Now that VITAMINS is published, it’s worth trying to look at the big picture of sepsis treatment with hydrocortisone, ascorbate, and thiamine (HAT).
Marik et al. 2017: The beginning
HAT therapy began with a single-center, before/after study.1 There was a stark mortality reduction following the routine adoption of HAT therapy in septic shock (figure below, p=0.0006).
This study has numerous limitations (single-center, before/after, retrospective design). It seems like HAT therapy is doing something, but the study cannot prove it.
subsequent before/after studies
HAT therapy was adopted in several centers, leading to additional before/after studies (comparing outcomes before versus institution of HAT protocols versus afterwards). One of these studies was neutral,2 but most showed benefit from HAT.3–5
These studies have the same limitations as Marik’s original study (single-center, before/after, retrospective design). Nonetheless, it is notable that several institutions did find that using HAT correlated with improved outcomes.
why might HAT therapy improve outcomes?
In the spirit of full disclosure, I drank some of the cool aid and used HAT in my septic patients. My impression is that this does improve outcomes (consistent with the above studies). Exactly how or why it might work, however, is complicated.
Applying HAT could lead to a host of downstream consequences. This creates numerous potential mechanisms whereby HAT might improve patient outcomes, perhaps most notably…
(#1) Ascorbate and thiamine might cause direct benefit.
- This is the most obvious potential mechanism of benefit – HAT works as intended.
- There are multiple theoretical mechanisms whereby ascorbate and thiamine could improve the pathophysiology of septic shock. Additionally, this is supported by a fair body of basic science and clinical evidence.5–9
(#2) HAT leads to early administration of hydrocortisone.
- Hydrocortisone has been proven in multi-center RCTs to improve organ function (including pulmonary function and cardiovascular stability).10,11
- Whether hydrocortisone affects mortality is debatable and probably unknowable. APPROCHSS did find mortality benefit, possibly related to early administration of hydrocortisone (more on this here).11
- Early steroid therapy is beneficial for the treatment of bacterial meningitis (whereas delayed steroid therapy is ineffective).12 It’s conceivable that early steroid treatment could have augmented benefits in other forms of infection as well.
(#3) Avoiding over-resuscitation and unnecessary procedures
- If you believe that HAT is going to save the patient’s life, then you may be more willing to tolerate mild instability while waiting for the patient to improve (rather than, for example, bolusing additional volume in efforts to immediately improve the hemodynamics).
- Likewise, if you feel that HAT will turn things around, you might be less likely to immediately intubate the patient or place a central line.
- In many cases, willingness to tolerate moderate abnormalities with a watch-and-wait mentality may avoid unnecessary procedures and iatrogenic harm.
(#4) Self-fulfilling prophecy
- Using HAT may promote a belief that patients shouldn’t die from septic shock. If clinicians believe that the patient will survive, this belief itself may improve survival. The team will be more willing to deploy extraordinary measures, and less willing to withdraw life-sustaining therapies.
- For example, the use of HAT has indirectly led me to deploy super-human doses of vasopressors in some scenarios which appeared hopeless. These patients have generally survived.
randomized controlled trials
Retrospective studies show that at some hospitals, the institution of HAT has correlated with improvements in outcomes. This doesn’t prove that HAT has caused improvements in outcome. Nor does it clarify whether improvements might result from ascorbate/thiamine, or result from other downstream consequences of HAT treatment. To clarify causality and mechanism, we need RCTs.
Unfortunately, RCTs have some inherent limitations. Enrollment, consent, and randomization all take time. This will inevitably delay the initiation of study therapies. This may render traditional RCTs a limited strategy for studying immediate, up-front initiation of HAT.
CITRIS-ALI isn’t actually a study of HAT, but it is the first large multi-center RCT investigating IV vitamin C. It investigated relatively high-dose IV vitamin C in patients with sepsis and ARDS.13
Interpreting this study is controversial, to say the least. Patients treated with IV vitamin C had lower mortality, but this wasn’t the primary endpoint. Mortality differences compromised the validity of the primary endpoint (changes in SOFA score), because SOFA score was recorded only in survivors. Thus, IV vitamin C may have been a victim of its own success (because sicker patients in the Vitamin C group survived – instead of dying – this dragged down SOFA scores in the Vitamin C group!).
It’s controversial how to deal with this statistical conundrum of survivorship bias. Re-analysis of the study is arguably warranted, but it will be difficult to achieve this in a fashion which will be widely accepted. Ultimately, mortality reduction is an important endpoint and a signal of potential clinical benefit (regardless of whether it was designated as a primary or secondary endpoint). This conundrum is discussed further here.
This is a multi-center RCT of patients in septic shock which compares hydrocortisone alone versus HAT therapy. 216 patients were included as shown here:
No impact was seen on the primary endpoint (vasopressor-free time) or mortality (table below). Ironically, HAT did cause an improvement in the SOFA score (the much-debated primary endpoint of CITRIS-ALI). However, since this is an isolated secondary endpoint, it cannot carry much weight.
The main limitation of VITAMINS is that it’s not a study of early metabolic resuscitation:
- The median delay from ICU admission to randomization was 12 hours. This doesn’t account for time delays prior to ICU arrival (which for some patients included inter-hospital transfer). All told, patients received HAT relatively late in the course of septic shock.
- 40% of patients had already been initiated on stress-dose steroid prior to study enrollment. This illustrates that VITAMINS wasn’t a study of the initial resuscitative strategy.
Timing of therapies in septic shock matters. A retrospective study of HAT suggests that early therapy is important (ideally within <6 hours):5
Overall, VITAMINS is an outstanding RCT which argues against benefit from delayed HAT therapy in septic shock. This suggests that progressive depletion of vitamin C levels over time isn’t clinically relevant (as such deficiencies often arise days after the initiation of critical illness). However, this study doesn’t investigate whether early HAT therapy could protect the vascular endothelium during the initial phase of sepsis (which is purported to be a mechanism of HAT treatment).14
CITRIS-ALI vs. VITAMINS:
Administration of IV vitamin C was delayed in both CITRIS-ALI and also VITAMINS. Why, then, might Vitamin C appear to have benefit in CITRIS-ALI, but not VITAMINS? There are a few potential reasons:
- CITRIS-ALI involved higher doses of IV vitamin C. A small pilot RCT on sepsis previously suggested that higher doses may be more effective.15
- CITRIS-ALI involved intubated patients with ARDS, who were likely experiencing ongoing stress on alveolar capillaries and endothelium. Vitamin C could be beneficial in this context, given the ongoing and progressive endothelial injury.
- Of course, another explanation is that both studies were actually negative (with mortality differences in CITRIS-ALI being a statistical fluke).
where do we go from here?
Since the publication of Marik’s 2017 paper, about a hundred studies have been published on HAT therapy. Despite this, equipoise persists. Pro and Con arguments regarding HAT might be summarized roughly as follows:
- Before/after studies suggest that HAT therapy was beneficial in multiple hospitals.
- CITRIS-ALI found a mortality reduction with high-dose IV vitamin C therapy in ARDS due to sepsis.
- Studies disagree about whether HAT is beneficial, but there is no persuasive evidence of harm. The worst-case scenario seems to be that vitamin C and thiamine are a harmless waste of resources.
- VITAMINS excludes delayed benefit from HAT, but doesn’t evaluate early HAT therapy.
- VITAMINS indicates that ascorbic acid and thiamine add nothing to hydrocortisone.
- CITRIS-ALI was a negative study (based on its primary endpoint of SOFA scores).
- Before/after studies are vulnerable to numerous biases and confounders.
There are currently several additional RCTs underway on vitamin C. Hopefully these studies will continue to completion (since equipoise on the topic persists). We may need to be patient and wait a couple more years for a plurality of additional data from these studies.
It is increasingly likely that when the dust finally settles, we may recognize that the benefit of early HAT therapy was solely due to early steroid paired with our conviction that sepsis is a survivable illness (with the vitamin C and thiamine functioning as placebos). That would be disappointing, but not a bad outcome. It’s possible that vitamin C and thiamine served as training wheels, allowing us to think about sepsis resuscitation and mortality in a fresh light. Perhaps the cure for sepsis was with us all along – early source control, antibiotics, steroid, gentle resuscitation, patience… and hope.
- Several retrospective before/after studies have suggested benefit from HAT therapy. However, these studies don’t clarify the mechanism of benefit (e.g. early hydrocortisone, ascorbic acid, or merely clinicians’ behavior when they are more confident that the patient will recover).
- VITAMINS is a multi-center RCT comparing hydrocortisone alone vs. HAT therapy. The study found no significant differences, suggesting that the effectiveness of HAT may be due largely to early hydrocortisone administration. However, HAT therapy was administered well after the initial resuscitation, potentially compromising its efficacy.
- Numerous additional RCTs are currently underway to investigate HAT therapy. Hopefully these will shed additional light on the topic.
- Accelerated therapeutic strategy for sepsis (2015)
- HAT therapy: evidentiary background (2017)
- ADRENAL (2018)
- APPROCHSS (2018)
- CITRIS-ALI (2019)
- 1.Marik P, Khangoora V, Rivera R, Hooper M, 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. doi:10.1016/j.chest.2016.11.036
- 2.Litwak J, Cho N, Nguyen H, Moussavi K, Bushell T. Vitamin C, Hydrocortisone, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Analysis of Real-World Application. J Clin Med. 2019;8(4). doi:10.3390/jcm8040478
- 3.Sadaka F, Grady J, Organti N, et al. Ascorbic Acid, Thiamine, and Steroids in Septic Shock: Propensity Matched Analysis. J Intensive Care Med. July 2019:885066619864541. doi:10.1177/0885066619864541
- 4.Kim W, Jo E, Eom J, et al. Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: Propensity score-based analysis of a before-after cohort study. J Crit Care. 2018;47:211-218. doi:10.1016/j.jcrc.2018.07.004
- 5.Long M, Frommelt M, Ries M, et al. Early Hydrocortisone, Ascorbate and Thiamine Therapy for Severe Septic Shock: A Retrospective Cohort Analysis. Critical Care and Shock. 2020:Pending.
- 6.Moskowitz A, Andersen L, Huang D, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care. 2018;22(1):283. doi:10.1186/s13054-018-2217-4
- 7.Marik P. Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol Ther. 2018;189:63-70. doi:10.1016/j.pharmthera.2018.04.007
- 8.Marik P. Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid. Nutrients. 2018;10(11). doi:10.3390/nu10111762
- 9.Badeaux J, Martin J. Emerging Adjunctive Approach for the Treatment of Sepsis: Vitamin C and Thiamine. Crit Care Nurs Clin North Am. 2018;30(3):343-351. doi:10.1016/j.cnc.2018.05.002
- 10.Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808. doi:10.1056/NEJMoa1705835
- 11.Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-818. doi:10.1056/NEJMoa1705716
- 12.Tunkel A, Hartman B, Kaplan S, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-1284. doi:10.1086/425368
- 13.Fowler A, Truwit J, Hite R, 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. doi:10.1001/jama.2019.11825
- 14.Barabutis N, Khangoora V, Marik P, Catravas J. Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction. Chest. 2017;152(5):954-962. doi:10.1016/j.chest.2017.07.014
- 15.Fowler A, Syed A, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32. doi:10.1186/1479-5876-12-32