<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03783091</url>
  </required_header>
  <id_info>
    <org_study_id>32950</org_study_id>
    <nct_id>NCT03783091</nct_id>
  </id_info>
  <brief_title>A Trial of Vitamin B12 in Septic Shock</brief_title>
  <acronym>B12</acronym>
  <official_title>A Phase II Double Blind Randomized Controlled Trial of High Dose Vitamin B12 in Septic Shock</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical College of Wisconsin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical College of Wisconsin</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will randomize 20 septic shock patients to receive either a single 5 gram dose of&#xD;
      IV vitamin B12 (Cyanokit® Meridian Medical Technologies, Columbia, MD) versus placebo in&#xD;
      addition to standard of care to test the feasibility of completing clinical and laboratory&#xD;
      protocols.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Following informed consent from patient's legally authorized representative, patients will be&#xD;
      randomized to hydroxocobalamin or saline. Patients will have blood samples drawn up to 3&#xD;
      hours pre-dose and 3 hours post-dose to measure for hydrogen sulfide levels. Patients will&#xD;
      also be followed for 3 hours after study drug infusion to monitor and record vasopressor&#xD;
      dependence in norepinephrine-equivalent dose. Patients will then be followed through their&#xD;
      medical record for 28 days to determine persistent organ dysfunction syndrome (PODS).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 5, 2019</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Vitamin B12a is bright red and excreted in the urine. Due to this, patient allocation cannot be masked for patients or individuals who may care for them.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Feasibility of completing clinical and laboratory protocols</measure>
    <time_frame>28 days</time_frame>
    <description>Feasibility of completing clinical and laboratory protocols</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hydrogen Sulfide Concentration</measure>
    <time_frame>3 hours</time_frame>
    <description>Difference between pre- and post-dose hydrogen sulfide levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Persistent Organ Dysfunction Syndrome (PODS)</measure>
    <time_frame>28 days</time_frame>
    <description>Prevalence of Persistent organ dysfunction syndrome (PODS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in vasopressor dose</measure>
    <time_frame>3, 24, and 48 hours</time_frame>
    <description>Vasopressor dose in mcg/kg/min (norepinephrine equivelents)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>28 days</time_frame>
    <description>Intensive care unit and hospital mortality</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Septic Shock</condition>
  <arm_group>
    <arm_group_label>Hydroxocobalamin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single IV infusion administered over a 10-15 minute period</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Saline Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single IV saline administered over a 10-15 minute period.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydroxocobalamin</intervention_name>
    <description>Single IV administration of Vitamin B12</description>
    <arm_group_label>Hydroxocobalamin</arm_group_label>
    <other_name>Cyanokit</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Single IV administration of saline</description>
    <arm_group_label>Saline Placebo</arm_group_label>
    <other_name>200-250 mL of intravenous saline or dextrose</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients at least 18 years of age&#xD;
&#xD;
          -  Admitted to the Medical Intensive Care Unit (MICU) service at Froedtert Hospital&#xD;
&#xD;
          -  Diagnosis of septic shock, as defined by sepsis-3 criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of calcium oxaluria&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jayshil J Patel, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical College of Wisconsin</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jayshil J Patel, MD</last_name>
    <phone>414-955-7040</phone>
    <email>jpatel2@mcw.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jeanette Graf, BS</last_name>
    <phone>414-955-6987</phone>
    <email>jgraf@mcw.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jayshil J Patel, MD</last_name>
      <phone>414-955-7040</phone>
    </contact>
    <contact_backup>
      <last_name>Jennifer Peterson, PhD</last_name>
      <phone>414-955-7085</phone>
      <email>jenpeterson@mcw.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>26903338</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>11700399</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>9070471</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>14707556</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>8370291</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22972094</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>10477776</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22096201</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>29980217</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>28757821</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>18768890</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21897337</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>15863703</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>28778773</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>17976885</PMID>
  </reference>
  <reference>
    <citation>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. Erratum In: Clin Toxicol (Phila). 2015 Jan;53(1):77.</citation>
    <PMID>24716792</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>30430872</PMID>
  </reference>
  <reference>
    <citation>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. Erratum In: Free Radic Biol Med. 2011 Oct 1;51(7):1471.</citation>
    <PMID>19328848</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>17209138</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>29573551</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>27749291</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>28012726</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>27838199</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>29209927</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>23991749</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>26912064</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22000659</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>17976798</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22828651</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>28528561</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22561703</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>26511963</PMID>
  </reference>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>December 19, 2018</study_first_submitted>
  <study_first_submitted_qc>December 19, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <last_update_submitted>November 30, 2021</last_update_submitted>
  <last_update_submitted_qc>November 30, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 15, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical College of Wisconsin</investigator_affiliation>
    <investigator_full_name>Jayshil J. Patel, MD</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Shock, Septic</mesh_term>
    <mesh_term>Shock</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydroxocobalamin</mesh_term>
    <mesh_term>Vitamin B 12</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03783091
org study id: 32950
nct id: NCT03783091
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
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.
Following informed consent from patient's legally authorized representative, patients will be
      randomized to hydroxocobalamin or saline. Patients will have blood samples drawn up to 3
      hours pre-dose and 3 hours post-dose to measure for hydrogen sulfide levels. Patients will
      also be followed for 3 hours after study drug infusion to monitor and record vasopressor
      dependence in norepinephrine-equivalent dose. Patients will then be followed through their
      medical record for 28 days to determine persistent organ dysfunction syndrome (PODS).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Vitamin B12a is bright red and excreted in the urine. Due to this, patient allocation cannot be masked for patients or individuals who may care for them.
measure: Feasibility of completing clinical and laboratory protocols
time frame: 28 days
description: Feasibility of completing clinical and laboratory protocols
measure: Hydrogen Sulfide Concentration
time frame: 3 hours
description: Difference between pre- and post-dose hydrogen sulfide levels
measure: Persistent Organ Dysfunction Syndrome (PODS)
time frame: 28 days
description: Prevalence of Persistent organ dysfunction syndrome (PODS)
measure: Change in vasopressor dose
time frame: 3, 24, and 48 hours
description: Vasopressor dose in mcg/kg/min (norepinephrine equivelents)
measure: Mortality
time frame: 28 days
description: Intensive care unit and hospital mortality
arm group label: Hydroxocobalamin
arm group type: Experimental
description: Single IV infusion administered over a 10-15 minute period
arm group label: Saline Placebo
arm group type: Placebo Comparator
description: Single IV saline administered over a 10-15 minute period.
intervention type: Drug
intervention name: Hydroxocobalamin
description: Single IV administration of Vitamin B12
arm group label: Hydroxocobalamin
other name: Cyanokit
intervention type: Drug
intervention name: Placebo
description: Single IV administration of saline
arm group label: Saline Placebo
other name: 200-250 mL of intravenous saline or dextrose
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jayshil J Patel, MD
role: Principal Investigator
affiliation: Medical College of Wisconsin
last name: Jayshil J Patel, MD
phone: 414-955-7040
email: jpatel2@mcw.edu
last name: Jeanette Graf, BS
phone: 414-955-6987
email: jgraf@mcw.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
citation: 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.
PMID: 26903338
citation: 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.
PMID: 11700399
citation: 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.
PMID: 9070471
citation: 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.
PMID: 14707556
citation: 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.
PMID: 8370291
citation: 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.
PMID: 22972094
citation: 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.
PMID: 10477776
citation: 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.
PMID: 22096201
citation: 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.
PMID: 29980217
citation: 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.
PMID: 28757821
citation: 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.
PMID: 18768890
citation: 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.
PMID: 21897337
citation: 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.
PMID: 15863703
citation: 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.
PMID: 28778773
citation: 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.
PMID: 17976885
citation: 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. Erratum In: Clin Toxicol (Phila). 2015 Jan;53(1):77.
PMID: 24716792
citation: 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.
PMID: 30430872
citation: 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. Erratum In: Free Radic Biol Med. 2011 Oct 1;51(7):1471.
PMID: 19328848
citation: 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.
PMID: 17209138
citation: 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.
PMID: 29573551
citation: 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.
PMID: 27749291
citation: 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.
PMID: 28012726
citation: 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.
PMID: 27838199
citation: 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.
PMID: 29209927
citation: 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.
PMID: 23991749
citation: 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.
PMID: 26912064
citation: 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.
PMID: 22000659
citation: 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.
PMID: 17976798
citation: 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.
PMID: 22828651
citation: 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.
PMID: 28528561
citation: 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.
PMID: 22561703
citation: 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.
PMID: 26511963
responsible party type: Principal Investigator
investigator affiliation: Medical College of Wisconsin
investigator full name: Jayshil J. Patel, MD
investigator title: Associate Professor of Medicine
mesh term: Shock, Septic
mesh term: Shock
mesh term: Hydroxocobalamin
mesh term: Vitamin B 12
sharing ipd: No