<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/NCT04406350</url>
  </required_header>
  <id_info>
    <org_study_id>AOC2019-6</org_study_id>
    <nct_id>NCT04406350</nct_id>
  </id_info>
  <brief_title>Tight End-tidal Gas Control During Anesthesia to Decrease Postoperative Delirium Anesthetic Management</brief_title>
  <official_title>Feasibility Study of Isoxic/Normocapnic End-tidal Gas Control to Decrease Incidence of Postoperative Delirium (POD) During Anesthetic Management</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Manitoba</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Manitoba</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Respiratory end-tidal gas control is a fundamental of anesthetic management. The range of&#xD;
      end-tidal (ET) O2 and CO2 during the conduct of anesthesia is far outside that found in the&#xD;
      awake state. Recent work has indicated that alterations in end-tidal gases may influence the&#xD;
      incidence of postoperative delirium (POD). This study will examine the feasibility of tight&#xD;
      end-tidal gas control during anesthesia to decrease the incidence of POD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A. Background and Rationale:&#xD;
&#xD;
      Although respiratory end-tidal gas control is a fundamental principle of anesthetic&#xD;
      management, the range of end-tidal (ET) O2 and CO2 typically seen during the conduct of&#xD;
      anesthesia can significantly deviate from the awake baseline state, but has not been&#xD;
      considered as a potential contributor to POD in previous investigations. Periods of both&#xD;
      hypocapnia during mechanical ventilation and hypercapnia during the reestablishment of&#xD;
      spontaneous ventilation are common. The use of 100% oxygen during anesthesia induction and&#xD;
      emergence and maintenance of anesthesia with O2 concentrations of 50% are typical. The&#xD;
      effects of these alterations in respiratory gases have significant effects on cerebral blood&#xD;
      flow and oxygenation, which may be implicated in cognitive dysfunction. The investigators&#xD;
      plan to examine the effects of controlled alterations in ET O2 and CO2 during anaesthesia and&#xD;
      surgery on the incidence of POD.&#xD;
&#xD;
      B. Hypothesis and Study Objectives:&#xD;
&#xD;
      The investigators advance the hypothesis that ET respiratory gas control is a critical&#xD;
      management consideration during anaesthesia; a much more important consideration than&#xD;
      previously thought. Older patients appear to be at greater risk of 'intracranial steal' of&#xD;
      regional CBF with alterations in CO2 and O2. The investigators previous study confirms an&#xD;
      association between CO2 management and POD. Prior MR imaging suggests that a combination of&#xD;
      hyperoxia and hypocapnia may be particularly worrisome, a very common situation during&#xD;
      anesthesia. The investigators suggest that anesthetic management may be optimized for&#xD;
      cerebral health by attempting to maintain respiratory gases at or near the patient baseline&#xD;
      values to stabilize CBF during the conduct of anesthesia. An exception occurs during&#xD;
      neurosurgical procedures where deliberate alterations to lower ET CO2 may be required. The&#xD;
      marked CBF fluctuations as seen with controlled ET gas manipulation in our prior work imply&#xD;
      that such CBF changes can occur under anesthesia where similar changes in ET gases routinely&#xD;
      occur. The investigators propose that such large alterations in CBF and oxygenation may be a&#xD;
      contributing factor to the development of POD in susceptible individuals. Here is proposed a&#xD;
      feasibility trial of rigorous maintenance of ET gases at a patient's own baseline to study if&#xD;
      such management has an influence on the incidence of POD.&#xD;
&#xD;
      C. Methodology: Summarize study location (facility), eligibility criteria, details regarding&#xD;
      recruitment, consent, and randomization, interventions(s), covariates, data sources as&#xD;
      applicable.&#xD;
&#xD;
      Twelve patients undergoing high-risk surgeries requiring a post-operative stay will be&#xD;
      approached to participate in the study through the Pre-Anesthesia Clinic (PAC) at the HSC.&#xD;
      Witnessed informed consent will be obtained from each patient. Exclusion criteria will&#xD;
      include simultaneous planned carotid endarterectomy, carotid stenosis-if previously&#xD;
      documented, planned neurosurgical procedures, contraindications to MRI including&#xD;
      claustrophobia, expected one-lung anesthesia, and known chronic obstructive lung disease with&#xD;
      CO2 retention. Patients will be seen pre-operatively in the week prior to surgery for&#xD;
      comprehensive neuropsychological testing followed immediately by the MRI BOLD CO2 and O2&#xD;
      stress test. A trained psychometrist will administer a battery of neuropsychological tests&#xD;
      over the span of approximately 1 hour. Subsequently, the MRI BOLD stress testing will be&#xD;
      undertaken. Patients will undergo their surgery with no alterations to their anesthesia&#xD;
      management except ET CO2 at ±2.5 mm Hg of baseline and FiO2 at 0.3, post induction This will&#xD;
      be correlated to arterial blood gases to maintain arterial O2 at 125±25 mm Hg. Following&#xD;
      surgery, trained personnel blinded to pre-operative performance on all assessments will&#xD;
      conduct daily POD assessments for up to 5 post-operative days including day 0 (day of&#xD;
      surgery). Patients will be contacted via phone at least 1 month post-operatively and asked&#xD;
      about their cognition since their surgery.&#xD;
&#xD;
      Diathesis Assessments- Pre-operative Psychiatric and Neuropsychological Assessments: Upon&#xD;
      initial recruitment in PAC, patients will complete the validated Patient Health Questionnaire&#xD;
      (PHQ-9) to assess depressive symptoms and the Generalized Anxiety Disorder Scale (GAD-7) to&#xD;
      assess anxiety symptoms, and self-report on psychiatric disorder diagnoses previously made by&#xD;
      health professionals. For neuropsychological testing, attention will be assessed using Trails&#xD;
      A and Weschler Adult Intelligence Scale (WAIS)-IV Digit Span; information processing speed&#xD;
      using WAIS-IV Digit Symbol Coding; verbal memory using Hopkins Verbal Learning Test-Revised;&#xD;
      visual construction, planning and organization using Rey's Complex Figure (copy trial);&#xD;
      visual memory using Rey's Complex Figure (immediate recall trial); executive&#xD;
      functioning/processing speed using Trails B and Delis-Kaplan Executive Function System&#xD;
      (DKEFS) Color Word Interference; verbal and semantic fluency using F-A-S and Animal Fluency;&#xD;
      spatial skills using CLOX I (free draw) and II (copy); and global cognitive and mental status&#xD;
      using the Mini-Mental Status Examination (MMSE).&#xD;
&#xD;
      Pre-operative Neuroimaging and CO2 and O2 Stress Test: The CO2 and O2 stress test will be&#xD;
      conducted during neuroimaging where all participants had model-based prospective end-tidal&#xD;
      (MPET) CO2 targeting achieved by precise delivery of CO2 and O2 at a fixed concentration&#xD;
      using a sequential breathing circuit regulated by a computerized gas-blender (RespirAct™,&#xD;
      Thornhill Research Inc., Toronto, ON). This device allows precisemanipulation of end tidal&#xD;
      CO2 levels and determines patient baseline ET CO2 values under isoxic conditions and precise&#xD;
      end tidal O2 under isocapnic conditions. All MR images will be acquired using a Siemens Verio&#xD;
      3.0T MR scanner with a 12-channel phased-array head coil.&#xD;
&#xD;
      Stressor Assessments - Intra-operative Assessments: An arterial cannula will be inserted to&#xD;
      monitor blood pressure and for serial ABG determination. A baseline ABG will be drawn to&#xD;
      determine resting arterial CO2 and O2 on room air. These measures will determine the target&#xD;
      points for end-tidal gas values for the duration of the anesthesia. All patients will receive&#xD;
      a general anesthetic-either sevoflurane or desflurane as volatile agent in air:O2.&#xD;
      Immediately following induction FiO2 will be set at 0.3 and end-tidal CO2 determined based on&#xD;
      the value of the arterial CO2 and the recorded difference in the A-a CO2 gradient as measured&#xD;
      from simultaneous end-tidal CO2. For the duration of the anesthetic, including emergence the&#xD;
      end-tidal CO2 will be adjusted to no greater than ±2.5 mmHg from the determined value. If&#xD;
      end-tidal O2 is satisfactory and pulse oximetry is above 98% then the FiO2 will be unchanged.&#xD;
      If FiO2 is greater than 0.5 for greater than 15 minutes at any time the study will be&#xD;
      terminated with patient management at the discretion of the attending anesthesiologist.&#xD;
      Hemodynamics, end-tidal gas tensions (O2, CO2 and anesthetic vapour) will be recorded at 1 hz&#xD;
      using a data acquisition system and stored on a laptop computer. At the end of their surgical&#xD;
      procedure all patients will be initially monitored in the recovery room and then transferred&#xD;
      either to the surgical intensive care, or the inpatient surgical wards. The data stream will&#xD;
      be processed, collated with Excel, and transferred to SPSS for analysis.&#xD;
&#xD;
      Post-operative Assessment for Delirium: A trained blinded interviewer will conduct the CAM-S,&#xD;
      a structured 10-15 min clinical interview, to assess the presence and severity of POD. The&#xD;
      total severity score will be based on a sum score that could range from 0 through 19. The&#xD;
      investigators will report the peak post-operative severity score for each patient throughout&#xD;
      their inpatient stay and the average severity score up to 5 post-operative days (unless&#xD;
      discharged prior to 5 days). Subthreshold delirium (ST-POD) will be defined as those not&#xD;
      meeting full criteria but displaying elevated severity scores (≥5) on the POD severity long&#xD;
      form on at least 1 post-operative day.&#xD;
&#xD;
      Statistical Analyses: BOLD imaging will be processed as 1st and 2nd level analysis by SPM.&#xD;
      Second level analysis has defined cut-points for abnormal image patterns for voxel counts&#xD;
      based on an adult atlas of normal controls developed at this institution. Perioperative data&#xD;
      will be analyzed using SPSS. Bivariate correlations will examine the relationship between&#xD;
      cognitive summary scores and psychiatric severity scores as indicated by PHQ-9 and GAD-7 with&#xD;
      continuous severity POD measures. If significant results are indicated, a bivariate linear&#xD;
      regression model will be conducted followed by a model controlling for age, education, sex&#xD;
      and pre-operative baseline POD severity. The investigators will also conduct analyses of&#xD;
      variance to examine mean score differences across primary diathesis and stress factors among&#xD;
      those classified as non-POD, ST-POD, and full POD.&#xD;
&#xD;
      D. Primary Outcome:&#xD;
&#xD;
      Feasibility study of ease of end-tidal gas control of CO2 and O2 to defined targets&#xD;
      intraoperatively.&#xD;
&#xD;
      E. Secondary Outcomes:&#xD;
&#xD;
      Correlations of POD using this management approach with other outcome markers in our&#xD;
      stress-diathesis model. Ease of maintenance of this anesthetic approach. Assessment of&#xD;
      adverse outcomes.&#xD;
&#xD;
      F. Feasibility: Justify the sample size with a power analysis. If a power analysis was not&#xD;
      done, state why. For prospective studies, discuss expected duration of study of terms of&#xD;
      expected number of eligible participants, recruitment rate and attrition rate. For&#xD;
      retrospective studies, relate the sample size to the available data.&#xD;
&#xD;
      All technical aspects of this proposed study have been established, including the&#xD;
      comprehensive psychometric testing, MR imaging and high fidelity data acquisition in the&#xD;
      operating room. A knowledgeable team capable of carrying out this feasibility study is in&#xD;
      place at HSC. This proposed study is underpowered to definitively make an assessment of the&#xD;
      merits of controlled end-tidal gas control. This study will examine the feasibility of the&#xD;
      approach in 12 patients. Based on a 50% reduction of POD (perhaps optimistic, at an α of 0.05&#xD;
      and a β of 0.80 the investigators envision requiring 136 patients to truly assess the merits&#xD;
      of the approach when compared to a standardly management group. This is within the&#xD;
      feasibility of a single centre but such an estimation may be overly zealous.&#xD;
&#xD;
      G. State the expected results:&#xD;
&#xD;
      The investigators expect to demonstrate a decrease in the incidence of POD in this&#xD;
      feasibility study at 50% of that seen in our prior study (25% incidence for full POD).&#xD;
      Outcome data from this study will be used to establish a formal power analysis of POD&#xD;
      incidence to permit a more formal and comprehensive RCT based on PACT participation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">June 15, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2021</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>A pilot study to determine the feasibility of tight control of end-tidal respiratory gases during the conduct of anesthesia in major surgery.</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of post-operative delirium</measure>
    <time_frame>5 days</time_frame>
    <description>Incidence of delirium will be assessed in the Pilot Study Group as measured by the number of positive Confusion Assessment Method (CAM) and CAM-S or CAM for intensive care unit (CAM-ICU) scores, coupled with Chart Review.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Length of Hospital stay</measure>
    <time_frame>Time (days) from admission to discharge from hospital (or through study completion at one year)</time_frame>
    <description>Length of hospital stay (days) will be assessed.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>Post-Operative Confusion</condition>
  <condition>Delirium</condition>
  <condition>Anesthesia Complication</condition>
  <arm_group>
    <arm_group_label>Study group - MRI CO2 and O2 stress test</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pilot Study of Feasibility of tight control of end-tidal respiratory gases during conduct of anesthesia</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Intraoperative tight control of respiratory end-tidal gases</intervention_name>
    <description>Control of ET CO2 and ET O2 during conduct of anesthesia.</description>
    <arm_group_label>Study group - MRI CO2 and O2 stress test</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  able to provide informed consent&#xD;
&#xD;
          -  elective major surgery requiring a minimum stay of 2 days postoperatively&#xD;
&#xD;
          -  no contraindication to MRI&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  unable to provide informed consent&#xD;
&#xD;
          -  CO2 retention with Chronic Obstructive Pulmonary Disease (COPD)&#xD;
&#xD;
          -  active congestive heart failure (CHF)&#xD;
&#xD;
          -  unable to participate adequately in delirium screening including those who are blind,&#xD;
             deaf, illiterate or not fluent English or French&#xD;
&#xD;
          -  prior episode of intraoperative awareness&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>W. Alan C Mutch, MD</last_name>
    <phone>2044896549</phone>
    <email>wacmutch@shaw.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Linda Girling, BSc</last_name>
    <phone>2047871414</phone>
    <email>lgirling@exchange.hsc.mb.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Health Sciences Centre</name>
      <address>
        <city>Winnipeg</city>
        <state>Manitoba</state>
        <zip>R3A 1R9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Mutch WAC, El-Gabalawy R, Girling L, Kilborn K, Jacobsohn E. End-Tidal Hypocapnia Under Anesthesia Predicts Postoperative Delirium. Front Neurol. 2018 Aug 17;9:678. doi: 10.3389/fneur.2018.00678. eCollection 2018.</citation>
    <PMID>30174647</PMID>
  </reference>
  <reference>
    <citation>Mutch WAC, El-Gabalawy R, Ryner L, Puig J, Essig M, Kilborn K, Fidler K, Graham MR. Brain BOLD MRI O2 and CO2 stress testing: implications for perioperative neurocognitive disorder following surgery. Crit Care. 2020 Mar 4;24(1):76. doi: 10.1186/s13054-020-2800-3.</citation>
    <PMID>32131878</PMID>
  </reference>
  <reference>
    <citation>Mutch WAC, El-Gabalawy RM, Graham MR. Postoperative Delirium, Learning, and Anesthetic Neurotoxicity: Some Perspectives and Directions. Front Neurol. 2018 Mar 20;9:177. doi: 10.3389/fneur.2018.00177. eCollection 2018.</citation>
    <PMID>29615969</PMID>
  </reference>
  <reference>
    <citation>El-Gabalawy R, Patel R, Kilborn K, Blaney C, Hoban C, Ryner L, Funk D, Legaspi R, Fisher JA, Duffin J, Mikulis DJ, Mutch WAC. A Novel Stress-Diathesis Model to Predict Risk of Post-operative Delirium: Implications for Intra-operative Management. Front Aging Neurosci. 2017 Aug 18;9:274. doi: 10.3389/fnagi.2017.00274. eCollection 2017.</citation>
    <PMID>28868035</PMID>
  </reference>
  <reference>
    <citation>Mutch WAC, El-Gabalawy R. Anesthesia and postoperative delirium: the agent is a strawman - the problem is CO2. Can J Anaesth. 2017 Jun;64(6):678-680. doi: 10.1007/s12630-017-0859-3. Epub 2017 Mar 10. No abstract available.</citation>
    <PMID>28283991</PMID>
  </reference>
  <reference>
    <citation>Ellis MJ, Ryner LN, Sobczyk O, Fierstra J, Mikulis DJ, Fisher JA, Duffin J, Mutch WA. Neuroimaging Assessment of Cerebrovascular Reactivity in Concussion: Current Concepts, Methodological Considerations, and Review of the Literature. Front Neurol. 2016 Apr 29;7:61. doi: 10.3389/fneur.2016.00061. eCollection 2016.</citation>
    <PMID>27199885</PMID>
  </reference>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>February 19, 2020</study_first_submitted>
  <study_first_submitted_qc>May 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 28, 2020</study_first_posted>
  <last_update_submitted>May 27, 2020</last_update_submitted>
  <last_update_submitted_qc>May 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 28, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>anesthesia</keyword>
  <keyword>post-operative delirium</keyword>
  <keyword>MRI</keyword>
  <keyword>BOLD imaging</keyword>
  <keyword>psychometric testing</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Delirium</mesh_term>
    <mesh_term>Emergence Delirium</mesh_term>
    <mesh_term>Confusion</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/NCT04406350
org study id: AOC2019-6
nct id: NCT04406350
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Respiratory end-tidal gas control is a fundamental of anesthetic management. The range of
      end-tidal (ET) O2 and CO2 during the conduct of anesthesia is far outside that found in the
      awake state. Recent work has indicated that alterations in end-tidal gases may influence the
      incidence of postoperative delirium (POD). This study will examine the feasibility of tight
      end-tidal gas control during anesthesia to decrease the incidence of POD.
A. Background and Rationale:

      Although respiratory end-tidal gas control is a fundamental principle of anesthetic
      management, the range of end-tidal (ET) O2 and CO2 typically seen during the conduct of
      anesthesia can significantly deviate from the awake baseline state, but has not been
      considered as a potential contributor to POD in previous investigations. Periods of both
      hypocapnia during mechanical ventilation and hypercapnia during the reestablishment of
      spontaneous ventilation are common. The use of 100% oxygen during anesthesia induction and
      emergence and maintenance of anesthesia with O2 concentrations of 50% are typical. The
      effects of these alterations in respiratory gases have significant effects on cerebral blood
      flow and oxygenation, which may be implicated in cognitive dysfunction. The investigators
      plan to examine the effects of controlled alterations in ET O2 and CO2 during anaesthesia and
      surgery on the incidence of POD.

      B. Hypothesis and Study Objectives:

      The investigators advance the hypothesis that ET respiratory gas control is a critical
      management consideration during anaesthesia; a much more important consideration than
      previously thought. Older patients appear to be at greater risk of 'intracranial steal' of
      regional CBF with alterations in CO2 and O2. The investigators previous study confirms an
      association between CO2 management and POD. Prior MR imaging suggests that a combination of
      hyperoxia and hypocapnia may be particularly worrisome, a very common situation during
      anesthesia. The investigators suggest that anesthetic management may be optimized for
      cerebral health by attempting to maintain respiratory gases at or near the patient baseline
      values to stabilize CBF during the conduct of anesthesia. An exception occurs during
      neurosurgical procedures where deliberate alterations to lower ET CO2 may be required. The
      marked CBF fluctuations as seen with controlled ET gas manipulation in our prior work imply
      that such CBF changes can occur under anesthesia where similar changes in ET gases routinely
      occur. The investigators propose that such large alterations in CBF and oxygenation may be a
      contributing factor to the development of POD in susceptible individuals. Here is proposed a
      feasibility trial of rigorous maintenance of ET gases at a patient's own baseline to study if
      such management has an influence on the incidence of POD.

      C. Methodology: Summarize study location (facility), eligibility criteria, details regarding
      recruitment, consent, and randomization, interventions(s), covariates, data sources as
      applicable.

      Twelve patients undergoing high-risk surgeries requiring a post-operative stay will be
      approached to participate in the study through the Pre-Anesthesia Clinic (PAC) at the HSC.
      Witnessed informed consent will be obtained from each patient. Exclusion criteria will
      include simultaneous planned carotid endarterectomy, carotid stenosis-if previously
      documented, planned neurosurgical procedures, contraindications to MRI including
      claustrophobia, expected one-lung anesthesia, and known chronic obstructive lung disease with
      CO2 retention. Patients will be seen pre-operatively in the week prior to surgery for
      comprehensive neuropsychological testing followed immediately by the MRI BOLD CO2 and O2
      stress test. A trained psychometrist will administer a battery of neuropsychological tests
      over the span of approximately 1 hour. Subsequently, the MRI BOLD stress testing will be
      undertaken. Patients will undergo their surgery with no alterations to their anesthesia
      management except ET CO2 at ±2.5 mm Hg of baseline and FiO2 at 0.3, post induction This will
      be correlated to arterial blood gases to maintain arterial O2 at 125±25 mm Hg. Following
      surgery, trained personnel blinded to pre-operative performance on all assessments will
      conduct daily POD assessments for up to 5 post-operative days including day 0 (day of
      surgery). Patients will be contacted via phone at least 1 month post-operatively and asked
      about their cognition since their surgery.

      Diathesis Assessments- Pre-operative Psychiatric and Neuropsychological Assessments: Upon
      initial recruitment in PAC, patients will complete the validated Patient Health Questionnaire
      (PHQ-9) to assess depressive symptoms and the Generalized Anxiety Disorder Scale (GAD-7) to
      assess anxiety symptoms, and self-report on psychiatric disorder diagnoses previously made by
      health professionals. For neuropsychological testing, attention will be assessed using Trails
      A and Weschler Adult Intelligence Scale (WAIS)-IV Digit Span; information processing speed
      using WAIS-IV Digit Symbol Coding; verbal memory using Hopkins Verbal Learning Test-Revised;
      visual construction, planning and organization using Rey's Complex Figure (copy trial);
      visual memory using Rey's Complex Figure (immediate recall trial); executive
      functioning/processing speed using Trails B and Delis-Kaplan Executive Function System
      (DKEFS) Color Word Interference; verbal and semantic fluency using F-A-S and Animal Fluency;
      spatial skills using CLOX I (free draw) and II (copy); and global cognitive and mental status
      using the Mini-Mental Status Examination (MMSE).

      Pre-operative Neuroimaging and CO2 and O2 Stress Test: The CO2 and O2 stress test will be
      conducted during neuroimaging where all participants had model-based prospective end-tidal
      (MPET) CO2 targeting achieved by precise delivery of CO2 and O2 at a fixed concentration
      using a sequential breathing circuit regulated by a computerized gas-blender (RespirAct™,
      Thornhill Research Inc., Toronto, ON). This device allows precisemanipulation of end tidal
      CO2 levels and determines patient baseline ET CO2 values under isoxic conditions and precise
      end tidal O2 under isocapnic conditions. All MR images will be acquired using a Siemens Verio
      3.0T MR scanner with a 12-channel phased-array head coil.

      Stressor Assessments - Intra-operative Assessments: An arterial cannula will be inserted to
      monitor blood pressure and for serial ABG determination. A baseline ABG will be drawn to
      determine resting arterial CO2 and O2 on room air. These measures will determine the target
      points for end-tidal gas values for the duration of the anesthesia. All patients will receive
      a general anesthetic-either sevoflurane or desflurane as volatile agent in air:O2.
      Immediately following induction FiO2 will be set at 0.3 and end-tidal CO2 determined based on
      the value of the arterial CO2 and the recorded difference in the A-a CO2 gradient as measured
      from simultaneous end-tidal CO2. For the duration of the anesthetic, including emergence the
      end-tidal CO2 will be adjusted to no greater than ±2.5 mmHg from the determined value. If
      end-tidal O2 is satisfactory and pulse oximetry is above 98% then the FiO2 will be unchanged.
      If FiO2 is greater than 0.5 for greater than 15 minutes at any time the study will be
      terminated with patient management at the discretion of the attending anesthesiologist.
      Hemodynamics, end-tidal gas tensions (O2, CO2 and anesthetic vapour) will be recorded at 1 hz
      using a data acquisition system and stored on a laptop computer. At the end of their surgical
      procedure all patients will be initially monitored in the recovery room and then transferred
      either to the surgical intensive care, or the inpatient surgical wards. The data stream will
      be processed, collated with Excel, and transferred to SPSS for analysis.

      Post-operative Assessment for Delirium: A trained blinded interviewer will conduct the CAM-S,
      a structured 10-15 min clinical interview, to assess the presence and severity of POD. The
      total severity score will be based on a sum score that could range from 0 through 19. The
      investigators will report the peak post-operative severity score for each patient throughout
      their inpatient stay and the average severity score up to 5 post-operative days (unless
      discharged prior to 5 days). Subthreshold delirium (ST-POD) will be defined as those not
      meeting full criteria but displaying elevated severity scores (≥5) on the POD severity long
      form on at least 1 post-operative day.

      Statistical Analyses: BOLD imaging will be processed as 1st and 2nd level analysis by SPM.
      Second level analysis has defined cut-points for abnormal image patterns for voxel counts
      based on an adult atlas of normal controls developed at this institution. Perioperative data
      will be analyzed using SPSS. Bivariate correlations will examine the relationship between
      cognitive summary scores and psychiatric severity scores as indicated by PHQ-9 and GAD-7 with
      continuous severity POD measures. If significant results are indicated, a bivariate linear
      regression model will be conducted followed by a model controlling for age, education, sex
      and pre-operative baseline POD severity. The investigators will also conduct analyses of
      variance to examine mean score differences across primary diathesis and stress factors among
      those classified as non-POD, ST-POD, and full POD.

      D. Primary Outcome:

      Feasibility study of ease of end-tidal gas control of CO2 and O2 to defined targets
      intraoperatively.

      E. Secondary Outcomes:

      Correlations of POD using this management approach with other outcome markers in our
      stress-diathesis model. Ease of maintenance of this anesthetic approach. Assessment of
      adverse outcomes.

      F. Feasibility: Justify the sample size with a power analysis. If a power analysis was not
      done, state why. For prospective studies, discuss expected duration of study of terms of
      expected number of eligible participants, recruitment rate and attrition rate. For
      retrospective studies, relate the sample size to the available data.

      All technical aspects of this proposed study have been established, including the
      comprehensive psychometric testing, MR imaging and high fidelity data acquisition in the
      operating room. A knowledgeable team capable of carrying out this feasibility study is in
      place at HSC. This proposed study is underpowered to definitively make an assessment of the
      merits of controlled end-tidal gas control. This study will examine the feasibility of the
      approach in 12 patients. Based on a 50% reduction of POD (perhaps optimistic, at an α of 0.05
      and a β of 0.80 the investigators envision requiring 136 patients to truly assess the merits
      of the approach when compared to a standardly management group. This is within the
      feasibility of a single centre but such an estimation may be overly zealous.

      G. State the expected results:

      The investigators expect to demonstrate a decrease in the incidence of POD in this
      feasibility study at 50% of that seen in our prior study (25% incidence for full POD).
      Outcome data from this study will be used to establish a formal power analysis of POD
      incidence to permit a more formal and comprehensive RCT based on PACT participation.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: A pilot study to determine the feasibility of tight control of end-tidal respiratory gases during the conduct of anesthesia in major surgery.
primary purpose: Diagnostic
masking: None (Open Label)
measure: Incidence of post-operative delirium
time frame: 5 days
description: Incidence of delirium will be assessed in the Pilot Study Group as measured by the number of positive Confusion Assessment Method (CAM) and CAM-S or CAM for intensive care unit (CAM-ICU) scores, coupled with Chart Review.
measure: Length of Hospital stay
time frame: Time (days) from admission to discharge from hospital (or through study completion at one year)
description: Length of hospital stay (days) will be assessed.
arm group label: Study group - MRI CO2 and O2 stress test
arm group type: Experimental
description: Pilot Study of Feasibility of tight control of end-tidal respiratory gases during conduct of anesthesia
intervention type: Procedure
intervention name: Intraoperative tight control of respiratory end-tidal gases
description: Control of ET CO2 and ET O2 during conduct of anesthesia.
arm group label: Study group - MRI CO2 and O2 stress test
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: W. Alan C Mutch, MD
phone: 2044896549
email: wacmutch@shaw.ca
last name: Linda Girling, BSc
phone: 2047871414
email: lgirling@exchange.hsc.mb.ca
facility: 
country: Canada
citation: Mutch WAC, El-Gabalawy R, Girling L, Kilborn K, Jacobsohn E. End-Tidal Hypocapnia Under Anesthesia Predicts Postoperative Delirium. Front Neurol. 2018 Aug 17;9:678. doi: 10.3389/fneur.2018.00678. eCollection 2018.
PMID: 30174647
citation: Mutch WAC, El-Gabalawy R, Ryner L, Puig J, Essig M, Kilborn K, Fidler K, Graham MR. Brain BOLD MRI O2 and CO2 stress testing: implications for perioperative neurocognitive disorder following surgery. Crit Care. 2020 Mar 4;24(1):76. doi: 10.1186/s13054-020-2800-3.
PMID: 32131878
citation: Mutch WAC, El-Gabalawy RM, Graham MR. Postoperative Delirium, Learning, and Anesthetic Neurotoxicity: Some Perspectives and Directions. Front Neurol. 2018 Mar 20;9:177. doi: 10.3389/fneur.2018.00177. eCollection 2018.
PMID: 29615969
citation: El-Gabalawy R, Patel R, Kilborn K, Blaney C, Hoban C, Ryner L, Funk D, Legaspi R, Fisher JA, Duffin J, Mikulis DJ, Mutch WAC. A Novel Stress-Diathesis Model to Predict Risk of Post-operative Delirium: Implications for Intra-operative Management. Front Aging Neurosci. 2017 Aug 18;9:274. doi: 10.3389/fnagi.2017.00274. eCollection 2017.
PMID: 28868035
citation: Mutch WAC, El-Gabalawy R. Anesthesia and postoperative delirium: the agent is a strawman - the problem is CO2. Can J Anaesth. 2017 Jun;64(6):678-680. doi: 10.1007/s12630-017-0859-3. Epub 2017 Mar 10. No abstract available.
PMID: 28283991
citation: Ellis MJ, Ryner LN, Sobczyk O, Fierstra J, Mikulis DJ, Fisher JA, Duffin J, Mutch WA. Neuroimaging Assessment of Cerebrovascular Reactivity in Concussion: Current Concepts, Methodological Considerations, and Review of the Literature. Front Neurol. 2016 Apr 29;7:61. doi: 10.3389/fneur.2016.00061. eCollection 2016.
PMID: 27199885
responsible party type: Sponsor
mesh term: Delirium
mesh term: Emergence Delirium
mesh term: Confusion
sharing ipd: Undecided