<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/NCT04428060</url>
  </required_header>
  <id_info>
    <org_study_id>UTHDA-AC02</org_study_id>
    <nct_id>NCT04428060</nct_id>
  </id_info>
  <brief_title>PERSEUS-PS Randomized Controlled Trial</brief_title>
  <acronym>PERSEUS-PS</acronym>
  <official_title>Assessment of the Efficacy of Personalized Physiology-guided Resuscitation in Patients With Cardiac Arrest: The PERSEUS Pilot Randomized Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Thessaly</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Thessaly</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>
      The PERSEUS protocol is a new approach to the resuscitation of highly monitored patients with&#xD;
      cardiac arrest. It aims at the optimization of all the available physiological parameters and&#xD;
      the full exploitation of both the &quot;cardiac pump&quot; and &quot;thoracic pump'. This protocol will help&#xD;
      to titrate chest compressions, ventilation, and vasopressor dosing to physiological&#xD;
      parameters, increasing survival after cardiac arrest with favorable neurological outcome&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND&#xD;
&#xD;
      Since 2000, resuscitation guidelines remain uniform across all cardiac arrest patients,&#xD;
      focusing on the delivery of chest compressions to a standardized rate and depth and&#xD;
      algorithmic vasopressor dosing. Although the concept of goal-directed hemodynamic&#xD;
      optimization as a treatment strategy to improve clinical outcome in critically ill patients&#xD;
      has been tested since the 1980s, no human study has established that prospectively targeting&#xD;
      hemodynamics during CPR improves outcomes until now. Nevertheless, individualizing&#xD;
      resuscitation to the appropriate hemodynamic and ventilatory goals rather than a standard&#xD;
      Bone-size-fits-all treatment seems a promising new therapeutic strategy that can be applied&#xD;
      during resuscitation attempts in highly monitored patients.&#xD;
&#xD;
      The PERSEUS protocol is a new approach to the resuscitation of highly monitored patients with&#xD;
      cardiac arrest. It has been developed based on our experience and the observation that the&#xD;
      most important determinant of survival is the optimization of all the available physiological&#xD;
      parameters and the full exploitation of both the &quot;cardiac pump&quot; and &quot;thoracic pump'.&#xD;
&#xD;
      Physiological and pathophysiological aspects of cardiac arrest Cardiac arrest interval&#xD;
      Immediately after the abrupt loss of effective blood flow, the hypotension-induced baroreflex&#xD;
      withdrawal with the net increase in the vascular resistance maintains an impaired antegrade&#xD;
      and pulmonary blood flow. The systemic and pulmonary blood flow continue for at least 30-60&#xD;
      s, until the pressure gradient between the aorta and the right side of the heart, as well as&#xD;
      between the pulmonary artery and the left atrium, has been completely dissipated, resulting&#xD;
      in a rapid increase in the volume of the right ventricle and the extrapericardial component&#xD;
      of the pulmonary veins. When arterial and systemic venous pressures reach equilibrium, the&#xD;
      mean systemic filling pressure (Pmsf) is approximately 6-12 mmHg. The coronary blood flow&#xD;
      declines to zero, but CPP remains positive because of the retrograde coronary flow. However,&#xD;
      this diminishes the removal of norepinephrine from the interstitial spaces, which together&#xD;
      with the formation of cardiac edema prolongs vasoconstriction and enhances myocardial&#xD;
      hypoperfusion and hypoxia.&#xD;
&#xD;
      At the same time, cerebral perfusion decreases while the damage of fatty acids of the&#xD;
      neuronal cell membrane by reactive oxygen species leads to a progressive increase in membrane&#xD;
      permeability and severe derangements of intracellular electrolytes, resulting in cell&#xD;
      swelling and brain edema formation. This, together with venous congestion, increases&#xD;
      intracranial pressure (ICP) and damages the neuropil and synaptic structures and/or contacts.&#xD;
&#xD;
      The PERSEUS personalized physiology-guided resuscitation protocol Recognizing cardiac arrest&#xD;
      in highly monitored areas can be more difficult than in other hospital areas, such as the&#xD;
      ward. Considering that the vast majority of alarms from sensors are false alarms, cardiac&#xD;
      arrest should be recognized and confirmed by the combined assessment of the rhythm, the&#xD;
      arterial blood pressure and waveform, the abrupt decrease of ETCO2, and the loss of carotid&#xD;
      pulse. Once cardiac arrest is confirmed, CPR should be initiated without delay with&#xD;
      high-quality chest compressions according to the recent resuscitation guidelines. However,&#xD;
      the effectiveness of chest compressions is depending on the venous return, which is&#xD;
      proportional to the pressure gradient between Pmsf and CVP, and particular attention is&#xD;
      needed by the rescuers to determine Pmsf within the first 5-7.5 s of cardiac arrest and prior&#xD;
      to the onset of chest compressions. The Pmsf is a quantitative measurement of the patient's&#xD;
      volume status and represents the tone of venous reservoir, indicating the pre-arrest&#xD;
      &quot;vasoreactivity&quot; status of the patients. Therefore, optimizing Pmsf during CPR is paramount&#xD;
      for increasing survival rates.&#xD;
&#xD;
      During the first cycle of CPR, the resuscitation efforts must maintain a relaxation DAP of ≥&#xD;
      40 mmHg (calculated at the time of full chest decompression). In patients with a lower DAP,&#xD;
      administration of epinephrine or vasopressin should be based on the pre-arrest value of Pmsf&#xD;
      and/or systemic vascular resistance (SVR) and is anticipated to be beneficial in those with&#xD;
      Pmsf &lt; 6 mmHg and/or SVR &lt; 800 dynes·sec·cm-5, enhancing volume recruitment from the&#xD;
      unstressed compartment and increasing the stressed volume. In all other patients, the&#xD;
      vasoreactivity will be maintained for some time provided that intravascular volume and chest&#xD;
      compressions are sufficient. Therefore, circulatory volume should be increased in patients&#xD;
      with a pre-arrest CVP &lt; 2 mmHg using a fluid bolus and/or the passive leg-raising maneuver.&#xD;
      However, it should be noted that rapid and liberal fluid administration during CPR may lead&#xD;
      to an excessive increase in RAP, aggravating venous return and CPP, especially when&#xD;
      administered via a jugular or subclavian central venous catheter. At the onset of cardiac&#xD;
      arrest, ventilatory parameters should be changed to tidal volume 6 ml/kg, respiratory rate 10&#xD;
      min-1, I:E 1:2, PEEP 0 cm H20, and FiO2 100%. During this cycle, all other treatment efforts&#xD;
      must follow current recommendations for standard CPR.&#xD;
&#xD;
      After the onset of the second cycle of CPR, the resuscitation efforts should be continued as&#xD;
      above while assessing ETCO2. As stated previously, ventilation during CPR by using currently&#xD;
      recommended chest compression rates may take place entirely below functional residual&#xD;
      capacity and may not provide adequate blood oxygenation due to small airway closure,&#xD;
      increasing pulmonary vascular resistance and impairing gas exchange. Therefore, mean airway&#xD;
      pressure should be maintained 40-45 cmH2O in patients with DAP ≥ 40 mmHg and ETCO2 &lt; 10 mmHg&#xD;
      to facilitate gas exchange. On the contrary, all patients with DAP &gt; 40 mmHg and ETCO2 &gt; 15&#xD;
      mmHg should be assessed for hypercapnia, and if present, they should be treated by increasing&#xD;
      the ventilatory rate by up to 50% (or less if necessary to maintain DAP ≥ 40 mmHg). Also,&#xD;
      severe acidosis should be treated immediately because it causes vasodilatation which may&#xD;
      decrease venous return and CPP.&#xD;
&#xD;
      During the third cycle of CPR, the resuscitation efforts should be continued as above while&#xD;
      assessing ScvO2, which should be maintained 65-80%. In patients with ScvO2 &lt; 65%, transfusion&#xD;
      of red blood cells should be initiated when Hb is ≤8 g/dl to improve oxygen delivery. In&#xD;
      patients with Hb &gt; 8 g/dl, a fluid bolus should be given to improve circulatory flow provided&#xD;
      that DAP is maintained ≥ 40 mmHg. In patients with DAP ≥ 40 mmHg and a ScvO2 value of &gt; 80%,&#xD;
      hypothermia should be excluded and treated aggressively if present, the FiO2 should be&#xD;
      decreased in case of hyperoxemia (PaO2 &gt; 200 mmHg), and a low-dose vasodilator may be&#xD;
      considered when microcirculatory shunting and loss of hemodynamic coherence between macro-&#xD;
      and microcirculation can be directly assessed or possible (e.g., DAP ≥ 40 mmHg, Hb &gt; 8 g/dl,&#xD;
      PaO2 &gt; 200 mmHg, ScvO2 &gt; 80%, and mixed venous oxygen tension ≤ 26 mmHg (if available), with&#xD;
      or without hyperlactatemia). In patients with normal ScvO2, trend cerebral oxygenation&#xD;
      monitoring (near-infrared spectroscopy - NIRS) should be used because it focuses more on the&#xD;
      amount of change from the pre-arrest baseline cerebral oxygenation value. Decreasing FiO2&#xD;
      until PaO2 is 200 mmHg can be considered when NIRS is &gt; 50% of the prearrest value, while&#xD;
      HUP-CPR (30°) should be considered in patients with NIRS ≤ 30% of the pre-arrest value and&#xD;
      signs or known increased intracranial pressure. The resuscitation efforts may be considered&#xD;
      as adequate in patients who have reached the pre-defined targets and have a NIRS of 30-50% of&#xD;
      the pre-arrest value, and should be continued by repeating the approach from the beginning.&#xD;
&#xD;
      AIM&#xD;
&#xD;
      The PERSEUS resuscitation protocol is a new approach to the resuscitation of highly monitored&#xD;
      patients with cardiac arrest and may help to titrate chest compressions, ventilation, and&#xD;
      vasopressor dosing to physiological parameters. The aim of this double-center study is to&#xD;
      investigate if resuscitation with the PERSEUS protocol can increase survival after cardiac&#xD;
      arrest with favorable neurological outcome.&#xD;
&#xD;
      METHODS&#xD;
&#xD;
      Design This is a prospective observational study designed in accordance with the declaration&#xD;
      of Helsinki. The study will be register at Clinical Trials.gov and has been approved by the&#xD;
      Institutional Review Board of the University Hospital of Larisa, under the reference number&#xD;
      2670/3-2-2020.&#xD;
&#xD;
      Patient eligibility All intubated and mechanically ventilated adult patients (≥ 18 years of&#xD;
      age) with a CPR event requiring chest compressions in a highly monitored area [Operating&#xD;
      Room, Intensive Care Unit (ICU), or Emergency Department] will be eligible for inclusion.&#xD;
      Each patient will be allocated into two groups; patients in group A will be resuscitated with&#xD;
      the PERSEUS protocol, while patients in group B will receive standard CPR according to the&#xD;
      latest European Resuscitation Council guidelines on resuscitation. Random allocation will be&#xD;
      carried out by a researcher who will not be involved in data collection using the sealed&#xD;
      envelope technique.&#xD;
&#xD;
      Data Collection and Monitoring Data analysis will be based on predefined data points on a&#xD;
      prospective data collection form. The staff will be blinded to measurements until the end of&#xD;
      the study and all data are analyzed. Clinical monitoring throughout the study will be&#xD;
      performed to maximize protocol adherence, while an independent Data and Safety Monitoring&#xD;
      research staff will monitor safety, ethical, and scientific aspects of the study.&#xD;
&#xD;
      We will use the Utstein-style templates for in-hospital cardiac arrest data. Return of&#xD;
      spontaneous circulation will be defined for all rhythms as the restoration of a spontaneous&#xD;
      perfusing rhythm for more than 20 minutes. Survival with a favorable neurological outcome&#xD;
      will be defined as a cerebral performance category (CPC) score of 1, 2 or no change from&#xD;
      baseline. The CPC scoring system assesses functional outcomes among survivors of cardiac&#xD;
      arrest and has been extensively validated and shown to reliably predict functional&#xD;
      neurological disability.&#xD;
&#xD;
      Data management The goal of the clinical data management plan is to provide high-quality data&#xD;
      by adopting standardized procedures to minimize the number of errors and missing data, and&#xD;
      consequently, to generate an accurate database for analysis. Remote monitoring is performed&#xD;
      to signal early aberrant patterns, issues with consistency, credibility and other anomalies.&#xD;
      Any missing and outlier data values will individually revised and completed or corrected&#xD;
      whenever possible.&#xD;
&#xD;
      Ethics and dissemination The study will be performed according to national and international&#xD;
      guidelines. The present research investigation was reviewed by the IRB at the Larisa&#xD;
      University Hospital and determined to be IRB exempt.&#xD;
&#xD;
      Competing interests None declared.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 12, 2020</start_date>
  <completion_date type="Anticipated">December 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2023</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>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>ROSC</measure>
    <time_frame>From start of CPR until return of spontaneous circulation, assessed up to 60 minutes</time_frame>
    <description>Return of spontaneous circulation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>ICU length of stay</measure>
    <time_frame>Up to 8 weeks</time_frame>
    <description>Days hospitalized in the intensive care unit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days on mechanical ventilation</measure>
    <time_frame>Up to 8 weeks</time_frame>
    <description>How many days the patient will be mechanically ventilated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival to hospital discharge</measure>
    <time_frame>Up to 8 weeks</time_frame>
    <description>Dead or alive at hospital discharge with favorable neurological outcome (CPC 1 or 2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>1-month survival</measure>
    <time_frame>At 1 month after hopsital discharge</time_frame>
    <description>Dead or alive at 1 month after hospital discharge with favorable neurological outcome (CPC 1 or 2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month survival</measure>
    <time_frame>At 3 months after hopsital discharge</time_frame>
    <description>Dead or alive at 3 months after hospital discharge with favorable neurological outcome (CPC 1 or 2)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">44</enrollment>
  <condition>Cardiac Arrest</condition>
  <condition>Cardiopulmonary Arrest With Successful Resuscitation</condition>
  <arm_group>
    <arm_group_label>PERSEUS CPR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be resuscitated according to the PERSEUS protocol</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CONTROL</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will be resuscitated according to current Advanced Life Support guidelines</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>PERSEUS CPR</intervention_name>
    <description>Resuscitation based on patient physiology</description>
    <arm_group_label>PERSEUS CPR</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard CPR</intervention_name>
    <description>Resuscitation based on current guidelines</description>
    <arm_group_label>CONTROL</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  invasive arterial blood pressure monitoring prior to and during CPR&#xD;
&#xD;
          -  first compression of CPR captured on transmitted arterial blood pressure waveform data&#xD;
&#xD;
          -  internal jugular or subclavian central venous catheter prior to and during CPR&#xD;
&#xD;
          -  patients with measurement of systemic vascular resistance prior to and during CPR&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  unable to determine any of the aforementioned parameters during CPR&#xD;
&#xD;
          -  unable to determine when CPR started and stopped&#xD;
&#xD;
          -  subjects within the exclusion period of another study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Athanasios Chalkias, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Thessaly</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Athanasios Chalkias, MD, PhD</last_name>
    <phone>00302413502953</phone>
    <email>thanoschalkias@yahoo.gr</email>
  </overall_contact>
  <location>
    <facility>
      <name>University Hospital of Larisa, Department of Anesthesiology</name>
      <address>
        <city>Larisa</city>
        <state>Thessaly</state>
        <zip>41110</zip>
        <country>Greece</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Athanasios Chalkias, MD, PhD</last_name>
      <phone>+302413502953</phone>
      <email>thanoschalkias@yahoo.gr</email>
    </contact>
    <contact_backup>
      <last_name>Varvara Boutsis</last_name>
      <phone>+302413502953</phone>
      <email>barbiebou@yahoo.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Greece</country>
  </location_countries>
  <reference>
    <citation>Sutton RM, French B, Meaney PA, Topjian AA, Parshuram CS, Edelson DP, Schexnayder S, Abella BS, Merchant RM, Bembea M, Berg RA, Nadkarni VM; American Heart Association's Get With The Guidelines-Resuscitation Investigators. Physiologic monitoring of CPR quality during adult cardiac arrest: A propensity-matched cohort study. Resuscitation. 2016 Sep;106:76-82. doi: 10.1016/j.resuscitation.2016.06.018. Epub 2016 Jun 24.</citation>
    <PMID>27350369</PMID>
  </reference>
  <reference>
    <citation>Jellinek H, Krenn H, Oczenski W, Veit F, Schwarz S, Fitzgerald RD. Influence of positive airway pressure on the pressure gradient for venous return in humans. J Appl Physiol (1985). 2000 Mar;88(3):926-32. doi: 10.1152/jappl.2000.88.3.926.</citation>
    <PMID>10710387</PMID>
  </reference>
  <reference>
    <citation>Aya HD, Cecconi M. Can (and should) the venous tone be monitored at the bedside? Curr Opin Crit Care. 2015 Jun;21(3):240-4. doi: 10.1097/MCC.0000000000000199.</citation>
    <PMID>25887298</PMID>
  </reference>
  <reference>
    <citation>Berg RA, Sutton RM, Reeder RW, Berger JT, Newth CJ, Carcillo JA, McQuillen PS, Meert KL, Yates AR, Harrison RE, Moler FW, Pollack MM, Carpenter TC, Wessel DL, Jenkins TL, Notterman DA, Holubkov R, Tamburro RF, Dean JM, Nadkarni VM; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) PICqCPR (Pediatric Intensive Care Quality of Cardio-Pulmonary Resuscitation) Investigators. Association Between Diastolic Blood Pressure During Pediatric In-Hospital Cardiopulmonary Resuscitation and Survival. Circulation. 2018 Apr 24;137(17):1784-1795. doi: 10.1161/CIRCULATIONAHA.117.032270. Epub 2017 Dec 26.</citation>
    <PMID>29279413</PMID>
  </reference>
  <reference>
    <citation>Chalkias A, Xanthos T. Timing positive-pressure ventilation during chest compression: the key to improving the thoracic pump? Eur Heart J Acute Cardiovasc Care. 2015 Feb;4(1):24-7. doi: 10.1177/2048872613516923. Epub 2013 Dec 12.</citation>
    <PMID>24381094</PMID>
  </reference>
  <reference>
    <citation>Chalkias A, Pavlopoulos F, Koutsovasilis A, d'Aloja E, Xanthos T. Airway pressure and outcome of out-of-hospital cardiac arrest: A prospective observational study. Resuscitation. 2017 Jan;110:101-106. doi: 10.1016/j.resuscitation.2016.10.023. Epub 2016 Nov 10.</citation>
    <PMID>27840003</PMID>
  </reference>
  <reference>
    <citation>Chalkias A, Arnaoutoglou E, Xanthos T. Personalized physiology-guided resuscitation in highly monitored patients with cardiac arrest-the PERSEUS resuscitation protocol. Heart Fail Rev. 2019 Jul;24(4):473-480. doi: 10.1007/s10741-019-09772-7.</citation>
    <PMID>30741366</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>June 4, 2020</study_first_submitted>
  <study_first_submitted_qc>June 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>May 8, 2023</last_update_submitted>
  <last_update_submitted_qc>May 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Thessaly</investigator_affiliation>
    <investigator_full_name>Athanasios Chalkias, MD, PhD</investigator_full_name>
    <investigator_title>Assistant Professor of Anesthesiology</investigator_title>
  </responsible_party>
  <keyword>Resuscitation</keyword>
  <keyword>Cardiac arrest</keyword>
  <keyword>Physiology-guided treatment</keyword>
  <keyword>Personalized treatment</keyword>
  <keyword>Outcome</keyword>
  <keyword>Physiology</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Arrest</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>PD may be shared with other researchers upon reasonable request</ipd_description>
  </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/NCT04428060
org study id: UTHDA-AC02
nct id: NCT04428060
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The PERSEUS protocol is a new approach to the resuscitation of highly monitored patients with
      cardiac arrest. It aims at the optimization of all the available physiological parameters and
      the full exploitation of both the "cardiac pump" and "thoracic pump'. This protocol will help
      to titrate chest compressions, ventilation, and vasopressor dosing to physiological
      parameters, increasing survival after cardiac arrest with favorable neurological outcome
BACKGROUND

      Since 2000, resuscitation guidelines remain uniform across all cardiac arrest patients,
      focusing on the delivery of chest compressions to a standardized rate and depth and
      algorithmic vasopressor dosing. Although the concept of goal-directed hemodynamic
      optimization as a treatment strategy to improve clinical outcome in critically ill patients
      has been tested since the 1980s, no human study has established that prospectively targeting
      hemodynamics during CPR improves outcomes until now. Nevertheless, individualizing
      resuscitation to the appropriate hemodynamic and ventilatory goals rather than a standard
      Bone-size-fits-all treatment seems a promising new therapeutic strategy that can be applied
      during resuscitation attempts in highly monitored patients.

      The PERSEUS protocol is a new approach to the resuscitation of highly monitored patients with
      cardiac arrest. It has been developed based on our experience and the observation that the
      most important determinant of survival is the optimization of all the available physiological
      parameters and the full exploitation of both the "cardiac pump" and "thoracic pump'.

      Physiological and pathophysiological aspects of cardiac arrest Cardiac arrest interval
      Immediately after the abrupt loss of effective blood flow, the hypotension-induced baroreflex
      withdrawal with the net increase in the vascular resistance maintains an impaired antegrade
      and pulmonary blood flow. The systemic and pulmonary blood flow continue for at least 30-60
      s, until the pressure gradient between the aorta and the right side of the heart, as well as
      between the pulmonary artery and the left atrium, has been completely dissipated, resulting
      in a rapid increase in the volume of the right ventricle and the extrapericardial component
      of the pulmonary veins. When arterial and systemic venous pressures reach equilibrium, the
      mean systemic filling pressure (Pmsf) is approximately 6-12 mmHg. The coronary blood flow
      declines to zero, but CPP remains positive because of the retrograde coronary flow. However,
      this diminishes the removal of norepinephrine from the interstitial spaces, which together
      with the formation of cardiac edema prolongs vasoconstriction and enhances myocardial
      hypoperfusion and hypoxia.

      At the same time, cerebral perfusion decreases while the damage of fatty acids of the
      neuronal cell membrane by reactive oxygen species leads to a progressive increase in membrane
      permeability and severe derangements of intracellular electrolytes, resulting in cell
      swelling and brain edema formation. This, together with venous congestion, increases
      intracranial pressure (ICP) and damages the neuropil and synaptic structures and/or contacts.

      The PERSEUS personalized physiology-guided resuscitation protocol Recognizing cardiac arrest
      in highly monitored areas can be more difficult than in other hospital areas, such as the
      ward. Considering that the vast majority of alarms from sensors are false alarms, cardiac
      arrest should be recognized and confirmed by the combined assessment of the rhythm, the
      arterial blood pressure and waveform, the abrupt decrease of ETCO2, and the loss of carotid
      pulse. Once cardiac arrest is confirmed, CPR should be initiated without delay with
      high-quality chest compressions according to the recent resuscitation guidelines. However,
      the effectiveness of chest compressions is depending on the venous return, which is
      proportional to the pressure gradient between Pmsf and CVP, and particular attention is
      needed by the rescuers to determine Pmsf within the first 5-7.5 s of cardiac arrest and prior
      to the onset of chest compressions. The Pmsf is a quantitative measurement of the patient's
      volume status and represents the tone of venous reservoir, indicating the pre-arrest
      "vasoreactivity" status of the patients. Therefore, optimizing Pmsf during CPR is paramount
      for increasing survival rates.

      During the first cycle of CPR, the resuscitation efforts must maintain a relaxation DAP of ≥
      40 mmHg (calculated at the time of full chest decompression). In patients with a lower DAP,
      administration of epinephrine or vasopressin should be based on the pre-arrest value of Pmsf
      and/or systemic vascular resistance (SVR) and is anticipated to be beneficial in those with
      Pmsf < 6 mmHg and/or SVR < 800 dynes·sec·cm-5, enhancing volume recruitment from the
      unstressed compartment and increasing the stressed volume. In all other patients, the
      vasoreactivity will be maintained for some time provided that intravascular volume and chest
      compressions are sufficient. Therefore, circulatory volume should be increased in patients
      with a pre-arrest CVP < 2 mmHg using a fluid bolus and/or the passive leg-raising maneuver.
      However, it should be noted that rapid and liberal fluid administration during CPR may lead
      to an excessive increase in RAP, aggravating venous return and CPP, especially when
      administered via a jugular or subclavian central venous catheter. At the onset of cardiac
      arrest, ventilatory parameters should be changed to tidal volume 6 ml/kg, respiratory rate 10
      min-1, I:E 1:2, PEEP 0 cm H20, and FiO2 100%. During this cycle, all other treatment efforts
      must follow current recommendations for standard CPR.

      After the onset of the second cycle of CPR, the resuscitation efforts should be continued as
      above while assessing ETCO2. As stated previously, ventilation during CPR by using currently
      recommended chest compression rates may take place entirely below functional residual
      capacity and may not provide adequate blood oxygenation due to small airway closure,
      increasing pulmonary vascular resistance and impairing gas exchange. Therefore, mean airway
      pressure should be maintained 40-45 cmH2O in patients with DAP ≥ 40 mmHg and ETCO2 < 10 mmHg
      to facilitate gas exchange. On the contrary, all patients with DAP > 40 mmHg and ETCO2 > 15
      mmHg should be assessed for hypercapnia, and if present, they should be treated by increasing
      the ventilatory rate by up to 50% (or less if necessary to maintain DAP ≥ 40 mmHg). Also,
      severe acidosis should be treated immediately because it causes vasodilatation which may
      decrease venous return and CPP.

      During the third cycle of CPR, the resuscitation efforts should be continued as above while
      assessing ScvO2, which should be maintained 65-80%. In patients with ScvO2 < 65%, transfusion
      of red blood cells should be initiated when Hb is ≤8 g/dl to improve oxygen delivery. In
      patients with Hb > 8 g/dl, a fluid bolus should be given to improve circulatory flow provided
      that DAP is maintained ≥ 40 mmHg. In patients with DAP ≥ 40 mmHg and a ScvO2 value of > 80%,
      hypothermia should be excluded and treated aggressively if present, the FiO2 should be
      decreased in case of hyperoxemia (PaO2 > 200 mmHg), and a low-dose vasodilator may be
      considered when microcirculatory shunting and loss of hemodynamic coherence between macro-
      and microcirculation can be directly assessed or possible (e.g., DAP ≥ 40 mmHg, Hb > 8 g/dl,
      PaO2 > 200 mmHg, ScvO2 > 80%, and mixed venous oxygen tension ≤ 26 mmHg (if available), with
      or without hyperlactatemia). In patients with normal ScvO2, trend cerebral oxygenation
      monitoring (near-infrared spectroscopy - NIRS) should be used because it focuses more on the
      amount of change from the pre-arrest baseline cerebral oxygenation value. Decreasing FiO2
      until PaO2 is 200 mmHg can be considered when NIRS is > 50% of the prearrest value, while
      HUP-CPR (30°) should be considered in patients with NIRS ≤ 30% of the pre-arrest value and
      signs or known increased intracranial pressure. The resuscitation efforts may be considered
      as adequate in patients who have reached the pre-defined targets and have a NIRS of 30-50% of
      the pre-arrest value, and should be continued by repeating the approach from the beginning.

      AIM

      The PERSEUS resuscitation protocol is a new approach to the resuscitation of highly monitored
      patients with cardiac arrest and may help to titrate chest compressions, ventilation, and
      vasopressor dosing to physiological parameters. The aim of this double-center study is to
      investigate if resuscitation with the PERSEUS protocol can increase survival after cardiac
      arrest with favorable neurological outcome.

      METHODS

      Design This is a prospective observational study designed in accordance with the declaration
      of Helsinki. The study will be register at Clinical Trials.gov and has been approved by the
      Institutional Review Board of the University Hospital of Larisa, under the reference number
      2670/3-2-2020.

      Patient eligibility All intubated and mechanically ventilated adult patients (≥ 18 years of
      age) with a CPR event requiring chest compressions in a highly monitored area [Operating
      Room, Intensive Care Unit (ICU), or Emergency Department] will be eligible for inclusion.
      Each patient will be allocated into two groups; patients in group A will be resuscitated with
      the PERSEUS protocol, while patients in group B will receive standard CPR according to the
      latest European Resuscitation Council guidelines on resuscitation. Random allocation will be
      carried out by a researcher who will not be involved in data collection using the sealed
      envelope technique.

      Data Collection and Monitoring Data analysis will be based on predefined data points on a
      prospective data collection form. The staff will be blinded to measurements until the end of
      the study and all data are analyzed. Clinical monitoring throughout the study will be
      performed to maximize protocol adherence, while an independent Data and Safety Monitoring
      research staff will monitor safety, ethical, and scientific aspects of the study.

      We will use the Utstein-style templates for in-hospital cardiac arrest data. Return of
      spontaneous circulation will be defined for all rhythms as the restoration of a spontaneous
      perfusing rhythm for more than 20 minutes. Survival with a favorable neurological outcome
      will be defined as a cerebral performance category (CPC) score of 1, 2 or no change from
      baseline. The CPC scoring system assesses functional outcomes among survivors of cardiac
      arrest and has been extensively validated and shown to reliably predict functional
      neurological disability.

      Data management The goal of the clinical data management plan is to provide high-quality data
      by adopting standardized procedures to minimize the number of errors and missing data, and
      consequently, to generate an accurate database for analysis. Remote monitoring is performed
      to signal early aberrant patterns, issues with consistency, credibility and other anomalies.
      Any missing and outlier data values will individually revised and completed or corrected
      whenever possible.

      Ethics and dissemination The study will be performed according to national and international
      guidelines. The present research investigation was reviewed by the IRB at the Larisa
      University Hospital and determined to be IRB exempt.

      Competing interests None declared.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: ROSC
time frame: From start of CPR until return of spontaneous circulation, assessed up to 60 minutes
description: Return of spontaneous circulation
measure: ICU length of stay
time frame: Up to 8 weeks
description: Days hospitalized in the intensive care unit
measure: Days on mechanical ventilation
time frame: Up to 8 weeks
description: How many days the patient will be mechanically ventilated
measure: Survival to hospital discharge
time frame: Up to 8 weeks
description: Dead or alive at hospital discharge with favorable neurological outcome (CPC 1 or 2)
measure: 1-month survival
time frame: At 1 month after hopsital discharge
description: Dead or alive at 1 month after hospital discharge with favorable neurological outcome (CPC 1 or 2)
measure: 3-month survival
time frame: At 3 months after hopsital discharge
description: Dead or alive at 3 months after hospital discharge with favorable neurological outcome (CPC 1 or 2)
arm group label: PERSEUS CPR
arm group type: Experimental
description: Patients will be resuscitated according to the PERSEUS protocol
arm group label: CONTROL
arm group type: Active Comparator
description: Patients will be resuscitated according to current Advanced Life Support guidelines
intervention type: Other
intervention name: PERSEUS CPR
description: Resuscitation based on patient physiology
arm group label: PERSEUS CPR
intervention type: Other
intervention name: Standard CPR
description: Resuscitation based on current guidelines
arm group label: CONTROL
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Athanasios Chalkias, MD, PhD
role: Principal Investigator
affiliation: University of Thessaly
last name: Athanasios Chalkias, MD, PhD
phone: 00302413502953
email: thanoschalkias@yahoo.gr
facility: 
status: Recruiting
contact: 
contact backup: 
country: Greece
citation: Sutton RM, French B, Meaney PA, Topjian AA, Parshuram CS, Edelson DP, Schexnayder S, Abella BS, Merchant RM, Bembea M, Berg RA, Nadkarni VM; American Heart Association's Get With The Guidelines-Resuscitation Investigators. Physiologic monitoring of CPR quality during adult cardiac arrest: A propensity-matched cohort study. Resuscitation. 2016 Sep;106:76-82. doi: 10.1016/j.resuscitation.2016.06.018. Epub 2016 Jun 24.
PMID: 27350369
citation: Jellinek H, Krenn H, Oczenski W, Veit F, Schwarz S, Fitzgerald RD. Influence of positive airway pressure on the pressure gradient for venous return in humans. J Appl Physiol (1985). 2000 Mar;88(3):926-32. doi: 10.1152/jappl.2000.88.3.926.
PMID: 10710387
citation: Aya HD, Cecconi M. Can (and should) the venous tone be monitored at the bedside? Curr Opin Crit Care. 2015 Jun;21(3):240-4. doi: 10.1097/MCC.0000000000000199.
PMID: 25887298
citation: Berg RA, Sutton RM, Reeder RW, Berger JT, Newth CJ, Carcillo JA, McQuillen PS, Meert KL, Yates AR, Harrison RE, Moler FW, Pollack MM, Carpenter TC, Wessel DL, Jenkins TL, Notterman DA, Holubkov R, Tamburro RF, Dean JM, Nadkarni VM; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) PICqCPR (Pediatric Intensive Care Quality of Cardio-Pulmonary Resuscitation) Investigators. Association Between Diastolic Blood Pressure During Pediatric In-Hospital Cardiopulmonary Resuscitation and Survival. Circulation. 2018 Apr 24;137(17):1784-1795. doi: 10.1161/CIRCULATIONAHA.117.032270. Epub 2017 Dec 26.
PMID: 29279413
citation: Chalkias A, Xanthos T. Timing positive-pressure ventilation during chest compression: the key to improving the thoracic pump? Eur Heart J Acute Cardiovasc Care. 2015 Feb;4(1):24-7. doi: 10.1177/2048872613516923. Epub 2013 Dec 12.
PMID: 24381094
citation: Chalkias A, Pavlopoulos F, Koutsovasilis A, d'Aloja E, Xanthos T. Airway pressure and outcome of out-of-hospital cardiac arrest: A prospective observational study. Resuscitation. 2017 Jan;110:101-106. doi: 10.1016/j.resuscitation.2016.10.023. Epub 2016 Nov 10.
PMID: 27840003
citation: Chalkias A, Arnaoutoglou E, Xanthos T. Personalized physiology-guided resuscitation in highly monitored patients with cardiac arrest-the PERSEUS resuscitation protocol. Heart Fail Rev. 2019 Jul;24(4):473-480. doi: 10.1007/s10741-019-09772-7.
PMID: 30741366
responsible party type: Principal Investigator
investigator affiliation: University of Thessaly
investigator full name: Athanasios Chalkias, MD, PhD
investigator title: Assistant Professor of Anesthesiology
mesh term: Heart Arrest
sharing ipd: No
ipd description: PD may be shared with other researchers upon reasonable request