What is the Cocktail for Sepsis?: Understanding the Controversial HAT Therapy

October 12, 2025 •

3 min read

Despite advances in modern medicine, sepsis remains a leading cause of death in Intensive Care Units, affecting an estimated 1.7 million Americans annually. In the past decade, a controversial treatment known as the 'cocktail for sepsis,' involving a combination of high-dose intravenous vitamin C, hydrocortisone, and thiamine, emerged as a potential adjunctive therapy, though its efficacy remains highly debated.

Quick Summary

The "sepsis cocktail" or HAT protocol is a proposed adjunctive therapy combining intravenous vitamin C, hydrocortisone, and thiamine. Early retrospective studies showed significant promise, but larger, high-quality randomized controlled trials failed to demonstrate a mortality benefit, causing major medical guidelines to withhold a recommendation.

Key Points

HAT Therapy: The cocktail for sepsis refers to a controversial adjunctive treatment protocol using high-dose intravenous vitamin C, hydrocortisone, and thiamine.
Conflicting Evidence: While early retrospective studies suggested a significant reduction in sepsis mortality, large-scale randomized controlled trials failed to replicate these benefits, leading to mixed and inconclusive findings.
Standard Care First: Major medical guidelines, including the Surviving Sepsis Campaign, do not recommend the routine use of the HAT cocktail and emphasize evidence-based standards like prompt antibiotics, fluid resuscitation, and source control.
Proposed Mechanisms: Proponents theorize the combination works synergistically by providing antioxidant support, normalizing metabolism, and aiding adrenal function, addressing cellular dysfunction in sepsis.
Limited Benefits: Some studies show potential for limited benefits, such as reducing the duration of vasopressor use, but these findings are inconsistent and not tied to a significant mortality reduction.
No Mortality Benefit: The most rigorous, high-quality RCTs, including the VICTAS and LOVIT trials, did not find a mortality benefit from the sepsis cocktail.
Potential Risks: Although generally considered safe, some trials have noted potential adverse effects, such as a higher rate of acute kidney injury or hypernatremia in certain subgroups.

What Is the 'Sepsis Cocktail'?

The "sepsis cocktail," also known as HAT therapy, consists of high-dose intravenous ascorbic acid (vitamin C), hydrocortisone, and thiamine (vitamin B1). This combination gained significant attention after a small, retrospective study in 2017 suggested it dramatically reduced mortality in patients with severe sepsis or septic shock compared to historical controls. The therapy's proponents believe it addresses cellular metabolic dysfunction and inflammation in sepsis, with each component working synergistically.

The Proposed Mechanisms of Action

Vitamin C (Ascorbic Acid)

Sepsis is associated with depleted vitamin C, which acts as an antioxidant, supports vasopressor synthesis, and helps maintain endothelial function. High-dose IV administration is proposed to overcome this deficiency and its effects.

Hydrocortisone

Corticosteroids are used in sepsis to treat shock unresponsive to fluids and vasopressors, potentially addressing relative adrenal insufficiency. Hydrocortisone in the HAT protocol is thought to have anti-inflammatory effects and potentially enhance vitamin C uptake.

Thiamine (Vitamin B1)

Thiamine is crucial for cellular energy metabolism and is often deficient in critically ill patients. Supplementation in the HAT protocol aims to improve energy production and potentially aid in lactate clearance. It may also help process high-dose vitamin C, reducing the theoretical risk of kidney stones.

The Shift from Promise to Controversy: A Tale of Clinical Trials

The initial excitement from the retrospective Marik study led to demands for more rigorous randomized controlled trials (RCTs) due to the study's design limitations and potential for bias. Subsequent large multicenter RCTs have presented conflicting and largely disappointing results regarding mortality benefits. Trials like VICTAS and LOVIT did not show a reduction in mortality with the cocktail. The LOVIT trial was even stopped early due to concerns that vitamin C might increase the risk of death or organ dysfunction in some patients. Some trials noted minor benefits in secondary outcomes, but these were inconsistent and did not improve survival.

Major Trials on the Sepsis Cocktail: A Comparison


Feature	Marik et al. (2017)	VICTAS (2021)	LOVIT (2022)
Study Design	Retrospective, before-and-after	Multicenter RCT, adaptive sample size	Multicenter RCT
Location	Single center, USA	Multicenter, USA	Multicenter, Canada
Primary Finding (Mortality)	8.5% in treatment group vs 40.4% in control (significant reduction)	No significant difference in mortality or organ failure	Higher composite outcome of death or persistent organ dysfunction in vitamin C group
Other Findings	Reduced vasopressor duration, less organ dysfunction	No reduction in ventilator- and vasopressor-free days	No significant difference in SOFA score at 96 hours
Limitations	Small sample size, high risk of bias, non-randomized	Protocol deviations, early termination	Early termination, potential for confounding factors

Why Consensus Is Lacking

The discrepancy between the initial study and later RCTs is attributed to factors like the heterogeneity of sepsis, which affects patients differently. More rigorous, blinded RCTs provided reliable evidence that the initial dramatic findings were not widely reproducible. Variations in dosing and timing in different studies may also play a role, though even optimized protocols failed to show a consistent benefit.

Current Guidelines and Standard of Care

Current sepsis management focuses on rapid, evidence-based interventions. The Surviving Sepsis Campaign (SSC) guidelines do not recommend routine use of the HAT cocktail. Standard care, as per the SSC's Hour-1 Bundle, includes rapid antibiotics, fluid resuscitation, lactate measurement, timely vasopressors, and source control. Corticosteroids are sometimes used for septic shock but based on specific criteria, not as part of the routine HAT protocol.

Conclusion

The search for an effective cocktail for sepsis highlights the challenges of medical research. Despite initial promise and a plausible biological rationale, rigorous RCTs have not confirmed that HAT therapy reduces mortality. Consequently, it is not recommended by major medical guidelines and is not part of the standard of care. Sepsis management continues to rely on prompt implementation of proven therapies. The pursuit of new sepsis treatments underscores the importance of robust evidence before widespread adoption.

For additional information on evidence-based sepsis management, the Surviving Sepsis Campaign website is an authoritative resource for both clinicians and patients. Surviving Sepsis Campaign

Frequently Asked Questions

The cocktail consists of three intravenous medications: high-dose ascorbic acid (vitamin C), hydrocortisone, and thiamine (vitamin B1).

Clinical evidence is mixed. While initial studies suggested a significant benefit, larger, high-quality randomized controlled trials have failed to confirm a reduction in mortality. Its use remains controversial in the medical community.

The cocktail is not standard practice because major medical bodies like the Surviving Sepsis Campaign do not recommend it, citing a lack of high-quality evidence proving its effectiveness, particularly in reducing mortality.

The standard of care for sepsis is focused on rapid, proven interventions known as the Hour-1 Bundle, including prompt administration of broad-spectrum antibiotics, fluid resuscitation, and vasopressors, along with source control of the infection.

While the components are generally safe at standard doses, some trials using high-dose vitamin C have reported a higher incidence of acute kidney injury or hypernatremia in some patients, though results are not always consistent.

The initial positive findings came from retrospective, before-and-after studies, which are known to have a higher risk of bias than randomized controlled trials. Factors other than the therapy, such as improved general care, may have contributed to the observed outcomes.

Yes, research into adjunctive therapies for sepsis continues. Scientists are exploring potential benefits in specific patient subgroups or different dosing strategies, but results have not yet led to a change in major treatment guidelines.

Critically ill patients with sepsis often have low vitamin C levels, which may contribute to pathophysiological issues seen in the condition {Link: ncbi.nlm.nih.gov https://pmc.ncbi.nlm.nih.gov/articles/PMC9693906/}.

The LOVIT trial, a major multicenter randomized controlled trial, was stopped early due to a potential for harm, with higher rates of death or persistent organ dysfunction in patients receiving high-dose vitamin C {Link: ncbi.nlm.nih.gov https://pmc.ncbi.nlm.nih.gov/articles/PMC9693906/}.