<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/NCT03014063</url>
  </required_header>
  <id_info>
    <org_study_id>16-1254</org_study_id>
    <nct_id>NCT03014063</nct_id>
  </id_info>
  <brief_title>Vasopressin Plasma Concentrations in Patients Receiving Exogenous Vasopressin Infusion for Septic Shock</brief_title>
  <official_title>Vasopressin Plasma Concentrations in Responders and Non-responders to Exogenous Vasopressin Infusion in Patients With Septic Shock</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Cleveland Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Cleveland Clinic</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective observational cohort trial evaluating a single plasma vasopressin&#xD;
      concentration in patients receiving exogenous, adjunctive vasopressin for septic shock. The&#xD;
      trial is designed to determine whether plasma vasopressin concentration influences the&#xD;
      likelihood of hemodynamic response to exogenous vasopressin therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Vasopressin is an endogenous hormone that decreases serum osmolarity and increases blood&#xD;
      pressure. As a part of the stress response to hypotension, vasopressin is released from the&#xD;
      posterior pituitary and leads to vasoconstriction through agonism of the vascular vasopressin&#xD;
      V1 receptor. In patients with septic shock, endogenous vasopressin levels are initially&#xD;
      elevated but quickly fall to levels at or below those of normal physiology (1.4-3.6pg/mL)&#xD;
      because of the depletion of endogenous store. Sharshar et al. evaluated two sets of patients&#xD;
      with septic shock, one of which was evaluated earlier in the septic shock course (3.6 ± 2.3&#xD;
      hours, n=18) and one evaluated at a later time from shock onset (mean 38.7 ± 28.4 hours,&#xD;
      n=44). The group of patients evaluated earlier in their septic shock course were more likely&#xD;
      than patients evaluated later to have elevated (&gt;3.6 pg/mL) plasma vasopressin levels (88.9%&#xD;
      vs. 38.6%, respectively). Similarly, a case series evaluated single vasopressin levels in&#xD;
      three patients with septic shock, one of whom was in the first day of shock onset and two of&#xD;
      whom were in the fifth and sixth day of shock onset. The patient in the earlier stages of&#xD;
      septic shock had a plasma vasopressin level that was increased (16pg/mL), while the two&#xD;
      patients in the later stages of septic shock had decreased plasma vasopressin levels (1.6 and&#xD;
      1.8pg/mL). The exact timing of when patients transition from having elevated endogenous&#xD;
      vasopressin levels to having normal levels of vasopressin is currently unclear. In a clinical&#xD;
      trial enrolling patients within the first 12 hours of shock onset, median endogenous&#xD;
      vasopressin levels were 3.5 pg/mL (interquartile range 1.8, 5.3 pg/mL; n=54). Some have even&#xD;
      hypothesized that vasopressin levels rise before clinical hypotension is apparent and the&#xD;
      decline in vasopressin levels is associated with the onset of apparent hypotension. Further&#xD;
      complicating this issue, endogenous vasopressin levels have been shown to be lower in&#xD;
      patients with septic shock compared to other shock etiologies such cardiogenic shock (3.1 ±&#xD;
      1pg/mL in patients with septic shock vs. 22.7 ± 2.2pg/mL in patients with cardiogenic shock,&#xD;
      p&lt;0.001). The etiology of this discrepancy in endogenous vasopressin response by shock type&#xD;
      is unclear, but a &quot;relative deficiency&quot; of vasopressin is theorized to exist in patients with&#xD;
      septic shock.&#xD;
&#xD;
      In light of these findings, exogenous arginine vasopressin (AVP) has been added to exogenous&#xD;
      catecholamines to increase mean arterial pressure (MAP) and to decrease catecholamine&#xD;
      requirements in patients with vasodilatory shock. The use of AVP for these purposes in&#xD;
      patients with septic shock is in keeping with the Surviving Sepsis Campaign Guidelines. In&#xD;
      the Vasopressin and Septic Shock Trial (VASST), low-dose AVP was infused at a rate of&#xD;
      0.01-0.03 units/min in combination with norepinephrine to achieve a goal MAP of 65-75mmHg.&#xD;
      Plasma vasopressin levels in patients receiving AVP were elevated at 6 (68.3pg/mL) and 24&#xD;
      hours (90.5pg/mL) in comparison to patients not receiving AVP (3.0pg/mL at baseline with no&#xD;
      significant change at 6 or 24 hours). Association of plasma vasopressin levels with&#xD;
      hemodynamic response to AVP, though, was not evaluated in VASST.&#xD;
&#xD;
      Concomitant corticosteroid use has been observed to decrease the total dose of administered&#xD;
      AVP, to increase the proportion of patients alive and free of vasopressors at day 7, to&#xD;
      increase plasma vasopressin concentrations by 33% at 6 hours and 67% at 24 hours, and to lead&#xD;
      to lower 28- and 90-day mortality (35.9% vs. 44.7%, p=0.03 and 42.5% vs. 55.5%, p=0.01,&#xD;
      respectively) than in those that received AVP alone. These findings generated the hypothesis&#xD;
      that concomitant administration of AVP and corticosteroids results in increased plasma&#xD;
      vasopressin levels versus AVP administration alone, leading to positive clinical outcomes in&#xD;
      septic shock. Furthering the hypothesis that plasma vasopressin levels may influence outcomes&#xD;
      in septic shock, genetic differences in leucyl/cystinyl aminopeptidase, the primary&#xD;
      vasopressin metabolic enzyme, have been associated with more rapid vasopressin clearance,&#xD;
      lower plasma vasopressin levels, and increased mortality in patients with septic shock.&#xD;
      However, a study evaluating vasopressin plasma concentrations in patients with multiple shock&#xD;
      types not administered exogenous AVP observed higher vasopressin concentrations in those with&#xD;
      hemodynamic dysfunction than in those without (mean 14.1 ± 26 vs. 8.7 ± 10.8pg/mL,&#xD;
      respectively) regardless of shock type. This suggests that plasma vasopressin concentration&#xD;
      may not directly correlate with MAP.&#xD;
&#xD;
      The impact of body mass (which may influence vasopressin levels when fixed-dose AVP is&#xD;
      administered) on hemodynamic response to AVP has been inconsistent. Studies have observed a&#xD;
      negative correlation between BMI and change in MAP at 6 hours and a correlation between&#xD;
      increasing weight-adjusted AVP dose and reduction in catecholamine requirements, suggesting&#xD;
      that hemodynamic response to AVP is associated with body mass. In contrast, a third study&#xD;
      observed no association between BMI and AVP dose required to meet goal MAP when AVP was&#xD;
      administered as the sole vasopressor. Finally, a fourth found an inverse correlation between&#xD;
      BMI and APACHE II-adjusted 28-day mortality, regardless of the fact that overweight and obese&#xD;
      patients received less weight-adjusted vasopressin than underweight or normal weight&#xD;
      patients. This suggests that while BMI may impact plasma vasopressin concentration, the&#xD;
      change in vasopressin concentration may not have an impact on clinical outcomes.&#xD;
&#xD;
      Recently, a retrospective study was completed at the Cleveland Clinic to evaluate predictors&#xD;
      of hemodynamic response to fixed-dose AVP in patients with septic shock. Patients were&#xD;
      considered to be responders to AVP if a decrease in catecholamine dose was achieved with&#xD;
      MAP≥65mmHg at 6 hours. The overall response rate to fixed-dose vasopressin was 45.4%. Within&#xD;
      this study, only admission to surgical or neurosciences intensive care units (ICU) vs.&#xD;
      medical ICU and lower lactate level were associated with increasing chance of response to AVP&#xD;
      (OR 1.71, 95% CI 1.175-2.463, p=0.0049 and OR 0.925, 95% CI 0.887-0.965, p=0.0003,&#xD;
      respectively) on logistic regression. Factors previously found to impact vasopressin levels&#xD;
      (such as concomitant use of corticosteroids) were not associated with hemodynamic response.&#xD;
      However, plasma vasopressin levels were not evaluated in this retrospective study.&#xD;
&#xD;
      The relationship between plasma vasopressin concentration and hemodynamic response in&#xD;
      patients receiving AVP is unclear. While concomitant corticosteroids have been observed to&#xD;
      increase plasma vasopressin concentrations, corticosteroids themselves have been shown to&#xD;
      shorten time in septic shock, possibly confounding any relationship between plasma&#xD;
      vasopressin concentration and hemodynamic response in patients receiving both agents. As&#xD;
      previously mentioned, data correlating body mass with hemodynamic response have been&#xD;
      inconsistent, but vasopressin levels in patients receiving fixed dose AVP seem to be lower in&#xD;
      patients with higher body mass. The recent study at the Cleveland Clinic found no association&#xD;
      between factors associated with increased plasma vasopressin level and hemodynamic response.&#xD;
      Together, these data call into question the idea of a dose-response relationship between&#xD;
      plasma vasopressin concentration and hemodynamic response. This study seeks to prospectively&#xD;
      evaluate whether plasma vasopressin levels are associated with improved rates of hemodynamic&#xD;
      response to fixed-dose AVP therapy in patients with septic shock.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2016</start_date>
  <completion_date type="Actual">June 2017</completion_date>
  <primary_completion_date type="Actual">June 2017</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Plasma vasopressin concentration</measure>
    <time_frame>3-6 hours from initiation of exogenous vasopressin administration</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mean arterial pressure</measure>
    <time_frame>Analyzed at time of vasopressin blood draw, 3-6 hours from initiation of exogenous vasopressin administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Catecholamine dose in norepinephrine equivalents</measure>
    <time_frame>Analyzed at time of vasopressin blood draw, 3-6 hours from initiation of exogenous vasopressin administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU mortality</measure>
    <time_frame>Analyzed at ICU discharge, up to 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In-hospital mortality</measure>
    <time_frame>Analyzed at hospital discharge, up to 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vasopressor-free days</measure>
    <time_frame>Day 14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU-free days</measure>
    <time_frame>Day 14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute kidney injury</measure>
    <time_frame>Analyzed at ICU discharge, up to 1 year</time_frame>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">18</enrollment>
  <condition>Septic Shock</condition>
  <arm_group>
    <arm_group_label>Hemodynamic responders</arm_group_label>
    <description>Those with a mean arterial pressure of at least 65mmHg and a decrease in catecholamine dose (in norepinephrine equivalents) from initiation of exogenous vasopressin therapy to the time of the sample collection used for analysis of plasma vasopressin concentration</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hemodynamic non-responders</arm_group_label>
    <description>Those without a mean arterial pressure of at least 65mmHg and/or a decrease in catecholamine dose (in norepinephrine equivalents) from initiation of exogenous vasopressin therapy to the time of the sample collection used for analysis of plasma vasopressin concentration</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Plasma vasopressin concentration in patients receiving exogenous vasopressin&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with septic shock that are receiving fixed-dose exogenous vasopressin as an&#xD;
        adjunct to catecholamines&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with septic shock as defined by The Third International Consensus Definitions&#xD;
             for Sepsis and Septic Shock&#xD;
&#xD;
          -  Patients ≥18 years of age&#xD;
&#xD;
          -  Treatment with exogenous vasopressin, as ordered by the primary medical team, at a&#xD;
             constant infusion rate for at least 3 hours as an adjunctive vasopressor to&#xD;
             catecholamine therapy&#xD;
&#xD;
          -  Admission to a medical, surgical, or neurosciences intensive care unit&#xD;
&#xD;
          -  Presence of a central venous catheter or arterial line (as determined by the primary&#xD;
             medical team)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients treated with vasopressin for indications other than septic shock&#xD;
&#xD;
          -  Patients administered vasopressin that is titrated within the first 3 hours&#xD;
&#xD;
          -  Patients receiving vasopressin as the sole vasoactive therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Cleveland Clinic</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Russell JA. Bench-to-bedside review: Vasopressin in the management of septic shock. Crit Care. 2011 Aug 11;15(4):226. doi: 10.1186/cc8224.</citation>
    <PMID>21892977</PMID>
  </reference>
  <reference>
    <citation>Sharshar T, Blanchard A, Paillard M, Raphael JC, Gajdos P, Annane D. Circulating vasopressin levels in septic shock. Crit Care Med. 2003 Jun;31(6):1752-8. doi: 10.1097/01.CCM.0000063046.82359.4A.</citation>
    <PMID>12794416</PMID>
  </reference>
  <reference>
    <citation>Sharshar T, Carlier R, Blanchard A, Feydy A, Gray F, Paillard M, Raphael JC, Gajdos P, Annane D. Depletion of neurohypophyseal content of vasopressin in septic shock. Crit Care Med. 2002 Mar;30(3):497-500. doi: 10.1097/00003246-200203000-00001.</citation>
    <PMID>11990905</PMID>
  </reference>
  <reference>
    <citation>Bauer SR, Lam SW. Arginine vasopressin for the treatment of septic shock in adults. Pharmacotherapy. 2010 Oct;30(10):1057-71. doi: 10.1592/phco.30.10.1057.</citation>
    <PMID>20874043</PMID>
  </reference>
  <reference>
    <citation>Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373.</citation>
    <PMID>18305265</PMID>
  </reference>
  <reference>
    <citation>Lin IY, Ma HP, Lin AC, Chong CF, Lin CM, Wang TL. Low plasma vasopressin/norepinephrine ratio predicts septic shock. Am J Emerg Med. 2005 Oct;23(6):718-24. doi: 10.1016/j.ajem.2005.02.055.</citation>
    <PMID>16182977</PMID>
  </reference>
  <reference>
    <citation>Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D'Alessandro D, Oz MC, Oliver JA. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997 Mar 4;95(5):1122-5. doi: 10.1161/01.cir.95.5.1122.</citation>
    <PMID>9054839</PMID>
  </reference>
  <reference>
    <citation>Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA 3rd. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med. 2001 Mar;29(3):487-93. doi: 10.1097/00003246-200103000-00004.</citation>
    <PMID>11373409</PMID>
  </reference>
  <reference>
    <citation>Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af.</citation>
    <PMID>23353941</PMID>
  </reference>
  <reference>
    <citation>Gordon AC, Mason AJ, Perkins GD, Stotz M, Terblanche M, Ashby D, Brett SJ. The interaction of vasopressin and corticosteroids in septic shock: a pilot randomized controlled trial. Crit Care Med. 2014 Jun;42(6):1325-33. doi: 10.1097/CCM.0000000000000212.</citation>
    <PMID>24557425</PMID>
  </reference>
  <reference>
    <citation>Southard RE, Boyle WA. Corticosteroids and the original vasopressin and septic shock trial subgroups. Crit Care Med. 2010 Jan;38(1):338; authore reply 338-9. doi: 10.1097/CCM.0b013e3181bc7ab8. No abstract available.</citation>
    <PMID>20023496</PMID>
  </reference>
  <reference>
    <citation>Bauer SR, Lam SW, Cha SS, Oyen LJ. Effect of corticosteroids on arginine vasopressin-containing vasopressor therapy for septic shock: a case control study. J Crit Care. 2008 Dec;23(4):500-6. doi: 10.1016/j.jcrc.2008.04.002. Epub 2008 Jun 30.</citation>
    <PMID>19056013</PMID>
  </reference>
  <reference>
    <citation>Russell JA, Walley KR, Gordon AC, Cooper DJ, Hebert PC, Singer J, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ; Dieter Ayers for the Vasopressin and Septic Shock Trial Investigators. Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock. Crit Care Med. 2009 Mar;37(3):811-8. doi: 10.1097/CCM.0b013e3181961ace.</citation>
    <PMID>19237882</PMID>
  </reference>
  <reference>
    <citation>Torgersen C, Luckner G, Schroder DC, Schmittinger CA, Rex C, Ulmer H, Dunser MW. Concomitant arginine-vasopressin and hydrocortisone therapy in severe septic shock: association with mortality. Intensive Care Med. 2011 Sep;37(9):1432-7. doi: 10.1007/s00134-011-2312-3. Epub 2011 Jul 21.</citation>
    <PMID>21779849</PMID>
  </reference>
  <reference>
    <citation>Nakada TA, Russell JA, Wellman H, Boyd JH, Nakada E, Thain KR, Thair SA, Hirasawa H, Oda S, Walley KR. Leucyl/cystinyl aminopeptidase gene variants in septic shock. Chest. 2011 May;139(5):1042-1049. doi: 10.1378/chest.10-2517. Epub 2011 Feb 17.</citation>
    <PMID>21330387</PMID>
  </reference>
  <reference>
    <citation>Jochberger S, Mayr VD, Luckner G, Wenzel V, Ulmer H, Schmid S, Knotzer H, Pajk W, Hasibeder W, Friesenecker B, Mayr AJ, Dunser MW. Serum vasopressin concentrations in critically ill patients. Crit Care Med. 2006 Feb;34(2):293-9. doi: 10.1097/01.ccm.0000198528.56397.4f.</citation>
    <PMID>16424705</PMID>
  </reference>
  <reference>
    <citation>Miller JT, Welage LS, Kraft MD, Alaniz C. Does body weight impact the efficacy of vasopressin therapy in the management of septic shock? J Crit Care. 2012 Jun;27(3):289-93. doi: 10.1016/j.jcrc.2011.06.018. Epub 2011 Aug 19.</citation>
    <PMID>21855282</PMID>
  </reference>
  <reference>
    <citation>Hodge EK, Hughes DW, Attridge RL. Effect of Body Weight on Hemodynamic Response in Patients Receiving Fixed-Dose Vasopressin for Septic Shock. Ann Pharmacother. 2016 Oct;50(10):816-23. doi: 10.1177/1060028016656384. Epub 2016 Jun 23.</citation>
    <PMID>27340145</PMID>
  </reference>
  <reference>
    <citation>Lam SW, Bauer SR, Cha SS, Oyen LJ. Lack of an effect of body mass on the hemodynamic response to arginine vasopressin during septic shock. Pharmacotherapy. 2008 May;28(5):591-9. doi: 10.1592/phco.28.5.591.</citation>
    <PMID>18447658</PMID>
  </reference>
  <reference>
    <citation>Wacharasint P, Boyd JH, Russell JA, Walley KR. One size does not fit all in severe infection: obesity alters outcome, susceptibility, treatment, and inflammatory response. Crit Care. 2013 Jun 20;17(3):R122. doi: 10.1186/cc12794.</citation>
    <PMID>23786836</PMID>
  </reference>
  <reference>
    <citation>Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaud P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21;288(7):862-71. doi: 10.1001/jama.288.7.862. Erratum In: JAMA. 2008 Oct 8;300(14):1652. Chaumet-Riffaut, Philippe [corrected to Chaumet-Riffaud, Philippe].</citation>
    <PMID>12186604</PMID>
  </reference>
  <reference>
    <citation>Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366.</citation>
    <PMID>18184957</PMID>
  </reference>
  <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>Sacha GL, Lam SW, Duggal A, Torbic H, Bass SN, Welch SC, Butler RS, Bauer SR. Predictors of response to fixed-dose vasopressin in adult patients with septic shock. Ann Intensive Care. 2018 Mar 6;8(1):35. doi: 10.1186/s13613-018-0379-5.</citation>
    <PMID>29511951</PMID>
  </reference>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 4, 2017</study_first_submitted>
  <study_first_submitted_qc>January 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 9, 2017</study_first_posted>
  <last_update_submitted>January 29, 2019</last_update_submitted>
  <last_update_submitted_qc>January 29, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 31, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>sepsis</keyword>
  <keyword>septic shock</keyword>
  <keyword>vasopressin</keyword>
  <keyword>AVP</keyword>
  <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>
  <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/NCT03014063
org study id: 16-1254
nct id: NCT03014063
lead sponsor: 
has dmc: No
This is a prospective observational cohort trial evaluating a single plasma vasopressin
      concentration in patients receiving exogenous, adjunctive vasopressin for septic shock. The
      trial is designed to determine whether plasma vasopressin concentration influences the
      likelihood of hemodynamic response to exogenous vasopressin therapy.
Vasopressin is an endogenous hormone that decreases serum osmolarity and increases blood
      pressure. As a part of the stress response to hypotension, vasopressin is released from the
      posterior pituitary and leads to vasoconstriction through agonism of the vascular vasopressin
      V1 receptor. In patients with septic shock, endogenous vasopressin levels are initially
      elevated but quickly fall to levels at or below those of normal physiology (1.4-3.6pg/mL)
      because of the depletion of endogenous store. Sharshar et al. evaluated two sets of patients
      with septic shock, one of which was evaluated earlier in the septic shock course (3.6 ± 2.3
      hours, n=18) and one evaluated at a later time from shock onset (mean 38.7 ± 28.4 hours,
      n=44). The group of patients evaluated earlier in their septic shock course were more likely
      than patients evaluated later to have elevated (>3.6 pg/mL) plasma vasopressin levels (88.9%
      vs. 38.6%, respectively). Similarly, a case series evaluated single vasopressin levels in
      three patients with septic shock, one of whom was in the first day of shock onset and two of
      whom were in the fifth and sixth day of shock onset. The patient in the earlier stages of
      septic shock had a plasma vasopressin level that was increased (16pg/mL), while the two
      patients in the later stages of septic shock had decreased plasma vasopressin levels (1.6 and
      1.8pg/mL). The exact timing of when patients transition from having elevated endogenous
      vasopressin levels to having normal levels of vasopressin is currently unclear. In a clinical
      trial enrolling patients within the first 12 hours of shock onset, median endogenous
      vasopressin levels were 3.5 pg/mL (interquartile range 1.8, 5.3 pg/mL; n=54). Some have even
      hypothesized that vasopressin levels rise before clinical hypotension is apparent and the
      decline in vasopressin levels is associated with the onset of apparent hypotension. Further
      complicating this issue, endogenous vasopressin levels have been shown to be lower in
      patients with septic shock compared to other shock etiologies such cardiogenic shock (3.1 ±
      1pg/mL in patients with septic shock vs. 22.7 ± 2.2pg/mL in patients with cardiogenic shock,
      p<0.001). The etiology of this discrepancy in endogenous vasopressin response by shock type
      is unclear, but a "relative deficiency" of vasopressin is theorized to exist in patients with
      septic shock.

      In light of these findings, exogenous arginine vasopressin (AVP) has been added to exogenous
      catecholamines to increase mean arterial pressure (MAP) and to decrease catecholamine
      requirements in patients with vasodilatory shock. The use of AVP for these purposes in
      patients with septic shock is in keeping with the Surviving Sepsis Campaign Guidelines. In
      the Vasopressin and Septic Shock Trial (VASST), low-dose AVP was infused at a rate of
      0.01-0.03 units/min in combination with norepinephrine to achieve a goal MAP of 65-75mmHg.
      Plasma vasopressin levels in patients receiving AVP were elevated at 6 (68.3pg/mL) and 24
      hours (90.5pg/mL) in comparison to patients not receiving AVP (3.0pg/mL at baseline with no
      significant change at 6 or 24 hours). Association of plasma vasopressin levels with
      hemodynamic response to AVP, though, was not evaluated in VASST.

      Concomitant corticosteroid use has been observed to decrease the total dose of administered
      AVP, to increase the proportion of patients alive and free of vasopressors at day 7, to
      increase plasma vasopressin concentrations by 33% at 6 hours and 67% at 24 hours, and to lead
      to lower 28- and 90-day mortality (35.9% vs. 44.7%, p=0.03 and 42.5% vs. 55.5%, p=0.01,
      respectively) than in those that received AVP alone. These findings generated the hypothesis
      that concomitant administration of AVP and corticosteroids results in increased plasma
      vasopressin levels versus AVP administration alone, leading to positive clinical outcomes in
      septic shock. Furthering the hypothesis that plasma vasopressin levels may influence outcomes
      in septic shock, genetic differences in leucyl/cystinyl aminopeptidase, the primary
      vasopressin metabolic enzyme, have been associated with more rapid vasopressin clearance,
      lower plasma vasopressin levels, and increased mortality in patients with septic shock.
      However, a study evaluating vasopressin plasma concentrations in patients with multiple shock
      types not administered exogenous AVP observed higher vasopressin concentrations in those with
      hemodynamic dysfunction than in those without (mean 14.1 ± 26 vs. 8.7 ± 10.8pg/mL,
      respectively) regardless of shock type. This suggests that plasma vasopressin concentration
      may not directly correlate with MAP.

      The impact of body mass (which may influence vasopressin levels when fixed-dose AVP is
      administered) on hemodynamic response to AVP has been inconsistent. Studies have observed a
      negative correlation between BMI and change in MAP at 6 hours and a correlation between
      increasing weight-adjusted AVP dose and reduction in catecholamine requirements, suggesting
      that hemodynamic response to AVP is associated with body mass. In contrast, a third study
      observed no association between BMI and AVP dose required to meet goal MAP when AVP was
      administered as the sole vasopressor. Finally, a fourth found an inverse correlation between
      BMI and APACHE II-adjusted 28-day mortality, regardless of the fact that overweight and obese
      patients received less weight-adjusted vasopressin than underweight or normal weight
      patients. This suggests that while BMI may impact plasma vasopressin concentration, the
      change in vasopressin concentration may not have an impact on clinical outcomes.

      Recently, a retrospective study was completed at the Cleveland Clinic to evaluate predictors
      of hemodynamic response to fixed-dose AVP in patients with septic shock. Patients were
      considered to be responders to AVP if a decrease in catecholamine dose was achieved with
      MAP≥65mmHg at 6 hours. The overall response rate to fixed-dose vasopressin was 45.4%. Within
      this study, only admission to surgical or neurosciences intensive care units (ICU) vs.
      medical ICU and lower lactate level were associated with increasing chance of response to AVP
      (OR 1.71, 95% CI 1.175-2.463, p=0.0049 and OR 0.925, 95% CI 0.887-0.965, p=0.0003,
      respectively) on logistic regression. Factors previously found to impact vasopressin levels
      (such as concomitant use of corticosteroids) were not associated with hemodynamic response.
      However, plasma vasopressin levels were not evaluated in this retrospective study.

      The relationship between plasma vasopressin concentration and hemodynamic response in
      patients receiving AVP is unclear. While concomitant corticosteroids have been observed to
      increase plasma vasopressin concentrations, corticosteroids themselves have been shown to
      shorten time in septic shock, possibly confounding any relationship between plasma
      vasopressin concentration and hemodynamic response in patients receiving both agents. As
      previously mentioned, data correlating body mass with hemodynamic response have been
      inconsistent, but vasopressin levels in patients receiving fixed dose AVP seem to be lower in
      patients with higher body mass. The recent study at the Cleveland Clinic found no association
      between factors associated with increased plasma vasopressin level and hemodynamic response.
      Together, these data call into question the idea of a dose-response relationship between
      plasma vasopressin concentration and hemodynamic response. This study seeks to prospectively
      evaluate whether plasma vasopressin levels are associated with improved rates of hemodynamic
      response to fixed-dose AVP therapy in patients with septic shock.
observational model: Cohort
time perspective: Prospective
measure: Plasma vasopressin concentration
time frame: 3-6 hours from initiation of exogenous vasopressin administration
measure: Mean arterial pressure
time frame: Analyzed at time of vasopressin blood draw, 3-6 hours from initiation of exogenous vasopressin administration
measure: Catecholamine dose in norepinephrine equivalents
time frame: Analyzed at time of vasopressin blood draw, 3-6 hours from initiation of exogenous vasopressin administration
measure: ICU mortality
time frame: Analyzed at ICU discharge, up to 1 year
measure: In-hospital mortality
time frame: Analyzed at hospital discharge, up to 1 year
measure: Vasopressor-free days
time frame: Day 14
measure: ICU-free days
time frame: Day 14
measure: Acute kidney injury
time frame: Analyzed at ICU discharge, up to 1 year
arm group label: Hemodynamic responders
description: Those with a mean arterial pressure of at least 65mmHg and a decrease in catecholamine dose (in norepinephrine equivalents) from initiation of exogenous vasopressin therapy to the time of the sample collection used for analysis of plasma vasopressin concentration
arm group label: Hemodynamic non-responders
description: Those without a mean arterial pressure of at least 65mmHg and/or a decrease in catecholamine dose (in norepinephrine equivalents) from initiation of exogenous vasopressin therapy to the time of the sample collection used for analysis of plasma vasopressin concentration
Plasma vasopressin concentration in patients receiving exogenous vasopressin
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
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responsible party type: Sponsor
mesh term: Shock, Septic
mesh term: Shock
sharing ipd: No