Role of Ascorbic Acid Infusion in Critically Ill Patients With Transfusion Related Acute Lung Injury

Summary

TRALI was defined as "acute noncardiogenic pulmonary edema typically occurs ≤ 6 hours following transfusion of plasma-containing blood products, such as packed red blood cells, fresh frozen plasma, platelets, or cryoprecipitate." In critically ill patients, TRALI remains the leading cause of transfusion-related fatalities and is accompanied by a very significant morbidity and mortality. Survival in such patients is as low as 53% compared with 83% in acute lung injury (ALI) controls. The incidence of TRALi is likely underreported. In densely populated developing countries, incidence has not decreased due to lack of male-only strategy for plasma donation. TRALI is associated with systemic inflammation characterized by low anti-inflammatory cytokine as interleukin (IL)-10, increased pro-inflammatory cytokine as IL-8. Regulation of inflammation should include avoidance of overproduction of inflammatory mediators. So, it can be dampened not only by increasing IL-10 but also by decreasing IL-1β release. C-reactive protein (CRP) is an acute phase protein which is up-regulated during infections and inflammation. CRP was recently identified as a novel first hit in TRALI. Till now, there is no established treatment for TRALI beyond supportive care and monitoring. Recently, potential therapies have been reviewed, and it was concluded that the most promising therapeutic strategies are IL-10 therapy, downregulation of CRP levels, targeting reactive oxygen species (ROS) or blocking IL-8 receptors. So, antioxidants (such as high dose vitamins), were recommended for future studies as potentially effective treatment. Vitamin C hypovitaminosis is observed in 70% of critically ill despite receiving recommended daily doses. The aim of this study is to investigate the role of intravenous vitamin C (ascorbic acid) as a targeted therapy for transfusion related acute lung injury (TRALI) in critically ill patients in terms of IL-8, IL-10, CRP, SOD, malondialdehyde (MDA), vasopressor use, duration of mechanical ventilation, ICU length of stay, 7-days mortality and 28-days mortality.

Timeline

Start

2019-11-30

Primary completion

2021-07-16

Completion

2021-07-16

Publications

• Background Peters AL, Van Stein D, Vlaar AP. Antibody-mediated transfusion-related acute lung injury; from discovery to prevention. Br J Haematol. 2015 Sep;170(5):597-614. doi: 10.1111/bjh.13459. Epub 2015 Apr 28.
• Background Vlaar AP, Juffermans NP. Transfusion-related acute lung injury: a clinical review. Lancet. 2013 Sep 14;382(9896):984-94. doi: 10.1016/S0140-6736(12)62197-7. Epub 2013 May 1.
• Background Roubinian N. TACO and TRALI: biology, risk factors, and prevention strategies. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):585-594. doi: 10.1182/asheducation-2018.1.585. Epub 2018 Dec 14.
• Background Peters AL, van Hezel ME, Juffermans NP, Vlaar AP. Pathogenesis of non-antibody mediated transfusion-related acute lung injury from bench to bedside. Blood Rev. 2015 Jan;29(1):51-61. doi: 10.1016/j.blre.2014.09.007. Epub 2014 Sep 20.
• Background Andreu G, Boudjedir K, Muller JY, Pouchol E, Ozier Y, Fevre G, Gautreau C, Quaranta JF, Drouet C, Rieux C, Mertes PM, Clavier B, Carlier M, Sandid I. Analysis of Transfusion-Related Acute Lung Injury and Possible Transfusion-Related Acute Lung Injury Reported to the French Hemovigilance Network From 2007 to 2013. Transfus Med Rev. 2018 Jan;32(1):16-27. doi: 10.1016/j.tmrv.2017.07.001. Epub 2017 Jul 15.
• Background Vlaar AP, Binnekade JM, Prins D, van Stein D, Hofstra JJ, Schultz MJ, Juffermans NP. Risk factors and outcome of transfusion-related acute lung injury in the critically ill: a nested case-control study. Crit Care Med. 2010 Mar;38(3):771-8. doi: 10.1097/CCM.0b013e3181cc4d4b.
• Background Vlaar APJ, Toy P, Fung M, Looney MR, Juffermans NP, Bux J, Bolton-Maggs P, Peters AL, Silliman CC, Kor DJ, Kleinman S. An update of the transfusion-related acute lung injury (TRALI) definition. Transfus Clin Biol. 2019 Nov;26(4):354-356. doi: 10.1016/j.tracli.2019.05.007. Epub 2019 Jun 12. No abstract available.
• Background Toy P, Gajic O, Bacchetti P, Looney MR, Gropper MA, Hubmayr R, Lowell CA, Norris PJ, Murphy EL, Weiskopf RB, Wilson G, Koenigsberg M, Lee D, Schuller R, Wu P, Grimes B, Gandhi MJ, Winters JL, Mair D, Hirschler N, Sanchez Rosen R, Matthay MA; TRALI Study Group. Transfusion-related acute lung injury: incidence and risk factors. Blood. 2012 Feb 16;119(7):1757-67. doi: 10.1182/blood-2011-08-370932. Epub 2011 Nov 23.
• Background Semple JW, Rebetz J, Kapur R. Transfusion-associated circulatory overload and transfusion-related acute lung injury. Blood. 2019 Apr 25;133(17):1840-1853. doi: 10.1182/blood-2018-10-860809. Epub 2019 Feb 26.
• Background Roubinian NH, Looney MR, Kor DJ, Lowell CA, Gajic O, Hubmayr RD, Gropper MA, Koenigsberg M, Wilson GA, Matthay MA, Toy P, Murphy EL; TRALI Study Group. Cytokines and clinical predictors in distinguishing pulmonary transfusion reactions. Transfusion. 2015 Aug;55(8):1838-46. doi: 10.1111/trf.13021. Epub 2015 Feb 23.
• Background Semple JW, McVey MJ, Kim M, Rebetz J, Kuebler WM, Kapur R. Targeting Transfusion-Related Acute Lung Injury: The Journey From Basic Science to Novel Therapies. Crit Care Med. 2018 May;46(5):e452-e458. doi: 10.1097/CCM.0000000000002989.
• Background Ducharme-Crevier L, Lacroix J. Interleukin-1 Receptor Antagonist and Interleukin-1beta: Risk Marker or Risk Factor for Pediatric Acute Respiratory Distress Syndrome? Pediatr Crit Care Med. 2018 Oct;19(10):993-995. doi: 10.1097/PCC.0000000000001713. No abstract available.
• Background Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003 Jun;111(12):1805-12. doi: 10.1172/JCI18921. No abstract available.
• Background Kapur R, Kim M, Shanmugabhavananthan S, Liu J, Li Y, Semple JW. C-reactive protein enhances murine antibody-mediated transfusion-related acute lung injury. Blood. 2015 Dec 17;126(25):2747-51. doi: 10.1182/blood-2015-09-672592. Epub 2015 Oct 9.
• Background Kapur R, Kim M, Rondina MT, Porcelijn L, Semple JW. Elevation of C-reactive protein levels in patients with transfusion-related acute lung injury. Oncotarget. 2016 Nov 22;7(47):78048-78054. doi: 10.18632/oncotarget.12872.
• Background McNamara R, Deane AM, Anstey J, Bellomo R. Understanding the rationale for parenteral ascorbate (vitamin C) during an acute inflammatory reaction: a biochemical perspective. Crit Care Resusc. 2018 Sep;20(3):174-179. No abstract available.
• Background Carr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017 Dec 11;21(1):300. doi: 10.1186/s13054-017-1891-y.
• Background Margaritelis NV, Paschalis V, Theodorou AA, Vassiliou V, Kyparos A, Nikolaidis MG. Rapid decreases of key antioxidant molecules in critically ill patients: A personalized approach. Clin Nutr. 2020 Apr;39(4):1146-1154. doi: 10.1016/j.clnu.2019.04.029. Epub 2019 Apr 29.
• Background Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients. 2017 Nov 3;9(11):1211. doi: 10.3390/nu9111211.
• Background Hartmann SE, Waltz X, Kissel CK, Szabo L, Walker BL, Leigh R, Anderson TJ, Poulin MJ. Cerebrovascular and ventilatory responses to acute isocapnic hypoxia in healthy aging and lung disease: effect of vitamin C. J Appl Physiol (1985). 2015 Aug 15;119(4):363-73. doi: 10.1152/japplphysiol.00389.2015. Epub 2015 Jun 18.
• Background Reynolds PS, Fisher BJ, McCarter J, Sweeney C, Martin EJ, Middleton P, Ellenberg M, Fowler E, Brophy DF, Fowler AA 3rd, Spiess BD, Natarajan R. Interventional vitamin C: A strategy for attenuation of coagulopathy and inflammation in a swine multiple injuries model. J Trauma Acute Care Surg. 2018 Jul;85(1S Suppl 2):S57-S67. doi: 10.1097/TA.0000000000001844.
• Background Wang Y, Lin H, Lin BW, Lin JD. Effects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis. Ann Intensive Care. 2019 May 20;9(1):58. doi: 10.1186/s13613-019-0532-9.
• Background Rozemeijer S, Spoelstra-de Man AME, Coenen S, Smit B, Elbers PWG, de Grooth HJ, Girbes ARJ, Oudemans-van Straaten HM. Estimating Vitamin C Status in Critically Ill Patients with a Novel Point-of-Care Oxidation-Reduction Potential Measurement. Nutrients. 2019 May 8;11(5):1031. doi: 10.3390/nu11051031.
• Background Buehner M, Pamplin J, Studer L, Hughes RL, King BT, Graybill JC, Chung KK. Oxalate Nephropathy After Continuous Infusion of High-Dose Vitamin C as an Adjunct to Burn Resuscitation. J Burn Care Res. 2016 Jul-Aug;37(4):e374-9. doi: 10.1097/BCR.0000000000000233.
• Background Schorah CJ, Downing C, Piripitsi A, Gallivan L, Al-Hazaa AH, Sanderson MJ, Bodenham A. Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients. Am J Clin Nutr. 1996 May;63(5):760-5. doi: 10.1093/ajcn/63.5.760.
• Background Long CL, Maull KI, Krishnan RS, Laws HL, Geiger JW, Borghesi L, Franks W, Lawson TC, Sauberlich HE. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res. 2003 Feb;109(2):144-8. doi: 10.1016/s0022-4804(02)00083-5.
• Background Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF, Gupta S; Medical Respiratory Intensive Care Unit Nursing; Fisher BJ, Natarajan R. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014 Jan 31;12:32. doi: 10.1186/1479-5876-12-32.
• Background de Grooth HJ, Manubulu-Choo WP, Zandvliet AS, Spoelstra-de Man AME, Girbes AR, Swart EL, Oudemans-van Straaten HM. Vitamin C Pharmacokinetics in Critically Ill Patients: A Randomized Trial of Four IV Regimens. Chest. 2018 Jun;153(6):1368-1377. doi: 10.1016/j.chest.2018.02.025. Epub 2018 Mar 6.
• Background Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, McFarland JG, Nathens AB, Silliman CC, Stroncek D; National Heart, Lung and Blood Institute Working Group on TRALI. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005 Apr;33(4):721-6. doi: 10.1097/01.ccm.0000159849.94750.51.
• Background Kleinman S, Caulfield T, Chan P, Davenport R, McFarland J, McPhedran S, Meade M, Morrison D, Pinsent T, Robillard P, Slinger P. Toward an understanding of transfusion-related acute lung injury: statement of a consensus panel. Transfusion. 2004 Dec;44(12):1774-89. doi: 10.1111/j.0041-1132.2004.04347.x. No abstract available.
• Background Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, Fisher B, Thacker LR 2nd, Natarajan R, Brophy DF, Sculthorpe R, Nanchal R, Syed A, Sturgill J, Martin GS, Sevransky J, Kashiouris M, Hamman S, Egan KF, Hastings A, Spencer W, Tench S, Mehkri O, Bindas J, Duggal A, Graf J, Zellner S, Yanny L, McPolin C, Hollrith T, Kramer D, Ojielo C, Damm T, Cassity E, Wieliczko A, Halquist M. 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. JAMA. 2019 Oct 1;322(13):1261-1270. doi: 10.1001/jama.2019.11825.
• Background Wagner DP, Draper EA. Acute physiology and chronic health evaluation (APACHE II) and Medicare reimbursement. Health Care Financ Rev. 1984;Suppl(Suppl):91-105.
• Background Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10. doi: 10.1007/BF01709751. No abstract available.
• Background Kdigo AJKIS. Work Group. KDIGO clinical practice guideline for acute kidney injury. 2012;2(1):1-138.
• Background Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973 Aug;60(8):646-9. doi: 10.1002/bjs.1800600817. No abstract available.
• Background Klimant E, Wright H, Rubin D, Seely D, Markman M. Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach. Curr Oncol. 2018 Apr;25(2):139-148. doi: 10.3747/co.25.3790. Epub 2018 Apr 30.
• Kassem AB, Ahmed I, Omran G, Megahed M, Habib T. Role of ascorbic acid infusion in critically ill patients with transfusion-related acute lung injury. Br J Clin Pharmacol. 2022 May;88(5):2327-2339. doi: 10.1111/bcp.15167. Epub 2022 Jan 7.

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