Vitamin C can shorten the length of stay in the ICU: a meta-analysis

Harri Hemilä and Elizabeth Chalker

Nutrients 2019

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The published paper has DOI-links, but some of the papers have other sources,
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Harri Hemilä
Department of Public Health
University of Helsinki, Helsinki, Finland
harri.hemila@helsinki.fi
Home: http://www.mv.helsinki.fi/home/hemila
This file: http://www.mv.helsinki.fi/home/hemila/N2019
version 2019-4-25

References

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186. Finkle, P. Vitamin C saturation levels in the body in normal subjects and in various pathological conditions. J. Clin. Invest. 1937, 16, 587-593.
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187. Lund, C.C. The effect of surgical operations on the level of cevitamic acid in the blood plasma. N. Engl. J. Med. 1939, 221, 123-127.
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188. Abbasy, M.A. Vitamin C and infection: excretion of vitamin C in osteomyelitis. Lancet 1937, 230, 177-180.
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189. Evans, W. Vitamin C in heart failure. Lancet 1938, 231, 308-309.
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190. Editorial. Ascorbic acid as a diuretic. Lancet 1944, 244, 6310.
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191. Hochwald, A. Vitamin C in the treatment of croupous pneumonia [in German]. Dtsch. Med. Wochenschr. 1937, 63, 182–184.
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192. Gander, J.; Niederberger, W. Vitamin C in the treatment of pneumonia [in German]. Münch. Med. Wochenschr. 1936, 83, 2074–2077.
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193. Bohnholtzer, E. Contribution to the question of pneumonia treatment with vitamin C [in German]. Dtsch. Med. Wochenschr. 1937, 63, 1001–1003.
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194. Klenner, F.R. Virus pneumonia and its treatment with vitamin C. South. Med. Surg. 1948, 110, 36–38.
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195. Klenner, F.R. Massive doses of vitamin C and the virus diseases. South. Med. Surg. 1951, 113, 101–107.
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196. Dalton, W.L. Massive doses of vitamin C in the treatment of viral diseases. J. Indiana State Med. Assoc. 1962, 55, 1151–1154.
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197. Stone, I. The Healing Factor: Vitamin C against Disease. Grosset Dunlap: New York, NY, USA, 1972.
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200. Hemilä, H.; Louhiala, P. Vitamin C for preventing and treating pneumonia. Cochrane Database Syst. Rev. 2007, CD005532.
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The above Cochrane review (2007) concluded in the Abstract:
https://www.ncbi.nlm.nih.gov/pubmed/17253561
”The prophylactic use of vitamin C to prevent pneumonia should be further investigated in populations who have high incidence of pneumonia, especially if dietary vitamin C intake is low. Similarly, the therapeutic effects of vitamin C should be studied, especially in patients with low plasma vitamin C levels.”

However, the strong evidence indicating that vitamin C influences pneumonia incidence in some contexts was shown one decade even earlier, in 1997, see:
https://www.ncbi.nlm.nih.gov/pubmed/9306475
https://doi.org/10.1097/00006454-199709000-00003
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201. Hume, R.; Weyers, E. Changes in leucocyte ascorbic acid during the common cold. Scott. Med. J. 1973, 18, 3–7.
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http://www.mv.helsinki.fi/home/hemila/H/HH_1996_JCE.pdf
http://www.mv.helsinki.fi/home/hemila/H/HH_1996_JCE2.pdf
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247. Sisto, T. Pretreatment with antioxidants and allopurinol diminishes cardiac onset events in coronary artery bypass grafting. Ann. Thorac. Surg. 1995, 59, 1519-1523.
https://doi.org/10.1016/0003-4975(95)00197-S
https://www.researchgate.net/publication/15427027_Pretreatment_with_antioxidants_and_allopurinol_diminishes_cardiac_onset_events_in_coronary_artery_bypass_grafting

248. Galley, H.F. The effects of intravenous antioxidants in patients with septic shock. Free Radic. Biol. Med. 1997, 23, 768-774.
https://doi.org/10.1016/S0891-5849(97)00059-2
https://www.researchgate.net/publication/13925731_The_Effects_of_Intravenous_Antioxidants_in_Patients_With_Septic_Shock

249. Nathens, A.B. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann. Surg. 2002, 236, 814-822.
http://dx.doi.org/10.1097/00000658-200212000-00014
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1422648

250. Crimi, E. The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: a prospective, randomized, double-blind, placebo-controlled trial. Anesth. Analg. 2004, 99, 857-863.
http://dx.doi.org/10.1213/01.ANE.0000133144.60584.F6
http://www.ccmpitt.com/ebm/nutrition/NUT-RCT%20antioxidants%20C%20and%20E%20in%20Enetral%20feeding%20critically%20i.pdf
https://www.researchgate.net/publication/258173522_The_Beneficial_Effects_of_Antioxidant_Supplementation_in_Enteral_Feeding_in_Critically_Ill_Patients_A_Prospective_Randomized_Double-Blind_Placebo-Controlled_Trial

251. Berger, M.M. Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients. Crit. Care 2008, 12, R101.
http://dx.doi.org/10.1186/cc6981
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2575590

252. Barbosa, E. Supplementation of vitamin E, vitamin C, and zinc attenuates oxidative stress in burned children: a randomized, double-blind, placebo-controlled pilot study. J. Burn Care Res. 2009, 30, 859-866.
http://dx.doi.org/10.1097/BCR.0b013e3181b487a8
https://www.researchgate.net/publication/26753577_Supplementation_of_Vitamin_E_Vitamin_C_and_Zinc_Attenuates_Oxidative_Stress_in_Burned_Children_A_Randomized_Double-Blind_Placebo-Controlled_Pilot_Study

253. Howe, K.P. Mechanical ventilation antioxidant trial. Am. J. Crit. Care 2015, 24, 440-445.
http://dx.doi.org/10.4037/ajcc2015335

254. Collier, B.R. Impact of high-dose antioxidants on outcomes in acutely injured patients. JPEN J. Parenter. Enteral Nutr. 2008, 32, 384-388.
http://dx.doi.org/10.1177/0148607108319808

255. Giladi, A.M. High-dose antioxidant administration is associated with a reduction in post-injury complications in critically ill trauma patients. Injury 2011, 42, 78-82.
http://dx.doi.org/10.1016/j.injury.2010.01.104
https://www.researchgate.net/publication/41423780_High-dose_antioxidant_administration_is_associated_with_a_reduction_in_post-injury_complications_in_critically_ill_trauma_patients

256. Kahn, S.A. Resuscitation after severe burn injury using high-dose ascorbic acid: a retrospective review. J. Burn Care Res. 2011, 32, 110-117.
http://dx.doi.org/10.1097/BCR.0b013e318204b336
https://www.researchgate.net/publication/49658561_Resuscitation_After_Severe_Burn_Injury_Using_High-Dose_Ascorbic_Acid_A_Retrospective_Review

257. Bedreag, O.H. Influence of antioxidant therapy on the clinical status of multiple trauma patients; a retrospective single center study. Rom. J. Anaesth. Intensive Care 2015, 22, 89-96.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505380

258. Marik, P.E. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest 2017, 151, 1229-1238.
http://dx.doi.org/10.1016/j.chest.2016.11.036
https://static1.squarespace.com/static/57313085a3360c6b87c17029/t/5937624ae6f2e1c6ae177ae6/1496801870388.pdf

259. Balakrishnan, M. Hydrocortisone, vitamin C and thiamine for the treatment of sepsis and septic shock following cardiac surgery. Indian J. Anaesth. 2018, 62, 934-939.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299773

260. Kim, W.Y. 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.
http://dx.doi.org/10.1016/j.jcrc.2018.07.004
https://www.researchgate.net/publication/326216930_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

261. Hemilä, H. Spectacular reduction in the mortality of acutely injured patients by the administration of vitamins C and E and selenium [reply in 2009, 33, 449]. JPEN J. Parenter. Enteral Nutr. 2009, 33, 447-448.
http://dx.doi.org/10.1177/0148607108328520
https://helda.helsinki.fi/handle/10138/16985
http://www.mv.helsinki.fi/home/hemila/H/2009_L_JPEN.pdf

262. Cathcart, R.F. Vitamin C, titrating to bowel tolerance, anascorbemia, and acute induced scurvy. Med. Hypotheses 1981, 7, 1359–1376.
http://dx.doi.org/10.1016/0306-9877(81)90126-2
Available via:
http://www.mv.helsinki.fi/home/hemila/klenner.htm
See also:
http://www.mv.helsinki.fi/home/hemila/CP/Luberoff_1978_ch.pdf

263. Buehner, M. Oxalate nephropathy after continuous infusion of high-dose vitamin C as an adjunct to burn resuscitation. J. Burn Care Res. 2016, 37, e374-e379.
https://doi.org/10.1097/BCR.0000000000000233
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933579

264. Chalmers, T.C. Effects of ascorbic acid on the common cold: an evaluation of the evidence. Am. J. Med. 1975, 58, 532–536.
https://dx.doi.org/10.1016/0002-9343(75)90127-8
http://www.mv.helsinki.fi/home/hemila/reviews/Chalmers_1975_ch.pdf
http://www.mv.helsinki.fi/home/hemila/reviews/Chalmers_1975_bm.pdf

The Chalmers review has been extensively cited in journal articles and textbooks, see:
http://www.mv.helsinki.fi/home/hemila/Chalmers1975CitedBy.htm

Thomas Chalmers was a very influential physician:
http://www.nytimes.com/1995/12/29/nyregion/dr-thomas-c-chalmers-a-president-of-mt-sinai-dies-at-78.html
https://en.wikipedia.org/wiki/Thomas_C._Chalmers
http://www.jameslindlibrary.org/articles/thomas-c-chalmers-1917-1995
https://circulatingnow.nlm.nih.gov/2014/12/18/thomas-c-chalmers-clinical-research-pragmatist
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878827 David Sackett describes in this paper that Thomas Chalmers' 1955 clinical trial report changed his career and led to the emergence of the EBM movement
https://doi.org/10.1136/bmj.g371 According to Richard Smith and Drummond Rennie, Thomas Chalmers was one of the "three individuals from an earlier generation [who] were particularly important in inspiring" the EBM movement
http://annals.org/aim/fullarticle/709574/tributes-thomas-chalmers
http://annals.org/aim/fullarticle/709576/tributes-thomas-chalmers
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1335248
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1335469
https://doi.org/10.1016/S0140-6736(96)90369-4
https://doi.org/10.1001/jama.1996.03540080078041
https://doi.org/10.1016/S0197-2456(96)90026-4
https://doi.org/10.1016/S0197-2456(97)82189-7
https://doi.org/10.1177/0141076815586354
https://doi.org/10.1177/0141076815606279

265. Hemilä, H. Do vitamins C and E affect respiratory infections?
University of Helsinki: Helsinki, Finland, 2006; pp. 21-45, 59-66.
https://hdl.handle.net/10138/20335
see also:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793763
https://www.mv.helsinki.fi/home/hemila/reviews/chalmers

https://www.mv.helsinki.fi/home/hemila/reviews/dykes

266. Council of Scientific Affairs, American Medical Association. Vitamin preparations as dietary supplements and as therapeutic agents. JAMA 1987, 257, 1929–1936.
https://doi.org/10.1001/jama.1987.03390140099035
http://www.mv.helsinki.fi/home/hemila/reviews/AMA_1987.pdf

267. Dykes, M.H.M.; Meier, P. Ascorbic acid and the common cold: evaluation of its efficacy and toxicity. JAMA 1975, 231, 1073–1079.
https://dx.doi.org/10.1001/jama.1975.03240220051025
http://www.mv.helsinki.fi/home/hemila/reviews/Dykes_1975_ch.pdf
http://www.mv.helsinki.fi/home/hemila/reviews/Dykes_1975_bm.pdf

Paul Meier was a very famous statistician, eg:
http://en.wikipedia.org/wiki/Paul_Meier_(statistician)
https://en.wikipedia.org/wiki/Kaplan%E2%80%93Meier_estimator
http://garfield.library.upenn.edu/classics1983/A1983QS51100001.pdf
https://doi.org/10.1136/bmj.d5507
https://doi.org/10.1016/S0140-6736(11)61438-4
https://doi.org/10.2105/AJPH.2012.300778
https://doi.org/10.1191/1740774504cn011xx
http://bulletin.imstat.org/2011/12/obituary-paul-meier-1924%E2%80%932011/
http://www.nytimes.com/2011/08/13/health/13meier.html
https://news.uchicago.edu/article/2011/08/11/paul-meier-statistician-who-helped-change-clinical-research-1924-2011
http://articles.latimes.com/2011/aug/22/local/la-me-paul-meier-20110822
https://www.telegraph.co.uk/news/obituaries/medicine-obituaries/8804883/Paul-Meier.html

268. Pauling, L. Ascorbic acid and the common cold: evaluation of its efficacy and toxicity. Part I. Medical Tribune 1976, 17, 18-19.
http://www.mv.helsinki.fi/home/hemila/pauling/Pauling_1976_MT_1.pdf

269. Pauling, L. Ascorbic acid and the common cold. Part II. Medical Tribune 1976, 17, 37-38.
http://www.mv.helsinki.fi/home/hemila/pauling/Pauling_1976_MT_2.pdf

270. Chalmers, T.C. Dissent to the preceding article by H. Hemilä. J. Clin. Epidemiol. 1996, 49, 1085.
https://dx.doi.org/10.1016/0895-4356(96)00190-4

271. Hemilä, H. To the dissent by Thomas Chalmers. J. Clin. Epidemiol. 1996, 49, 1087.
https://dx.doi.org/10.1016/0895-4356(96)00191-6
https://helda.helsinki.fi/handle/10138/225873
http://www.mv.helsinki.fi/home/hemila/H/HH_1996_JCE2.pdf

272. Richards, E. The politics of therapeutic evaluation: the vitamin C and cancer controversy. Soc. Stud. Sci. 1988, 18, 653-701.
https://doi.org/10.1177/030631288018004004
https://www.researchgate.net/publication/313577764_The_Politics_of_Therapeutic_Evaluation_The_Vitamin_C_and_Cancer_Controversy

273. Richards, E. Vitamin C and Cancer: Medicine or Politics?
St. Martins Press: New York, NY, USA, 1991.
http://www.springer.com/gp/book/9781349096060
https://link.springer.com/book/10.1007/978-1-349-09606-0
https://www.palgrave.com/us/book/9781349096060
https://www.amazon.com/Vitamin-C-Cancer-Medicine-Politics/dp/0312052421
https://doi.org/10.1038/353125a0
https://doi.org/10.1086/356441
https://doi.org/10.1080/08109029208629523
https://doi.org/10.1016/0165-6147(92)90029-6
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2399293
https://www.newscientist.com/article/mg13518295-400-review-the-trials-and-tribulations-of-vitamin-c

274. Segerstråle, U. Beleaguering the cancer establishment. Science 1992, 255, 613–615.
https://doi.org/10.1126/science.255.5044.613
https://www.jstor.org/stable/2876833

275. Goodwin, J.S. Battling quackery: attitudes about micronutrient supplements in American Academic medicine. Arch. Intern. Med. 1998, 158, 2187–2191.
https://doi.org/10.1001/archinte.158.20.2187
https://www.researchgate.net/publication/13467491_Battling_Quackery_Attitudes_About_Micronutrient_Supplements_in_American_Academic_Medicine
www.mv.helsinki.fi/home/hemila/safety/Goodwin_1998_p2188.pdf

276. Goodwin, J.S. Failure to recognize efficacious treatments: a history of salicylate therapy in rheumatoid arthritis. Persp. Biol. Med. 1981, 31, 78-92.
https://doi.org/10.1353/pbm.1981.0053
https://muse.jhu.edu/article/404496/pdf

277. Goodwin, J.S. The tomato effect: rejection of highly efficacious therapies. JAMA 1984, 251, 2387–2390.
https://dx.doi.org/10.1001/jama.1984.03340420053025
https://www.researchgate.net/publication/16827181_The_Tomato_effect_Rejection_of_highly_efficacious_therapies
www.mv.helsinki.fi/home/hemila/birkhauser/Goodwin_1984.pdf

278. Louhiala, P.; Hemilä, H. Can CAM treatments be evidence-based? Focus Altern. Complement. Ther. 2014, 19, 84–89.
https://dx.doi.org/10.1111/fct.12110
https://helda.helsinki.fi/handle/10138/228056
https://www.mv.helsinki.fi/home/hemila/H/HH_2014_FACT.pdf