Response

      To the Editor:
      We thank Drs Walter and Singer for their comments regarding our study.
      • Marik P.E.
      • Khangoora V.
      • Rivera R.
      • et al.
      Hydrocortisone, vitamin C and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study.
      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. Furthermore, it is true that we believe that the treatment was effective for patients with sepsis. This strong belief was the reason that we applied the therapy to additional patients and why we analyzed those results after the fact. We agree that additional well-designed studies are necessary to convince the medical community of the efficacy of this treatment.
      Vitamin C levels are universally low or undetectable in patients with critical illness, especially in those with sepsis. Vitamin C is a key antioxidant and an essential cofactor for many important biological reactions.
      • May J.M.
      • Harrison F.E.
      Role of vitamin C in the function of the vascular endothelium.
      Vitamin C is synthesized by all vertebrates except primates and guinea pigs, and the synthesis of vitamin C increases during stress. Furthermore, vitamin C is secreted by the human adrenal gland,
      • Padayatty S.J.
      Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone.
      and therefore vitamin C acts more like a “stress hormone” than a “nutrient.” The comparison between studies administering vitamin C with other nutritional studies is therefore not relevant. Additionally, the biological properties (and safety) of vitamin C are quite distinct from that of glutamine. The statement that “vitamin C supplementation in critical illness has been studied in high-quality trials without a signal of benefit” is not correct. IV vitamin C has been successfully used to treat patients in the general surgical ICU
      • Nathens A.B.
      • Neff M.J.
      • Jurkovich G.J.
      • et al.
      Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients.
      ; patients with traumatic injuries
      • Collier B.R.
      • Giladi A.
      • Dossett L.A.
      • et al.
      Impact of high-dose antioxidants on outcomes in acutely injured patients.
      • Giladi A.M.
      • Dossett L.A.
      • Fleming S.B.
      • et al.
      High-dose antioxidant administration is associated with a reduction in post-injury complications in critically ill trauma patients.
      ; and patients with sepsis,
      • Fowler A.A.
      • Syed A.A.
      • Knowlson S.
      • et al.
      Phase 1 safety trial of intravenous ascorbic acid in patients with severe sepsis.
      • Zabet M.H.
      • Mohammadi M.
      • Ramezani M.
      • et al.
      Effect of high-dose ascorbic acid on vasopressor requirement in septic shock.
      pancreatitis,
      • Du W.D.
      • Yan Z.R.
      • Sun J.
      • et al.
      Therapeutic efficay of high-dose vitamin C on acute pancreatitis and its potential mechanisms.
      burns,
      • 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.
      • Matsuda T.
      • Tanaka H.
      • Reyes H.M.
      • et al.
      Antioxidant therapy using high dose vitamin C: reduction of postburn resuscitation fluid volume requirements.
      and tetanus
      • Jahan K.
      • Ahmad K.
      • Ali M.A.
      Effect of ascorbic acid in the treatmen tof tetanus.
      ; as well as patients undergoing coronary artery bypass surgery.
      • Harling L.
      • Rasoli S.
      • Vecht J.A.
      • et al.
      Do antioxidant vitamins have an anti-arrhythmic effect following cardiac surgery? A meta-analysis of randomised controlled trials.
      No adverse effects of IV vitamin C were noted in any of these studies. Patients with malignancy have received adjunctive treatment with IV vitamin C in doses of up to 150 g (100 times the dose that we recommend) without untoward side effects. We therefore believe that the administration of vitamin C in the dosage that we recommend is an exceedingly safe intervention.

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