The HAT Protocol: Vitamin C, Thiamine and Hydrocortisone in Sepsis

Table of Contents

1. How the Protocol Began
2. Vitamin C as a “Stress Hormone”
3. The Three Parts of HAT Therapy
4. The 2017 Before-After Study
5. Patterns of Death and Choosing Patients
6. Marik’s Reply to CITRIS-ALI
7. Randomized Trials of the Three-Drug Combination
8. LOVIT: Vitamin C Given Alone
9. Pooled Analyses and a 2023 Guideline
10. Side Effects Reported in the Trials
11. Key Research Papers
12. Connections
13. Featured Videos

1. How the Protocol Began

Sepsis is the body’s overwhelming and damaging response to an infection. In its most severe form, septic shock, blood pressure collapses and has to be held up with vasopressors, drugs that tighten the blood vessels. Marik’s 2017 paper opens with the scale of the problem: an estimated 15 to 19 million cases of sepsis a year worldwide, with a death rate approaching 60% in low-income countries.

Marik has described the start of the protocol in personal terms. In the preface to his later book Cancer Care he wrote: “Time after time when I gave patients vitamin C, hydrocortisone, and thiamine, their condition turned around within hours.”

The idea was already taking shape in 2016, when he published a short commentary in Critical Care Medicine titled “‘Vitamin S’ (Steroids) and Vitamin C for the Treatment of Severe Sepsis and Septic Shock!” — pairing a corticosteroid with vitamin C, two of the three drugs that became the protocol.

In his 2018 review in Nutrients, which gave the treatment the name “HAT therapy”, he set out the thinking behind it. He noted that “over 100 novel pharmacologic agents that targeted specific molecules or pathways have failed to improve the outcome of sepsis”, and wrote that HAT therapy “is based on the concept that a combination of readily available, safe and cheap agents, which target multiple components of the host’s response to an infectious agent, will synergistically restore the dysregulated immune response and thereby prevent organ failure and death.”

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2. Vitamin C as a “Stress Hormone”

The central idea in Marik’s writing on vitamin C is that it belongs to the body’s stress response alongside cortisol and adrenaline. In a 2020 paper titled “Vitamin C: an essential ‘stress hormone’ during sepsis”, he wrote that in mammals the stress response includes “the increased synthesis and secretion of vitamin C”, and that “Cortisol, catecholamines, and vitamin C act synergistically to increase hemodynamic reserve, maintain immune function and protect the host against excessive oxidant injury.”

The key step in his argument is evolutionary: “Humans (and anthropoid apes) have lost the ability to synthesize vitamin C and therefore have an impaired stress response.” Most other vertebrates make their own vitamin C and make more of it under stress, he wrote in his 2018 review of the scientific rationale. In his view, “Treatment with vitamin C appears to restore the stress response and improve the survival of stressed humans.”

The same 2018 review describes sepsis as producing an overwhelming burst of reactive oxygen species, with injury to the blood-vessel lining, to cells and to mitochondria, and states that “Sepsis is associated with an acute deficiency of vitamin C.” He reported that in experimental sepsis models (animal studies) intravenous vitamin C reduced organ injury and improved survival.

He put the point bluntly in a 2018 editorial with Hooper titled “Doctor—your septic patients have scurvy!”. Scurvy is the disease of severe vitamin C deficiency.

A related study looked at a different group. In 2019 Marik and Liggett measured vitamin C on admission in 69 patients with alcohol use disorders admitted to their medical intensive care unit (septic patients were excluded). The mean level was 17.0 µmol/l against a normal range of 40–60; 88% were below normal and 75% met their definition of hypovitaminosis C (below 23 µmol/l). The abstract notes that thiamine replacement is already standard care for these patients; the paper’s title, “Adding an orange to the banana bag”, proposes adding vitamin C to it.

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3. The Three Parts of HAT Therapy

Marik’s papers give each of the three drugs a role.

• Vitamin C (ascorbic acid) is the centre of the protocol, for the reasons in the section above. His 2018 Nutrients review is subtitled “Focus on Ascorbic Acid”.
• Hydrocortisone is a corticosteroid, a synthetic form of the body’s own cortisol. Marik had written about corticosteroids in critical illness long before the protocol and was first author of a 2008 international consensus statement on corticosteroid insufficiency in critically ill adults.
• Thiamine (vitamin B1) completes the combination. In a 2018 commentary he called it “An Essential Component of the Metabolic Resuscitation Protocol” — “metabolic resuscitation” being another name used for the three-drug treatment.

The claim that the drugs work better together than apart rests partly on laboratory work. In a 2017 study with Catravas and colleagues, human lung microvascular endothelial cells (the cells lining the smallest blood vessels of the lung) were exposed to a bacterial toxin, lipopolysaccharide, which made the cell layer leaky. According to the abstract, vitamin C alone “did not exhibit barrier enhancement properties” and hydrocortisone alone had “only a minor barrier-enhancing and protective effect”, but the two together, given before or after the toxin, “dramatically reversed” the leak. This was a study in cells grown in the laboratory, not in patients; the authors wrote that it suggests “one possible pathway” for the effects seen in patients.

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4. The 2017 Before-After Study

The study that launched the protocol was published in the journal Chest in June 2017 (online December 2016) by Marik, Khangoora, Rivera, Hooper and Catravas, under the title “Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study.”

How the study was designed. It was not a randomized trial. The authors looked back at their own records (a retrospective study) and compared two groups treated at different times in the same intensive care unit:

• a treatment group: consecutive septic patients given intravenous vitamin C, hydrocortisone and thiamine during a 7-month period;
• a control group: septic patients treated in the same unit during the preceding 7 months, before the protocol was used.

The primary outcome was survival to leaving hospital. To adjust for differences between the groups, the authors calculated a propensity score, a statistical method for comparing like with like.

What the paper reported.

• There were 47 patients in each group, with “no significant differences in baseline characteristics between the two groups.”
• Hospital mortality was 8.5% (4 of 47) in the treatment group against 40.4% (19 of 47) in the control group.
• After propensity adjustment, the odds of death in the treated patients were 0.13 of those in the control group (95% confidence interval 0.04 to 0.48).
• The organ-failure score (the Sequential Organ Failure Assessment) fell in every treated patient, and none developed progressive organ failure.
• Every treated patient was weaned off vasopressors, on average 18.3 hours after the vitamin C protocol was started. In the control group vasopressors were used for an average of 54.9 hours.

What the authors concluded. The abstract states that the results “suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, are effective in preventing progressive organ dysfunction, including acute kidney injury, and in reducing the mortality of patients with severe sepsis and septic shock”, and adds: “Additional studies are required to confirm these preliminary findings.”

The doses. The 2017 abstract names the three drugs but not their doses. The VITAMINS trial (section 7), which set out to test the combination, gave intravenous vitamin C 1.5 g every 6 hours, hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours; other trials used somewhat different doses, listed with each trial below.

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5. Patterns of Death and Choosing Patients

In a 2018 paper in Surgical Infections, Marik argued that “patients with sepsis die from the host response to the infecting pathogen rather than from the infecting pathogen itself.” He described four patterns of death in sepsis:

1. vasoplegic shock, in which the blood vessels lose their tone and blood pressure cannot be held up;
2. single-organ respiratory failure, the acute respiratory distress syndrome;
3. multi-system organ failure;
4. persistent multi-system organ failure with ongoing inflammation, immune suppression and repeated infections (the persistent inflammation-immunosuppression and catabolism syndrome).

He noted that immune-modulating therapies aimed at single molecules or pathways had “universally failed”, and proposed that HAT therapy, “which synergistically targets multiple pathways, restores the dysregulated immune system and organ injury, and reduces the risk of death and organ failure following sepsis.”

Marik also wrote on which patients the protocol fits and on its practical safety:

• In a 2019 letter he called procalcitonin, a blood marker that rises in bacterial infection, “an essential biomarker” for HAT therapy in sepsis. (See also the site’s page on the procalcitonin test.)
• He addressed a safety question in a 2019 letter titled “Is intravenous vitamin C contraindicated in patients with G6PD deficiency?” Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited enzyme disorder in which red blood cells can break down under oxidant stress, which is why high-dose intravenous vitamin C has been questioned for people who have it.

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6. Marik’s Reply to CITRIS-ALI

The first large randomized trial of high-dose intravenous vitamin C in sepsis was not a test of the full HAT combination. CITRIS-ALI, published in JAMA in 2019, gave vitamin C alone (50 mg per kilogram every 6 hours for 96 hours) or placebo to 167 patients with sepsis and the acute respiratory distress syndrome in 7 American intensive care units.

According to its abstract, there were no significant differences between the groups in the primary outcomes: the change in the organ-failure score from the start to 96 hours (a fall of 3 points with vitamin C and 3.5 points with placebo), or the blood markers of inflammation (C-reactive protein) and blood-vessel injury (thrombomodulin) at 168 hours. The authors called it a “preliminary study” and wrote that further research was needed on other outcomes.

Marik and Payen answered with an editorial titled “CITRIS-ALI: How statistics were used to obfuscate the true findings.” As the title makes plain, they argued that the way the results were analysed and presented hid what the trial had found.

In 2020, with Varon and Surani, Marik published “Hydrocortisone, ascorbic acid and thiamine for sepsis: Is the jury out?” The authors wrote that “It has been known for decades that patients with sepsis have reduced levels of antioxidants, most notably vitamin C”, that preliminary data suggest the therapy “improves the outcome of patients with sepsis with the potential to save millions of lives”, and that “this intervention has met with much resistance and has not been widely adopted.” They closed: “Ultimately, we await the final jury verdict on this simple, safe and cheap intervention.”

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7. Randomized Trials of the Three-Drug Combination

After 2017, research groups on several continents ran randomized trials of the combination. In a randomized trial, chance decides which patients receive the treatment, so the groups are comparable at the start. The results below are given as each trial’s abstract states them.

• VITAMINS (JAMA, 2020). An open-label trial in 10 intensive care units in Australia, New Zealand and Brazil, with 216 patients in septic shock. It compared vitamin C 1.5 g every 6 hours, hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours with hydrocortisone 50 mg every 6 hours alone, until shock resolved or up to 10 days. Time alive and free of vasopressors up to day 7 was 122.1 hours with the combination and 124.6 hours with hydrocortisone alone. Nine of ten secondary outcomes showed no statistically significant difference. Ninety-day mortality was 28.6% (30 of 105) with the combination and 24.5% (25 of 102) with hydrocortisone alone. No serious adverse events were reported.
• ACTS (JAMA, 2020). A blinded trial at 14 American centres with 205 patients in septic shock. Patients received ascorbic acid 1,500 mg, hydrocortisone 50 mg and thiamine 100 mg every 6 hours for 4 days, or placebo. The organ-failure score fell from 9.1 to 4.4 with the combination and from 9.2 to 5.1 with placebo, a difference that was not statistically significant. Kidney failure occurred in 31.7% against 27.3%, and 30-day mortality was 34.7% against 29.3%, neither difference statistically significant. The authors concluded that the data “do not support routine use of this combination therapy for patients with septic shock.”
• ORANGES (Chest, 2020). A double-blind, placebo-controlled trial with 137 patients with sepsis or septic shock. Patients in the combination group needed vasopressors for 27 hours on average against 53 hours in the comparison group, which the authors describe as quicker reversal of shock. There were no significant differences in the change in organ-failure score, in intensive care unit or hospital mortality, in length of stay, or in ventilator-free days. The authors called for more studies to confirm the finding and to assess any effect on survival.
• VICTAS (JAMA, 2021). A double-blind, placebo-controlled trial at 43 American hospitals. Patients received vitamin C 1.5 g, thiamine 100 mg and hydrocortisone 50 mg every 6 hours, or placebo, for up to 96 hours. After 501 patients had joined, funding was withheld and the trial was stopped. Ventilator- and vasopressor-free days were a median of 25 with the combination and 26 with placebo; 30-day mortality was 22% against 24%. The authors noted that, because the trial ended early, it “may have been underpowered to detect a clinically important difference.”
• Early-treatment trial, China (Critical Care, 2022). A single-centre, double-blind trial of 426 adults in septic shock, treated within 12 hours of diagnosis with hydrocortisone 200 mg daily, vitamin C 2 g every 6 hours and thiamine 200 mg every 12 hours, or saline placebo, for 5 days. Ninety-day mortality was 39.9% with the combination and 39.0% with placebo among the 408 patients analysed per protocol; 28-day mortality was 36.5% against 36.1%. No secondary outcome, including shock reversal, differed significantly.
• HYVITS (Shock, 2023). An open-label trial in four intensive care units in Qatar with 106 patients in septic shock, stopped early for lack of funding. In-hospital mortality at 60 days was 28.3% with the three drugs and 35.8% in the control group, a difference that was not statistically significant. Vasopressor duration among survivors was 50 against 58 hours, also not significantly different.
• Children’s pilot trial (Pediatric Critical Care Medicine, 2024). An open-label pilot in six pediatric intensive care units in Australia and New Zealand with 60 children in septic shock, testing whether a larger trial could be run. Children received hydrocortisone 1 mg per kilogram every 6 hours, ascorbic acid 30 mg per kilogram every 6 hours and thiamine 4 mg per kilogram every 12 hours, or standard care. The trial was judged feasible. Median survival free of organ dysfunction was 20.0 days with the combination and 21.0 days with standard care; shock reversed at a median of 35.2 against 47.3 hours. The authors wrote that the findings would help design a larger trial.

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8. LOVIT: Vitamin C Given Alone

The largest trial described on this page tested vitamin C on its own, without hydrocortisone or thiamine. LOVIT, published in the New England Journal of Medicine in 2022, enrolled adults who had been in the intensive care unit for no more than 24 hours, had proven or suspected infection and were receiving a vasopressor. They received vitamin C at 50 mg per kilogram of body weight, or placebo, every 6 hours for up to 96 hours.

According to the abstract:

• 872 patients were randomized (435 to vitamin C, 437 to placebo).
• The primary outcome, death or persistent organ dysfunction at day 28, occurred in 44.5% (191 of 429) of the vitamin C group and 38.5% (167 of 434) of the placebo group, a risk ratio of 1.21 (95% confidence interval 1.04 to 1.40).
• Death by day 28 occurred in 35.4% against 31.6% (risk ratio 1.17, 95% confidence interval 0.98 to 1.40), and persistent organ dysfunction in 9.1% against 6.9%.
• Organ-dysfunction scores, biomarkers, 6-month survival, quality of life, severe acute kidney injury and episodes of low blood sugar were similar in the two groups.

The authors concluded that adults with sepsis on vasopressors “who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo.”

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9. Pooled Analyses and a 2023 Guideline

Several groups have pooled the randomized trials. Their abstracts report the following.

• Zayed and colleagues (Journal of Intensive Care Medicine, 2022) pooled 6 trials with 839 patients. They found no significant difference in long-term mortality (risk ratio 1.05), intensive care unit mortality, acute kidney injury or length of stay, but a significant reduction in the organ-failure score on day 3 (mean difference −0.92). Their trial sequential analysis for mortality was “inconclusive for excluding lack of benefit”, and they called for larger studies.
• Assouline and colleagues (Critical Care Medicine, 2021) pooled 8 trials with 1,335 patients. They found a greater fall in the organ-failure score within 72 hours with the combination (weighted mean difference −0.82) and a shorter duration of vasopressor need, with no evidence of a difference in intensive care unit mortality or severe kidney injury. They described the improvement as “modest and its clinical relevance is questionable”, and the effect on kidney failure and mortality as unclear.
• Fujii and colleagues (Intensive Care Medicine, 2022), a network meta-analysis that separated the effects of each drug, covered 43 trials and 10,257 patients. They found no significant differences in longer-term mortality (90 days to 1 year) between any of the treatments and placebo or usual care, and no evidence that vitamin C or vitamin B1 affected organ dysfunction or length of stay. Adding a glucocorticoid such as hydrocortisone shortened vasopressor therapy by about 29.8 hours and intensive care unit stay by about 1.3 days.
• Deng and colleagues (International Archives of Allergy and Immunology, 2024) pooled 15 trials with 2,594 patients. Compared with placebo or standard care, the combination reduced the organ-failure score at 72 hours (mean difference −1.16) and the duration of vasopressor use (by 18.8 hours), both on moderate-quality evidence, and lengthened hospital stay by about 2 days on very low-quality evidence. It did not increase adverse events. The authors wrote that its “advantages over hydrocortisone alone remain unclear”, and suggested that future trials use hydrocortisone as the comparison.

The 2023 rapid practice guideline. A panel of 21 experts from 16 countries, supported by the Guidelines in Intensive Care, Development, and Evaluation group, reviewed intravenous vitamin C in adults with sepsis. Its abstract reports that at 90 days intravenous vitamin C “probably does not substantially impact” mortality (relative risk 1.05; 6 trials, 2,148 patients, moderate certainty); that it may slightly shorten vasopressor support (by about 18.9 hours, low certainty); and that it may not reduce organ-failure scores. The panel judged that the undesirable consequences probably outweigh the desirable ones and issued a conditional recommendation against using intravenous vitamin C in adults with sepsis, “beyond that of standard nutritional supplementation”.

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10. Side Effects Reported in the Trials

The trial abstracts report these safety findings:

• VITAMINS reported no serious adverse events.
• In ACTS, the most common serious adverse events were high blood sugar (12 patients on the combination, 7 on placebo), high blood sodium (11 and 7) and new hospital-acquired infection (13 and 12).
• In LOVIT, one patient in the vitamin C group had a severe episode of low blood sugar and another had a serious allergic reaction (anaphylaxis).
• HYVITS reported that its safety endpoints were similar between the groups, and the 2024 meta-analysis by Deng and colleagues found no increase in adverse events with the combination.
• The 2023 guideline panel reported that few adverse events were recorded with vitamin C.

Marik went on to build the vitamin C, thiamine and corticosteroid backbone of HAT therapy into his 2020 COVID-19 hospital protocol; that story is told on the page on MATH+ and his COVID-19 protocols. For an earlier physician who gave large doses of vitamin C, see the page on Frederick Klenner.

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Key Research Papers

1. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229-1238. — PubMed PMID: 27940189
2. Marik PE. “Vitamin S” (Steroids) and Vitamin C for the Treatment of Severe Sepsis and Septic Shock! Crit Care Med. 2016;44(6):1228-9. — PubMed PMID: 27182850
3. Barabutis N, Khangoora V, Marik PE, Catravas JD. Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction. Chest. 2017;152(5):954-962. — PubMed PMID: 28739448
4. Marik PE, Hooper MH. Doctor-your septic patients have scurvy! Crit Care. 2018;22(1):23. — PubMed PMID: 29378661
5. Marik PE. Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol Ther. 2018;189:63-70. — PubMed PMID: 29684467
6. Marik PE. Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid. Nutrients. 2018;10(11):1762. — PubMed PMID: 30441816
7. Marik PE. Patterns of Death in Patients with Sepsis and the Use of Hydrocortisone, Ascorbic Acid, and Thiamine to Prevent These Deaths. Surg Infect (Larchmt). 2018;19(8):812-820. — PubMed PMID: 30040533
8. Marik PE. Thiamine: An Essential Component of the Metabolic Resuscitation Protocol. Crit Care Med. 2018;46(11):1869-1870. — PubMed PMID: 30312231
9. Marik PE. Procalcitonin is an essential biomarker for hydrocortisone, ascorbic acid, and thiamine (HAT) therapy in patients with sepsis. Crit Care. 2019;23(1):151. — PubMed PMID: 31046800
10. Marik PE. Is intravenous vitamin C contraindicated in patients with G6PD deficiency? Crit Care. 2019;23(1):109. — PubMed PMID: 30944032
11. Marik PE, Liggett A. Adding an orange to the banana bag: vitamin C deficiency is common in alcohol use disorders. Crit Care. 2019;23(1):165. — PubMed PMID: 31077227
12. Marik PE, Payen D. CITRIS-ALI: How statistics were used to obfuscate the true findings. Anaesth Crit Care Pain Med. 2019;38(6):575-577. — PubMed PMID: 31785700
13. Marik PE. Vitamin C: an essential “stress hormone” during sepsis. J Thorac Dis. 2020;12(Suppl 1):S84-S88. — PubMed PMID: 32148930
14. Marik PE, Varon J, Surani SR. Hydrocortisone, ascorbic acid and thiamine for sepsis: Is the jury out? World J Diabetes. 2020;11(4):90-94. — PubMed PMID: 32313607
15. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36(6):1937-49. — PubMed PMID: 18496365
16. Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019;322(13):1261-1270. — PubMed PMID: 31573637
17. Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al. 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;323(5):423-431. — PubMed PMID: 31950979
18. Moskowitz A, Huang DT, Hou PC, Gong J, Doshi PB, Grossestreuer AV, 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. — PubMed PMID: 32809003
19. 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;158(1):164-173. — PubMed PMID: 32194058
20. Sevransky JE, Rothman RE, Hager DN, Bernard GR, Brown SM, Buchman TG, et al. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA. 2021;325(8):742-750. — PubMed PMID: 33620405
21. Lamontagne F, Masse MH, Menard J, Sprague S, Pinto R, Heyland DK, et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. N Engl J Med. 2022;386(25):2387-2398. — PubMed PMID: 35704292
22. Lyu QQ, Zheng RQ, Chen QH, Yu JQ, Shao J, Gu XH. Early administration of hydrocortisone, vitamin C, and thiamine in adult patients with septic shock: a randomized controlled clinical trial. Crit Care. 2022;26(1):295. — PubMed PMID: 36171582
23. Mohamed A, Abdelaty M, Saad MO, Shible A, Mitwally H, Akkari AR, et al. Evaluation of Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Septic Shock: A Randomized Controlled Trial (The HYVITS Trial). Shock. 2023;59(5):697-701. — PubMed PMID: 36870070
24. Schlapbach LJ, Raman S, Buckley D, George S, King M, Ridolfi R, et al. Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study. Pediatr Crit Care Med. 2024;25(2):159-170. — PubMed PMID: 38240537
25. Assouline B, Faivre A, Verissimo T, Sangla F, Berchtold L, Giraud R, et al. Thiamine, Ascorbic Acid, and Hydrocortisone As a Metabolic Resuscitation Cocktail in Sepsis: A Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis. Crit Care Med. 2021;49(12):2112-2120. — PubMed PMID: 34582409
26. Zayed Y, Alzghoul BN, Banifadel M, Venigandla H, Hyde R, Sutchu S, et al. Vitamin C, Thiamine, and Hydrocortisone in the Treatment of Sepsis: A Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials. J Intensive Care Med. 2022;37(3):327-336. — PubMed PMID: 33511898
27. Fujii T, Salanti G, Belletti A, Bellomo R, Carr A, Furukawa TA, et al. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. Intensive Care Med. 2022;48(1):16-24. — PubMed PMID: 34750650
28. Reintam Blaser A, Alhazzani W, Belley-Cote E, Møller MH, Adhikari NKJ, Burry L, et al. Intravenous vitamin C therapy in adult patients with sepsis: A rapid practice guideline. Acta Anaesthesiol Scand. 2023;67(10):1423-1431. — PubMed PMID: 37500083
29. Deng J, Zuo QK, Venugopal K, Hung J, Zubair A, Blais S, et al. Efficacy and Safety of Hydrocortisone, Ascorbic Acid, and Thiamine Combination Therapy for the Management of Sepsis and Septic Shock: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Int Arch Allergy Immunol. 2024;185(10):997-1018. — PubMed PMID: 38870923

PubMed Topic Searches

1. Hydrocortisone, ascorbic acid and thiamine in sepsis
2. Intravenous vitamin C in septic shock: randomized trials
3. Vitamin C deficiency in critically ill patients
4. Thiamine in septic shock
5. Marik PE: sepsis and vitamin C papers

Further Reading

• Marik PE. Cancer Care: The Role of Repurposed Drugs and Metabolic Interventions in Treating Cancer, 2nd ed. (preface quoted above). Independent Medical Alliance research page

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Connections

• Dr. Paul Marik: Critical Care, Vitamin C and Repurposed Drugs
• Paul Marik: Life and Career
• MATH+ and Paul Marik’s COVID-19 Treatment Protocols
• Cancer Care: Paul Marik’s Book on Repurposed Drugs
• Paul Marik’s Metabolic Approach to Cancer
• Paul Marik’s Critical Care Research and Textbooks
• Contemporary Practitioners
• Sepsis
• Vitamin C (Ascorbic Acid)
• Vitamin C and Intensive Care Unit Recovery
• Vitamin B1 (Thiamine)
• Adrenal Insufficiency

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