Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock

A Retrospective Before-After Study
Published:February 03, 2017DOI:https://doi.org/10.1016/j.chest.2016.11.036


      The global burden of sepsis is estimated as 15 to 19 million cases annually, with a mortality rate approaching 60% in low-income countries.


      In this retrospective before-after clinical study, we compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period (treatment group) with a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome.


      There were 47 patients in both treatment and control groups, with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group ( P < .001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04-0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure. All patients in the treatment group were weaned off vasopressors, a mean of 18.3 ± 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 h in the control group ( P < .001).


      Our 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. Additional studies are required to confirm these preliminary findings.

      Key Words


      AKI ( acute kidney injury), APACHE ( Acute Physiology and Chronic Health Evaluation), D5W ( dextrose 5% in water), EHR ( electronic health record), LOS ( length of stay), PCT ( procalcitonin), SOFA ( Sepsis-Related Organ Failure Assessment), SVCT2 ( sodium-vitamin C transporter-2)
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      Linked Article

      • Vitamin C in Sepsis
        CHESTVol. 152Issue 2
        • In Brief
          We read with great interest the paper by Marik et al1 published in CHEST (June 2017). The authors described their experience using a vitamin C-containing regimen as adjunctive therapy in sepsis. Whether this approach is prime for clinical practice is open to debate; however, we wish to issue a cautionary note to clinicians who may adopt this approach regarding the “fictitious hyperglycemia” that has been described with the use of vitamin C in the population of burn patients.2 Significant discrepancies between point-of-care (POC) and central laboratory-analyzed blood glucose values have been previously reported in burn patients receiving high-dose vitamin C (mean of 225 mg/dL vs 138 mg/dL, respectively).
        • Full-Text
        • PDF
      • Response
        CHESTVol. 154Issue 1
        • In Brief
          In a retrospective before and after study, we demonstrated that the combination of vitamin C, hydrocortisone, and thiamine limited the progression of organ failure and reduced the mortality of patients with severe sepsis and septic shock.1 In their letter, Hager et al correctly note that with point of care (POC) glucose monitors that use the glucose-dehydrogenase method of testing (eg, Accu-Chek), spuriously elevated POC glucose levels have been reported in patients with burns who received large doses of vitamin C (> 50 g/d).
        • Full-Text
        • PDF
      • Response
        CHESTVol. 152Issue 4
        • In Brief
          We thank Drs Walter and Singer for their comments regarding our study.1 However, we believe that a number of the quoted statements have been taken out of context or misinterpreted. It is true that we did not expect our therapy to have a dramatic impact on the initial treated patients and we did not expect to see the dramatic impact on mortality that we witnessed vs historical control subjects. Although the standards for applying the term cure are different in the lay press, we were responding to the apparent size of the effect from our intervention.
        • Full-Text
        • PDF
      • Glucometry When Using Vitamin C in Sepsis
        CHESTVol. 154Issue 1
        • In Brief
          A recent before and after study in CHEST (June 2017) of IV vitamin C, thiamine, and hydrocortisone suggested a remarkable mortality benefit in patients with sepsis.1 A subsequent letter to the editor in CHEST (August 2017) raised a safety concern related to discrepancies between point of care (POC) and central laboratory glucose measurements when serum vitamin C concentrations are high.2 Different oxidation reactions are used by different POC devises to measure glucose. Vitamin C (and other molecules) can be oxidized by sensors and cause erroneous readings that are higher than actual serum glucose.
        • Full-Text
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      • Response
        CHESTVol. 152Issue 3
        • In Brief
          We thank Gritsenko et al for their thoughtful letter in response to our study in the June issue of CHEST, which evaluated the role of intravenous vitamin C, hydrocortisone, and thiamine in patients with severe sepsis and septic shock.1 Hydrolysis of the lactone ring of dehydroascorbate irreversibly converts it to 2,3-diketo-1-gulonic acid, which is then converted to oxalate. Oxalate is normally excreted by the kidney, and serum levels will increase with renal impairment. Thiamine deficiency is common in patients with sepsis, and thiamine deficiency increases the conversion of glyoxylate to oxalate, resulting in hyperoxalosis.
        • Full-Text
        • PDF
      • Thiamine
        CHESTVol. 152Issue 3
        • In Brief
          It is interesting that Oudemans van-Straaten and colleagues, in their editorial1 accompanying Marik and co-workers’ observational study of hydrocortisone, thiamine, and vitamin C in severe sepsis in CHEST (June 2017),2 regard thiamine only in the role of minimizing renal oxalate excretion without any possible benefit in its own right.
        • Full-Text
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      • The Unsung Hero
        CHESTVol. 152Issue 3
        • In Brief
          The study by Marik and colleagues,1 published in the June issue of CHEST, is thought-provoking and exciting. Combining intravenous vitamin C with corticosteroids and thiamine reduced mortality by 31.9% in a before-and-after cohort. This research has sparked much interest and debate regarding the efficacy of this “cocktail,” with the majority of focus placed on the vitamin C component. The effects of corticosteroids in sepsis have long been discussed and debated, and the potential synergism between corticosteroids and vitamin C is interesting.
        • Full-Text
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      • Response
        CHESTVol. 152Issue 3
        • In Brief
          We sincerely appreciate the comment by Dr Thomas concerning our editorial on the before-after study by Marik and coworkers using hydrocortisone, vitamin C, and thiamine in severe sepsis (both in CHEST).1,2 Use of this cocktail was associated with an impressive reduction in organ failure and mortality. Yet, effectiveness remains to be proven in a randomized design. In our editorial, we specifically highlighted the beneficial effects of vitamin C, but fully agree with Thomas that the relative contribution of the ingredients in the cocktail currently remains unknown and that thiamine may intrinsically contribute to the metabolic resuscitation in sepsis.
        • Full-Text
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      • Response
        CHESTVol. 152Issue 3
        • In Brief
          Kalil et al raise many concerns regarding our retrospective before-after study in which we investigated the use of vitamin C, hydrocortisone, and thiamine in the treatment of severe sepsis and septic shock.1 Regarding the methodological issues raised, we have acknowledged that this was not a prospective randomized blinded study.1 However, our findings were so compelling that we believed we had an ethical obligation to report our results. Furthermore, we articulated that “this inexpensive and readily available intervention has the potential to reduce the global mortality from sepsis.
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      • Response
        CHESTVol. 152Issue 2
        • In Brief
          We appreciate the correspondence of Flannery et al regarding their concerns regarding point-of-care (POC) glucose testing in patients receiving IV vitamin C.1 We are aware of this potential interaction. Vitamin C and glucose have very similar molecular structures, both being six-carbon molecules, with glucose-6-phospate being the precursor molecule of vitamin C. Spuriously elevated POC glucose levels have been reported in patients with burns who have received large pharmacologic doses of vitamin C (in excess of 50 g/d).
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      • Vitamin C Is Not Ready for Prime Time in Sepsis but a Solution Is Close
        CHESTVol. 152Issue 3
        • In Brief
          We read with interest the report by Marik et al1 published in CHEST (June 2017). However, the study lacked blinding, randomization, concurrent control subjects, and case-control propensity matching; it also had a small sample size, thus substantially increasing the risk of false benefits due to confounding combined with selection and ascertainment biases. Many baseline imbalances favored the treatment arm, as control subjects had more diabetes, heart failure, hypertension, chronic respiratory failure, malignancy, and morbid obesity.
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      • Vitamin C and Sepsis
        CHESTVol. 152Issue 4
        • In Brief
          We read with interest the recent study by Marik et al1 published in the June 2017 issue of CHEST. The trial has many notable limitations, which, in our opinion, render its findings hypothesis generating. However, given the long history of frustrated attempts to identify novel pharmacotherapies for patients with sepsis, efforts to advance the care of critically ill patients should be applauded.
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      • Response
        CHESTVol. 152Issue 3
        • In Brief
          We thank Dr Michelow et al1 for their commentary regarding our study. As was clearly indicated in the paper, our study was approved by our institutional review board; the submitted institutional review board protocol was provided as e-Appendix 1. A short course of low-dose corticosteroids is well-established practice in the treatment of severe sepsis and septic shock.2 Critically ill patients, particularly those with severe sepsis and septic shock, universally have an acute severe deficiency of vitamin C; this has been known for decades.
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      • Hydrocortisone, Vitamin C and Thiamine for Sepsis
        CHESTVol. 152Issue 3
        • In Brief
          Marik et al1 reported the clinical benefits of treating severe sepsis with a combination of hydrocortisone, vitamin C, and thiamine at a single center using a before-after study design. The authors stated that “because of the lack of clinical equipoise and the ethics of withholding a potentially lifesaving intervention, we were unable to initiate a randomized controlled trial.” This study raises fundamental questions about ethics in clinical research as it relates to individual vs clinical equipoise,2 quality improvement vs human subject research, informed consent, research oversight by an institutional review board (IRB), the fine distinction between observational and interventional research, and the rigor of peer review that is designed to hold investigators accountable.
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      • The Magic Bullet in Sepsis or the Inflation of Chance Findings?
        CHESTVol. 152Issue 1
        • In Brief
          In the June 2017 issue of CHEST, Marik et al1 presented a single-center retrospective before and after study assessing the effects of treating patients with severe sepsis/septic shock with IV vitamin C, hydrocortisone, and thiamine. Forty-seven patients were treated with IV vitamin C, hydrocortisone, and thiamine within 24 hours of ICU admission during a 7-month period (treatment group) and compared with 47 patients admitted to the same ICU over the preceding 7 months (control group). The authors reported a hospital mortality of 8.5% in the treatment group compared with 40.4% in the control group (P < .001; adjusted odds of mortality, 0.13; 95% CI, 0.04-0.48).
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      • Response
        CHESTVol. 152Issue 1
        • In Brief
          We appreciate Dr Møller et al for their correspondence regarding our experience with the use of IV vitamin C, hydrocortisone, and thiamine in patients with severe sepsis/septic shock.1 First and foremost, it is important to state that we do not refute, nor did we attempt to mask, the characteristics of our study: a retrospective, single-center, nonrandomized, and unblinded. We initiated this therapy after our review of small trials in similar populations.2,3 We agree that the supporting data on efficacy were as not robust but believed that the available safety data on these particular interventions justified their introduction as salvage therapy in patients who were unlikely to survive.
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