Abstract: TYPE Opinion
PUBLISHED 21 May 2024
DOI 10.3389/fmed.2024.1391346
OPEN ACCESS
EDITED BY
Sebastien Gibot,
Centre Hospitalier Universitaire de
Nancy, France
REVIEWED BY
Margreet C. M. Vissers,
University of Otago, New Zealand
*CORRESPONDENCE
Harri Hemilä
harri.hemila@helsinki.fi
Rebound effect explains the
divergence in survival after 5 days
in a controlled trial on vitamin C
for COVID-19 patients
Harri Hemilä1* and Elizabeth Chalker2
Department of Public Health, University of Helsinki, Helsinki, Finland, 2 National Centre for
Epidemiology and Population Health, Australian National University, Canberra, ACT, Australia
1
RECEIVED 25 February 2024
ACCEPTED 06 May 2024
PUBLISHED 21 May 2024
KEYWORDS
CITATION
ascorbic acid, intensive care, mortality, SARS-CoV-2, scurvy, sepsis, time factors,
vitamins
Hemilä H and Chalker E (2024) Rebound
effect explains the divergence in survival after
5 days in a controlled trial on vitamin C for
COVID-19 patients. Front. Med. 11:1391346.
doi: 10.3389/fmed.2024.1391346
DOI record:
{
"DOI": "10.3389/fmed.2024.1391346",
"ISSN": [
"2296-858X"
],
"URL": "http://dx.doi.org/10.3389/fmed.2024.1391346",
"alternative-id": [
"10.3389/fmed.2024.1391346"
],
"author": [
{
"affiliation": [],
"family": "Hemilä",
"given": "Harri",
"sequence": "first"
},
{
"affiliation": [],
"family": "Chalker",
"given": "Elizabeth",
"sequence": "additional"
}
],
"container-title": "Frontiers in Medicine",
"container-title-short": "Front. Med.",
"content-domain": {
"crossmark-restriction": true,
"domain": [
"frontiersin.org"
]
},
"created": {
"date-parts": [
[
2024,
5,
22
]
],
"date-time": "2024-05-22T12:30:08Z",
"timestamp": 1716381008000
},
"deposited": {
"date-parts": [
[
2024,
5,
22
]
],
"date-time": "2024-05-22T12:30:13Z",
"timestamp": 1716381013000
},
"indexed": {
"date-parts": [
[
2024,
5,
23
]
],
"date-time": "2024-05-23T00:30:55Z",
"timestamp": 1716424255182
},
"is-referenced-by-count": 0,
"issued": {
"date-parts": [
[
2024,
5,
21
]
]
},
"license": [
{
"URL": "https://creativecommons.org/licenses/by/4.0/",
"content-version": "vor",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2024,
5,
21
]
],
"date-time": "2024-05-21T00:00:00Z",
"timestamp": 1716249600000
}
}
],
"link": [
{
"URL": "https://www.frontiersin.org/articles/10.3389/fmed.2024.1391346/full",
"content-type": "unspecified",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "1965",
"original-title": [],
"prefix": "10.3389",
"published": {
"date-parts": [
[
2024,
5,
21
]
]
},
"published-online": {
"date-parts": [
[
2024,
5,
21
]
]
},
"publisher": "Frontiers Media SA",
"reference": [
{
"DOI": "10.1136/bmj.4.5888.354-b",
"article-title": "Ascorbic acid and common colds",
"author": "Spero",
"doi-asserted-by": "publisher",
"first-page": "354",
"journal-title": "Br Med J.",
"key": "B1",
"volume": "4",
"year": "1973"
},
{
"DOI": "10.1016/0306-9877(84)90163-4",
"article-title": "Evidence of rebound effect with ascorbic acid",
"author": "Tsao",
"doi-asserted-by": "publisher",
"first-page": "303",
"journal-title": "Med Hypotheses.",
"key": "B2",
"volume": "13",
"year": "1984"
},
{
"DOI": "10.1093/ajcn/44.2.257",
"article-title": "Plasma ascorbic acid in adult males: effects of depletion and supplementation",
"author": "Omaye",
"doi-asserted-by": "publisher",
"first-page": "257",
"journal-title": "Am J Clin Nutr.",
"key": "B3",
"volume": "44",
"year": "1986"
},
{
"DOI": "10.1093/ajcn/48.2.379",
"article-title": "Rebound effect with ascorbic acid in adult males",
"author": "Omaye",
"doi-asserted-by": "publisher",
"first-page": "379",
"journal-title": "Am J Clin Nutr.",
"key": "B4",
"volume": "48",
"year": "1988"
},
{
"DOI": "10.5281/zenodo.11066294",
"article-title": "Can water-soluble vitamins be over-dosed? Research on vitamin C [In German, translation available]",
"author": "Gordonoff",
"doi-asserted-by": "publisher",
"first-page": "726",
"journal-title": "Schweiz Med Wochenschr.",
"key": "B5",
"volume": "90",
"year": "1960"
},
{
"DOI": "10.1056/nejmoa2200644",
"article-title": "Intravenous vitamin C in adults with sepsis in the intensive care unit",
"author": "Lamontagne",
"doi-asserted-by": "publisher",
"first-page": "2387",
"journal-title": "N Engl J Med.",
"key": "B6",
"volume": "386",
"year": "2022"
},
{
"DOI": "10.1038/s41430-022-01254-8",
"article-title": "Abrupt termination of vitamin C from ICU patients may increase mortality: secondary analysis of the LOVIT trial",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "490",
"journal-title": "Eur J Clin Nutr.",
"key": "B7",
"volume": "77",
"year": "2023"
},
{
"DOI": "10.1001/jama.2019.11825",
"article-title": "Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial",
"author": "Fowler",
"doi-asserted-by": "publisher",
"first-page": "1261",
"journal-title": "JAMA.",
"key": "B8",
"volume": "322",
"year": "2019"
},
{
"DOI": "10.1001/jama.2019.21981",
"article-title": "Vitamin C for sepsis and acute respiratory failure [discussion]",
"author": "de Grooth",
"doi-asserted-by": "publisher",
"first-page": "792",
"journal-title": "JAMA.",
"key": "B9",
"volume": "323",
"year": "2020"
},
{
"DOI": "10.3389/fmed.2020.590853",
"article-title": "Reanalysis of the effect of vitamin C on mortality in the CITRIS-ALI trial: important findings dismissed in the trial report",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "590853",
"journal-title": "Front Med.",
"key": "B10",
"volume": "7",
"year": "2020"
},
{
"DOI": "10.1002/14651858.CD000980.pub4",
"article-title": "Vitamin C for preventing and treating the common cold",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "CD000980",
"journal-title": "Cochrane Database Syst Rev.",
"key": "B11",
"volume": "31",
"year": "2013"
},
{
"DOI": "10.1186/s12889-023-17229-8",
"article-title": "Vitamin C reduces the severity of common colds: a meta-analysis",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "2468",
"journal-title": "BMC Public Health.",
"key": "B12",
"volume": "23",
"year": "2023"
},
{
"DOI": "10.3389/fmed.2020.559811",
"article-title": "Vitamin C and COVID-19",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "559811",
"journal-title": "Front Med.",
"key": "B13",
"volume": "7",
"year": "2021"
},
{
"DOI": "10.1001/jamanetworkopen.2021.0369",
"article-title": "Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARSCoV-2 infection: the COVID A to Z randomized clinical trial",
"author": "Thomas",
"doi-asserted-by": "publisher",
"first-page": "e210369",
"journal-title": "JAMA Netw Open.",
"key": "B14",
"volume": "4",
"year": "2021"
},
{
"DOI": "10.3389/fimmu.2021.674681",
"article-title": "Vitamin C may increase the recovery rate of outpatient cases of SARS-CoV-2 infection by 70%: reanalysis of the COVID A to Z randomized clinical trial",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "674681",
"journal-title": "Front Immunol.",
"key": "B15",
"volume": "12",
"year": "2021"
},
{
"DOI": "10.3390/life12010062",
"article-title": "Bias against vitamin C in mainstream medicine: examples from trials of vitamin C for infections",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "62",
"journal-title": "Life.",
"key": "B16",
"volume": "12",
"year": "2022"
},
{
"DOI": "10.1001/jama.2023.21407",
"article-title": "Intravenous vitamin C for patients hospitalized with COVID-19: two harmonized randomized clinical trials",
"author": "Adhikari",
"doi-asserted-by": "publisher",
"first-page": "1745",
"journal-title": "JAMA.",
"key": "B17",
"volume": "330",
"year": "2023"
},
{
"DOI": "10.1001/jama.2019.22176",
"article-title": "Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial",
"author": "Fujii",
"doi-asserted-by": "publisher",
"first-page": "423",
"journal-title": "JAMA.",
"key": "B18",
"volume": "323",
"year": "2020"
},
{
"DOI": "10.1001/jama.2020.24505",
"article-title": "Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial",
"author": "Sevransky",
"doi-asserted-by": "publisher",
"first-page": "742",
"journal-title": "JAMA.",
"key": "B19",
"volume": "325",
"year": "2021"
},
{
"DOI": "10.1186/s13054-021-03872-3",
"article-title": "Vitamin C for ≥5 days is associated with decreased hospital mortality in sepsis subgroups: a nationwide cohort study",
"author": "Jung",
"doi-asserted-by": "publisher",
"first-page": "3",
"journal-title": "Crit Care.",
"key": "B20",
"volume": "26",
"year": "2022"
},
{
"DOI": "10.1186/s40560-023-00702-2",
"article-title": "Concerns with the revised Japanese recommendation for administering vitamin C to septic patients",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "52",
"journal-title": "J Intensive Care.",
"key": "B21",
"volume": "11",
"year": "2023"
},
{
"DOI": "10.3390/nu11040708",
"article-title": "Vitamin C can shorten the length of stay in the ICU: a meta-analysis",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "708",
"journal-title": "Nutrients.",
"key": "B22",
"volume": "11",
"year": "2019"
},
{
"DOI": "10.1186/s40560-020-0432-y",
"article-title": "Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "15",
"journal-title": "J Intensive Care.",
"key": "B23",
"volume": "8",
"year": "2020"
},
{
"DOI": "10.1056/NEJMcps2108909",
"article-title": "Inadequate support",
"author": "Pichan",
"doi-asserted-by": "publisher",
"first-page": "938",
"journal-title": "N Engl J Med.",
"key": "B24",
"volume": "385",
"year": "2021"
},
{
"DOI": "10.1177/23247096211067970",
"article-title": "Scurvy in the intensive care unit",
"author": "Baluch",
"doi-asserted-by": "publisher",
"first-page": "23247096211067970",
"journal-title": "J Investig Med High Impact Case Rep.",
"key": "B25",
"volume": "9",
"year": "2021"
},
{
"DOI": "10.1016/j.chest.2019.06.043",
"article-title": "Vitamin C deficiency induced pulmonary arterial hypertension",
"author": "Gayen",
"doi-asserted-by": "publisher",
"first-page": "e21",
"journal-title": "Chest.",
"key": "B26",
"volume": "157",
"year": "2020"
},
{
"DOI": "10.1161/CIRCULATIONAHA.119.040894",
"article-title": "A shocking deficiency",
"author": "Penn",
"doi-asserted-by": "publisher",
"first-page": "613",
"journal-title": "Circulation.",
"key": "B27",
"volume": "140",
"year": "2019"
},
{
"DOI": "10.1016/j.jaccas.2019.07.006",
"article-title": "Missing vitamin C: a case of scorbutic cardiac tamponade",
"author": "Alnaimat",
"doi-asserted-by": "publisher",
"first-page": "192",
"journal-title": "JACC Case Rep.",
"key": "B28",
"volume": "1",
"year": "2019"
},
{
"DOI": "10.1056/NEJMcpc1802826",
"article-title": "Case 22-2018: a 64-year-old man with progressive leg weakness, recurrent falls, and anemia",
"author": "Bennett",
"doi-asserted-by": "publisher",
"first-page": "282",
"journal-title": "N Engl J Med.",
"key": "B29",
"volume": "379",
"year": "2018"
},
{
"DOI": "10.1161/CIRCHEARTFAILURE.116.003497",
"article-title": "Reversible right heart failure in scurvy: rediscovery of an old observation",
"author": "Abbas",
"doi-asserted-by": "publisher",
"first-page": "e003497",
"journal-title": "Circ Heart Fail.",
"key": "B30",
"volume": "9",
"year": "2016"
},
{
"DOI": "10.1056/NEJMcpc1214217",
"article-title": "Case records of the Massachusetts General Hospital. Case 1-2014. A 32-year-old man with loss of vision and a rash",
"author": "Blanchard",
"doi-asserted-by": "publisher",
"first-page": "159",
"journal-title": "N Engl J Med",
"key": "B31",
"volume": "370",
"year": "2014"
},
{
"DOI": "10.1378/chest.11-1857",
"article-title": "Reversible pulmonary hypertension associated with vitamin C deficiency",
"author": "Kupari",
"doi-asserted-by": "publisher",
"first-page": "225",
"journal-title": "Chest.",
"key": "B32",
"volume": "142",
"year": "2012"
},
{
"DOI": "10.1111/j.1445-5994.2010.02413.x",
"article-title": "Scurvy: historically a plague of the sailor that remains a consideration in the modern intensive care unit",
"author": "Holley",
"doi-asserted-by": "publisher",
"first-page": "283",
"journal-title": "Intern Med J.",
"key": "B33",
"volume": "41",
"year": "2011"
},
{
"DOI": "10.1007/s001340000830",
"article-title": "Multiple organ dysfunction dramatically improving with the infusion of vitamin C: more support for the persistence of scurvy in our “welfare” society",
"author": "Kieffer",
"doi-asserted-by": "publisher",
"first-page": "448",
"journal-title": "Intensive Care Med.",
"key": "B34",
"volume": "27",
"year": "2001"
},
{
"DOI": "10.1056/NEJM199512213332508",
"article-title": "Case 39-1995: a 72-year-old man with exertional dyspnea, fatigue, and extensive ecchymoses and purpuric lesions",
"author": "Meisel",
"doi-asserted-by": "publisher",
"first-page": "1695",
"journal-title": "N Engl J Med.",
"key": "B35",
"volume": "333",
"year": "1995"
},
{
"DOI": "10.1186/s12890-024-02941-x",
"article-title": "Vitamin C deficiency can lead to pulmonary hypertension: a systematic review of case reports",
"author": "Hemilä",
"doi-asserted-by": "publisher",
"first-page": "140",
"journal-title": "BMC Pulm Med.",
"key": "B36",
"volume": "24",
"year": "2024"
},
{
"DOI": "10.1007/s12603-010-0032-y",
"article-title": "Scurvy in hospitalized elderly patients",
"author": "Raynaud-Simon",
"doi-asserted-by": "publisher",
"first-page": "407",
"journal-title": "J Nutr Health Aging.",
"key": "B37",
"volume": "14",
"year": "2010"
},
{
"DOI": "10.1111/1346-8138.16891",
"article-title": "Modern scurvy revisited: Japanese cases of a “forgotten” disease",
"author": "Hashizume",
"doi-asserted-by": "publisher",
"first-page": "e388",
"journal-title": "J Dermatol.",
"key": "B38",
"volume": "50",
"year": "2023"
},
{
"DOI": "10.12691/ajmcr-7-5-2",
"article-title": "A very uncommon case of pulmonary arterial hypertension",
"author": "Azar",
"doi-asserted-by": "publisher",
"first-page": "79",
"journal-title": "Am J Med Case Rep.",
"key": "B39",
"volume": "7",
"year": "2019"
},
{
"DOI": "10.1038/ejcn.2013.42",
"article-title": "Severe vitamin C deficiency in a critically ill adult: a case report",
"author": "Doll",
"doi-asserted-by": "publisher",
"first-page": "881",
"journal-title": "Eur J Clin Nutr.",
"key": "B40",
"volume": "67",
"year": "2013"
},
{
"DOI": "10.6061/clinics/2012(04)16",
"article-title": "Scurvy in an alcoholic malnourished cirrhotic man with spontaneous bacterial peritonitis",
"author": "Maltos",
"doi-asserted-by": "publisher",
"first-page": "405",
"journal-title": "Clinics.",
"key": "B41",
"volume": "67",
"year": "2012"
},
{
"DOI": "10.1093/jat/6.4.202",
"article-title": "Post mortem tissue levels of ascorbic acid in a scurvy case",
"author": "Allender",
"doi-asserted-by": "publisher",
"first-page": "202",
"journal-title": "J Anal Toxicol.",
"key": "B42",
"volume": "6",
"year": "1982"
},
{
"DOI": "10.1186/s12937-021-00727-z",
"article-title": "COVID-19: Up to 82% critically ill patients had low vitamin C values",
"author": "Tomasa-Irriguible",
"doi-asserted-by": "publisher",
"first-page": "66",
"journal-title": "Nutr J.",
"key": "B43",
"volume": "20",
"year": "2021"
},
{
"DOI": "10.3389/fmed.2023.1301001",
"article-title": "Vitamin C deficiency in critically ill COVID-19 patients admitted to intensive care unit",
"author": "Chiscano-Camón",
"doi-asserted-by": "publisher",
"first-page": "1301001",
"journal-title": "Front Med.",
"key": "B44",
"volume": "10",
"year": "2023"
},
{
"DOI": "10.7759/cureus.38687",
"article-title": "Scurvy in a pediatric patient unable to bear weight: a case report",
"author": "Jafri",
"doi-asserted-by": "publisher",
"first-page": "e38687",
"journal-title": "Cureus.",
"key": "B45",
"volume": "15",
"year": "2023"
},
{
"key": "B46",
"unstructured": "Divergence in mortality at 5 days is overlooked by Adhikari et al\n HemiläH\n PubPeer.2024"
}
],
"reference-count": 46,
"references-count": 46,
"relation": {},
"resource": {
"primary": {
"URL": "https://www.frontiersin.org/articles/10.3389/fmed.2024.1391346/full"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [],
"subtitle": [],
"title": "Rebound effect explains the divergence in survival after 5 days in a controlled trial on vitamin C for COVID-19 patients",
"type": "journal-article",
"update-policy": "http://dx.doi.org/10.3389/crossmark-policy",
"volume": "11"
}