (IQR, 5.7-19 hours). 13.7 + 12.1 = 25.8 hours PLUS time for patients to get randomized! Why in the world did they take so long to start the study drugs? Another problem with the study is the fact that, since it was published in JAMA, a very high impact factor journal, clinicians are going to take it as gospel and dismiss the therapy entirely. If they would have provided the study drugs appropriately, would we have seen a difference? Maybe I’m just wrong on everything.

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HYVCTTSSS: Another Negative HAT trial… until you think about it.

Another negative study of the combination of IV Vitamin C, thiamine, and hydrocortisone. At least that’s what you’ll get out of it if you read the abstract. Heck, I’ll just share the direct conclusions here: “Among patients with sepsis or septic shock, the combination of hydrocortisone, vitamin C, and thiamine did not reduce mortality compared with placebo.” Well, that settles the whole discussion. It doesn’t help. Case closed. Let’s take a closer look at the HYVCTTSSS trial, though.

Administered Medications and Doses

Our colleagues in China replicated the Marik protocol/regimen of IV vitamin C (1.5g every 6 h for 4 days or until ICU discharge), IV thiamine (200mg every 12 h for 4 days or until ICU discharge) and hydrocortisone (50 mg every 6 h for 7 days or until ICU discharge). They gave it to patients with septic shock.

HYVCTTSSS: The Patients

They recruited a total 80 patients into this study before it was terminated early for futility and harm due to hypernatremia. This will keep many people from assessing their other findings. These were found in the midterm analysis. All in all, 40 patients in the control arm and 40 patients in the experimental arm.

Unless you read the article, you won’t be aware that most of the patients enrolled in the study were transferred from a secondary hospital to the hospital where the study takes place. I don’t know how it works in China, but transferring someone in the US isn’t exactly an instantaneous process. My interpretation of this that there was a delay in the time to administration of the study therapy. This was my same concern with the VITAMINS trial listed above.

In the patients who were diagnosed with septic shock within 48 hours, it was a completely different ballgame.

HYVCTTSSS: Improved Survival (if diagnosed early)!

The authors found an improvement in patients who were diagnosed with septic shock within 48 hours of admission. The survival rate increased by 34% with earlier diagnosis. I have been beating this drum for a while now. Everything in sepsis is starting early with aggressive therapy. Don’t let the patients go beyond the early phases. We see these patients routinely. They smolder with worsening organ function until they ultimately succumb of septic shock.

Now, there are limitations to this. Of the 80 patients, only 43 were diagnosed within 48 hours. 3 patients died in the experimental group while 10 died in the control group. I’m stretching quite a bit here with my statistical analysis (given the extremely small sample size) but that would mean that the NNT to save a life is just 2.9. Okay, I stretched a lot. Then again, you all know my bias.

This confirms my issue with the VITAMINS trial and adds to the data where, if you start HAT therapy late, your patient will not benefit from it.

My opinion on the harms noted.

First of all, there was no increase in acute kidney injury (p=0.57). In fact, although not statistically significant, there was 3% of the study group required dialysis while 11.5% of the control arm required dialysis (p=0.1).

Interpreting the subgroup analysis in the same way I did to show a benefit, I must point out that if you wait longer than 48 hours to initiate this therapy you may potentially be causing harm. Like many things in critical care, you have a window. Seems like this data shows the window to be 48 hours long due to the increased risk ratio.

Hypernatremia concerns: this is something that has been discussed in other articles. There are different formulations for IV ascorbic acid. I cannot find the details on the formulation used in this study provided by Shanxi Jinxin Shuanghe Pharmaceutical Co., Ltd. Perhaps a different formulation containing less sodium could do the trick to avoiding this.

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Bias disclaimer: I am an IV Vit C fanboy. “HYVCTTSSS”, What a forgettable name for a trial. Links and my full takedown on eddyjoemd.com. Another negative study of the combination of IV VitC, thiamine & hydrocortisone. At least that’s what you’ll learn if you read the abstract. Conclusions: “Among patients with sepsis or septic shock, the combination of hydrocortisone, vitamin C, and thiamine did not reduce mortality compared with placebo.” Well, that settles the whole discussion. It doesn’t help. Case closed. Well, it’s not that easy. Dosing: Our colleagues in China replicated the Marik regimen of IV vitamin C (1.5g q6h x 4d or until ICU dc), IV thiamine (200mg q12h x 4d or until ICU dc) + hydrocortisone (50mg q6h x 7d or until ICU dc). They gave it to patients with septic shock. They recruited 80 pts (40 in each arm) before it was terminated early for futility and harm (hypernatremia) noted in the midterm analysis. Unless you read the article, you won’t be aware that most of the pts enrolled in the study were transferred from a secondary hospital. I don’t know how it works in China, but transferring someone in the US isn’t exactly an instantaneous process. My interpretation of this that there was a delay in the time to administration of the study therapy. This was my same concern w/the VITAMINS trial. The authors found an improvement in pts who were diagnosed within 48h of admit. The survival rate increased by 34% w/earlier diagnosis. I have been beating this drum for a while now. Everything in sepsis is starting early with aggressive therapy. Don’t let the patients go beyond the early phases. They smolder w/worsening organ function until they ultimately succumb of septic shock. Now, there are limitations. Of the 80 pt, only 43 were dx within 48h. 3 patients died in the experimental group while 10 died in the control group. I’m stretching quite a bit here with my statistical analysis (given the extremely small sample size) but that would mean that the NNT to save a life is just 2.9. Okay, I stretched a lot. Then again, you all know my bias. See the breakdown of the adverse effects on eddyjoemd.com. It doesn’t fit here. 😬 Thanks for your support

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ORANGES Trial

Let’s get the good stuff out of the way. This is actually a positive study which showed a faster resolution of shock! This is good because people could get off of pressors faster. We should see shorter times where central lines are in place (decreasing the likelihood of CLABSI’s). Patients could be discharged from the ICU faster leading to a decreased cost. It also obviously decreases the need for vasopressors which can same some fingers and toes.

Peeling the ORANGES: The Design

This was a randomized, double-blind, placebo controlled trial. Only the best here. They also used the same regimen provided by the Marik Protocol, as well as the VITAMINS and HYVCTTSSS trials. I like that it took place in non-academic community hospitals because I work at one of these shops. Patients were able to receive hydrocortisone in the control arm at the discretion of the clinician. They included 137 patients in the analysis when it was said and done. Unlike the HYVCTTSSS trial, they excluded patients transferred from other hospitals.

Hypovitaminosis C: ORANGES collected this data

Something a little different: they drew baseline ascorbic acid and thiamine levels. They found that 50% of the patients had hypovitaminosis C. 14% had severe hypovitaminosis C. The incidence of hypovitaminosis C is lower than prior data, but remains worth considering. Having fewer patients with hypovitaminosis C overall is a reason why the authors suggest they didn’t note additional benefits of this therapy. They didn’t subgroup the analysis on the patients who had hypovitaminosis C, though. Insert sad face emoji.

They defined hypovitaminosis as an ascorbic acid level less than or equal to 23mmol/L and severe as an ascorbic acid level less than or equal to 11.3mmol/L.

Expedient enrollment, unlike the others…

The ORANGES researchers can teach the VITAMINS team a thing or two as their patients received the study drugs between 3-14 hours from presentation to the ED. Treatment was allowed to begin in the ED.

Outcome targets for ORANGES

Rather than mortality, this study looked reducing organ dysfunction via SOFA scores as well as resolution of shock.

Patients got off of vasopressors faster in the HAT therapy group (p<0.001). This makes fundamental sense as ascorbic acid is a known co-factor for endogenous catecholamine production. Remember how I mentioned that some patients in the control group got steroids as well? Well, HAT therapy got patients off of vasopressors faster in those patients, too. They did fancy statistics to show this. Patients in the control arm were in shock 59% longer. Think about what this benefit could do for your length of stay metrics.

Regarding the SOFA scores, there was no difference. Funny that the HYVCTTSSS study as well as the VITAMINS study had improvements in the SOFA scores.

There were no differences in any of the secondary outcomes. They looked at the other typical outcomes like mortality, length of stay, ventilator days, etc. But there was also no increase in acute kidney injury, either (p=0.098). To those fixated on calcium oxalate crystals, there was no difference in urinary oxalate (p=0.35). In other words, no harm.

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I don’t have much time to redo the full breakdown here but you can learn a whole bunch on IV Vitamin C, thiamine, and stress dose steroids in resuscitation of patients in shock on eddyjoemd.com/vitaminc. Link to this and my most popular blog posts in bio. Let’s get started. Many different studies coming out regarding Metabolic Resuscitation. It’s very challenging to draw any concrete conclusions and they all have different methodologies, sample sizes, demographics, time of initiation of study drugs. This study, the ORANGES trial, was conducted in non-academic community hospitals. They actually got the study drugs into the patients within 3-14 hours. Some patients were even enrolled in the ED! This study is by no means perfect. They did find that the resolution of Shock was faster in patients who received HAT therapy. This is yet another study where there are no adverse effects noted with the therapy. No worsening renal function. No calcium oxalate crystals. This is not medical advice but for the time being, I will continue to give patients in septic shock this cocktail. Some studies have shown an improvement in mortality, some have shown and improvement in SOFA scores, some shown a decrease in ventilator days, some have shown a hastening of Shock. You know what none of them have shown? Harm.

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ATESS Trial

First of all, hat tip to the authors. At the time of this writing I am not doing any research myself.
Citation
Hwang, S.Y., Ryoo, S.M., Park, J.E. et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study. Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-06191-3
Link to Article
Link to FULL FREE PDF

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The engines are slowing down on my IV Vitamin C, thiamine and steroids train. Another negative study. I can admittedly pick apart the data but if it were to help out large segments of the population, we likely would’ve seen it by now. I never felt that this was a cure for sepsis, let that be clear, but I felt that it was an adjunct that could help decrease mortality and organ dysfunction, at least a tad. Most of the benefits in the studies could be secondary to the effects of the hydrocortisone but in this study the control group didn’t get it. Empiric data is the worst, I know. But I could have sworn I have seen this just turn certain patients around. Some of you said the same thing about tocilizumab which was proven in the data to not decrease mortality, but some of us have watched it completely change the trajectory of patients right in our faces. The challenge moving forward will potentially be finding in whom, if anyone, this will benefit. A 🎩 tip to the authors. You can find links to this article on eddyjoemd.com/vitaminc. I have also recorded a podcast taking apart the article. I’ll also upload it onto youtube later today. And 🎩 tip to @mchocas who was the first to send me this paper published today.

A post shared by Eddy J. Gutierrez, MD (@eddyjoemd) on Aug 18, 2020 at 1:09pm PDT

ACTS Trial

First off, hat tip to @mchocas who was the first person to link me to this trial. It was published today in JAMA.

Another day, another IV vitamin C trial. It appears as if the dust is settling a bit on all this. This paper will be known as the ACTS trial for Ascorbic acid, Corticosteroids and Thiamine in Septic shock.

Citation:
Moskowitz A, Huang DT, Hou PC, et al. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial. JAMA. 2020;324(7):642–650. doi:10.1001/jama.2020.11946
Link to FULL ARTICLE (FULL FREE PDF in the link)

VICTAS Trial

Citation:
Sevransky JE, Rothman RE, Hager DN, Bernard GR, Brown SM, Buchman TG, Busse LW, Coopersmith CM, DeWilde C, Ely EW, Eyzaguirre LM, Fowler AA, Gaieski DF, Gong MN, Hall A, Hinson JS, Hooper MH, Kelen GD, Khan A, Levine MA, Lewis RJ, Lindsell CJ, Marlin JS, McGlothlin A, Moore BL, Nugent KL, Nwosu S, Polito CC, Rice TW, Ricketts EP, Rudolph CC, Sanfilippo F, Viele K, Martin GS, Wright DW; VICTAS Investigators. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA. 2021 Feb 23;325(8):742-750. doi: 10.1001/jama.2020.24505. PMID: 33620405; PMCID: PMC7903252.
Link to Article (NOT FREE)

Meta-analysis and Systematic Review

Sato R, Hasegawa D, Prasitlumkum N, Ueoka M, Nishida K, Takahashi K, Nasu M, Dugar S. Effect of IV High-Dose Vitamin C on Mortality in Patients With Sepsis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Crit Care Med. 2021 Sep 8. doi: 10.1097/CCM.0000000000005263. Epub ahead of print. PMID: 34495877.
Link to Article (NOT FREE)

IV Vitamin C in Burn Patients

I can already hear it in my head. “But Eddy, there’s no data that Vitamin C does anything for anyone so I refuse to give it even though it’s inexpensive and has no side effects based on the CITRIS-ALI study, as well as other studies which have flaws for x, y, and z reasons. I’m going to wait for more data while my patients wait for my ego to come around. And then when that data comes out, I’m going to wait another year just because I’m a contrarian-contrarian.”

There are a multitude of reasons why high dose IV Vitamin C (defined as greater than 10gm in 24 hours) should work. This study is wrought with limitations, admitted to by the authors. They conducted some statistical jumping jacks and made some assumptions to make the numbers work. That’s just the issue with retrospective studies such as this one where they’re trying to make heterogenous populations look alike. It’s free meaning you have no excuse to not read it for yourself. I personally do not take care of burn patients. They honestly frighten me. Definite kudos to all the burn unit crews out there who take care of these patients.

I understand that some burn centers in the US are already using IV Vitamin C. Is this a thing at your shop? A hat tip to the authors!
– EJ

Link to Abstract
Link to FULL FREE Article
Nakajima, M., Kojiro, M., Aso, S. et al. Effect of high-dose vitamin C therapy on severe burn patients: a nationwide cohort study. Crit Care 23, 407 (2019)

Cite this post as:

Eddy J. Gutierrez, “IV Vitamin C & Metabolic Resuscitation in Septic Shock: Ultimate Guide”, eddyjoemd.com blog, Date you accessed it. Available at: eddyjoemd.com/vitaminc

Citations:

Marik PE. Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid. Nutrients. 2018 Nov 14;10(11):1762. doi: 10.3390/nu10111762. PMID: 30441816; PMCID: PMC6265973.
Link to Abstract
Link to PDF

Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, Wesley RA, Levine M. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004 Apr 6;140(7):533-7. doi: 10.7326/0003-4819-140-7-200404060-00010. PMID: 15068981.
Link to Article

VITAMINS
Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, Deane AM, Shehabi Y, Hajjar LA, Oliveira G, Udy AA, Orford N, Edney SJ, Hunt AL, Judd HL, Bitker L, Cioccari L, Naorungroj T, Yanase F, Bates S, McGain F, Hudson EP, Al-Bassam W, Dwivedi DB, Peppin C, McCracken P, Orosz J, Bailey M, Bellomo R; VITAMINS Trial Investigators. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020 Feb 4;323(5):423-431. doi: 10.1001/jama.2019.22176. PMID: 31950979; PMCID: PMC7029761.
Link to Abstract
Link to FULL FREE Article

HYVCTTSSS
Chang P, Liao Y, Guan J, Guo Y, Zhao M, Hu J, Zhou J, Wang H, Cen Z, Tang Y, Liu Z. Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial. Chest. 2020 Jul;158(1):174-182. doi: 10.1016/j.chest.2020.02.065. Epub 2020 Mar 31. PMID: 32243943.
Link to Abstract
Link to FULL FREE Article

ORANGES
Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial. Chest. 2020 Jul;158(1):164-173. doi: 10.1016/j.chest.2020.02.049. Epub 2020 Mar 17. PMID: 32194058.
Link to Abstract
Link to FULL FREE Article

ATESS
Hwang SY, Ryoo SM, Park JE, Jo YH, Jang DH, Suh GJ, Kim T, Kim YJ, Kim S, Cho H, Jo IJ, Chung SP, Choi SH, Shin TG, Kim WY; Korean Shock Society (KoSS). Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study. Intensive Care Med. 2020 Nov;46(11):2015-2025. doi: 10.1007/s00134-020-06191-3. Epub 2020 Aug 11. PMID: 32780166; PMCID: PMC7417779.
Link to Article
Link to FULL FREE PDF

ACTS
Moskowitz A, Huang DT, Hou PC, Gong J, Doshi PB, Grossestreuer AV, Andersen LW, Ngo L, Sherwin RL, Berg KM, Chase M, Cocchi MN, McCannon JB, Hershey M, Hilewitz A, Korotun M, Becker LB, Otero RM, Uduman J, Sen A, Donnino MW; ACTS Clinical Trial Investigators. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial. JAMA. 2020 Aug 18;324(7):642-650. doi: 10.1001/jama.2020.11946. PMID: 32809003; PMCID: PMC7435341.
Link to FULL ARTICLE (FULL FREE PDF in the link)

VICTAS
Sevransky JE, Rothman RE, Hager DN, Bernard GR, Brown SM, Buchman TG, Busse LW, Coopersmith CM, DeWilde C, Ely EW, Eyzaguirre LM, Fowler AA, Gaieski DF, Gong MN, Hall A, Hinson JS, Hooper MH, Kelen GD, Khan A, Levine MA, Lewis RJ, Lindsell CJ, Marlin JS, McGlothlin A, Moore BL, Nugent KL, Nwosu S, Polito CC, Rice TW, Ricketts EP, Rudolph CC, Sanfilippo F, Viele K, Martin GS, Wright DW; VICTAS Investigators. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA. 2021 Feb 23;325(8):742-750. doi: 10.1001/jama.2020.24505. PMID: 33620405; PMCID: PMC7903252.
Link to Article (NOT FREE)

Effect of IV High-Dose Vitamin C on Mortality in Patients With Sepsis A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Sato R, Hasegawa D, Prasitlumkum N, Ueoka M, Nishida K, Takahashi K, Nasu M, Dugar S. Effect of IV High-Dose Vitamin C on Mortality in Patients With Sepsis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Crit Care Med. 2021 Sep 8. doi: 10.1097/CCM.0000000000005263. Epub ahead of print. PMID: 34495877.
Link to Article (NOT FREE)

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