<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/NCT02185885</url>
  </required_header>
  <id_info>
    <org_study_id>H-3-2013-110</org_study_id>
    <secondary_id>E-22329-01</secondary_id>
    <secondary_id>4142, PPCI</secondary_id>
    <nct_id>NCT02185885</nct_id>
  </id_info>
  <brief_title>Perfusion Pressure Cerebral Infarction Trial (PPCI)</brief_title>
  <acronym>PPCI</acronym>
  <official_title>The Importance of Mean Arterial Pressure During Cardiopulmonary Bypass to Prevent Cerebral Complications After Cardiac Surgery - a Randomised Clinical Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Danish Heart Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Rigshospitalet, Denmark</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      STUDY HYPOTHESIS&#xD;
&#xD;
      In cardiac surgery the volume of perioperative cerebral infarctions can be reduced by&#xD;
      increasing mean arterial pressure (MAP) during the cardiopulmonary bypass procedure.&#xD;
&#xD;
      BRIEF STUDY SUMMARY&#xD;
&#xD;
      Heart surgery using cardiopulmonary bypass (CPB) can be complicated by injury to the brain.&#xD;
      Previous studies using brain scans have reported small stroke-like lesions in up to 51% of&#xD;
      patients after cardiac surgery. However, only 1-6 % of patients have permanent symptoms of&#xD;
      severe brain damage.&#xD;
&#xD;
      The majority of brain lesions seem to be caused by particulate matter (emboli) that wedge in&#xD;
      blood vessels of the brain thereby compromising flow. In addition, insufficient blood flow to&#xD;
      areas of the brain supplied by narrowed, calcified vessels may contribute. MAP during CPB&#xD;
      usually stabilizes below the lower limit of cerebral autoregulation, which is accepted since&#xD;
      sufficient total blood flow is guaranteed during CPB.&#xD;
&#xD;
      The aim of the PPCI trial is to investigate if increased MAP during CPB can prevent or reduce&#xD;
      the extent of brain injury after cardiac surgery. A beneficial effect could result from&#xD;
      reduced embolic injury through increased blood flow in collateral vessels and/or by increased&#xD;
      blood flow in calcified arteries.&#xD;
&#xD;
      180 patients scheduled for cardiac surgery will be randomly allocated to increased MAP (70-80&#xD;
      mm Hg) or 'usual practice' (typically 45-50 mm Hg) during CPB, whereas CPB blood flow is&#xD;
      intended equal and fixed in the two groups. Patients are examined before and 3-6 days after&#xD;
      surgery with magnetic resonance imaging (MRI) brain scans, mental tests and by blood borne&#xD;
      markers of brain injury.&#xD;
&#xD;
      If higher MAP during CPB is beneficial, a change of practice can easily be implemented in the&#xD;
      clinical routine.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      TRIAL DESIGN&#xD;
&#xD;
      The PPCI trial is a randomized, controlled, outcomes assessor and patient blinded,&#xD;
      single-center superiority trial with two parallel groups in a 1:1 allocation ratio. The&#xD;
      randomization will be stratified according to age (stratum 1 &lt; 70 years; stratum 2 ≥ 70&#xD;
      years) and type of surgery (stratum 1 - surgery involving the aortic and/or mitral valve;&#xD;
      stratum 2 - surgery not involving these valves).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2014</start_date>
  <completion_date type="Actual">April 2016</completion_date>
  <primary_completion_date type="Actual">January 2016</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>Prevention</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Total volume of new ischemic cerebral lesions</measure>
    <time_frame>6 days</time_frame>
    <description>The total volume of new ischemic cerebral lesions (sum in mL) assessed by diffusion-weighed-magnetic resonance imaging conducted preoperatively and again once postoperatively on day 3 to 6.&#xD;
The analysis will be adjusted for the randomization stratification variables age and type of surgery.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Total number of new ischemic cerebral lesions</measure>
    <time_frame>6 days</time_frame>
    <description>The total number of new ischemic cerebral lesions (sum in mL) assessed by diffusion-weighed-magnetic resonance imaging conducted preoperatively and again once postoperatively on day 3 to 6.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Magnetic resonance spectroscopy - change from baseline N-acetylaspartate-creatine (NAA/Cr) ratio at day 6</measure>
    <time_frame>6 days</time_frame>
    <description>Diffuse cerebral injury is investigated using Single-Voxel Magnetic Resonance Spectroscopy (MRS) in grey and white cerebral matter and expressed as the difference in N-acetylaspartate-creatine (NAA/Cr) ratio between a scan conducted preoperatively and one conducted postoperatively on day 3 to 6.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Magnetic resonance spectroscopy - change from baseline MRS Choline-creatine (Cho/Cr ratio) at day 6</measure>
    <time_frame>6 days</time_frame>
    <description>Diffuse cerebral injury is investigated using Single-Voxel Magnetic Resonance Spectroscopy (MRS) in grey and white cerebral matter and expressed as the difference in Choline-creatine (Cho/Cr ratio) between a scan conducted preoperatively and one conducted postoperatively on day 3 to 6.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative cognitive dysfunction (POCD) - change from baseline neuropsychological test performance at day 5-8</measure>
    <time_frame>5-8 days</time_frame>
    <description>The presence of cognitive dysfunction is evaluated preoperatively and on day 5-8 using the following collection of specific tests each time: &quot;Visual Verbal Learning test&quot;, &quot;Concept Shifting test&quot;, &quot;Stroop Colour Word Interference test&quot; and &quot;Letter Digit Coding test&quot;.&#xD;
Cognitive dysfunction is defined as a deterioration corresponding to a Z-score &gt; 2 (as defined by the ISPOCD group).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative cognitive dysfunction (POCD) - change from baseline neuropsychological test performance at 3 months</measure>
    <time_frame>3 months</time_frame>
    <description>The presence of cognitive dysfunction is evaluated preoperatively and 3 months postoperatively using the following collection of specific tests each time: &quot;Visual Verbal Learning test&quot;, &quot;Concept Shifting test&quot;, &quot;Stroop Colour Word Interference test&quot; and &quot;Letter Digit Coding test&quot;.&#xD;
Cognitive dysfunction is defined as a deterioration corresponding to a Z-score &gt; 2 (as defined by the ISPOCD group).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak value of biochemical markers of brain injury</measure>
    <time_frame>Prior to surgery on day 1 and 24 hours, 48 hours and 6 days after surgery</time_frame>
    <description>Blood samples will be drawn at 4 different time points during the admission. Serum concentration and time course of the following markers of brain injury will be assessed: Phosphorylated Neurofilament Heavy Protein (pNfH), Glial Fibrillary Acidic Protein (GFAP), Matrix Metallopeptidase 9 (MMP-9) and Ubiquitin C-terminal Hydrolase 1 (UCH-L1).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Near Infrared Spectroscopy (NIRS) - lowest value</measure>
    <time_frame>End of surgery</time_frame>
    <description>Near Infrared Spectroscopy (NIRS) NIRS values from the right and left frontal lobes of the brain will be continuously monitored during the intraoperative period and saved for later analysis. The NIRS monitor will be hidden and muted during the procedure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Near Infrared Spectroscopy (NIRS) - total time below 25% of the baseline value on right and left side</measure>
    <time_frame>End of surgery</time_frame>
    <description>Near Infrared Spectroscopy (NIRS) NIRS values from the right and left frontal lobes of the brain will be continuously monitored during the intraoperative period and saved for later analysis. The NIRS monitor will be hidden and muted during the procedure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline performance at neurological examination day 6</measure>
    <time_frame>6 days</time_frame>
    <description>New neurological deficits are assessed by performing an objective, clinical neurological examination.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>GAMPT BCC200 count</measure>
    <time_frame>End of cardiopulmonary bypass procedure</time_frame>
    <description>The GAMPT BCC200 is integrated into the heart-lung-machine (HLM), and through the use of ultrasound Doppler techniques, detection of gaseous micro-emboli (GME, volume between 5-500 µl) is enabled. The system can be used to quantify the GME that pass from the HLM into the bloodstream of the patient.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">197</enrollment>
  <condition>Embolic Stroke</condition>
  <condition>Postoperative Cognitive Dysfunction</condition>
  <arm_group>
    <arm_group_label>Increased bloodpressure during CPB</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The cardiopulmonary bypass (CPB) procedure is conducted according to department guidelines with the modification that MAP is kept between 70 and 80 mm Hg. This is achieved by refract intravenous doses of phenylephrine to a total maximum of 2.0 mg, and after that continuous intravenous infusion of norepinephrine up to 0.4 μg/kg/min if necessary.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Regular bloodpressure during CPB</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The cardiopulmonary bypass (CPB) procedure is conducted in accordance with departmental guidelines, where MAP is sought to be ≥ 45 mm Hg. This is achieved by refract intravenous doses of phenylephrine to a total maximum of 2.0 mg, and after that continuous intravenous infusion of norepinephrine up to 0.4 μg/kg/min if necessary.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Increased bloodpressure during CPB.</intervention_name>
    <arm_group_label>Increased bloodpressure during CPB</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥ 18 years of age.&#xD;
&#xD;
          -  scheduled elective or subacute cardiac surgery with the use of CPB.&#xD;
&#xD;
          -  type of surgery either coronary artery bypass grafting (CABG) and/or heart valve&#xD;
             surgery (provided that the valve prosthesis used is MRI compatible).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  a history of stroke.&#xD;
&#xD;
          -  a history of reversible ischemic deficits (duration of symptoms 24-72 hours)&#xD;
&#xD;
          -  a history of transitory ischemic attacks (duration of symptoms &lt; 24 hours)&#xD;
&#xD;
          -  diagnosis of neurodegenerative disorders such as Alzheimers, Multiple Sclerosis etc.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jens C. Nilsson, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rigshospitalet, Denmark</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hanne B. Ravn, MD, DMSc</last_name>
    <role>Study Chair</role>
    <affiliation>Rigshospitalet, Denmark</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Cardiothoracic Surgery 2152 and Department of Cardiothoracic Anesthesiology 4142, Rigshospitalet / Copenhagen University Hospital</name>
      <address>
        <city>Copenhagen</city>
        <zip>DK-2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Biedler A, van Beem H, Fraidakis O, Silverstein JH, Beneken JE, Gravenstein JS. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998 Mar 21;351(9106):857-61. doi: 10.1016/s0140-6736(97)07382-0. Erratum In: Lancet 1998 Jun 6;351(9117):1742.</citation>
    <PMID>9525362</PMID>
  </reference>
  <verification_date>April 2016</verification_date>
  <study_first_submitted>July 7, 2014</study_first_submitted>
  <study_first_submitted_qc>July 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 10, 2014</study_first_posted>
  <last_update_submitted>April 8, 2016</last_update_submitted>
  <last_update_submitted_qc>April 8, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 11, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Jens C. Nilsson</investigator_full_name>
    <investigator_title>Consultant, MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Ischemic stroke</keyword>
  <keyword>Embolic stroke</keyword>
  <keyword>Postoperative Cognitive Dysfunction</keyword>
  <keyword>Cardiac Bypass Surgery</keyword>
  <keyword>Cardiac Anaesthesia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Embolic Stroke</mesh_term>
    <mesh_term>Postoperative Cognitive Complications</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <!-- 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/NCT02185885
org study id: H-3-2013-110
secondary id: E-22329-01
secondary id: 4142, PPCI
nct id: NCT02185885
lead sponsor: 
collaborator: 
has dmc: No
STUDY HYPOTHESIS

      In cardiac surgery the volume of perioperative cerebral infarctions can be reduced by
      increasing mean arterial pressure (MAP) during the cardiopulmonary bypass procedure.

      BRIEF STUDY SUMMARY

      Heart surgery using cardiopulmonary bypass (CPB) can be complicated by injury to the brain.
      Previous studies using brain scans have reported small stroke-like lesions in up to 51% of
      patients after cardiac surgery. However, only 1-6 % of patients have permanent symptoms of
      severe brain damage.

      The majority of brain lesions seem to be caused by particulate matter (emboli) that wedge in
      blood vessels of the brain thereby compromising flow. In addition, insufficient blood flow to
      areas of the brain supplied by narrowed, calcified vessels may contribute. MAP during CPB
      usually stabilizes below the lower limit of cerebral autoregulation, which is accepted since
      sufficient total blood flow is guaranteed during CPB.

      The aim of the PPCI trial is to investigate if increased MAP during CPB can prevent or reduce
      the extent of brain injury after cardiac surgery. A beneficial effect could result from
      reduced embolic injury through increased blood flow in collateral vessels and/or by increased
      blood flow in calcified arteries.

      180 patients scheduled for cardiac surgery will be randomly allocated to increased MAP (70-80
      mm Hg) or 'usual practice' (typically 45-50 mm Hg) during CPB, whereas CPB blood flow is
      intended equal and fixed in the two groups. Patients are examined before and 3-6 days after
      surgery with magnetic resonance imaging (MRI) brain scans, mental tests and by blood borne
      markers of brain injury.

      If higher MAP during CPB is beneficial, a change of practice can easily be implemented in the
      clinical routine.
TRIAL DESIGN

      The PPCI trial is a randomized, controlled, outcomes assessor and patient blinded,
      single-center superiority trial with two parallel groups in a 1:1 allocation ratio. The
      randomization will be stratified according to age (stratum 1 < 70 years; stratum 2 ≥ 70
      years) and type of surgery (stratum 1 - surgery involving the aortic and/or mitral valve;
      stratum 2 - surgery not involving these valves).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Outcomes Assessor)
measure: Total volume of new ischemic cerebral lesions
time frame: 6 days
description: The total volume of new ischemic cerebral lesions (sum in mL) assessed by diffusion-weighed-magnetic resonance imaging conducted preoperatively and again once postoperatively on day 3 to 6.
The analysis will be adjusted for the randomization stratification variables age and type of surgery.
measure: Total number of new ischemic cerebral lesions
time frame: 6 days
description: The total number of new ischemic cerebral lesions (sum in mL) assessed by diffusion-weighed-magnetic resonance imaging conducted preoperatively and again once postoperatively on day 3 to 6.
measure: Magnetic resonance spectroscopy - change from baseline N-acetylaspartate-creatine (NAA/Cr) ratio at day 6
time frame: 6 days
description: Diffuse cerebral injury is investigated using Single-Voxel Magnetic Resonance Spectroscopy (MRS) in grey and white cerebral matter and expressed as the difference in N-acetylaspartate-creatine (NAA/Cr) ratio between a scan conducted preoperatively and one conducted postoperatively on day 3 to 6.
measure: Magnetic resonance spectroscopy - change from baseline MRS Choline-creatine (Cho/Cr ratio) at day 6
time frame: 6 days
description: Diffuse cerebral injury is investigated using Single-Voxel Magnetic Resonance Spectroscopy (MRS) in grey and white cerebral matter and expressed as the difference in Choline-creatine (Cho/Cr ratio) between a scan conducted preoperatively and one conducted postoperatively on day 3 to 6.
measure: Postoperative cognitive dysfunction (POCD) - change from baseline neuropsychological test performance at day 5-8
time frame: 5-8 days
description: The presence of cognitive dysfunction is evaluated preoperatively and on day 5-8 using the following collection of specific tests each time: "Visual Verbal Learning test", "Concept Shifting test", "Stroop Colour Word Interference test" and "Letter Digit Coding test".
Cognitive dysfunction is defined as a deterioration corresponding to a Z-score > 2 (as defined by the ISPOCD group).
measure: Postoperative cognitive dysfunction (POCD) - change from baseline neuropsychological test performance at 3 months
time frame: 3 months
description: The presence of cognitive dysfunction is evaluated preoperatively and 3 months postoperatively using the following collection of specific tests each time: "Visual Verbal Learning test", "Concept Shifting test", "Stroop Colour Word Interference test" and "Letter Digit Coding test".
Cognitive dysfunction is defined as a deterioration corresponding to a Z-score > 2 (as defined by the ISPOCD group).
measure: Peak value of biochemical markers of brain injury
time frame: Prior to surgery on day 1 and 24 hours, 48 hours and 6 days after surgery
description: Blood samples will be drawn at 4 different time points during the admission. Serum concentration and time course of the following markers of brain injury will be assessed: Phosphorylated Neurofilament Heavy Protein (pNfH), Glial Fibrillary Acidic Protein (GFAP), Matrix Metallopeptidase 9 (MMP-9) and Ubiquitin C-terminal Hydrolase 1 (UCH-L1).
measure: Near Infrared Spectroscopy (NIRS) - lowest value
time frame: End of surgery
description: Near Infrared Spectroscopy (NIRS) NIRS values from the right and left frontal lobes of the brain will be continuously monitored during the intraoperative period and saved for later analysis. The NIRS monitor will be hidden and muted during the procedure.
measure: Near Infrared Spectroscopy (NIRS) - total time below 25% of the baseline value on right and left side
time frame: End of surgery
description: Near Infrared Spectroscopy (NIRS) NIRS values from the right and left frontal lobes of the brain will be continuously monitored during the intraoperative period and saved for later analysis. The NIRS monitor will be hidden and muted during the procedure.
measure: Change from baseline performance at neurological examination day 6
time frame: 6 days
description: New neurological deficits are assessed by performing an objective, clinical neurological examination.
measure: GAMPT BCC200 count
time frame: End of cardiopulmonary bypass procedure
description: The GAMPT BCC200 is integrated into the heart-lung-machine (HLM), and through the use of ultrasound Doppler techniques, detection of gaseous micro-emboli (GME, volume between 5-500 µl) is enabled. The system can be used to quantify the GME that pass from the HLM into the bloodstream of the patient.
arm group label: Increased bloodpressure during CPB
arm group type: Experimental
description: The cardiopulmonary bypass (CPB) procedure is conducted according to department guidelines with the modification that MAP is kept between 70 and 80 mm Hg. This is achieved by refract intravenous doses of phenylephrine to a total maximum of 2.0 mg, and after that continuous intravenous infusion of norepinephrine up to 0.4 μg/kg/min if necessary.
arm group label: Regular bloodpressure during CPB
arm group type: No Intervention
description: The cardiopulmonary bypass (CPB) procedure is conducted in accordance with departmental guidelines, where MAP is sought to be ≥ 45 mm Hg. This is achieved by refract intravenous doses of phenylephrine to a total maximum of 2.0 mg, and after that continuous intravenous infusion of norepinephrine up to 0.4 μg/kg/min if necessary.
intervention type: Procedure
intervention name: Increased bloodpressure during CPB.
arm group label: Increased bloodpressure during CPB
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jens C. Nilsson, MD, PhD
role: Principal Investigator
affiliation: Rigshospitalet, Denmark
last name: Hanne B. Ravn, MD, DMSc
role: Study Chair
affiliation: Rigshospitalet, Denmark
facility: 
country: Denmark
citation: Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Biedler A, van Beem H, Fraidakis O, Silverstein JH, Beneken JE, Gravenstein JS. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998 Mar 21;351(9106):857-61. doi: 10.1016/s0140-6736(97)07382-0. Erratum In: Lancet 1998 Jun 6;351(9117):1742.
PMID: 9525362
responsible party type: Principal Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Jens C. Nilsson
investigator title: Consultant, MD, PhD
mesh term: Embolic Stroke
mesh term: Postoperative Cognitive Complications
mesh term: Cognitive Dysfunction