Many think that the interest in IV thiamine in septic shock is a relatively novel idea after Paul Marik’s paper was published in CHEST back in 2017. It actually goes a lot further than that. We’ve actually known that 20% of critically ill patients have a thiamine deficiency upon presentation to the ICU. More recent data shows that this could be up to 70%. Over the life of this page, I have covered the renal benefits of thiamine on an older post, including a YouTube video on the matter. In addition, I have covered data reflecting on how you need thiamine to clear lactate and how this all decreases mortality on an older post. In this post, I am going to be thoroughly covering a couple recent studies looking at IV thiamine in sepsis and septic shock.

IV Thiamine on Mortality in Japan

This paper I am going to be discussing first was published in 2020 in Critical Care Medicine. A link to the paper is down below. Unfortunately, it is not open access. In this Japanese study, which is a retrospective observational cohort over the course of 7 years, they wanted to look at the effect of thiamine administration on mortality in patients with septic shock who were on vasopressors. In this case, norepinephrine. I really like that the initiation of thiamine was early in the sepsis course. Sounds great! I hope they leverage their data collection to also look at other proposed benefits listed above and currently in the process of being studied such as lactate clearance and renal function. That would be very helpful as those parameters could more easily be powered by this sample size than mortality.

Something is bothering me about this paper right from the start. In the introduction, they cited a paper written by Donnino et al. where, as the authors of this paper state “found no differences in shock reversal or mortality”. While that is technically true for the entire study, in the subgroup analysis of the patients who were actually thiamine deficient, 35% of the participants, it reduced mortality from 46% to 13%. That’s a number needed to treat of just 3. Small sample size makes NNT less reliable, but you understand where I’m heading with that.

Defining Study Outcomes

When defining the study outcomes, they only looked at mortality. They did not check thiamine levels on these patients which is completely okay with me. Ultimately, the cost of the lab is around $90 in the US per data I’ve found. The cost of 4 days of 200mg IV twice a day for 4 days is only a little more than that. Every institution is different on cost, of course. Countries may vary even more.

IV Thiamine Dosing

The other trials looking at IV thiamine used larger doses than what was used here. Marik and Donnino, for example, used 200mg IV BID. Another study showing benefit written by Woolum, et al. used 500mg IV TID as their most common dose.
The dosing here is either 100 or 200mg IV daily.

Outcomes:

Ultimately, there was no difference in outcomes. They ONLY looked at mortality. They did a bunch of statistical jumping jacks to no avail. No difference. It leaves us with an answer but more questions.
Could the dose not been high enough?
Could the prevalence of thiamine deficiency not be as high in Japan as it is in other parts of the country where the incidence of such is between 20-70%?
They harnessed the power of their national database for the mortality data, but it was unable to give them lactate levels. I wonder if renal function data is stored in there as they used ICD-10 codes. Could the authors leverage this data into two studies?

What does this paper offer regarding IV Thiamine?

It gives us a dose, 100mg or 200mg of thiamine IV daily, that may be too low in Japan, and perhaps the rest of the world. It tells us that IV thiamine on its own will likely not change mortality. But the questions I present still remain. Hopefully the many studies on clinicaltrials.gov regarding thiamine will show something, including a much larger Donnino trial that will be complete in 2021 or 2022 (update: it’s 2023 and still not out).

Brazilian IV Thiamine study

In April of 2023 there was a new RCT looking at IV thiamine. The study is titled “Effect of thiamine on clinical outcomes in septic shock patients: a randomized, double blinded pilot study“. At first, I had high hopes for this as it is published in the Blue Journal. To those unfamiliar with the “lingo”, the Blue Journal is the nickname for the American Journal of Respiratory and Critical Care Medicine. It is the highest impact factor journal in Critical Care so what’s published in there is usually top notch. Key word is usually.

Upon reading this study the first thing that caught my eye was that the study was performed between 2018 and 2019. The issue with the dates is that it is formally published in 2023. Almost 4 years to be sitting on data. The exclusion criteria included > 24 hours in the ICU (good) and norepinephrine doses > 2mcg/kg/min. This dose of norepinephrine has me a bit confused. Perhaps someone will clarify it for me or I could email the authors. I believe this 2mcg/kg/min might be a typo. The reason I say that is because we’d be talking about NE at 140mcg/min in a 70kg patient. That’s definitely a dose high enough to exclude them from a study because, well, those patients aren’t likely to survive anyway. That’s a higher dose of jet fuel than what most people use in their practice anyway.

Dosing the IV Thiamine

Here, a 200mg IV of thiamine twice a day dose was provided for these patients. The duration of the IV thiamine was 5 days. The placebo group received, well, placebo. An interesting thing they did in this study was check the baseline level of thiamine. More on that later.

Comparing the two groups

Both the placebo and IV thiamine group were well matched, except in some key points. The placebo group had more thiamine deficiency at 10.9% of those patients being thiamine deficient vs. just 5.4% in the thiamine group. Right off the bat the alarms went off in my head reminding me of the 2016 Donnino study which showed that the greatest benefit to administering IV thiamine was in those patients who were already thiamine deficient. These percentages are lower than the 20-70% that was reference in the Mallat et al. paper back in 2016.

Underlying malignancies were more common in the thiamine group at 21% vs. 10.3%. The authors also mentioned a difference in the creatinine levels between the two groups but I just can’t seem to find where this is listed in the paper. I neglected to mention that they enrolled a total of 115 patients so it’s not a large study. Hence it being a “pilot study”.

Outcomes

As I just mentioned, this is a pilot study. Pilot studies are usually not powered for any real findings. This is why I am curious as to why it is in the Blue Journal. 28 day mortality is higher than what we most see in our ICU’s and higher than the ARISE, PROMISE and PROCESS trials at 56 and 60% respectively. In addition, no difference exists in the survival curves, length of stay for both ICU and hospital, vasopressor-free days, and ventilator-free days. It’s interesting that they did not look at lactate clearance as was done in the Woolum retrospective trial back in 2018. They also did not report any renal-related outcomes as were documented in the Moskowitz paper from 2017.

Where do we go from here with IV Thiamine?

Do I personally feel it is the magic cure? No. Do I feel that we are undertreating people with underlying thiamine deficiency? Yes. I am definitely looking forward to the Donnino study that is currently listed on clinical trials.gov. It also has me a bit worried that their results are not going to be positive because they’ve been sitting on those data for a while. If it were earth shattering or practice-changing, I’m sure it would be published by not. At least in pre-print form.

Citations of IV Thiamine

Miyamoto Y, Aso S, Iwagami M, Yasunaga H, Matsui H, Fushimi K, Hamasaki Y, Nangaku M, Doi K. Association Between IV Thiamine and Mortality in Patients With Septic Shock: A Nationwide Observational Study. Crit Care Med. 2020 Aug;48(8):1135-1139. doi: 10.1097/CCM.0000000000004394. PMID: 32697483.
Link to Abstract (NOT FREE)

Pereira AG, Costa NA, Amancio SC, Okoshi MP, Zornoff LA, Azevedo PS, Minicucci MF, de Paiva SA, Polegato BF. Effect of Thiamine on Clinical Outcomes in Septic Shock Patients: A Randomized, Double-Blinded Pilot Study. Am J Respir Crit Care Med. 2023 Apr 13. doi: 10.1164/rccm.202208-1583LE. Epub ahead of print. PMID: 37053464.
Link to Abstract (NOT FREE)

Donnino MW, Andersen LW, Chase M, Berg KM, Tidswell M, Giberson T, Wolfe R, Moskowitz A, Smithline H, Ngo L, Cocchi MN; Center for Resuscitation Science Research Group. Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med. 2016 Feb;44(2):360-7. doi: 10.1097/CCM.0000000000001572. PMID: 26771781; PMCID: PMC4754670.
Link to Article
Link to FULL FREE PDF

Mallat J, Lemyze M, Thevenin D. Do not forget to give thiamine to your septic shock patient! J Thorac Dis. 2016 Jun;8(6):1062-6. doi: 10.21037/jtd.2016.04.32. PMID: 27293820; PMCID: PMC4885988.
Link to Article
Link to FULL FREE PDF

Woolum JA, Abner EL, Kelly A, Thompson Bastin ML, Morris PE, Flannery AH. Effect of Thiamine Administration on Lactate Clearance and Mortality in Patients With Septic Shock. Crit Care Med. 2018 Nov;46(11):1747-1752. doi: 10.1097/CCM.0000000000003311. PMID: 30028362.
Link to Abstract (NOT FREE)

Moskowitz A, Andersen LW, Cocchi MN, Karlsson M, Patel PV, Donnino MW. Thiamine as a Renal Protective Agent in Septic Shock. A Secondary Analysis of a Randomized, Double-Blind, Placebo-controlled Trial. Ann Am Thorac Soc. 2017 May;14(5):737-741. doi: 10.1513/AnnalsATS.201608-656BC. PMID: 28207287; PMCID: PMC5427738.
Link to Article
Link to FULL FREE PDF

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