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

      Background

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

      Methods

      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.

      Results

      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).

      Conclusions

      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

      Abbreviations:

      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)
      To read this article in full you will need to make a payment
      Subscribe to CHEST
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Adhikari N.K.
        • Fowler R.A.
        • Bhagwanjee S.
        • et al.
        Critical care and the global burden of critical illness in adults.
        Lancet. 2010; 376: 1339-1346
        • Kaukonen K.M.
        • Bailey M.
        • Suzuki S.
        • et al.
        Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012.
        JAMA. 2014; 311: 1308-1316
        • Gaieski D.F.
        • Edwards J.M.
        • Kallan M.J.
        • et al.
        Benchmarking the incidence and mortality of severe sepsis in the United States.
        Crit Care Med. 2013; 41: 1167-1174
        • Kadri S.S.
        • Rhee C.
        • Strich J.R.
        • et al.
        Estimating ten-year trends in septic shock incidence and morality in United States Academic Medical Centers using clinical data.
        Chest. 2017; 151: 278-285
      1. Marik PE, Linde-Zwirble WT, Bittner EA, et al. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database [published online ahead of print January 27, 2017]. Intensive Care Med. http://dx.doi.org/10.1007/s00134-016-4675-y.

        • Silva E.
        • de Almeida Pedro M.
        • Beltrami Sogayar A.C.
        • et al.
        Brazilian Sepsis Epidemiological Study (BASES study).
        Crit Care. 2004; 8: R251-R260
        • Sales J.A.
        • David C.M.
        • Hatum R.
        • et al.
        • Sepsis Brazil Study
        Sepse Brasil: Estudo Epidemiologico da Sepse em Unidades de Terapia Intensiva Brasileiras [An epidemiological study of sepsis in intensive care units].
        Rev Bras Ter Int. 2006; 18: 9-17
      2. World Health Organization. The top 10 causes of death: the 10 leading causes of death by country income group 2012. WHO fact sheet. http://www.who.int/mediacentre/factsheets/fs310/en/index1.html. Published 2016. Accessed December 15, 2016.

        • Karlsson S.
        • Ruokonen E.
        • Varpula T.
        • et al.
        Long-term outcome and quality-adjusted life years after severe sepsis.
        Crit Care Med. 2009; 37: 1268-1274
        • Yende S.
        • Austin S.
        • Rhodes A.
        • et al.
        Long-term quality of life among survivors of severe sepsis: analyses of two international trials.
        Crit Care Med. 2016; 44: 1461-1467
        • Ou S.M.
        • Chu H.
        • Chao P.W.
        • et al.
        Long-term mortality and major adverse cardiovascular events in sepsis survivors: a nationwide population-based study.
        Am J Respir Crit Care Med. 2016; 194: 209-217
        • Artenstein A.W.
        • Higgins T.L.
        • Opal S.M.
        Sepsis and scientific revolutions.
        Crit Care Med. 2013; 41: 2770-2772
        • Fisher B.J.
        • Kraskauskas D.
        • Martin E.J.
        • et al.
        Attenuation of sepsis-induced organ injury in mice by vitamin C.
        JPEN. 2014; 38: 825-839
        • Fisher B.J.
        • Seropian I.M.
        • Masanori Y.
        • et al.
        Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury.
        Crit Care Med. 2011; 39: 1454-1460
        • Zhou G.
        • Kamenos G.
        • Pendem S.
        • et al.
        Ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis.
        Am J Physiol Regulatory Integrative Comp Physiol. 2012; 302: R409-R416
        • Fowler A.A.
        • Syed A.A.
        • Knowlson S.
        • et al.
        Phase 1 safety trial of intravenous ascorbic acid in patients with severe sepsis.
        J Transl Med. 2014; 12: 32
        • Tanaka H.
        • Matsuda T.
        • Miyagantani Y.
        • et al.
        Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study.
        Arch Surg. 2000; 135: 326-331
        • Long C.L.
        • Maull K.L.
        • Krishman R.S.
        • et al.
        Ascorbic acid dynamics in the seriously ill and injured.
        J Surg Res. 2003; 109: 144-148
        • de Grooth H.J.
        • Choo W.P.
        • Spoelstra-de Man A.M.
        • et al.
        Pharmacokinetics of four high-dose regime[n]s of intravenous vitamin C in critically ill patients.
        Intensive Care Med Exp. 2016; 4 ([abstract]): A52
        • Padayatty S.J.
        • Sun H.
        • Wang Y.
        • et al.
        Vitamin C pharmacokinetics: implications for oral and intravenous use.
        Ann Intern Med. 2004; 140: 533-537
        • Nathens A.B.
        • Neff M.J.
        • Jurkovich G.J.
        • et al.
        Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients.
        Ann Surg. 2002; 236: 814-822
        • Zabet M.H.
        • Mohammadi M.
        • Ramezani M.
        • et al.
        Effect of high-dose ascorbic acid on vasopressor requirement in septic shock.
        J Res Pharm Pract. 2016; 5: 94-100
      3. Ascorbic acid injection. Torrance Company. http://medlibrary.org/lib/rx/meds/ascorbic-acid-5/. Updated November 18, 2016. Accessed December 15, 2016.

        • Ohno S.
        • Ohno Y.
        • Suzuki N.
        • et al.
        High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer.
        Anticancer Res. 2009; 29: 809-815
        • Stephenson C.M.
        • Levin R.D.
        • Spector T.
        • et al.
        Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer.
        Cancer Chemother Pharmacol. 2013; 72: 139-146
        • Marik P.E.
        • Pastores S.M.
        • Annane D.
        • 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: 1937-1949
        • Marik P.E.
        “Vitamin S” (steroids) and vitamin C for the treatment of severe sepsis and septic shock!.
        Crit Care Med. 2016; 44: 1228-1229
        • Fiore L.D.
        • Lavori P.W.
        Integrating randomized comparative effectiveness research with patient care.
        N Engl J Med. 2016; 374: 2152-2158
        • Wacker C.
        • Prkno A.
        • Brunkhorst F.M.
        • et al.
        Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis.
        Lancet Infect Dis. 2013; 13: 426-435
        • Schuetz P.
        • Maurer P.
        • Punjabi V.
        • et al.
        Procalcitonin decrease over 72 hours in US critical care units predicts fatal outcome in sepsis patients.
        Crit Care. 2013; 17: R115
        • Charles P.E.
        • Tinel C.
        • Barbar S.
        • et al.
        Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and outcome.
        Crit Care. 2016; 13: R38
        • Reynolds S.C.
        • Shorr A.F.
        • Muscedere J.
        • et al.
        Longitudinal changes in procalcitonin in a heterogeneous group of critically ill patients.
        Crit Care Med. 2012; 40: 2781-2787
        • Arora S.
        • Singh P.
        • Singh P.M.
        • et al.
        Procalcitonin levels in survivors and non survivors of sepsis: systematic review and meta-analysis.
        Shock. 2015; 43: 212-221
        • Kutz A.
        • Briel M.
        • Christ-Crain M.
        • et al.
        Prognostic value of procalcitonin in respiratory tract infections across clinical settings.
        Crit Care. 2015; 19: 74
        • Society of Critical Care Medicine Consensus Conference Committee
        American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.
        Crit Care Med. 1992; 20: 864-874
        • Mancl E.E.
        • Muzevich K.M.
        Tolerability and safety of enteral nutrition in critically ill patients receiving intravenous vasopressor therapy.
        JPEN. 2013; 37: 641-651
        • Russell J.A.
        • Walley K.R.
        • Singer J.
        • et al.
        Vasopressin versus norepinephrine infusion in patients with septic shock.
        N Engl J Med. 2008; 358: 877-887
        • Kellum J.A.
        • Lameire N.
        Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1).
        Crit Care. 2013; 17: 204
        • Knaus W.A.
        • Draper E.A.
        • Wagner D.P.
        • et al.
        APACHE II: a severity of disease classification system.
        Crit Care Med. 1985; 13: 818-828
        • Zimmerman J.E.
        • Kramer A.A.
        • McNair D.S.
        • et al.
        Acute Physiology and Chronic Health Evaluation (APACHE) IV: hospital mortality assessment for today's critically ill patients.
        Crit Care Med. 2006; 34: 1297-1310
        • Vincent J.L.
        • Moreno R.
        • Takala J.
        • et al.
        • Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine
        The SOFA (Sepsis-Related Organ Failure Assessment) score to describe organ dysfunction/failure.
        Intensive Care Med. 1996; 22: 707-710
        • Marik P.E.
        Early management of severe sepsis: current concepts and controversies.
        Chest. 2014; 145: 1407-1418
        • Siemieniuk R.A.
        • Meade M.P.
        • Alonso-Coello P.
        • et al.
        Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis.
        Ann Intern Med. 2015; 163: 519-528
        • Garnacho-Montero J.
        • Gutierrez-Pizarraya A.
        • Escoresca-Ortega A.
        • et al.
        De-escalation of emperical therapy is associated with lower mortality in patients with severe sepsis and septic shock.
        Intensive Care Med. 2014; 40: 32-40
        • Marik P.
        • Bellomo R.
        A rational apprach to fluid therapy in sepsis.
        Br J Anaesth. 2016; 116: 339-349
        • Marik P.E.
        Fluid responsiveness and the six guiding principles of fluid resuscitation.
        Crit Care Med. 2016; 44: 1920-1922
        • Acute Respiratory Distress Syndrome Network
        Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
        N Engl J Med. 2000; 342: 1301-1308
        • Girardis M.
        • Busani S.
        • Damiani E.
        • et al.
        Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-ICU randomized clinical trial.
        JAMA. 2016; 316: 1583-1589
        • Barr J.
        • Fraser G.L.
        • Puntillo K.
        • et al.
        Clinical practice guidelines for the management of pain, agitation and delirium in adult patients in the intensive care unit.
        Crit Care Med. 2013; 41: 263-306
        • Marik P.E.
        Feeding critically ill patients the right “whey”: thinking outside of the box: a personal view.
        Ann Intensive Care. 2015; 5: 51
        • Marik P.E.
        Is early starvation beneficial for the critically ill patient?.
        Curr Opin Clin Nutr Metab Care. 2016; 19: 155-160
        • Marik P.E.
        Tight glycemic control in acutely ill patients: low evidence of benefit, high evidence of harm!.
        Intensive Care Med. 2016; 42: 1475-1477
        • Marik P.E.
        Stress ulcer prophylaxis de-adoption: what is the barrier?.
        Crit Care Med. 2016; 44: 1939-1941
        • Sprung C.L.
        • Annane D.
        • Keh D.
        • et al.
        Hydrocortisone therapy for patients with septic shock.
        N Engl J Med. 2008; 358: 111-124
        • Karlsson S.
        • Heikkinen M.
        • Pettila V.
        • et al.
        Predictive value of procalcitonin decrease in patients with severe sepsis: a prospective observational study.
        Crit Care. 2010; 14: R205
        • Ferreira F.L.
        • Bota D.P.
        • Bross A.
        • et al.
        Serial evaluation of the SOFA score to predict outcome in critically ill patients.
        JAMA. 2001; 286: 1754-1758
        • de Azevedo J.R.
        • Torres O.J.
        • Beraldi R.A.
        • et al.
        Prognostic evaluation of severe sepsis and septic shock: procalcitonin clearance vs Δ Sequential Organ Failure Assessment.
        J Crit Care. 2015; 30 (219-212)
        • Guan J.
        • Lin Z.
        • Lue H.
        Dynamic change of procalcitonin, rather than concentration itself, is predictive of survival in septic shock patients when beyond 10 ng/mL.
        Shock. 2011; 36: 570-574
        • Ruiz-Rodriguez J.C.
        • Caballero J.
        • Ruiz-Sanmartin A.
        • et al.
        Usefulness of procalcitonin clearance as a prognostic biomarker in septic shock: a prospective pilot study.
        Medicina Intensiva. 2012; 36: 475-480
        • D’Agostino R.B.
        Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group.
        Stat Med. 1998; 17: 2265-2281
        • Marik P.E.
        • Pastores S.M.
        • Kavanaugh B.P.
        Selection bias negates conclusions from the CORTICUS study?.
        N Engl J Med. 2008; 358: 2069-2070
        • Klenner F.R.
        The treatment of poliomyelitis and other virus diseases with vitamin C.
        South Med Surg. 1949; 111: 209-214
        • Hench P.S.
        • Kendall E.C.
        • Slocumb C.H.
        • et al.
        The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: compound E) and the pituitary adenocorticotrophic hormone on rheumatoid arthritis: preliminary report.
        Ann Rheum Dis. 1949; 8: 97-104
        • Donnino M.W.
        • Andersen L.W.
        • Chase M.
        • et al.
        Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study.
        Crit Care Med. 2016; 44: 360-367
        • Gibot S.
        • Cravoisy A.
        • Kolopp-Sarda M.N.
        • et al.
        Time-course of sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis.
        Crit Care Med. 2005; 33: 792-796
        • Gordon A.C.
        • Mason A.J.
        • Thirunavukkarasu N.
        • et al.
        Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial.
        JAMA. 2016; 316: 509-518
        • Hayes M.A.
        • Yau E.H.
        • Hinds C.J.
        • et al.
        Symmetrical peripheral gangrene: association with noradrenaline administration.
        Intensive Care Med. 1992; 18: 433-436
        • Dunser M.W.
        • Wenzel V.
        • Hasibeder W.R.
        Ischemic skin lesions and microcirculatory collapse during vasopressin therapy: a possible role of the microcirculation?.
        Acta Anaesthesiol Scand. 2006; 50: 637-638
        • Stolk R.F.
        • van der Poll T.
        • Angus D.C.
        • et al.
        Potentially inadvertant immunomodulation: norepinephrine use in sepsis.
        Am J Respir Crit Care Med. 2016; 194: 550-558
        • May J.M.
        Role of vitamin C in the function of the vascular endothelium.
        Antioxid Redox Signal. 2013; 19: 2068-2083
        • Wilson J.X.
        Evaluation of vitamin C for adjuvant sepsis therapy.
        Antioxid Redox Signal. 2013; 19: 2129-2140
        • Wilson J.X.
        Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium.
        Biofactors. 2009; 35: 5-13
        • Han M.
        • Pendem S.
        • Teh S.L.
        • et al.
        Ascorbate protects endothelial barrier function during septic insult: role of protein phosphatase type 2A.
        Free Radic Biol Med. 2010; 48: 128-135
        • Dillon P.F.
        • Root-Bernstein R.S.
        • Lieder C.M.
        Antioxidant-independent ascorbate enhancement of catecholamine-induced contractions of vascular smooth muscle.
        Am J Physiol Heart Circ Physiol. 2004; 286: H2353-H2360
        • Marik P.E.
        Critical illness related corticosteroid insufficiency.
        Chest. 2009; 135: 181-193
        • Kalden J.R.
        Prolonged skin allograft survival in vitamin C-deficient guinea-pigs: preliminary communication.
        Eur Surg Res. 1972; 4: 114-119
        • Kim S.R.
        Ascorbic acid reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and improves survival rate in septic mice by activation of Nrf2/HO-1 signals.
        Biochem Pharmacol. 2015; 95: 279-289
        • Manning J.
        • Mitchell B.
        • Appadurai D.A.
        • et al.
        Vitamin C promotes maturation of T-cells.
        Antioxid Redox Signal. 2013; 19: 2054-2067
        • Fogarty A.
        • Scrivener S.L.
        • Antoniak M.
        • et al.
        Corticosteroid sparing effects of vitamin C and magnesium in asthma: a randomised trial.
        Respir Med. 2006; 100: 174-179
        • Bodwell J.E.
        • Holbrook N.J.
        • Munck A.
        Sulfhydryl-modifying reagents reversibly inhibit binding of glucocorticoid-receptor complexes to DNA-cellulose.
        Biochemistry. 1984; 23: 1392-1398
        • Okamoto K.
        • Tanaka H.
        • Ogawa H.
        • et al.
        Redox-dependent regulation of nuclear import of the glucocorticoid receptor.
        J Biol Chem. 1999; 274: 10363-10371
        • Okamoto K.
        • Tanaka H.
        • Makino Y.
        • et al.
        Restoration of the glucocorticoid receptor function by the phosphodiester compound of vitamins C and E, EPC-K1 (l-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl hydrogen phosphate] potassium salt), via a redox-dependent mechanism.
        Biochem Pharmacol. 1998; 56: 79-86
        • Burzle M.
        • Hediger M.A.
        Functional and physiological role of vitamin C transporters.
        Curr Top Membr. 2012; 70: 357-375
        • Seno T.
        • Inoue N.
        • Matsui K.
        • et al.
        Functional expression of sodium-dependent vitamin C transporter 2 in human endothelial cells.
        J Vasc Res. 2004; 41: 345-351
        • Fujita I.
        • Hirano J.
        • Itoh N.
        • et al.
        Dexamethasone induces sodium-dependant vitamin C transporter in a mouse osteoblastic cell line MC3T3-E1.
        Br J Nutr. 2001; 86: 145-149
      4. Barabutis N, Khangoora V, Marik PE, et al. Hydrocortisone and ascorbic acid synergistically protect against LPS-induced pulmonary endothelial barrier dysfunction. Chest. In press.

        • Keh D.
        • Trips E.
        • Marx G.
        • et al.
        • SepNet-Critical Care Trials Group
        Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS Randomized Clinical Trial.
        JAMA. 2016; 316: 1775-1785
        • Minneci P.C.
        • Deans K.J.
        • Eichacker P.Q.
        • et al.
        The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis.
        Clin Microbiol Infect. 2009; 15: 308-318
        • Massey L.K.
        Ascorbate increases human oxaluria and kidney stone risk.
        J Nutr. 2005; 135: 1673-1677
        • Wandzilak T.R.
        Effect of high dose vitamin C on urinary oxalate levels.
        J Urol. 1994; 151: 834-837
        • Hoppe B.
        • Beck B.B.
        • Milliner D.
        The primary hyperoxalurias.
        Kidney Int. 2009; 75: 1264-1271
        • Sidhu H.
        • Gupta R.
        • Thind S.K.
        • et al.
        Oxalate metabolism in thiamine-deficient rats.
        Ann Nutr Metab. 1987; 31: 354-361
        • Ortiz-Alvarado O.
        • Muyaoka R.
        • Kriedberg C.
        • et al.
        Pyridoxine and dietary counseling for the management of idiopathic hyperoxaluria in stone-forming patients.
        Urology. 2011; 77: 1054-1058

      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
        • PDF
      • 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
        • PDF
      • 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
        • PDF
      • 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
        • PDF
      • 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.
        • Full-Text
        • PDF
      • 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).
        • Full-Text
        • PDF
      • 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.
        • Full-Text
        • PDF
      • 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.
        • Full-Text
        • PDF
      • 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.
        • Full-Text
        • PDF
      • 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.
        • Full-Text
        • PDF
      • 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).
        • Full-Text
        • PDF
      • 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.
        • Full-Text
        • PDF