A Trial of Vitamin B12 in Septic Shock

Summary

This study will randomize 20 septic shock patients to receive either a single 5 gram dose of IV vitamin B12 (Cyanokit® Meridian Medical Technologies, Columbia, MD) versus placebo in addition to standard of care to test the feasibility of completing clinical and laboratory protocols.

Timeline

Start

2019-08-05

Primary completion

2023-02-23

Completion

2023-02-23

Publications

• Background Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
• Background Abraham E, Reinhart K, Svoboda P, Seibert A, Olthoff D, Dal Nogare A, Postier R, Hempelmann G, Butler T, Martin E, Zwingelstein C, Percell S, Shu V, Leighton A, Creasey AA. Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit Care Med. 2001 Nov;29(11):2081-9. doi: 10.1097/00003246-200111000-00007.
• Background Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997 Mar 27;336(13):912-8. doi: 10.1056/NEJM199703273361303.
• Background Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D, Silverman MS, Takala J, Donaldson J, Arneson C, Grove G, Grossman S, Grover R. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med. 2004 Jan;32(1):21-30. doi: 10.1097/01.CCM.0000105581.01815.C6.
• Background Lorente JA, Landin L, De Pablo R, Renes E, Liste D. L-arginine pathway in the sepsis syndrome. Crit Care Med. 1993 Sep;21(9):1287-95. doi: 10.1097/00003246-199309000-00010.
• Background Szakmany T, Hauser B, Radermacher P. N-acetylcysteine for sepsis and systemic inflammatory response in adults. Cochrane Database Syst Rev. 2012 Sep 12;2012(9):CD006616. doi: 10.1002/14651858.CD006616.pub2.
• Background Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999 Sep 9;341(11):785-92. doi: 10.1056/NEJM199909093411102.
• Background Shatalin K, Shatalina E, Mironov A, Nudler E. H2S: a universal defense against antibiotics in bacteria. Science. 2011 Nov 18;334(6058):986-90. doi: 10.1126/science.1209855.
• Background Lambden S, Creagh-Brown BC, Hunt J, Summers C, Forni LG. Definitions and pathophysiology of vasoplegic shock. Crit Care. 2018 Jul 6;22(1):174. doi: 10.1186/s13054-018-2102-1.
• Background Kosir M, Podbregar M. Advances in the Diagnosis of Sepsis: Hydrogen Sulfide as a Prognostic Marker of Septic Shock Severity. EJIFCC. 2017 May 1;28(2):134-141. eCollection 2017 May.
• Background Zhang H, Moochhala SM, Bhatia M. Endogenous hydrogen sulfide regulates inflammatory response by activating the ERK pathway in polymicrobial sepsis. J Immunol. 2008 Sep 15;181(6):4320-31. doi: 10.4049/jimmunol.181.6.4320.
• Background Goslar T, Mars T, Podbregar M. Total plasma sulfide as a marker of shock severity in nonsurgical adult patients. Shock. 2011 Oct;36(4):350-5. doi: 10.1097/SHK.0b013e31822bcfd0.
• Background Li L, Bhatia M, Zhu YZ, Zhu YC, Ramnath RD, Wang ZJ, Anuar FB, Whiteman M, Salto-Tellez M, Moore PK. Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse. FASEB J. 2005 Jul;19(9):1196-8. doi: 10.1096/fj.04-3583fje. Epub 2005 Apr 29.
• Background Zundel MT, Feih JT, Rinka JRG, Boettcher BT, Freed JK, Kaiser M, Ghadiali HY, Tawil JN, Woehlck HJ, Pagel PS. Hydroxocobalamin With or Without Methylene Blue May Improve Fluid Balance in Critically Ill Patients With Vasoplegic Syndrome After Cardiac Surgery: A Report of Two Cases. J Cardiothorac Vasc Anesth. 2018 Feb;32(1):452-457. doi: 10.1053/j.jvca.2017.04.002. Epub 2017 Apr 5. No abstract available.
• Background Truong DH, Mihajlovic A, Gunness P, Hindmarsh W, O'Brien PJ. Prevention of hydrogen sulfide (H2S)-induced mouse lethality and cytotoxicity by hydroxocobalamin (vitamin B(12a)). Toxicology. 2007 Dec 5;242(1-3):16-22. doi: 10.1016/j.tox.2007.09.009. Epub 2007 Sep 15.
• Background Brenner M, Benavides S, Mahon SB, Lee J, Yoon D, Mukai D, Viseroi M, Chan A, Jiang J, Narula N, Azer SM, Alexander C, Boss GR. The vitamin B12 analog cobinamide is an effective hydrogen sulfide antidote in a lethal rabbit model. Clin Toxicol (Phila). 2014 Jun;52(5):490-7. doi: 10.3109/15563650.2014.904045. Epub 2014 Apr 9.
• Background Ng PC, Hendry-Hofer TB, Garrett N, Brenner M, Mahon SB, Maddry JK, Haouzi P, Boss GR, Gibbons TF, Arana AA, Bebarta VS. Intramuscular cobinamide versus saline for treatment of severe hydrogen sulfide toxicity in swine. Clin Toxicol (Phila). 2019 Mar;57(3):189-196. doi: 10.1080/15563650.2018.1504955. Epub 2018 Nov 15.
• Background Weinberg JB, Chen Y, Jiang N, Beasley BE, Salerno JC, Ghosh DK. Inhibition of nitric oxide synthase by cobalamins and cobinamides. Free Radic Biol Med. 2009 Jun 15;46(12):1626-32. doi: 10.1016/j.freeradbiomed.2009.03.017. Epub 2009 Mar 27.
• Background Zhang H, Zhi L, Moochhala S, Moore PK, Bhatia M. Hydrogen sulfide acts as an inflammatory mediator in cecal ligation and puncture-induced sepsis in mice by upregulating the production of cytokines and chemokines via NF-kappaB. Am J Physiol Lung Cell Mol Physiol. 2007 Apr;292(4):L960-71. doi: 10.1152/ajplung.00388.2006. Epub 2007 Jan 5.
• Background An SS, Henson CP, Freundlich RE, McEvoy MD. Case report of high-dose hydroxocobalamin in the treatment of vasoplegic syndrome during liver transplantation. Am J Transplant. 2018 Jun;18(6):1552-1555. doi: 10.1111/ajt.14736. Epub 2018 Apr 2.
• Background Woehlck HJ, Boettcher BT, Lauer KK, Cronin DC, Hong JC, Zimmerman MA, Kim J, Selim M. Hydroxocobalamin for Vasoplegic Syndrome in Liver Transplantation: Restoration of Blood Pressure Without Vasospasm. A A Case Rep. 2016 Dec 15;7(12):247-250. doi: 10.1213/XAA.0000000000000398.
• Background Boettcher BT, Woehlck HJ, Reck SE, Hong JC, Zimmerman MA, Kim J, Zundel MT, Freed JK, Pagel PS. Treatment of Vasoplegic Syndrome With Intravenous Hydroxocobalamin During Liver Transplantation. J Cardiothorac Vasc Anesth. 2017 Aug;31(4):1381-1384. doi: 10.1053/j.jvca.2016.10.011. Epub 2016 Oct 14. No abstract available.
• Background Burnes ML, Boettcher BT, Woehlck HJ, Zundel MT, Iqbal Z, Pagel PS. Hydroxocobalamin as a Rescue Treatment for Refractory Vasoplegic Syndrome After Prolonged Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth. 2017 Jun;31(3):1012-1014. doi: 10.1053/j.jvca.2016.08.019. Epub 2016 Aug 18. No abstract available.
• Background Shah PR, Reynolds PS, Pal N, Tang D, McCarthy H, Spiess BD. Hydroxocobalamin for the treatment of cardiac surgery-associated vasoplegia: a case series. Can J Anaesth. 2018 May;65(5):560-568. doi: 10.1007/s12630-017-1029-3. Epub 2017 Dec 5.
• Background Modis K, Bos EM, Calzia E, van Goor H, Coletta C, Papapetropoulos A, Hellmich MR, Radermacher P, Bouillaud F, Szabo C. Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part II. Pathophysiological and therapeutic aspects. Br J Pharmacol. 2014 Apr;171(8):2123-46. doi: 10.1111/bph.12368.
• Background Bice JS, Jones BR, Chamberlain GR, Baxter GF. Nitric oxide treatments as adjuncts to reperfusion in acute myocardial infarction: a systematic review of experimental and clinical studies. Basic Res Cardiol. 2016 Mar;111(2):23. doi: 10.1007/s00395-016-0540-y. Epub 2016 Feb 24.
• Background Ozaki KS, Kimura S, Murase N. Use of carbon monoxide in minimizing ischemia/reperfusion injury in transplantation. Transplant Rev (Orlando). 2012 Apr;26(2):125-39. doi: 10.1016/j.trre.2011.01.004. Epub 2011 Oct 13.
• Background Eckstein M. Enhancing public health preparedness for a terrorist attack involving cyanide. J Emerg Med. 2008 Jul;35(1):59-65. doi: 10.1016/j.jemermed.2007.03.040. Epub 2007 Aug 29.
• Background Anseeuw K, Delvau N, Burillo-Putze G, De Iaco F, Geldner G, Holmstrom P, Lambert Y, Sabbe M. Cyanide poisoning by fire smoke inhalation: a European expert consensus. Eur J Emerg Med. 2013 Feb;20(1):2-9. doi: 10.1097/MEJ.0b013e328357170b.
• Background Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hastbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM; ATHOS-3 Investigators. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154. Epub 2017 May 21.
• Background Shen X, Peter EA, Bir S, Wang R, Kevil CG. Analytical measurement of discrete hydrogen sulfide pools in biological specimens. Free Radic Biol Med. 2012 Jun 1-15;52(11-12):2276-83. doi: 10.1016/j.freeradbiomed.2012.04.007. Epub 2012 Apr 19.
• Background Puskarich MA, Kline JA, Watts JA, Shirey K, Hosler J, Jones AE. Early alterations in platelet mitochondrial function are associated with survival and organ failure in patients with septic shock. J Crit Care. 2016 Feb;31(1):63-7. doi: 10.1016/j.jcrc.2015.10.005. Epub 2015 Oct 26.
• Patel JJ, Willoughby R, Peterson J, Carver T, Zelten J, Markiewicz A, Spiegelhoff K, Hipp LA, Canales B, Szabo A, Heyland DK, Stoppe C, Zielonka J, Freed JK. High-Dose IV Hydroxocobalamin (Vitamin B12) in Septic Shock: A Double-Blind, Allocation-Concealed, Placebo-Controlled Single-Center Pilot Randomized Controlled Trial (The Intravenous Hydroxocobalamin in Septic Shock Trial). Chest. 2023 Feb;163(2):303-312. doi: 10.1016/j.chest.2022.09.021. Epub 2022 Sep 26.

Drugs

Indications