Posted on Authorea 29 Mar 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161632383.34100016/v2 — This a preprint and has not been peer reviewed. Data may be preliminary. lv May Clive COVID-19 organ and reverse sepsis to in C dysfunction vitamin mega-dose of potential Therapeutic eue aclrrsosvns onrdeaie h rmr aorso sdciial,i omnin common 2017). is al., clinically, et used aggressive (Rhodes vasopressor with pressure primary treated arterial the is mean noradrenaline, that target to sepsis restore responsiveness of to vascular hallmark therapy vasopressor a Reduced is and (Lankadeva, vasodilatation resuscitation 2021) peripheral fluid Hellman, to & secondary thought (Joffre Hypotension inflammation- is dysfunction 2019). vasoplegia, inflammation May, multi-organ in excessive & and homeostasis Bellomo resulting with hypoxia redox Evans, dysfunction, together Okazaki, that tissue microvascular which evidence injury, is and stress, tissue There endothelial oxidative mediated pathophysiology progresses. in mitochondrial, complex infection resulting cause the the sepsis to to to in response due the disrupted unclear as is remain changes dysfunction that organ sepsis of sepsis-induced causing factors dysfunction sepsis-induce The renal reverse and frequently that cardiovascular treatments sepsis sepsis-induced no severe of are Pathophysiology from there recover Currently who dysfunction. patients organ should dysfunction. However, chronic function organ organ of infection. that degree expectation the a the in- exhibit consists of These in sepsis alive replacement resolution 2021). patient for Kellum, renal following the treatment & continuous keeping recover Ronco incidence care towards with Baldwin, global aimed of (Bellomo, 2017), mostly annual patients Standard al., ill are an (Singer 2020). terventions critically et with in al., death (Rhodes used units et vasopressors and increasingly care (Rudd being and dysfunction intensive therapy deaths resuscitation in multi-organ million mortality fluid to 11 antibiotics, of lead and re- cause of can cases leading immune million that the and 49 infection is inflammatory of Sepsis fungal overwhelming or 2016). an viral al., by et bacterial, characterised a syndrome to pathophysiological sponse a is Sepsis mega-dose of effectiveness the testing Introduction are trials Clinical pressure, treatment levels. arterial This and restored oxygen patients. g) function septic blood sepsis. (60 renal in arterial ascorbate of C and sodium increased model intravenous vitamin hepatic and patient, ovine pulmonary, COVID-19 relevant function cardiovascular, ill clinically renal critically improved a improved a 3-7-h (6-16 In in effects over C the kg) temperature. and vitamin studied body g/40 we intravenous state reduced patients, (150 of clinical burns ascorbate high-doses and the immune cancer sodium of improved in that intravenous and trials dramatically side-effects treatments of clinical anticoagulant without no are mega-dose Recent anti-inflammatory, doses are a antioxidant, higher sepsis. there much of has for but Since treatment units, C effects. variable potential care Vitamin had intensive a g/day) in is sepsis. death so of actions, of cause modulatory effects major pathophysiological a the is and reverse dysfunction multi-organ causes Sepsis Abstract 2021 29, March 2 1 h lryIsiueo ersineadMna Health Melbourne Mental of and University Neuroscience The of Institute Florey The 1 iad Bellomo Rinaldo , 2 n ues Lankadeva Yugeesh and , 1 1 Posted on Authorea 29 Mar 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161632383.34100016/v2 — This a preprint and has not been peer reviewed. Data may be preliminary. aebe hw ob aei un n acrptet Yns ta. 00,w eetyinvestigated recently sepsis. we experimental sepsis 2020), in in al., C treatment vitamin et C (Yanase of vitamin (mega-dose) patients dose mega-dose cancer vitamin larger for and intravenous much of Rationale burns a doses to in high of due very safe efficacy be that might and be fact sepsis the safety to in and the C shown findings, vitamin these been of of C have trials view 2019). vitamin clinical In C al., of the doses. in patient) inadequate et of (Fowler benefit kg use consistent 30% 80 the of to an lack (Hwang in 46% the that g/day 2020) from hypothesized thiamine (16 mortality al., We with mg/kg/day 28-day et days 200 reduced (Moskowitz 10 used however, 2020) to days, that up al., trial, for 4 et g/day CITRUS-ALI for (Fujii 6 The placebo of ATESS 2020). C above and al., vitamin benefit 2020) et of However, significant al., dose no maximum organ et 2017). a Catravas, had (Moskowitz reduced trialled ACTS & corticosteroid, thiamine, that using 2020), Hooper 2020) and (n=47), al., Rivera, al., hydrocortisone et study et Khangoora, (Hwang with (Fujii (Marik, after VITAMINS times/day) 8.5% and RCTs, 4 to multi-centre Moham- before g 40.4% subsequent (Zabet, single-centre from (1.5 n=28) mortality publicised C times/day, and widely vitamin 4 failure A of g therapy (2 2016). combination sensitivity Khalili, a mg/kg/day, vasopressor 200 improved & 100, and Ramezani (50, 2014) madi, scores (SOFA) al., assessment inflam- et failure reduced (Fowler C organ n=24) sequential vitamin intravenous reduced that and showed biomarkers (RCT) matory sepsis trials for clinical human randomised impetus in controlled the therapy Single-centre provided sepsis. C observations is in vitamin These C there high-dose vitamin as with 2004). intravenous C Controversies al., of vitamin C. effects et of vitamin (Padayatty the synthesise levels examining absorption to plasma trials intestinal humans high clinical 2018) the of produce al., inability on Sabui, to the et limit (Subramanian, by required Grooth a ab- (SVCTs) compounded is (de have is administration transporters turnover which patients intravenous C metabolic 2018), Importantly, septic increased Said, vitamin Furthermore, & to sodium-dependent Marchant due benefit cellular Moradi, 2020). likely of of levels, al., be downregulation C to et and vitamin predicted caused (Holford stimulant plasma be scurvy and synthesis low would of immune-modulator vasopressin that normally anticoagulant, symptoms and anti-inflammatory, effects in the anti-oxidant, pleiotropic noradrenaline for enzyme be an numerous of accounting biosynthetic cannot as has synthesis, it final including also diet; collagen the sepsis, C the for in oxidase, Vitamin in essential gluconolactone deficiency. obtained is for its be C by must gene Vitamin that the humans synthesis. in in mutations its vitamin of essential an because a is synthesised as acid, ascorbic C been sepsis C, vitamin not in Vitamin have of therapy effects effects C its the but vitamin 2005), in for al., interest Rational et increasing (Matejovic been sepsis of has sepsis. model there for shown porcine however, treatment has been a Recently, has which many in tempol over N-acetylcysteine, clinically. AKI antioxidant antioxidant interest of The examined level The been 2018). the (Chertoff, has clinical reduce sepsis. findings but to there disappointing for studies, experimental largely stress, treatment in yielded oxidative promise a have some and studies showed as properties, hypoxia antioxidants anti-inflammatory tissue and of antioxidant of both use effects the damaging in the decades of dysfunction view organ pathophysiological In sepsis-induced Bellomo sepsis-induced for Evans, these therapy AKI. Okazaki, target a mitigate dysfunction, (Lankadeva, that as and mitochondrial Therapies Antioxidants AKI management to circulatory in 2014). better lead culminating Singh, confer can (Calzavacca, function may & hypoxia 12-h processes Nourbakhsh renal to medullary 2019; of 8 Renal May, by loss & (AKI) progressive 2015). injury May, a kidney & acute initiating ovine of Bellomo of development features Bailey, pathophysiological the critical Evans, itself, precede are in medulla that failure. renal which, sepsis multi-organ the 1998), in hyperdynamic and hypoxia dysfunction al., and mitochondrial hypoperfusion et tissue hypoxia, (Annane Indeed, and hypotension hypoperfusion refractory tissue sometimes in and result can persistent in resulting sepsis 2 ± Posted on Authorea 29 Mar 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161632383.34100016/v2 — This a preprint and has not been peer reviewed. Data may be preliminary. ess ihafcso t nioiatadat-namtr cin.Sc tde r seta oprovide to RCTs. essential multi-centre are double-blinded Further studies large legend Such in regimen. of Figure actions. dysfunction dosing design multi-organ anti-inflammatory optimum the reverses and for the anti-oxidant C rationale determine its vitamin studies scientific which on to dose-response the by focus complete measured mechanisms to a are the critical with safety C determine now sepsis, the vitamin to is demonstrated It necessary of also patient. are levels We COVID-19 studies sepsis. plasma a of dysfunction the in model organ which benefit ovine reverse relevant its in to clinically and C treatment a vitamin this in intravenous of state mega-dose clinical of the ability improve potent and a demonstrate findings Our an Columbia. with Australia in in commence (ACTRN12620000651987p) to Conclusions patients scheduled septic patients 30 COVID-19 in in vitamin g) RCT mega-dose intravenous 60 additional of ascorbate, effects (sodium the examining treatment underway C currently is RCT placebo-controlled pilot C A vitamin mega-dose of reduced trials while treatment. by Clinical improved hospital C levels from accompanied vitamin discharged oxygen and mega-dose noradrenaline, blood extubated after sodium subsequently Arterial of was days sheep, ill rate. patient withdrawal 22 septic The heart critically reduced. in of reduced treated was a As oxygen and face was inspired 2021). flow sepsis, fractional the al., AKI urine ovine et increased in and (Lankadeva creatinine, in pressure hours) hypotension plasma C 7 arterial syndrome, over vitamin restored g distress mega-dose (60 ascorbate respiratory ascorbate of acute sodium effects intravenous mild induced with beneficial with COVID-19 patients potent with studied. COVID-19 of patient been in not finding investigated have actions our mega-doses been beneficial Following of have has effects may into g) the it SARS-CoV-2 (1.5-14.0 but that for effects, indicate C point further beneficial entry vitamin 2021), the Intravenous Rath, 2, COVID-19. and are & enzyme in levels 2020), Niedzwiecki converting Ivanova, C Ferrer, angiotensin vitamin Goc, & of (Ivanov, plasma Roca expression that cells that lowers Ruiz-Sanmartin, indicate findings C C The Ruiz-Rodriguez, vitamin vitamin COVID-19. 2021) (Chiscano-Camon, of that for al., patients actions treatment et COVID-19 known adjunct The (Group in plausible patients. a low dexamethasone such be and for also treatments 2021) would beneficial al., it be et to (Salama shown monoclonal receptor) been humanized have interleukin-6 (a the tocilizumab like against coa- agents intravascular antibody Immunosuppressive disseminated dysfunction. response, multi-organ inflammatory and excessive an gulation bioavailability develop patients oxide COVID-19 ill nitric Critically C thus mitochondrial vitamin and reduce with to activity COVID-19 likely eNOS of are Treatment C increase vitamin to of injury. effects ability cellular antioxidant and its the Furthermore, dysfunction from 2012). dysfunction al., result microcirculatory et medullary may (Ladurner renal (eNOS) synthase of C oxide reversal May, nitric vitamin The & endothelial 2008). by medullary Bellomo Bellomo, Bailey, renal & Evans, of May (Calzavacca, expression Bagshaw, gene AKI (Langenberg, reduced septic by ovine accompanied in is perfusion 2015) creatinine intra-renal levels. and and of flow creatinine re-distribution urine hypoperfusion plasma in The of increases medullary dramatic normalisation lactate by renal a shown blood reversed as to arterial AKI, leading reduced also improvements septic clearance in and of treatment reversal levels indicative a The levels, normal by oxygen accompanied to function. hypoxia, febrile blood to metabolic from arterial decreased increased improved temperature which C body al., indicating requirements, vitamin restored et noradrenaline Mega-dose (Lankadeva function, ovine reduced cases. state lung 5 with mobile in established of levels responsive, in 4 alert, pre-septic in 7-h) an to zero to restored kg somnolence was g/˜40 and MAP lethargy (150 2021). malaise, ascorbate from live state sodium of clinical infusion of by induced mega-dose sepsis, a hyperdynamic of administration Intravenous shrci.coli Escherichia. 3 asdarmral mrvmn nthe in improvement remarkable a caused , Posted on Authorea 29 Mar 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161632383.34100016/v2 — This a preprint and has not been peer reviewed. Data may be preliminary. tmltsedteilnti xd ytaeezm ciiyb ai ouaino t phosphorylation its of modulation rapid VM by 52 Dirsch Medicine activity ER, & enzyme Biology Werner synthase Radical AG, Free oxide Atanasov status. nitric D, Schachner endothelial inflammation. CA, stimulates acute print. Schmitt and of sepsis A, ahead in Online Ladurner dysfunction 26. endothelial Ascorbic Feb and by Signaling. stress Expression Redox Oxidative 14 ACE2 (2021). & (Auckl) Antioxidants of J Dis Hellman Infect Inhibition & Compounds. (2021). J, Natural M Joffre Other Rath with & Combinations A, its Niedzwiecki and Alone S, Ivanova Acid Care A, Intensive Goc study. V, controlled Ivanov randomized, double-blinded GJ multi-centre, Suh a DH, 46 shock: Jang Medicine YH, septic Jo for JE, thiamine PE Park and SM, Marik 12. Ryoo IS, Nutrients SY, COVID-19. Whitaker Hwang and SR, Sepsis Ali Infection, TH, Respiratory Jovic for 384 Therapy AC, Medicine of Carr Journal P, JL England Bell Holford New M, The Mafham Covid-19. JR, with Emberson Patients WS, Support the lized Lim of Vasopressor P, Journal Horby of the RC, Free : Group JAMA and CJ Trial. Alive Clinical French 323 Randomized Time Association GM, VITAMINS Medical on The Eastwood American Shock: Alone Septic DR, Hydrocortisone With Frei Patients vs Among PJ, Thiamine Young and the N, of Hydrocortisone, Luethi Journal the T, : and Fujii JAMA Sepsis Trial. With Clinical 322 Patients Randomized in Association Injury CITRIS-ALI Medical A Vascular The American Priday and Failure: C, Inflammation Respiratory of DeWilde Acute Biomarkers PE, Severe and 12 Morris Failure Med RD, Organ Transl Hite on J Infusion JD, sepsis. Truwit severe C 3rd, with DeWilde AA, patients D, Fowler Farthing in R, acid Regimens. Sculthorpe ascorbic IV intravenous S, Four of Knowlson of trial AA, Trial EL Syed 3rd, Swart Randomized AA, AR, A Fowler Patients: Girbes Ill AME, Critically Man in 153 Spoelstra-de Chest Pharmacokinetics levels AS, C C Zandvliet WP, Vitamin Vitamin 24 Manubulu-Choo (2018). Care (2020). Crit HJ, R syndrome. Ferrer Grooth distress & de respiratory O, acute Roca SARS-CoV-2-associated A, with Ruiz-Sanmartin patients in JC, Ruiz-Rodriguez Microcirculatory L, With Patients 33 Chiscano-Camon in Medicine Benefit Care Potential Intensive and of 43 Sepsis Perfusion Journal Medicine in Tissue Derangements. Role Care Medullary N-Acetylcysteine’s Critical and (2018). Injury. Cortical J Kidney (2015). Chertoff Acute CN Septic May Experimental & in R, Bellomo Oxygenation M, and Care Bailey Critical RG, Therapy. Evans Replacement P, Renal Calzavacca ICU-Based reserve. (2021). JA function Kellum adrenal & 49 C, impaired Medicine Ronco JC I, without Raphael Baldwin and R, B, Bellomo with 46 Mathieu patients Pharmacology Clinical O, shock of septic Lesieur Journal in British V, noradrenaline Sebille to E, sensitivity Bellissant D, Annane REFERENCES with action. observed have of we mechanisms Interest: treatment ( possible of the of effects and the sepsis Conflicts sepsis, ovine of in effects C specific vitamin organ mega-dose and intravenous systemic the of Overview 2020901120). : 1368-1377. : : 2015-2025. 406-418. R,R n N aeapoiinlptn nVtmnCuei sepsis in use C Vitamin on patent provisional a have CNM and RB YRL, : : 423-431. 1261-1270. : : 2082-2090. 589-597. 4 : 87-96. tal. et , 22) obnto hrp fvtmnC vitamin of therapy Combination (2020). tal. et , tal. et , tal. et , 22) eaehsn nHospita- in Dexamethasone (2021). tal. et , : 22) iai -nAdjunctive C-An Vitamin (2020). tal. et , 693-704. 22) ffc fVtmnC, Vitamin of Effect (2020). tal. et , 21) ffc fVtmnC Vitamin of Effect (2019). : tal. et , 32. 19) mardpressor Impaired (1998). 21) hs safety I Phase (2014). : 1178633721994605. : 21) Ascorbate (2012). e431-439. : 522. tal. et , Posted on Authorea 29 Mar 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161632383.34100016/v2 — This a preprint and has not been peer reviewed. Data may be preliminary. covid-19 figure.pptx therapeutic-potential-of-mega-dose-vitamin-c-to-reverse-organ-dysfunction-in-sepsis-and- Topic Hot vasopres-BJP on acid 5 Ascorbic Pract high-dose Pharm file of Res Effect Hosted J (2016). shock. 48 H septic Khalili Medicine in & Care requirement M, Critical Ramezani sor’s Review. AC M, Scoping Mohammadi Carr A MH, N, Patients: Zabet Luethi Adult in A, Therapy Belletti C T, Vitamin Naorungroj Dose T, Fujii acid Biomembr F, ascorbic Acta Yanase intestinal Biophys of the Biochim Inhibition mechanisms. of (2018). transcriptional HM Journal via Said mediated 1860 & the is JS, : Marchant lipopolysaccharide H, by JAMA Moradi uptake S, (Sepsis-3). Sabui Shock VS, Subramanian Septic M and Bauer 315 D, Sepsis Association Annane Medical for M, American Shankar-Hari Definitions CW, Consensus 384 Seymour International Medicine CS, of JD Deutschman Journal Neidhart M, England B, Singer New Kramer The WG, Pneumonia. Reiss Covid-19 L, with Yau Lancet talized Study. J, Disease Han of C, Burden Salama Global the for analysis DR Kievlan 1990-2017: mortality, D, 395 and Tsoi Medicine KA, incidence Care Shackelford sepsis KM, Critical national Agesa 2016. SC, Johnson Shock: KE, Septic Rudd and R Sepsis Ferrer of M, Management Antonelli 45 for MM, Levy Guidelines W, International 140 Alhazzani paign: Medicine LE, Internal Evans of A, Annals Rhodes use. A pathophy- intravenous Katz SM, and the Hewitt oral in HD, for function Riordan implications Y, mitochondrial Wang 127 and H, Practice Sun oxygenation SJ, Clinical Padayatty renal Nephron of injury. Role kidney acute (2014). of P 324 siology Singh Association & Trial. Medical N, Clinical American Randomized Nourbakhsh ACTS the AV The of Grossestreuer Shock: Journal Septic PB, the in Doshi Injury : J, Organ JAMA on Gong Thiamine PC, and Corticosteroids, Hou Acid, DT, H 33 Huang Kralova Medicine Care A, J, Critical Moskowitz Radej bacteremia. porcine Jr., hyperdynamic R, long-term on Rokyta scavenger, 1057-1063. and radical V, C, free Martinkova Chest a Vitamin Study. A, tempol, Before-After Hydrocortisone, Krouzecky Retrospective (2017). M, A J Shock: Matejovic Catravas Septic & and Sepsis MH, Severe Hooper of 151 Treatment R, the Rivera for V, Thiamine Khangoora Medicine PE, Care Marik Critical C. A Vitamin Dornom Megadose New A, by Trask-Marino A Sepsis 49 Gram-Negative IE, Hypoxia: to Birchall Medullary Responses N, Pathophysiological Renal Okazaki the 39 (2019). RM, Nephrol kidney CN Peiris Semin acute May YR, Injury? Lankadeva & septic Kidney R, Acute of Septic Bellomo histopathology for RG, Target The Evans Therapeutic (2008). N, Okazaki R YR, 12 Bellomo Lankadeva Care & Crit CN, review. systematic May a SM, injury: Bagshaw C, Langenberg : : : : 486-552. e179-e190. : 200-211. 1229-1238. 556-565. vial at available : 801-810. : R38. https://authorea.com/users/402905/articles/514619- 5 : 94-100. : tal. et , : 149-152. 642-650. tal. et , tal. et , 22) oiiua nPtet Hospi- Patients in Tocilizumab (2021). tal. et , 20) iai pharmacokinetics: C Vitamin (2004). : tal. et , 543-553. 22) amo nrvnu High Intravenous of Harm (2020). tal. et , : 533-537. 21) uvvn essCam- Sepsis Surviving (2017). : 22) lbl einl and regional, Global, (2020). 20-30. tal. et , tal. et , tal. et , 22) ffc fAscorbic of Effect (2020). 22) eeslof Reversal (2021). 21) h Third The (2016). 20) ffcsof Effects (2005). : e620-e628. :