<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/NCT03762005</url>
  </required_header>
  <id_info>
    <org_study_id>170323007</org_study_id>
    <nct_id>NCT03762005</nct_id>
  </id_info>
  <brief_title>Peripheral Perfusion Versus Lactate Targeted Fluid Resuscitation in Septic Shock</brief_title>
  <official_title>Peripheral Perfusion Versus Lactate Targeted Fluid Resuscitation in Septic Shock: ANDROMEDA-SHOCK PHYSIOLOGY STUDY</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Pontificia Universidad Catolica de Chile</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Comisión Nacional de Investigación Científica y Tecnológica</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Pontificia Universidad Catolica de Chile</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Persistent hyperlactatemia has been traditionally considered as representing tissue hypoxia,&#xD;
      and lactate normalization is recommended as a resuscitation target by the Surviving Sepsis&#xD;
      Campaign (SSC). However, other sources contribute to hyperlactatemia such as sustained&#xD;
      adrenergic activity and impaired lactate clearance. Only hypoperfusion-related&#xD;
      hyperlactatemia might be reversed by optimizing systemic blood flow.&#xD;
&#xD;
      Fluid resuscitation (FR) is used to improve cardiac output (CO) in septic shock to correct&#xD;
      hypoperfusion. Nevertheless, if persistent hyperlactatemia is not hypoxia-related, excessive&#xD;
      FR could lead to flow overload. In addition, kinetics of recovery of lactate is relatively&#xD;
      slow, and thus it might be a suboptimal target for FR.&#xD;
&#xD;
      Peripheral perfusion appears as a promising alternative target. Abnormal capillary refill&#xD;
      time (CRT) is frequently used as trigger for FR in septic shock. Studies demonstrated the&#xD;
      strong prognostic value of persistent abnormal peripheral perfusion, and some recent data&#xD;
      suggest that targeting FR on CRT normalization could be associated with less fluid loading&#xD;
      and organ dysfunctions. The excellent prognosis associated with CRT recovery, the&#xD;
      rapid-response time to fluid loading, its simplicity, and its availability in&#xD;
      resource-limited settings, constitute a strong background to promote studies evaluating its&#xD;
      usefulness to guide FR .&#xD;
&#xD;
      The study hypothesis is that a CRT-targeted FR is associated with less positive fluid&#xD;
      balances, organ dysfunctions, and at least similar improvement of tissue hypoperfusion or&#xD;
      hypoxia, when compared to a lactate-targeted FR. To test this hypothesis, the investigators&#xD;
      designed a clinical physiological, randomized controlled trial in septic shock patients.&#xD;
      Recruited patients will be randomized to FR aimed at normalizing CRT or normalizing or&#xD;
      decreasing lactate &gt;20% every 2 h during the study period. Fluid challenges (500 ml in 30 min&#xD;
      intervals) will be repeated until perfusion target is achieved, or dynamic predictors of&#xD;
      fluid responsiveness become negative, or a safety limit is reached. The design of our study&#xD;
      is aimed at: a) determining if CRT targeted resuscitation is associated with less fluid&#xD;
      resuscitation and fluid balances; b) determining if this strategy is associated with less&#xD;
      organ dysfunctions; and c) if it results in similar improvement in markers of tissue&#xD;
      hypoperfusion or hypoxia such as hepato-splanchnic blood flow or microcirculatory perfusion.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      GENERAL OBJECTIVE To demonstrate that a CRT-targeted FR is associated with less positive&#xD;
      fluid balances, organ dysfunctions, and similar improvement of markers of tissue&#xD;
      hypoperfusion and hypoxia, when compared to a lactate- targeted FR.&#xD;
&#xD;
      SPECIFIC OBJECTIVES&#xD;
&#xD;
        1. To determine if normalization of CRT is associated with less fluid resuscitation and&#xD;
           positive 24-h fluid balances as compared to lactate-targeted resuscitation.&#xD;
&#xD;
        2. To determine if normalization of CRT is associated with less organ dysfunctions as&#xD;
           compared to lactate-targeted resuscitation.&#xD;
&#xD;
        3. To determine if CRT-targeted resuscitation compared to lactate-targeted resuscitation&#xD;
           leads to similar improvement in markers of tissue hypoperfusion or hypoxia at the end of&#xD;
           fluid resuscitation&#xD;
&#xD;
        4. To determine if normality of all the selected hypoperfusion variables (central venous&#xD;
           oxygen saturation (ScvO2), central venous to arterial carbon dioxide pressure difference&#xD;
           (P(cv-a)CO2), and CRT) at different time-points in septic shock patients can predict the&#xD;
           absence of tissue hypoperfusion and hypoxia.&#xD;
&#xD;
      For this Research Project, several variables of tissue hypoperfusion that can only be&#xD;
      assessed by special perfusion-monitoring techniques were included.&#xD;
&#xD;
      Sublingual microcirculatory assessment: Sublingual microcirculatory alterations have been&#xD;
      well described in septic shock patients. Functional capillary density and microvascular blood&#xD;
      flow are decreased, while heterogeneity is markedly enhanced. These alterations have been&#xD;
      shown to be prognostic, with a rapid improvement in survivors but a progressive decline in&#xD;
      nonsurvivors. A microcirculatory flow index (MFI) ≤ 2.5 and a proportion of perfused vessels&#xD;
      (PPV) &lt; 80% will be considered as categorical of microcirculatory hypoperfusion Liver blood&#xD;
      flow: Plasma disappearance rate (PDR) of indocyanine green (ICG), with a non-invasive&#xD;
      transcutaneous assessment of ICG clearance. Normal range is 18% to 25% per minute with a&#xD;
      value &lt; 15%/min categorically abnormal.&#xD;
&#xD;
      Muscle tissue O2 saturation: Muscle tissue O2 saturation (StO2). A decrease in this variable&#xD;
      to &lt;70% suggests profound tissue hypoperfusion.&#xD;
&#xD;
      Assessment of tissue hypoxia: There are two clinically calculable variables that have been&#xD;
      proposed as closely representing tissue hypoxia: the venous- arterial CO2 (Cv- aCO2) to&#xD;
      arterial-venous O2 content (Da-vO2) difference ratio (Cv- aCO2/Da-vO2) and the&#xD;
      lactate/pyruvate (L/P) ratio . Both ratios are an expression of anaerobic metabolism at the&#xD;
      cellular level and thus can be linked to hypoxia. For this research project, these variables&#xD;
      were considered to ascertain the presence and resolution of tissue hypoxia.&#xD;
&#xD;
        -  Cv-aCO2/Da-vO2 ratio: This ratio might be useful as a surrogate of the respiratory&#xD;
           quotient. A ratio ≥ 1.4 could identify anaerobic CO2 generation. A high Cv-aCO2/Da-vO2&#xD;
           ratio in the setting of hyperlactatemia may favor anaerobic metabolism as the possible&#xD;
           source of lactate, while a normal Cv-aCO2/Da-vO2 ratio suggesting that lactate&#xD;
           accumulation is due to non-hypoperfusion- related causes.&#xD;
&#xD;
        -  L/P ratio: In anaerobic conditions, pyruvate is transformed to lactate and thus the L/P&#xD;
           ratio increases to ≥ 18. The L/P ratio is considered to be one of the most reliable&#xD;
           indexes of hypoxia in critically ill patients.&#xD;
&#xD;
      METHODOLOGY A randomized controlled study of parallel groups was designed: Group A with a&#xD;
      CRT-targeted fluid resuscitation strategy and group B with a lactate-targeted one.&#xD;
&#xD;
      This prospective study will be performed at the Hospital of the Pontifical Catholic&#xD;
      University and at the Public Hospital of the South of Santiago, Chile.&#xD;
&#xD;
      The study was approved by the Institutional Review Board of both centers. A signed informed&#xD;
      consent will be asked to the next of kin of all eligible patients, and confirmed by the&#xD;
      patients when feasible.&#xD;
&#xD;
      The study intervention period will be of 6 hours I. Randomization A randomization sequence&#xD;
      with an allocation of 1:1 will be generated by a computer program. Study-group assignment&#xD;
      will be performed by means of randomized permuted blocks of eight. Allocation concealment&#xD;
      will be maintained by means of central randomization.&#xD;
&#xD;
      Fluid challenges (500 ml of Ringer's lactate administered in 30 min intervals) are repeated&#xD;
      until the perfusion target is normalized, or fluid responsiveness becomes negative, or a&#xD;
      safety limit of an increase in central venous pressure (CVP) ≥ 5 mmHg after a fluid bolus is&#xD;
      reached. The perfusion target in group A is a normal CRT ≤3 sec. The perfusion target in&#xD;
      group B is an arterial lactate ≤ 2 mmol/l or a decrease &gt;20% every 2h.&#xD;
&#xD;
      CRT will be assessed every 30 minutes and lactate every 2 hours during the 6h study&#xD;
      intervention period, after which the treatment is liberalized for attending physicians.&#xD;
&#xD;
      If fluid resuscitation is stopped because the perfusion target is normalized, the time is&#xD;
      registered, and the patient subjected to the specific research-related assessment protocol&#xD;
      and followed until hospital discharge.&#xD;
&#xD;
      II. General management algorithm Besides sepsis source aggressive management, all patients&#xD;
      will be treated according to our local algorithm aimed at macrohemodynamic stabilization and&#xD;
      improvement of hypoperfusion. The algorithm has been described elsewhere. Co-interventions&#xD;
      will be registered and considered in statistical analysis.&#xD;
&#xD;
      III. Specific research-related assessments For the purposes of this research protocol,&#xD;
      several variables will be periodically measured or calculated as follows: at baseline, at 2h,&#xD;
      at 6h and at 24h.&#xD;
&#xD;
        1. Macrohemodynamic variables such as mean arterial pressure,M, heart rate, norepinephrine&#xD;
           dose, CVP, dynamic predictors.&#xD;
&#xD;
        2. Continuous cardiac output (CO) monitoring: this will be performed with non-invasive&#xD;
           pulse-contour CO assessment acquired with this project (PiCCO device).&#xD;
&#xD;
        3. Metabolic-perfusion variables such as arterial lactate, ScvO2, and P(cva)CO2.&#xD;
&#xD;
        4. Peripheral perfusion assessment: CRT and mottling score&#xD;
&#xD;
        5. Sublingual microcirculation: It will be assessed with the side dark field (SDF) device.&#xD;
           At each assessment, at least five 10-20 sec video images will be recorded. The analysis&#xD;
           will be performed by eye following recent recommendations . From image analysis the&#xD;
           following variables will be calculated (i) proportion of perfused vessels; (ii)&#xD;
           microcirculatory flow index (MFI); All these indexes will be calculated separately for&#xD;
           small (&lt;20 microm diameter) and large vessels (&gt; 20 microm diameter) .&#xD;
&#xD;
        6. Liver blood flow: An ICG finger clip well be fixed in every patient and then connected&#xD;
           to a liver function monitor (LiMON; Pulsion Medical Systems, Munich, Germany). A dose of&#xD;
           0.25 mg/kg of ICG (LiMon Pulsion Medical Systems, Germany) will be injected through a&#xD;
           central venous catheter.&#xD;
&#xD;
        7. Near infrared spectroscopy (NIRS): StO2 will be measured by a tissue spectrometer&#xD;
           (InSpectra Model 325; Hutchinson Tc, Mn, USA). A NIRS probe will be placed on the skin&#xD;
           of the thenar eminence&#xD;
&#xD;
        8. Ccv-aCO2/Da-vO2 ratio: This ratio will be calculated after taking arterial and central&#xD;
           venous blood gases with the Douglas formula.&#xD;
&#xD;
        9. L/P ratio: This ratio will be assessed at 0, 6 and 24h during the study period, at&#xD;
           baseline and when fluid resuscitation is stopped. Arterial blood samples for pyruvate&#xD;
           will be taken and processed in our laboratory before 3h according to the method&#xD;
           described by De Backer et al , including immediate deproteinization of the sample and&#xD;
           analysis by enzymatic fluorometric-assay (Sigma-Aldrich, USA)&#xD;
&#xD;
       10. Sequential organ failure assessment (SOFA) at baseline, 24, 48 and at 72h . Finally, all&#xD;
           patients will be followed until hospital discharge, and all data including demographic&#xD;
           aspects, sepsis sources and management, inflammatory biomarkers, and severity scores and&#xD;
           major outcomes will be registered.&#xD;
&#xD;
      STATISTICAL ANALYSIS Sample size calculation: the simple size calculation was based in some&#xD;
      small clinical studies. In a recent study, a resuscitation strategy guided by peripheral&#xD;
      perfusion offered important benefits in terms of fluid administration at 6 hours (4227 ± 1081&#xD;
      ml vs 6069 ± 1715 ml) and organ dysfunction, when compared with standard fluid therapy. In&#xD;
      consequence, a 1600 ml difference in the mean 24-h total fluid administration between the&#xD;
      experimental CRT group and the conventional lactate group was considered to be the critical&#xD;
      threshold for hypothesis testing. If there is truly no difference between the standard and&#xD;
      experimental treatment, then 46 patients are required (23 patients per arm) to be 90% sure&#xD;
      that the lower limit of a two-sided confidence interval will be above the limit of -1600 mL&#xD;
      at an alpha level of 0.05. Statistical analysis Intention to treat analysis will be performed&#xD;
      in order to minimize bias.&#xD;
&#xD;
      Analyses will be performed as follows: Specific Objective #1: between study groups, the&#xD;
      amount of fluids administered at the end of fluid resuscitation, and at 6, 24, 48 and 72h&#xD;
      will be compared exclusively at each time-point with t-test, and comprehensively using ANOVA.&#xD;
      Total 24-h fluid balance will be compared using t-test. Specific Objective #2, the status of&#xD;
      peripheral perfusion normalization will be assessed in a categorical way (normal/abnormal)&#xD;
      with chi-square at specific time-points (at the end of fluid resuscitation, 6, and 24h), and&#xD;
      with means of SOFA score at each time-point up to 72h using t-test or Wilcoxon rank sum test&#xD;
      if appropriate. A total comparison using ANOVA will be also performed. In the same line, the&#xD;
      relative change of SOFA among time-points (with baseline value as the reference) and between&#xD;
      study groups will be assessed with analysis of proportions, using the binomial distribution.&#xD;
      Specific Objective #3: comparison of improvement on markers of tissue hypoperfusion and&#xD;
      hypoxia between study groups will be mainly assessed in a categorical way using chi-square at&#xD;
      different time-points, since those markers are qualitatively attributed a dichotomic&#xD;
      normal/abnormal status. For some of them (ICG, StO2) as continuous variables, t-test or&#xD;
      Wilcoxon rank sum test will be used at specific time points (at the end of fluid&#xD;
      resuscitation, 6, 24h), and ANOVA for a global analysis. Specific Objective #4: For this&#xD;
      objective, pooled data from all the studied patients will be used. Pearson correlations&#xD;
      between selected hypoperfusion variables (ScvO2, P(cv-a)CO2, and CRT) with markers of tissue&#xD;
      hypoperfusion/hypoxia will be explored at different time-points.&#xD;
&#xD;
      All statistical calculations will be performed using Stata Statistical Software, Release 14&#xD;
      (College Station, TX). A probability value (p-value) of less than 0.05 will be considered&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">June 1, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2019</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2019</primary_completion_date>
  <phase>N/A</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>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Amount of resuscitation fluids</measure>
    <time_frame>at six hours</time_frame>
    <description>The total amount of fluids administered as fluid challenges from baseline to 6 hours after starting protocol</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Total fluid balance</measure>
    <time_frame>at 24 hours</time_frame>
    <description>Balance of fluids in the first 24h (inputs-outputs)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Multiple organ dysfunction</measure>
    <time_frame>At 24 hours, 48 hours and 72 hours</time_frame>
    <description>Sequential Organ Failure Assessment (SOFA) scores assessed at baseline, 24 hours, 48 hours and 72 hours. The scale range is from 0 points to 24 points, where 0 points represent normality and no organ dysfunction, and 24 points severe organ dysfunction for the six organs evaluated. More than 10 points is considered severe organ dysfunction.&#xD;
The six organs evaluated in the Sequential Organ Failure Assessment score are: lungs, cardiovascular system, coagulation, liver, kidneys, and central nervous system. All six organs are evaluated from 0 (normal function) to 4 (severe dysfunction) and these sub-scores are summed to get the total SOFA score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sublingual microcirculation</measure>
    <time_frame>at baseline, 6 hours and 24 hours</time_frame>
    <description>Evaluation of sublingual microcirculation by SDF: Videos will be taken at the sublingual mucosa with the SDF device. Two parameters will be calculated systematically by off-line video analysis according to consensus recommendations: MFI (normal value 3.0, with &lt;2.5 considered as abnormal (range 0-3); and PPV where 100% is normal, with &lt;80% representing clear abnormalities (range 0-100%)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hepato-splanchnic blood flow</measure>
    <time_frame>At baseline, 6 hours and 24 hours</time_frame>
    <description>Evaluation of hepato-splanchnic blood flow by ICG clearance: calculation of plasma dissapearance of ICG with normal values &gt;18% in 15 minutes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Muscle tissue oxygenation</measure>
    <time_frame>At baseline, 6 hours and 24 hours</time_frame>
    <description>Evaluation of muscle tissue oxygen saturation by NIRS (normal value &gt;75%)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ccv-aCO2/Da-vO2 ratio</measure>
    <time_frame>At baseline, 6 hours and 24 hours</time_frame>
    <description>Assessed by the Ccv-aCO2/Da-vO2 ratio as a marker of tissue hypoxia: normal value &lt;1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lactate/Pyruvate ratio</measure>
    <time_frame>At baseline, 6 hours and 24 hours</time_frame>
    <description>Assessed by the L/P ratio as another marker of tissue hypoxia. Normal value 10</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">46</enrollment>
  <condition>Septic Shock</condition>
  <condition>Hyperlactatemia</condition>
  <condition>Peripheral Perfusion</condition>
  <arm_group>
    <arm_group_label>CRT guided resuscitation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fluid resuscitation will be aimed at normalizing capillary refill time (CRT) during the intervention period. Fluid challenges will be administered at a rate of 500 ml of crystalloids over 30 minutes, with reassessment of CRT until achieving normal values, or the patient becomes fluid unresponsive, or a safety issue develops.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Lactate guided resuscitation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Fluid resuscitation will be aimed at normalizing or decreasing lactate levels by more than 20% every 2 hours during the intervention during the intervention period. Fluid challenges will be administered at a rate of 500 ml of crystalloids over 30 minutes, with reassessment of lactate every 2 hours until reaching target, or the patient becomes fluid unresponsive, or a safety issue develops.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>CRT guided resuscitation</intervention_name>
    <description>Sequential approach with fluids (guided by dynamic predictors of fluid responsiveness), according to capillary refill time (CRT)</description>
    <arm_group_label>CRT guided resuscitation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Lactate guided resuscitation</intervention_name>
    <description>Sequential approach with fluids (guided by dynamic predictors of fluid responsiveness), according to lactate levels</description>
    <arm_group_label>Lactate guided resuscitation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Septic shock diagnosed at ICU admission according to the Sepsis-3 Consensus Conference&#xD;
             [35], basically septic patients with hypotension requiring norepinephrine (NE) to&#xD;
             maintain a mean arterial pressure (MAP) of 65 mmHg, and serum lactate levels &gt; 2&#xD;
             mmol/l after initial fluid resuscitation.&#xD;
&#xD;
          -  Less than 24 h after fulfilling criteria for septic shock&#xD;
&#xD;
          -  Positive fluid responsiveness assessment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1. Pregnancy&#xD;
&#xD;
          -  Anticipated surgery or dialytic procedure during the first 6h after septic shock&#xD;
             diagnosis&#xD;
&#xD;
          -  Do-not-resuscitate status&#xD;
&#xD;
          -  Child B or C liver cirrhosis&#xD;
&#xD;
          -  Active bleeding&#xD;
&#xD;
          -  Severe concomitant acute respiratory distress syndrome (ARDS)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Glenn Hernandez, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Pontificia Universidad Catolica de Chile</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Glenn Hernandez, PhD</last_name>
    <phone>+56940209609</phone>
    <email>glennguru@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Pontificia Universidad Catolica de Chile</name>
      <address>
        <city>Santiago</city>
        <state>Metropolitana</state>
        <zip>7500000</zip>
        <country>Chile</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Glenn Hernandez, PhD</last_name>
      <phone>+56942106223</phone>
      <email>glennguru@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Ricardo Castro, MPh</last_name>
      <phone>+31630717622</phone>
      <email>rcastro.med@gmail.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Chile</country>
  </location_countries>
  <results_reference>
    <citation>Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2014 Feb 6;370(6):583. doi: 10.1056/NEJMc1314999. No abstract available.</citation>
    <PMID>24499231</PMID>
  </results_reference>
  <results_reference>
    <citation>Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, Jaeschke R, Mebazaa A, Pinsky MR, Teboul JL, Vincent JL, Rhodes A. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med. 2014 Dec;40(12):1795-815. doi: 10.1007/s00134-014-3525-z. Epub 2014 Nov 13.</citation>
    <PMID>25392034</PMID>
  </results_reference>
  <results_reference>
    <citation>Dougnac AL, Mercado MF, Cornejo RR, Cariaga MV, Hernandez GP, Andresen MH, Bugedo GT, Castillo LF; Grupo Chileno del Estudio de la Sepsis. [Prevalence of severe sepsis in intensive care units. A national multicentric study]. Rev Med Chil. 2007 May;135(5):620-30. doi: 10.4067/s0034-98872007000500010. Epub 2007 Jul 9. Spanish.</citation>
    <PMID>17657331</PMID>
  </results_reference>
  <results_reference>
    <citation>Hernandez G, Bruhn A, Castro R, Regueira T. The holistic view on perfusion monitoring in septic shock. Curr Opin Crit Care. 2012 Jun;18(3):280-6. doi: 10.1097/MCC.0b013e3283532c08.</citation>
    <PMID>22473257</PMID>
  </results_reference>
  <results_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 S, 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. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30.</citation>
    <PMID>23361625</PMID>
  </results_reference>
  <results_reference>
    <citation>Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014 Sep 9;18(5):503. doi: 10.1186/s13054-014-0503-3.</citation>
    <PMID>25394679</PMID>
  </results_reference>
  <results_reference>
    <citation>Tapia P, Soto D, Bruhn A, Alegria L, Jarufe N, Luengo C, Kattan E, Regueira T, Meissner A, Menchaca R, Vives MI, Echeverria N, Ospina-Tascon G, Bakker J, Hernandez G. Impairment of exogenous lactate clearance in experimental hyperdynamic septic shock is not related to total liver hypoperfusion. Crit Care. 2015 Apr 22;19(1):188. doi: 10.1186/s13054-015-0928-3.</citation>
    <PMID>25898244</PMID>
  </results_reference>
  <results_reference>
    <citation>Hernandez G, Pedreros C, Veas E, Bruhn A, Romero C, Rovegno M, Neira R, Bravo S, Castro R, Kattan E, Ince C. Evolution of peripheral vs metabolic perfusion parameters during septic shock resuscitation. A clinical-physiologic study. J Crit Care. 2012 Jun;27(3):283-8. doi: 10.1016/j.jcrc.2011.05.024. Epub 2011 Jul 27.</citation>
    <PMID>21798706</PMID>
  </results_reference>
  <results_reference>
    <citation>Centers for Disease Control (CDC). Ectopic pregnancy--United States, 1987. MMWR Morb Mortal Wkly Rep. 1990 Jun 22;39(24):401-4. No abstract available.</citation>
    <PMID>2112685</PMID>
  </results_reference>
  <results_reference>
    <citation>Hernandez G, Bruhn A, Castro R, Pedreros C, Rovegno M, Kattan E, Veas E, Fuentealba A, Regueira T, Ruiz C, Ince C. Persistent Sepsis-Induced Hypotension without Hyperlactatemia: A Distinct Clinical and Physiological Profile within the Spectrum of Septic Shock. Crit Care Res Pract. 2012;2012:536852. doi: 10.1155/2012/536852. Epub 2012 Apr 18.</citation>
    <PMID>22570774</PMID>
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    <citation>Hernandez G, Regueira T, Bruhn A, Castro R, Rovegno M, Fuentealba A, Veas E, Berrutti D, Florez J, Kattan E, Martin C, Ince C. Relationship of systemic, hepatosplanchnic, and microcirculatory perfusion parameters with 6-hour lactate clearance in hyperdynamic septic shock patients: an acute, clinical-physiological, pilot study. Ann Intensive Care. 2012 Oct 15;2(1):44. doi: 10.1186/2110-5820-2-44.</citation>
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    <citation>Hernandez G, Boerma EC, Dubin A, Bruhn A, Koopmans M, Edul VK, Ruiz C, Castro R, Pozo MO, Pedreros C, Veas E, Fuentealba A, Kattan E, Rovegno M, Ince C. Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients. J Crit Care. 2013 Aug;28(4):538.e9-14. doi: 10.1016/j.jcrc.2012.11.022. Epub 2013 Apr 6.</citation>
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    <PMID>23740284</PMID>
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    <citation>Ospina-Tascon GA, Bautista-Rincon DF, Umana M, Tafur JD, Gutierrez A, Garcia AF, Bermudez W, Granados M, Arango-Davila C, Hernandez G. Persistently high venous-to-arterial carbon dioxide differences during early resuscitation are associated with poor outcomes in septic shock. Crit Care. 2013 Dec 13;17(6):R294. doi: 10.1186/cc13160.</citation>
    <PMID>24330804</PMID>
  </results_reference>
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    <citation>Ospina-Tascon GA, Umana M, Bermudez W, Bautista-Rincon DF, Hernandez G, Bruhn A, Granados M, Salazar B, Arango-Davila C, De Backer D. Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O 2 content difference ratio as markers of resuscitation in patients with septic shock. Intensive Care Med. 2015 May;41(5):796-805. doi: 10.1007/s00134-015-3720-6. Epub 2015 Mar 20.</citation>
    <PMID>25792204</PMID>
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    <citation>Ospina-Tascon GA, Umana M, Bermudez WF, Bautista-Rincon DF, Valencia JD, Madrinan HJ, Hernandez G, Bruhn A, Arango-Davila C, De Backer D. Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? Intensive Care Med. 2016 Feb;42(2):211-21. doi: 10.1007/s00134-015-4133-2. Epub 2015 Nov 17.</citation>
    <PMID>26578172</PMID>
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    <PMID>26154408</PMID>
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    <PMID>20463176</PMID>
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    <PMID>20179283</PMID>
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    <PMID>23740148</PMID>
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    <PMID>26831675</PMID>
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    <PMID>18607565</PMID>
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    <PMID>25827585</PMID>
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    <PMID>25679107</PMID>
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    <PMID>27481743</PMID>
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    <PMID>23506495</PMID>
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    <PMID>25126880</PMID>
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    <PMID>26873834</PMID>
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    <PMID>22577907</PMID>
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    <PMID>26903338</PMID>
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    <citation>Monnet X, Teboul JL. Assessment of volume responsiveness during mechanical ventilation: recent advances. Crit Care. 2013 Mar 19;17(2):217. doi: 10.1186/cc12526. No abstract available.</citation>
    <PMID>23510457</PMID>
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    <citation>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.</citation>
    <PMID>8844239</PMID>
  </results_reference>
  <results_reference>
    <citation>Castro R, Regueira T, Aguirre ML, Llanos OP, Bruhn A, Bugedo G, Dougnac A, Castillo L, Andresen M, Hernandez G. An evidence-based resuscitation algorithm applied from the emergency room to the ICU improves survival of severe septic shock. Minerva Anestesiol. 2008 Jun;74(6):223-31. Epub 2008 Mar 21.</citation>
    <PMID>18356807</PMID>
  </results_reference>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>November 26, 2018</study_first_submitted>
  <study_first_submitted_qc>November 29, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 3, 2018</study_first_posted>
  <last_update_submitted>November 29, 2018</last_update_submitted>
  <last_update_submitted_qc>November 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 3, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Pontificia Universidad Catolica de Chile</investigator_affiliation>
    <investigator_full_name>Glenn Hernández</investigator_full_name>
    <investigator_title>Titular Professor</investigator_title>
  </responsible_party>
  <keyword>Septic Shock</keyword>
  <keyword>Lactate</keyword>
  <keyword>Capillary refill time</keyword>
  <keyword>Fluid Responsiveness</keyword>
  <keyword>Mortality</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Shock, Septic</mesh_term>
    <mesh_term>Hyperlactatemia</mesh_term>
    <mesh_term>Shock</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03762005
org study id: 170323007
nct id: NCT03762005
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Persistent hyperlactatemia has been traditionally considered as representing tissue hypoxia,
      and lactate normalization is recommended as a resuscitation target by the Surviving Sepsis
      Campaign (SSC). However, other sources contribute to hyperlactatemia such as sustained
      adrenergic activity and impaired lactate clearance. Only hypoperfusion-related
      hyperlactatemia might be reversed by optimizing systemic blood flow.

      Fluid resuscitation (FR) is used to improve cardiac output (CO) in septic shock to correct
      hypoperfusion. Nevertheless, if persistent hyperlactatemia is not hypoxia-related, excessive
      FR could lead to flow overload. In addition, kinetics of recovery of lactate is relatively
      slow, and thus it might be a suboptimal target for FR.

      Peripheral perfusion appears as a promising alternative target. Abnormal capillary refill
      time (CRT) is frequently used as trigger for FR in septic shock. Studies demonstrated the
      strong prognostic value of persistent abnormal peripheral perfusion, and some recent data
      suggest that targeting FR on CRT normalization could be associated with less fluid loading
      and organ dysfunctions. The excellent prognosis associated with CRT recovery, the
      rapid-response time to fluid loading, its simplicity, and its availability in
      resource-limited settings, constitute a strong background to promote studies evaluating its
      usefulness to guide FR .

      The study hypothesis is that a CRT-targeted FR is associated with less positive fluid
      balances, organ dysfunctions, and at least similar improvement of tissue hypoperfusion or
      hypoxia, when compared to a lactate-targeted FR. To test this hypothesis, the investigators
      designed a clinical physiological, randomized controlled trial in septic shock patients.
      Recruited patients will be randomized to FR aimed at normalizing CRT or normalizing or
      decreasing lactate >20% every 2 h during the study period. Fluid challenges (500 ml in 30 min
      intervals) will be repeated until perfusion target is achieved, or dynamic predictors of
      fluid responsiveness become negative, or a safety limit is reached. The design of our study
      is aimed at: a) determining if CRT targeted resuscitation is associated with less fluid
      resuscitation and fluid balances; b) determining if this strategy is associated with less
      organ dysfunctions; and c) if it results in similar improvement in markers of tissue
      hypoperfusion or hypoxia such as hepato-splanchnic blood flow or microcirculatory perfusion.
GENERAL OBJECTIVE To demonstrate that a CRT-targeted FR is associated with less positive
      fluid balances, organ dysfunctions, and similar improvement of markers of tissue
      hypoperfusion and hypoxia, when compared to a lactate- targeted FR.

      SPECIFIC OBJECTIVES

        1. To determine if normalization of CRT is associated with less fluid resuscitation and
           positive 24-h fluid balances as compared to lactate-targeted resuscitation.

        2. To determine if normalization of CRT is associated with less organ dysfunctions as
           compared to lactate-targeted resuscitation.

        3. To determine if CRT-targeted resuscitation compared to lactate-targeted resuscitation
           leads to similar improvement in markers of tissue hypoperfusion or hypoxia at the end of
           fluid resuscitation

        4. To determine if normality of all the selected hypoperfusion variables (central venous
           oxygen saturation (ScvO2), central venous to arterial carbon dioxide pressure difference
           (P(cv-a)CO2), and CRT) at different time-points in septic shock patients can predict the
           absence of tissue hypoperfusion and hypoxia.

      For this Research Project, several variables of tissue hypoperfusion that can only be
      assessed by special perfusion-monitoring techniques were included.

      Sublingual microcirculatory assessment: Sublingual microcirculatory alterations have been
      well described in septic shock patients. Functional capillary density and microvascular blood
      flow are decreased, while heterogeneity is markedly enhanced. These alterations have been
      shown to be prognostic, with a rapid improvement in survivors but a progressive decline in
      nonsurvivors. A microcirculatory flow index (MFI) ≤ 2.5 and a proportion of perfused vessels
      (PPV) < 80% will be considered as categorical of microcirculatory hypoperfusion Liver blood
      flow: Plasma disappearance rate (PDR) of indocyanine green (ICG), with a non-invasive
      transcutaneous assessment of ICG clearance. Normal range is 18% to 25% per minute with a
      value < 15%/min categorically abnormal.

      Muscle tissue O2 saturation: Muscle tissue O2 saturation (StO2). A decrease in this variable
      to <70% suggests profound tissue hypoperfusion.

      Assessment of tissue hypoxia: There are two clinically calculable variables that have been
      proposed as closely representing tissue hypoxia: the venous- arterial CO2 (Cv- aCO2) to
      arterial-venous O2 content (Da-vO2) difference ratio (Cv- aCO2/Da-vO2) and the
      lactate/pyruvate (L/P) ratio . Both ratios are an expression of anaerobic metabolism at the
      cellular level and thus can be linked to hypoxia. For this research project, these variables
      were considered to ascertain the presence and resolution of tissue hypoxia.

        -  Cv-aCO2/Da-vO2 ratio: This ratio might be useful as a surrogate of the respiratory
           quotient. A ratio ≥ 1.4 could identify anaerobic CO2 generation. A high Cv-aCO2/Da-vO2
           ratio in the setting of hyperlactatemia may favor anaerobic metabolism as the possible
           source of lactate, while a normal Cv-aCO2/Da-vO2 ratio suggesting that lactate
           accumulation is due to non-hypoperfusion- related causes.

        -  L/P ratio: In anaerobic conditions, pyruvate is transformed to lactate and thus the L/P
           ratio increases to ≥ 18. The L/P ratio is considered to be one of the most reliable
           indexes of hypoxia in critically ill patients.

      METHODOLOGY A randomized controlled study of parallel groups was designed: Group A with a
      CRT-targeted fluid resuscitation strategy and group B with a lactate-targeted one.

      This prospective study will be performed at the Hospital of the Pontifical Catholic
      University and at the Public Hospital of the South of Santiago, Chile.

      The study was approved by the Institutional Review Board of both centers. A signed informed
      consent will be asked to the next of kin of all eligible patients, and confirmed by the
      patients when feasible.

      The study intervention period will be of 6 hours I. Randomization A randomization sequence
      with an allocation of 1:1 will be generated by a computer program. Study-group assignment
      will be performed by means of randomized permuted blocks of eight. Allocation concealment
      will be maintained by means of central randomization.

      Fluid challenges (500 ml of Ringer's lactate administered in 30 min intervals) are repeated
      until the perfusion target is normalized, or fluid responsiveness becomes negative, or a
      safety limit of an increase in central venous pressure (CVP) ≥ 5 mmHg after a fluid bolus is
      reached. The perfusion target in group A is a normal CRT ≤3 sec. The perfusion target in
      group B is an arterial lactate ≤ 2 mmol/l or a decrease >20% every 2h.

      CRT will be assessed every 30 minutes and lactate every 2 hours during the 6h study
      intervention period, after which the treatment is liberalized for attending physicians.

      If fluid resuscitation is stopped because the perfusion target is normalized, the time is
      registered, and the patient subjected to the specific research-related assessment protocol
      and followed until hospital discharge.

      II. General management algorithm Besides sepsis source aggressive management, all patients
      will be treated according to our local algorithm aimed at macrohemodynamic stabilization and
      improvement of hypoperfusion. The algorithm has been described elsewhere. Co-interventions
      will be registered and considered in statistical analysis.

      III. Specific research-related assessments For the purposes of this research protocol,
      several variables will be periodically measured or calculated as follows: at baseline, at 2h,
      at 6h and at 24h.

        1. Macrohemodynamic variables such as mean arterial pressure,M, heart rate, norepinephrine
           dose, CVP, dynamic predictors.

        2. Continuous cardiac output (CO) monitoring: this will be performed with non-invasive
           pulse-contour CO assessment acquired with this project (PiCCO device).

        3. Metabolic-perfusion variables such as arterial lactate, ScvO2, and P(cva)CO2.

        4. Peripheral perfusion assessment: CRT and mottling score

        5. Sublingual microcirculation: It will be assessed with the side dark field (SDF) device.
           At each assessment, at least five 10-20 sec video images will be recorded. The analysis
           will be performed by eye following recent recommendations . From image analysis the
           following variables will be calculated (i) proportion of perfused vessels; (ii)
           microcirculatory flow index (MFI); All these indexes will be calculated separately for
           small (<20 microm diameter) and large vessels (> 20 microm diameter) .

        6. Liver blood flow: An ICG finger clip well be fixed in every patient and then connected
           to a liver function monitor (LiMON; Pulsion Medical Systems, Munich, Germany). A dose of
           0.25 mg/kg of ICG (LiMon Pulsion Medical Systems, Germany) will be injected through a
           central venous catheter.

        7. Near infrared spectroscopy (NIRS): StO2 will be measured by a tissue spectrometer
           (InSpectra Model 325; Hutchinson Tc, Mn, USA). A NIRS probe will be placed on the skin
           of the thenar eminence

        8. Ccv-aCO2/Da-vO2 ratio: This ratio will be calculated after taking arterial and central
           venous blood gases with the Douglas formula.

        9. L/P ratio: This ratio will be assessed at 0, 6 and 24h during the study period, at
           baseline and when fluid resuscitation is stopped. Arterial blood samples for pyruvate
           will be taken and processed in our laboratory before 3h according to the method
           described by De Backer et al , including immediate deproteinization of the sample and
           analysis by enzymatic fluorometric-assay (Sigma-Aldrich, USA)

       10. Sequential organ failure assessment (SOFA) at baseline, 24, 48 and at 72h . Finally, all
           patients will be followed until hospital discharge, and all data including demographic
           aspects, sepsis sources and management, inflammatory biomarkers, and severity scores and
           major outcomes will be registered.

      STATISTICAL ANALYSIS Sample size calculation: the simple size calculation was based in some
      small clinical studies. In a recent study, a resuscitation strategy guided by peripheral
      perfusion offered important benefits in terms of fluid administration at 6 hours (4227 ± 1081
      ml vs 6069 ± 1715 ml) and organ dysfunction, when compared with standard fluid therapy. In
      consequence, a 1600 ml difference in the mean 24-h total fluid administration between the
      experimental CRT group and the conventional lactate group was considered to be the critical
      threshold for hypothesis testing. If there is truly no difference between the standard and
      experimental treatment, then 46 patients are required (23 patients per arm) to be 90% sure
      that the lower limit of a two-sided confidence interval will be above the limit of -1600 mL
      at an alpha level of 0.05. Statistical analysis Intention to treat analysis will be performed
      in order to minimize bias.

      Analyses will be performed as follows: Specific Objective #1: between study groups, the
      amount of fluids administered at the end of fluid resuscitation, and at 6, 24, 48 and 72h
      will be compared exclusively at each time-point with t-test, and comprehensively using ANOVA.
      Total 24-h fluid balance will be compared using t-test. Specific Objective #2, the status of
      peripheral perfusion normalization will be assessed in a categorical way (normal/abnormal)
      with chi-square at specific time-points (at the end of fluid resuscitation, 6, and 24h), and
      with means of SOFA score at each time-point up to 72h using t-test or Wilcoxon rank sum test
      if appropriate. A total comparison using ANOVA will be also performed. In the same line, the
      relative change of SOFA among time-points (with baseline value as the reference) and between
      study groups will be assessed with analysis of proportions, using the binomial distribution.
      Specific Objective #3: comparison of improvement on markers of tissue hypoperfusion and
      hypoxia between study groups will be mainly assessed in a categorical way using chi-square at
      different time-points, since those markers are qualitatively attributed a dichotomic
      normal/abnormal status. For some of them (ICG, StO2) as continuous variables, t-test or
      Wilcoxon rank sum test will be used at specific time points (at the end of fluid
      resuscitation, 6, 24h), and ANOVA for a global analysis. Specific Objective #4: For this
      objective, pooled data from all the studied patients will be used. Pearson correlations
      between selected hypoperfusion variables (ScvO2, P(cv-a)CO2, and CRT) with markers of tissue
      hypoperfusion/hypoxia will be explored at different time-points.

      All statistical calculations will be performed using Stata Statistical Software, Release 14
      (College Station, TX). A probability value (p-value) of less than 0.05 will be considered
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Amount of resuscitation fluids
time frame: at six hours
description: The total amount of fluids administered as fluid challenges from baseline to 6 hours after starting protocol
measure: Total fluid balance
time frame: at 24 hours
description: Balance of fluids in the first 24h (inputs-outputs)
measure: Multiple organ dysfunction
time frame: At 24 hours, 48 hours and 72 hours
description: Sequential Organ Failure Assessment (SOFA) scores assessed at baseline, 24 hours, 48 hours and 72 hours. The scale range is from 0 points to 24 points, where 0 points represent normality and no organ dysfunction, and 24 points severe organ dysfunction for the six organs evaluated. More than 10 points is considered severe organ dysfunction.
The six organs evaluated in the Sequential Organ Failure Assessment score are: lungs, cardiovascular system, coagulation, liver, kidneys, and central nervous system. All six organs are evaluated from 0 (normal function) to 4 (severe dysfunction) and these sub-scores are summed to get the total SOFA score.
measure: Sublingual microcirculation
time frame: at baseline, 6 hours and 24 hours
description: Evaluation of sublingual microcirculation by SDF: Videos will be taken at the sublingual mucosa with the SDF device. Two parameters will be calculated systematically by off-line video analysis according to consensus recommendations: MFI (normal value 3.0, with <2.5 considered as abnormal (range 0-3); and PPV where 100% is normal, with <80% representing clear abnormalities (range 0-100%)
measure: Hepato-splanchnic blood flow
time frame: At baseline, 6 hours and 24 hours
description: Evaluation of hepato-splanchnic blood flow by ICG clearance: calculation of plasma dissapearance of ICG with normal values >18% in 15 minutes
measure: Muscle tissue oxygenation
time frame: At baseline, 6 hours and 24 hours
description: Evaluation of muscle tissue oxygen saturation by NIRS (normal value >75%)
measure: Ccv-aCO2/Da-vO2 ratio
time frame: At baseline, 6 hours and 24 hours
description: Assessed by the Ccv-aCO2/Da-vO2 ratio as a marker of tissue hypoxia: normal value <1
measure: Lactate/Pyruvate ratio
time frame: At baseline, 6 hours and 24 hours
description: Assessed by the L/P ratio as another marker of tissue hypoxia. Normal value 10
arm group label: CRT guided resuscitation
arm group type: Experimental
description: Fluid resuscitation will be aimed at normalizing capillary refill time (CRT) during the intervention period. Fluid challenges will be administered at a rate of 500 ml of crystalloids over 30 minutes, with reassessment of CRT until achieving normal values, or the patient becomes fluid unresponsive, or a safety issue develops.
arm group label: Lactate guided resuscitation
arm group type: Active Comparator
description: Fluid resuscitation will be aimed at normalizing or decreasing lactate levels by more than 20% every 2 hours during the intervention during the intervention period. Fluid challenges will be administered at a rate of 500 ml of crystalloids over 30 minutes, with reassessment of lactate every 2 hours until reaching target, or the patient becomes fluid unresponsive, or a safety issue develops.
intervention type: Other
intervention name: CRT guided resuscitation
description: Sequential approach with fluids (guided by dynamic predictors of fluid responsiveness), according to capillary refill time (CRT)
arm group label: CRT guided resuscitation
intervention type: Other
intervention name: Lactate guided resuscitation
description: Sequential approach with fluids (guided by dynamic predictors of fluid responsiveness), according to lactate levels
arm group label: Lactate guided resuscitation
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Glenn Hernandez, PhD
role: Principal Investigator
affiliation: Pontificia Universidad Catolica de Chile
last name: Glenn Hernandez, PhD
phone: +56940209609
email: glennguru@gmail.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: Chile
citation: Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2014 Feb 6;370(6):583. doi: 10.1056/NEJMc1314999. No abstract available.
PMID: 24499231
citation: Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, Jaeschke R, Mebazaa A, Pinsky MR, Teboul JL, Vincent JL, Rhodes A. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med. 2014 Dec;40(12):1795-815. doi: 10.1007/s00134-014-3525-z. Epub 2014 Nov 13.
PMID: 25392034
citation: Dougnac AL, Mercado MF, Cornejo RR, Cariaga MV, Hernandez GP, Andresen MH, Bugedo GT, Castillo LF; Grupo Chileno del Estudio de la Sepsis. [Prevalence of severe sepsis in intensive care units. A national multicentric study]. Rev Med Chil. 2007 May;135(5):620-30. doi: 10.4067/s0034-98872007000500010. Epub 2007 Jul 9. Spanish.
PMID: 17657331
citation: Hernandez G, Bruhn A, Castro R, Regueira T. The holistic view on perfusion monitoring in septic shock. Curr Opin Crit Care. 2012 Jun;18(3):280-6. doi: 10.1097/MCC.0b013e3283532c08.
PMID: 22473257
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 S, 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. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30.
PMID: 23361625
citation: Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014 Sep 9;18(5):503. doi: 10.1186/s13054-014-0503-3.
PMID: 25394679
citation: Tapia P, Soto D, Bruhn A, Alegria L, Jarufe N, Luengo C, Kattan E, Regueira T, Meissner A, Menchaca R, Vives MI, Echeverria N, Ospina-Tascon G, Bakker J, Hernandez G. Impairment of exogenous lactate clearance in experimental hyperdynamic septic shock is not related to total liver hypoperfusion. Crit Care. 2015 Apr 22;19(1):188. doi: 10.1186/s13054-015-0928-3.
PMID: 25898244
citation: Hernandez G, Pedreros C, Veas E, Bruhn A, Romero C, Rovegno M, Neira R, Bravo S, Castro R, Kattan E, Ince C. Evolution of peripheral vs metabolic perfusion parameters during septic shock resuscitation. A clinical-physiologic study. J Crit Care. 2012 Jun;27(3):283-8. doi: 10.1016/j.jcrc.2011.05.024. Epub 2011 Jul 27.
PMID: 21798706
citation: Centers for Disease Control (CDC). Ectopic pregnancy--United States, 1987. MMWR Morb Mortal Wkly Rep. 1990 Jun 22;39(24):401-4. No abstract available.
PMID: 2112685
citation: Hernandez G, Bruhn A, Castro R, Pedreros C, Rovegno M, Kattan E, Veas E, Fuentealba A, Regueira T, Ruiz C, Ince C. Persistent Sepsis-Induced Hypotension without Hyperlactatemia: A Distinct Clinical and Physiological Profile within the Spectrum of Septic Shock. Crit Care Res Pract. 2012;2012:536852. doi: 10.1155/2012/536852. Epub 2012 Apr 18.
PMID: 22570774
citation: Hernandez G, Regueira T, Bruhn A, Castro R, Rovegno M, Fuentealba A, Veas E, Berrutti D, Florez J, Kattan E, Martin C, Ince C. Relationship of systemic, hepatosplanchnic, and microcirculatory perfusion parameters with 6-hour lactate clearance in hyperdynamic septic shock patients: an acute, clinical-physiological, pilot study. Ann Intensive Care. 2012 Oct 15;2(1):44. doi: 10.1186/2110-5820-2-44.
PMID: 23067578
citation: Hernandez G, Boerma EC, Dubin A, Bruhn A, Koopmans M, Edul VK, Ruiz C, Castro R, Pozo MO, Pedreros C, Veas E, Fuentealba A, Kattan E, Rovegno M, Ince C. Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients. J Crit Care. 2013 Aug;28(4):538.e9-14. doi: 10.1016/j.jcrc.2012.11.022. Epub 2013 Apr 6.
PMID: 23566729
citation: Hernandez G, Bruhn A, Luengo C, Regueira T, Kattan E, Fuentealba A, Florez J, Castro R, Aquevedo A, Pairumani R, McNab P, Ince C. Effects of dobutamine on systemic, regional and microcirculatory perfusion parameters in septic shock: a randomized, placebo-controlled, double-blind, crossover study. Intensive Care Med. 2013 Aug;39(8):1435-43. doi: 10.1007/s00134-013-2982-0. Epub 2013 Jun 6.
PMID: 23740284
citation: Ospina-Tascon GA, Bautista-Rincon DF, Umana M, Tafur JD, Gutierrez A, Garcia AF, Bermudez W, Granados M, Arango-Davila C, Hernandez G. Persistently high venous-to-arterial carbon dioxide differences during early resuscitation are associated with poor outcomes in septic shock. Crit Care. 2013 Dec 13;17(6):R294. doi: 10.1186/cc13160.
PMID: 24330804
citation: Ospina-Tascon GA, Umana M, Bermudez W, Bautista-Rincon DF, Hernandez G, Bruhn A, Granados M, Salazar B, Arango-Davila C, De Backer D. Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O 2 content difference ratio as markers of resuscitation in patients with septic shock. Intensive Care Med. 2015 May;41(5):796-805. doi: 10.1007/s00134-015-3720-6. Epub 2015 Mar 20.
PMID: 25792204
citation: Ospina-Tascon GA, Umana M, Bermudez WF, Bautista-Rincon DF, Valencia JD, Madrinan HJ, Hernandez G, Bruhn A, Arango-Davila C, De Backer D. Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? Intensive Care Med. 2016 Feb;42(2):211-21. doi: 10.1007/s00134-015-4133-2. Epub 2015 Nov 17.
PMID: 26578172
citation: Hernandez G, Tapia P, Alegria L, Soto D, Luengo C, Gomez J, Jarufe N, Achurra P, Rebolledo R, Bruhn A, Castro R, Kattan E, Ospina-Tascon G, Bakker J. Effects of dexmedetomidine and esmolol on systemic hemodynamics and exogenous lactate clearance in early experimental septic shock. Crit Care. 2016 Aug 2;20(1):234. doi: 10.1186/s13054-016-1419-x.
PMID: 27480413
citation: Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, Van Regenmortel N. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014 Nov-Dec;46(5):361-80. doi: 10.5603/AIT.2014.0060.
PMID: 25432556
citation: Hernandez G, Luengo C, Bruhn A, Kattan E, Friedman G, Ospina-Tascon GA, Fuentealba A, Castro R, Regueira T, Romero C, Ince C, Bakker J. When to stop septic shock resuscitation: clues from a dynamic perfusion monitoring. Ann Intensive Care. 2014 Oct 11;4:30. doi: 10.1186/s13613-014-0030-z. eCollection 2014.
PMID: 25593746
citation: Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care. 2014 Jun 21;4:21. doi: 10.1186/s13613-014-0021-0. eCollection 2014.
PMID: 25110606
citation: Gu WJ, Zhang Z, Bakker J. Early lactate clearance-guided therapy in patients with sepsis: a meta-analysis with trial sequential analysis of randomized controlled trials. Intensive Care Med. 2015 Oct;41(10):1862-3. doi: 10.1007/s00134-015-3955-2. Epub 2015 Jul 8. No abstract available.
PMID: 26154408
citation: Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J; LACTATE study group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010 Sep 15;182(6):752-61. doi: 10.1164/rccm.200912-1918OC. Epub 2010 May 12.
PMID: 20463176
citation: Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-46. doi: 10.1001/jama.2010.158.
PMID: 20179283
citation: Puskarich MA, Trzeciak S, Shapiro NI, Albers AB, Heffner AC, Kline JA, Jones AE. Whole blood lactate kinetics in patients undergoing quantitative resuscitation for severe sepsis and septic shock. Chest. 2013 Jun;143(6):1548-1553. doi: 10.1378/chest.12-0878.
PMID: 23740148
citation: Bakker J, de Backer D, Hernandez G. Lactate-guided resuscitation saves lives: we are not sure. Intensive Care Med. 2016 Mar;42(3):472-474. doi: 10.1007/s00134-016-4220-z. Epub 2016 Feb 1. No abstract available.
PMID: 26831675
citation: Vallee F, Vallet B, Mathe O, Parraguette J, Mari A, Silva S, Samii K, Fourcade O, Genestal M. Central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock? Intensive Care Med. 2008 Dec;34(12):2218-25. doi: 10.1007/s00134-008-1199-0. Epub 2008 Jul 8.
PMID: 18607565
citation: Lima A, Bakker J. Clinical assessment of peripheral circulation. Curr Opin Crit Care. 2015 Jun;21(3):226-31. doi: 10.1097/MCC.0000000000000194.
PMID: 25827585
citation: van Genderen ME, Engels N, van der Valk RJ, Lima A, Klijn E, Bakker J, van Bommel J. Early peripheral perfusion-guided fluid therapy in patients with septic shock. Am J Respir Crit Care Med. 2015 Feb 15;191(4):477-80. doi: 10.1164/rccm.201408-1575LE. No abstract available.
PMID: 25679107
citation: Hernandez G, Teboul JL. Is the macrocirculation really dissociated from the microcirculation in septic shock? Intensive Care Med. 2016 Oct;42(10):1621-1624. doi: 10.1007/s00134-016-4416-2. Epub 2016 Jun 11. No abstract available.
PMID: 27289357
citation: Brunauer A, Kokofer A, Bataar O, Gradwohl-Matis I, Dankl D, Bakker J, Dunser MW. Changes in peripheral perfusion relate to visceral organ perfusion in early septic shock: A pilot study. J Crit Care. 2016 Oct;35:105-9. doi: 10.1016/j.jcrc.2016.05.007. Epub 2016 May 12.
PMID: 27481743
citation: Hernandez G, Bruhn A, Ince C. Microcirculation in sepsis: new perspectives. Curr Vasc Pharmacol. 2013 Mar 1;11(2):161-9.
PMID: 23506495
citation: Vellinga NA, Boerma EC, Koopmans M, Donati A, Dubin A, Shapiro NI, Pearse RM, Machado FR, Fries M, Akarsu-Ayazoglu T, Pranskunas A, Hollenberg S, Balestra G, van Iterson M, van der Voort PH, Sadaka F, Minto G, Aypar U, Hurtado FJ, Martinelli G, Payen D, van Haren F, Holley A, Pattnaik R, Gomez H, Mehta RL, Rodriguez AH, Ruiz C, Canales HS, Duranteau J, Spronk PE, Jhanji S, Hubble S, Chierego M, Jung C, Martin D, Sorbara C, Tijssen JG, Bakker J, Ince C; microSOAP Study Group. International study on microcirculatory shock occurrence in acutely ill patients. Crit Care Med. 2015 Jan;43(1):48-56. doi: 10.1097/CCM.0000000000000553.
PMID: 25126880
citation: Ospina-Tascon GA, Hernandez G, Cecconi M. Understanding the venous-arterial CO2 to arterial-venous O2 content difference ratio. Intensive Care Med. 2016 Nov;42(11):1801-1804. doi: 10.1007/s00134-016-4233-7. Epub 2016 Feb 12. No abstract available.
PMID: 26873834
citation: Rimachi R, Bruzzi de Carvahlo F, Orellano-Jimenez C, Cotton F, Vincent JL, De Backer D. Lactate/pyruvate ratio as a marker of tissue hypoxia in circulatory and septic shock. Anaesth Intensive Care. 2012 May;40(3):427-32. doi: 10.1177/0310057X1204000307.
PMID: 22577907
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: Monnet X, Teboul JL. Assessment of volume responsiveness during mechanical ventilation: recent advances. Crit Care. 2013 Mar 19;17(2):217. doi: 10.1186/cc12526. No abstract available.
PMID: 23510457
citation: 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.
PMID: 8844239
citation: Castro R, Regueira T, Aguirre ML, Llanos OP, Bruhn A, Bugedo G, Dougnac A, Castillo L, Andresen M, Hernandez G. An evidence-based resuscitation algorithm applied from the emergency room to the ICU improves survival of severe septic shock. Minerva Anestesiol. 2008 Jun;74(6):223-31. Epub 2008 Mar 21.
PMID: 18356807
responsible party type: Principal Investigator
investigator affiliation: Pontificia Universidad Catolica de Chile
investigator full name: Glenn Hernández
investigator title: Titular Professor
mesh term: Shock, Septic
mesh term: Hyperlactatemia
mesh term: Shock
sharing ipd: Undecided