Document Type : Original Article
Authors
1 Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Intensive Care Unit, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
Abstract
Objective: Effects of ascorbic acid on hemodynamic parameters of septic shock were
evaluated in nonsurgical critically ill patients in limited previous studies. In this study,
the effect of high‑dose ascorbic acid on vasopressor drug requirement was evaluated
in surgical critically ill patients with septic shock.
Methods: Patients with septic shock who required a vasopressor drug to maintain mean
arterial pressure >65 mmHg were assigned to receive either 25 mg/kg intravenous
ascorbic acid every 6 h or matching placebo for 72 h. Vasopressor dose and duration
were considered as the primary outcomes. Duration of Intensive Care Unit (ICU) stay
and 28‑day mortality has been defined as secondary outcomes.
Findings: During the study period, 28patients(14 in each group) completed the trial. Mean
dose of norepinephrine during the study period (7.44 ± 3.65 vs. 13.79 ± 6.48 mcg/min,
P=0.004) and duration of norepinephrine administration(49.64±25.67vs. 71.57±1.60h,
P = 0.007) were significantly lower in the ascorbic acid than the placebo group. No
statistically significant difference was detected between the groups regarding the length
of ICU stay. However, 28‑day mortality was significantly lower in the ascorbic acid than
the placebo group (14.28% vs. 64.28%, respectively; P = 0.009).
Conclusion: High‑dose ascorbic acid may be considered as an effective and safe adjuvant
therapy in surgical critically ill patients with septic shock. The most effective dose of
ascorbic acid and the best time for its administration should be determined in future
studies.
Keywords
2007;170:1435‑44.
2. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid
increase in hospitalization and mortality rates for severe sepsis
in the United States: A trend analysis from 1993 to 2003. Crit
Care Med 2007;35:1244‑50.
3. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H,
Opal SM, et al. Surviving sepsis campaign: International
guidelines for management of severe sepsis and septic shock,
2012. Intensive Care Med 2013;39:165‑228.
4. Angus DC, van der Poll T. Severe sepsis and septic shock.
N Engl J Med 2013;369:840‑51.
5. Vasu TS, Cavallazzi R, HiraniA, Kaplan G, Leiby B, Marik PE.
Norepinephrine or dopamine for septic shock: Systematic
review of randomized clinical trials. J Intensive Care Med
2012;27:172‑8.
6. Landry DW, Levin HR, Gallant EM, Seo S, D’Alessandro D,
Oz MC, et al. Vasopressin pressor hypersensitivity in
vasodilatory septic shock. Crit Care Med 1997;25:1279‑82.
7. Sharshar T, Carlier R, Blanchard A, Feydy A, Gray F,
Paillard M, et al. Depletion of neurohypophyseal content of
vasopressin in septic shock. Crit Care Med 2002;30:497‑500.
8. Petros A, Bennett D, Vallance P. Effect of nitric oxide synthase
inhibitors on hypotension in patients with septic shock. Lancet
1991;338:1557‑8.
9. PetrosA, Lamb G, LeoneA, Moncada S, Bennett D, Vallance P.
Effects of a nitric oxide synthase inhibitor in humans with
septic shock. Cardiovasc Res 1994;28:34‑9.
10. Preiser JC, Lejeune P, Roman A, Carlier E, De Backer D,
Leeman M, et al. Methylene blue administration in septic
shock: A clinical trial. Crit Care Med 1995;23:259-64.
11. O’Brien A, Clapp L, Singer M. Terlipressin for
norepinephrine‑resistant septic shock. Lancet 2002;359:1209‑10.
12. Carr A, Frei B. Does Vitamin C act as a pro‑oxidant under
physiological conditions? FASEB J 1999;13:1007‑24.
13. Carr AC, Frei B. Toward a new recommended dietary
allowance for Vitamin C based on antioxidant and health
effects in humans. Am J Clin Nutr 1999;69:1086‑107.
14. Hunt C, Chakravorty NK, Annan G, Habibzadeh N,
Schorah CJ. The clinical effects of Vitamin C supplementation
in elderly hospitalised patients with acute respiratory
infections. Int J Vitam Nutr Res 1994;64:212‑9.
15. Fowler AA 3rd, SyedAA, Knowlson S, SculthorpeR, FarthingD,
DeWilde C, et al. Phase I safety trial of intravenous ascorbic
acid in patients with severe sepsis. J Transl Med 2014;12:32.
16. Schorah CJ, Downing C, Piripitsi A, Gallivan L, Al-Hazaa AH,
Sanderson MJ, et al. Total Vitamin C, ascorbic acid, and
dehydroascorbic acid concentrations in plasma of critically
ill patients. Am J Clin Nutr 1996;63:760-5.
17. Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H,
Shimazaki S. Reduction of resuscitation fluid volumes in
severely burned patients using ascorbic acid administration:
A randomized, prospective study. Arch Surg 2000;135:326‑31.
18. Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, et al. Randomized, prospective trial of antioxidant
supplementation in critically ill surgical patients. Ann Surg
2002;236:814‑22.
19. Wilson JX. Evaluation of Vitamin C for adjuvant sepsis
therapy. Antioxid Redox Signal 2013;19:2129‑40.
20. Oudemans‑van Straaten HM, Spoelstra‑de Man A, de
Waard MC. Vitamin C revisited. Crit Care Med 2014;18:460.
21. Riordan HD, Hunninghake RB, Riordan NH, Jackson JJ,
Meng X, Taylor P, et al. Intravenous ascorbic acid: Protocol
for its application and use. P R Health Sci J 2003;22:287‑90.
22. Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ,
Rosadiuk K, et al. Phase I clinical trial of i.v. ascorbic acid in
advanced malignancy. Ann Oncol 2008;19:1969‑74.
23. Mak S, Newton GE. Vitamin C augments the inotropic
response to dobutamine in humans with normal left
ventricular function. Circulation 2001;103:826‑30.
24. Nooraee N, Fathi M, Edalat L, Behnaz F, Mohajerani SA,
Dabbagh A. Effect of Vitamin C on serum cortisol reduction
after etomidate induction of anesthesia. J Cell Mol Anesth
2015;1:28‑33.
25. Kieffer P, Thannberger P, Wilhelm JM, Kieffer C, Schneider F.
Multiple organ dysfunction dramatically improving with the
infusion of Vitamin C: More support for the persistence of
scurvy in our “welfare” society. Intensive Care Med 2001;27:448.
26. Zipursky JS, Alhashemi A, Juurlink D. A rare presentation
of an ancient disease: Scurvy presenting as orthostatic
hypotension. BMJ Case Rep 2014;2014. pii: Bcr2013201982.
27. Holley AD, Osland E, Barnes J, Krishnan A, Fraser JF. Scurvy:
Historically a plague of the sailor that remains a consideration
in the modern intensive care unit. Intern Med J 2011;41:283‑5.
28. Long CL, Maull KI, Krishnan RS, Laws HL, Geiger JW,
Borghesi L, et al. Ascorbic acid dynamics in the seriously ill
and injured. J Surg Res 2003;109:144‑8.
29 Fukushima R, Yamazaki E. Vitamin C requirement in surgical
patients. Curr Opin Clin Nutr Metab Care 2010;13:669-76.
30. Crandon JH, Landau B, Mikal S, Balmanno J, Jefferson M,
Mahoney N. Ascorbic acid economy in surgical patients
as indicated by blood ascorbic acid levels. N Engl J Med
1958;258:105‑13.
31. Kirkemo AK, Burt ME, Brennan MF. Serum Vitamin level
maintenance in cancer patients on total parenteral nutrition.
Am J Clin Nutr 1982;35:1003‑9.
32. Lowry SF, Goodgame JT Jr., Maher MM, Brennan MF.
Parenteral Vitamin requirements during intravenous feeding.
Am J Clin Nutr 1978;31:2149‑58.
33. De Backer D, Scolletta S. Clinical management of the
cardiovascular failure in sepsis. Curr Vasc Pharmacol
2013;11:222‑42.
34. Hornig D. Distribution of ascorbic acid, metabolites
and analogues in man and animals. Ann N Y Acad Sci
1975;258:103‑18.
35. May JM, Qu ZC, Nazarewicz R, Dikalov S. Ascorbic acid
efficiently enhances neuronal synthesis of norepinephrine
from dopamine. Brain Res Bull 2013;90:35‑42.
36. Levine M. Ascorbic acid specifically enhances dopamine
beta‑monooxygenase activity in resting and stimulated
chromaffin cells. J Biol Chem 1986;261:7347‑56.
37. Deana R, Bharaj BS, Verjee ZH, Galzigna L. Changes relevant
to catecholamine metabolism in liver and brain of ascorbic acid
deficient guinea‑pigs. Int J Vitam Nutr Res 1975;45:175‑82.
38. Hoehn SK, Kanfer JN. Effects of chronic ascorbic acid
deficiency on guinea pig lysosomal hydrolase activities. J Nutr
1980;110:2085‑94.
39. Bornstein SR, Yoshida‑Hiroi M, Sotiriou S, Levine M,
Hartwig HG, Nussbaum RL, et al. Impaired adrenal
catecholamine system function in mice with deficiency of the
ascorbic acid transporter (SVCT2). FASEB J 2003;17:1928‑30.
40. Duggan M, Browne I, Flynn C. Adrenal failure in the critically
ill. Br J Anaesth 1998;81:468‑70.
41. Nieboer P, van der Werf TS, Beentjes JA, Tulleken JE,
Zijlstra JG, Ligtenberg JJ. Catecholamine dependency in a
polytrauma patient: Relative adrenal insufficiency? Intensive
Care Med 2000;26:125‑7.
42. Treschan TA, Peters J. The vasopressin system: Physiology
and clinical strategies. Anesthesiology 2006;105:599‑612.
43. Russell JA. Bench‑to‑bedside review: Vasopressin in the
management of septic shock. Crit Care Med 2011;15:226.
44. Sharshar T, Blanchard A, Paillard M, Raphael JC, Gajdos P,
Annane D. Circulating vasopressin levels in septic shock. Crit
Care Med 2003;31:1752‑8.
45. Prigge ST, Mains RE, Eipper BA, Amzel LM. New insights into
copper monooxygenases and peptide amidation: Structure,
mechanism and function. Cell Mol Life Sci 2000;57:1236‑59.
46. Landry DW, Levin HR, Gallant EM, Ashton RC Jr., Seo S,
D’Alessandro D, et al. Vasopressin deficiency contributes to
the vasodilation of septic shock. Circulation 1997;95:1122‑5.
47. Giusti‑Paiva A, Domingues VG. Centrally administered
ascorbic acid induces antidiuresis, natriuresis and
neurohypophyseal hormone release in rats. Neuro Endocrinol
Lett 2010;31:87‑91.
48. Kahn SA, Beers RJ, Lentz CW. Resuscitation after severe burn
injury using high‑dose ascorbic acid: A retrospective review.
J Burn Care Res 2011;32:110‑7.
49. Morelli A, Ertmer C, Rehberg S, Lange M, Orecchioni A,
Laderchi A, et al. Phenylephrine versus norepinephrine
for initial hemodynamic support of patients with septic
shock: A randomized, controlled trial. Crit Care Med
2008;12:R143.