<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/NCT01661907</url>
  </required_header>
  <id_info>
    <org_study_id>PUCRP201101</org_study_id>
    <secondary_id>ChiCTR-TRC-09000543</secondary_id>
    <nct_id>NCT01661907</nct_id>
  </id_info>
  <brief_title>Anesthesia-analgesia Methods and Postoperative Delirium</brief_title>
  <official_title>Effects of Two Different Anesthesia-analgesia Methods on the Incidence of Postoperative Delirium: a Multicenter, Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Peking University First Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Peking University People's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Peking University Third Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Beijing Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Beijing Shijitan Hospital, Capital Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Peking University First Hospital</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>
      Postoperative delirium is a common complication in elderly patients after surgery. Its&#xD;
      occurrence is associated with worse outcomes. The pathophysiology of delirium remains poorly&#xD;
      understood. However, an universal phenomenon is that delirium frequently occurs in elderly&#xD;
      patients after major complicated surgery, but is rarely seen after minor ambulatory surgery&#xD;
      (such as cataract surgery). This indicates that stress response produced by surgery might&#xD;
      have an important role in the pathogenesis of delirium. It has been reported that, when&#xD;
      compared with general anesthesia and postoperative intravenous analgesia, neuraxial&#xD;
      anesthesia and analgesia reduced the occurrence of postoperative complications and mortality&#xD;
      in high risk patients. Combined epidural-general anesthesia is frequently used in clinical&#xD;
      practice. This anesthetic method provides advantages of both epidural and general anesthesia,&#xD;
      i.e. it blocks the afferent pathway of nociceptive stimulus by neuraxial blockade during and&#xD;
      after surgery, and allows patients to endure long-duration surgery without any awareness. The&#xD;
      investigators hypothesize that combined epidural-general anesthesia and postoperative&#xD;
      epidural analgesia can decrease the incidence of delirium in elderly patients after major&#xD;
      surgery when compared with general anesthesia alone and postoperative intravenous analgesia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Delirium is an acutely occurred and transient mental syndrome characterized by global&#xD;
      impairment of cognitive functions, reduced level of consciousness, abnormalities of&#xD;
      attention, increased or decreased psychomotor activity, and disordered sleep-wake cycle.&#xD;
      Postoperative delirium is a common complication in elderly patients after surgery. Dyer et al&#xD;
      reviewed 80 primary studies and found that the mean incidence of postoperative delirium is&#xD;
      about 36.8% (range 0%-73.5%) after surgery. It occurs in up to 80% of patients in the&#xD;
      intensive care unit (ICU). Our recent studies found that delirium occurred in 51.0% of&#xD;
      patients after cardiac surgery and in 44.5% of patients after non-cardiac surgery.&#xD;
&#xD;
      The occurrence of postoperative delirium is associated with worse outcomes. Studies showed&#xD;
      that delirious patients have prolonged ICU stay, increased incidence of complications,&#xD;
      prolonged hospitalization, high mortality rate, and increased health care costs. Delirium is&#xD;
      also associated with increased risk of long-term cognitive decline and poor quality of life.&#xD;
      A recent follow-up study (mean follow-up time 27.9 ± 3.1 months) by our research group found&#xD;
      that, after adjusting factors such as age, occurrence of postoperative complications, and&#xD;
      stage of cancer, etc, the occurrence of postoperative delirium still remained an independent&#xD;
      predictor of long-term mortality.&#xD;
&#xD;
      The pathophysiology of delirium remains poorly understood. An universal phenomenon is that&#xD;
      delirium frequently occurs in elderly patients after major complicated surgery, but is rarely&#xD;
      seen after minor ambulatory surgery (such as cataract surgery). Studies also found that&#xD;
      postoperative pain is an independent risk factor of delirium, whereas effective pain relief&#xD;
      may help to reduce the incidence of delirium. Our recent studies showed that high serum&#xD;
      cortisol level is an independent risk factor of postoperative delirium. In addition,&#xD;
      inflammatory response may also contribute to the pathogenesis of delirium. Trauma, pain,&#xD;
      cortisol secretion and inflammation are all important components of surgical stress response.&#xD;
      The above results indicated that stress response produced by surgery might have an important&#xD;
      role in the pathogenesis of delirium.&#xD;
&#xD;
      Previous studies demonstrated that, when compared with general anesthesia, neuraxial&#xD;
      anesthesia attenuates the hypersecretion of cortisol, and decreases the intensity of&#xD;
      inflammatory response more effectively after surgery. And epidural analgesia provides better&#xD;
      postoperative pain relief than intravenous analgesia. It was also reported that, when&#xD;
      compared with general anesthesia and intravenous analgesia, neuraxial anesthesia and&#xD;
      analgesia reduces the occurrence of postoperative complications and mortality in high risk&#xD;
      patients. Combined epidural-general anesthesia is frequently used in clinical practice, and&#xD;
      is performed in about 1/4 of patients undergoing surgery in the applicant's hospital.&#xD;
      Theoretically, this anesthetic method provides advantages of both epidural and general&#xD;
      anesthesia, i.e. it blocks the afferent pathway of nociceptive stimulus by neuraxial blockade&#xD;
      during and after surgery, and allow patients to endure long-duration complicated surgeries&#xD;
      without any awareness. However, there is no evidence whether combined epidural-general&#xD;
      anesthesia/postoperative epidural analgesia can decrease the incidence of postoperative&#xD;
      delirium in elderly patients undergoing major surgery.&#xD;
&#xD;
      The objective of the study is to compare the effects of combined epidural-general&#xD;
      anesthesia/postoperative epidural analgesia and general anesthesia/postoperative intravenous&#xD;
      analgesia on the incidence of postoperative delirium in elderly patients undergoing major&#xD;
      noncardiac surgery.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 21, 2011</start_date>
  <completion_date type="Actual">June 24, 2015</completion_date>
  <primary_completion_date type="Actual">May 25, 2015</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>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of postoperative delirium</measure>
    <time_frame>During the first 7 days after surgery.</time_frame>
    <description>Patients will be visited twice daily during the first seven days after surgery (between 08:00 h and 10:00 h, and between 18:00 h and 20:00 h). Delirium will be assessed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). The incidence is calculated as percentage of patients who develope any episode of delirium during that period.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Intensive care unit (ICU) admission after surgery</measure>
    <time_frame>During the day of surgery.</time_frame>
    <description>The proportion of patients admitted to the ICU after surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>APACHE II score at ICU admission</measure>
    <time_frame>Within 24 hours after surgery.</time_frame>
    <description>For patients admitted to the ICU after surgery, the worst Acute Physiology and Chronic Health Evaluation II (APACHE II) score within 24 h will be recorded.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The percentage of ICU admission with endotracheal intubation</measure>
    <time_frame>During the day of surgery.</time_frame>
    <description>The percentage of ICU admission with endotracheal intubation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The duration of Mechanical Ventilation in ICU</measure>
    <time_frame>Up to 30 days after surgery.</time_frame>
    <description>For patients admitted to the ICU after surgery, the duration of mechanical ventilation (for those with endotracheal tubes) will be recorded.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Length of ICU stay</measure>
    <time_frame>Up to 30 days after surgery.</time_frame>
    <description>For patients admitted to the ICU after surgery, the length of ICU stay will be recorded.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to the first onset of delirium</measure>
    <time_frame>Up to 7 days after surgery.</time_frame>
    <description>Patients will be visited twice daily during the first seven days after surgery (between 08:00 h and 10:00 h, and between 18:00 h and 20:00 h). Delirium will be assessed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to fluid/food intake</measure>
    <time_frame>Up to 30 days after surgery.</time_frame>
    <description>Patients will be followed-up until 30 days after surgery and time to fluid and food intake after surgery will be recorded.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of stay in hospital after surgery</measure>
    <time_frame>Up to 30 days after surgery.</time_frame>
    <description>Patients will be followed-up until 30 days after surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause 30-day mortality</measure>
    <time_frame>Within the first 30 days after surgery.</time_frame>
    <description>All-cause 30-day mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-delirium complications within 30 days after surgery surgery</measure>
    <time_frame>Within the first 30 days after surgery.</time_frame>
    <description>Defined as newly occurred medical conditions other than delirium that are harmful to patients' postoperative recovery and required therapeutic intervention (i.e., grade II or higher on the Clavien-Dindo classification).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The intensity of postoperative pain</measure>
    <time_frame>During the first 3 postoperative days.</time_frame>
    <description>The intensity of postoperative pain both at rest and with movement will be evaluated twice daily at the same time of delirium assessment (between 08:00 h and 10:00 h, and between 18:00 h and 20:00 h) with the numeric rating scale (NRS, an 11-point scale where 0=no pain and 10=the worst pain).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Serum cortisol concentration (substudy)</measure>
    <time_frame>Blood samples will be collected from selected patients before surgery, and in the morning of the 1st and 3rd day after surgery.</time_frame>
    <description>Serum cortisol concentration (substudy)</description>
  </other_outcome>
  <other_outcome>
    <measure>Serum IL-6 concentration (substudy)</measure>
    <time_frame>Blood samples will be collected from selected patients before surgery, and in the morning of the 1st and 3rd day after surgery.</time_frame>
    <description>Serum IL-6 concentration (substudy)</description>
  </other_outcome>
  <other_outcome>
    <measure>Serum IL-8 concentration (substudy)</measure>
    <time_frame>Blood samples will be collected from selected patients before surgery, and in the morning of the 1st and 3rd day after surgery.</time_frame>
    <description>Serum IL-8 concentration (substudy)</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1800</enrollment>
  <condition>Elderly</condition>
  <condition>Epidural Anesthesia</condition>
  <condition>General Anesthesia</condition>
  <condition>Major Surgery</condition>
  <condition>Postoperative Delirium</condition>
  <arm_group>
    <arm_group_label>Combined Epi-GA/PCEA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients assigned to this group (experimental group) will receive combined epidural-general anesthesia (combined Epi-GA) and patient-controlled epidural analgesia (PCEA).&#xD;
An epidural catheter will be placed before anesthesia induction. General anesthesia will be induced and maintained in the same manner as in the control group, with the addition of a continuous infusion or intermittent boluses of 0.375%-0.5% ropivacaine given through the epidural catheter for analgesia maintenance. Patient-controlled epidural analgesia will be provided for postoperative analgesia (established with 0.12% ropivacaine and 0.5 μg/mL sufentanil in 250 mL normal saline, programmed to deliver a 2-mL bolus with a lockout interval of 20 minutes and a background infusion of 4 mL/hr).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>GA/PCIA</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients assigned to this group (control group) will receive general anesthesia (GA) and patient-controlled intravenous analgesia (PCIA).&#xD;
General anesthesia will be induced with midazolam, sufentanil, propofol and rocuronium. Anesthesia will then be maintained by inhalation of sevoflurane with or without nitrous oxide, and/or continuous intravenous infusion of propofol. Sufentanil and rocuronium will be given when needed. Patient-controlled intravenous analgesia will be provided for postoperative analgesia (established with 50 mg morphine in 100 mL normal saline, programmed to deliver a 2-mL bolus with a 6-10 minutes lockout interval and a 1 mL/hr background infusion).</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Combined Epi-GA/PCEA</intervention_name>
    <description>An epidural catheter will be placed before the induction of general anesthesia. General anesthesia will be induced and maintained as in the control group, with the addition of epidural anesthesia which will be maintained with the use of 0.375%-0.5% ropivacaine during surgery. Patient-controlled epidural analgesia will be provided after surgery.</description>
    <arm_group_label>Combined Epi-GA/PCEA</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>GA/PCIA</intervention_name>
    <description>General anesthesia will be induced with midazolam, propofol, sufentanil and rocuronium. Anesthesia will be maintained with either intravenous (propofol), inhalational (sevoflurane with or without nitrous oxide), or combined intravenous-inhalational anesthetics. Additional opioids (remifentanil, sufentanil, fentanyl, or morphine) and muscle relaxant (rocuronium, atracurium, or cisatracurium) will be administered when deemed necessary by the attending anesthesiologists. Patient-controlled intravenous analgesia will be provided after surgery.</description>
    <arm_group_label>GA/PCIA</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          1. elderly patients (age range 60-90 years);&#xD;
&#xD;
          2. scheduled to undergo noncardiac thoracic or abdominal surgery with an expected&#xD;
             duration of 2 hours or longer. For those who undergo thoracoscopic or laparoscopic&#xD;
             surgery, the expected length of incision must be 5 centimeters or more;&#xD;
&#xD;
          3. agree to receive patient-controlled postoperative analgesia.&#xD;
&#xD;
        Exclusion criteria (patients who meet any of the following criteria will be excluded):&#xD;
&#xD;
          1. previous history of schizophrenia, epilepsy or Parkinson disease, or unable to&#xD;
             complete preoperative assessment due to severe dementia, language barrier or end-stage&#xD;
             disease;&#xD;
&#xD;
          2. history of myocardial infarction within 3 months before surgery;&#xD;
&#xD;
          3. any contraindication to epidural anesthesia and analgesia, including abnormal&#xD;
             vertebral anatomy, previous spinal trauma or surgery, severe chronic back pain,&#xD;
             coagulation disorder (prothrombin time or activated partial prothrombin time longer&#xD;
             than 1.5 times of the upper limit of normal, or platelet count of less than 80 ×&#xD;
             10^9/L), local infection near the site of puncture, and severe sepsis;&#xD;
&#xD;
          4. severe heart dysfunction (New York Heart Association functional classification 3 or&#xD;
             above), hepatic insufficiency (Child-Pugh grades C), or renal insufficiency (serum&#xD;
             creatinine of 442 μmol/L or above, with or without serum potassium of 6.5 mmol/L or&#xD;
             above, or requirement of renal replacement therapy); or&#xD;
&#xD;
          5. any other conditions that were considered unsuitable for study participation.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dong-Xin Wang, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Peking University First Hopital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital</name>
      <address>
        <city>Beijing</city>
        <zip>100034</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
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  <reference>
    <citation>Behera BK, Puri GD, Ghai B. Patient-controlled epidural analgesia with fentanyl and bupivacaine provides better analgesia than intravenous morphine patient-controlled analgesia for early thoracotomy pain. J Postgrad Med. 2008 Apr-Jun;54(2):86-90. doi: 10.4103/0022-3859.40772.</citation>
    <PMID>18480522</PMID>
  </reference>
  <reference>
    <citation>Pisani MA, Murphy TE, Araujo KL, Slattum P, Van Ness PH, Inouye SK. Benzodiazepine and opioid use and the duration of intensive care unit delirium in an older population. Crit Care Med. 2009 Jan;37(1):177-83. doi: 10.1097/CCM.0b013e318192fcf9.</citation>
    <PMID>19050611</PMID>
  </reference>
  <reference>
    <citation>Saeki H, Ishimura H, Higashi H, Kitagawa D, Tanaka J, Maruyama R, Katoh H, Shimazoe H, Yamauchi K, Ayabe H, Kakeji Y, Morita M, Maehara Y. Postoperative management using intensive patient-controlled epidural analgesia and early rehabilitation after an esophagectomy. Surg Today. 2009;39(6):476-80. doi: 10.1007/s00595-008-3924-2. Epub 2009 May 27.</citation>
    <PMID>19468802</PMID>
  </reference>
  <reference>
    <citation>Ballantyne JC, Kupelnick B, McPeek B, Lau J. Does the evidence support the use of spinal and epidural anesthesia for surgery? J Clin Anesth. 2005 Aug;17(5):382-91. doi: 10.1016/j.jclinane.2004.10.005.</citation>
    <PMID>16102692</PMID>
  </reference>
  <reference>
    <citation>Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ, Parsons RW, Collins KS; MASTER Anaethesia Trial Study Group. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet. 2002 Apr 13;359(9314):1276-82. doi: 10.1016/S0140-6736(02)08266-1.</citation>
    <PMID>11965272</PMID>
  </reference>
  <reference>
    <citation>Park WY, Thompson JS, Lee KK. Effect of epidural anesthesia and analgesia on perioperative outcome: a randomized, controlled Veterans Affairs cooperative study. Ann Surg. 2001 Oct;234(4):560-9; discussion 569-71. doi: 10.1097/00000658-200110000-00015.</citation>
    <PMID>11573049</PMID>
  </reference>
  <reference>
    <citation>Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van Zundert A, Sage D, Futter M, Saville G, Clark T, MacMahon S. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ. 2000 Dec 16;321(7275):1493. doi: 10.1136/bmj.321.7275.1493.</citation>
    <PMID>11118174</PMID>
  </reference>
  <reference>
    <citation>Bryson GL, Wyand A. Evidence-based clinical update: general anesthesia and the risk of delirium and postoperative cognitive dysfunction. Can J Anaesth. 2006 Jul;53(7):669-77. doi: 10.1007/BF03021625.</citation>
    <PMID>16803914</PMID>
  </reference>
  <reference>
    <citation>Kamitani K, Higuchi A, Asahi T, Yoshida H. [Postoperative delirium after general anesthesia vs. spinal anesthesia in geriatric patients]. Masui. 2003 Sep;52(9):972-5. Japanese.</citation>
    <PMID>14531256</PMID>
  </reference>
  <reference>
    <citation>Papaioannou A, Fraidakis O, Michaloudis D, Balalis C, Askitopoulou H. The impact of the type of anaesthesia on cognitive status and delirium during the first postoperative days in elderly patients. Eur J Anaesthesiol. 2005 Jul;22(7):492-9. doi: 10.1017/s0265021505000840.</citation>
    <PMID>16045136</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>August 2, 2012</study_first_submitted>
  <study_first_submitted_qc>August 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 10, 2012</study_first_posted>
  <last_update_submitted>July 6, 2020</last_update_submitted>
  <last_update_submitted_qc>July 6, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 8, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Peking University First Hospital</investigator_affiliation>
    <investigator_full_name>Dong-Xin Wang</investigator_full_name>
    <investigator_title>Professor and Chairman, Department of Anesthesiology and Critical Care Medicine</investigator_title>
  </responsible_party>
  <keyword>Elderly</keyword>
  <keyword>Epidural anesthesia</keyword>
  <keyword>General anesthesia</keyword>
  <keyword>Major surgery</keyword>
  <keyword>Postoperative delirium</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>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Data will be provided on 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/NCT01661907
org study id: PUCRP201101
secondary id: ChiCTR-TRC-09000543
nct id: NCT01661907
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Postoperative delirium is a common complication in elderly patients after surgery. Its
      occurrence is associated with worse outcomes. The pathophysiology of delirium remains poorly
      understood. However, an universal phenomenon is that delirium frequently occurs in elderly
      patients after major complicated surgery, but is rarely seen after minor ambulatory surgery
      (such as cataract surgery). This indicates that stress response produced by surgery might
      have an important role in the pathogenesis of delirium. It has been reported that, when
      compared with general anesthesia and postoperative intravenous analgesia, neuraxial
      anesthesia and analgesia reduced the occurrence of postoperative complications and mortality
      in high risk patients. Combined epidural-general anesthesia is frequently used in clinical
      practice. This anesthetic method provides advantages of both epidural and general anesthesia,
      i.e. it blocks the afferent pathway of nociceptive stimulus by neuraxial blockade during and
      after surgery, and allows patients to endure long-duration surgery without any awareness. The
      investigators hypothesize that combined epidural-general anesthesia and postoperative
      epidural analgesia can decrease the incidence of delirium in elderly patients after major
      surgery when compared with general anesthesia alone and postoperative intravenous analgesia.
Delirium is an acutely occurred and transient mental syndrome characterized by global
      impairment of cognitive functions, reduced level of consciousness, abnormalities of
      attention, increased or decreased psychomotor activity, and disordered sleep-wake cycle.
      Postoperative delirium is a common complication in elderly patients after surgery. Dyer et al
      reviewed 80 primary studies and found that the mean incidence of postoperative delirium is
      about 36.8% (range 0%-73.5%) after surgery. It occurs in up to 80% of patients in the
      intensive care unit (ICU). Our recent studies found that delirium occurred in 51.0% of
      patients after cardiac surgery and in 44.5% of patients after non-cardiac surgery.

      The occurrence of postoperative delirium is associated with worse outcomes. Studies showed
      that delirious patients have prolonged ICU stay, increased incidence of complications,
      prolonged hospitalization, high mortality rate, and increased health care costs. Delirium is
      also associated with increased risk of long-term cognitive decline and poor quality of life.
      A recent follow-up study (mean follow-up time 27.9 ± 3.1 months) by our research group found
      that, after adjusting factors such as age, occurrence of postoperative complications, and
      stage of cancer, etc, the occurrence of postoperative delirium still remained an independent
      predictor of long-term mortality.

      The pathophysiology of delirium remains poorly understood. An universal phenomenon is that
      delirium frequently occurs in elderly patients after major complicated surgery, but is rarely
      seen after minor ambulatory surgery (such as cataract surgery). Studies also found that
      postoperative pain is an independent risk factor of delirium, whereas effective pain relief
      may help to reduce the incidence of delirium. Our recent studies showed that high serum
      cortisol level is an independent risk factor of postoperative delirium. In addition,
      inflammatory response may also contribute to the pathogenesis of delirium. Trauma, pain,
      cortisol secretion and inflammation are all important components of surgical stress response.
      The above results indicated that stress response produced by surgery might have an important
      role in the pathogenesis of delirium.

      Previous studies demonstrated that, when compared with general anesthesia, neuraxial
      anesthesia attenuates the hypersecretion of cortisol, and decreases the intensity of
      inflammatory response more effectively after surgery. And epidural analgesia provides better
      postoperative pain relief than intravenous analgesia. It was also reported that, when
      compared with general anesthesia and intravenous analgesia, neuraxial anesthesia and
      analgesia reduces the occurrence of postoperative complications and mortality in high risk
      patients. Combined epidural-general anesthesia is frequently used in clinical practice, and
      is performed in about 1/4 of patients undergoing surgery in the applicant's hospital.
      Theoretically, this anesthetic method provides advantages of both epidural and general
      anesthesia, i.e. it blocks the afferent pathway of nociceptive stimulus by neuraxial blockade
      during and after surgery, and allow patients to endure long-duration complicated surgeries
      without any awareness. However, there is no evidence whether combined epidural-general
      anesthesia/postoperative epidural analgesia can decrease the incidence of postoperative
      delirium in elderly patients undergoing major surgery.

      The objective of the study is to compare the effects of combined epidural-general
      anesthesia/postoperative epidural analgesia and general anesthesia/postoperative intravenous
      analgesia on the incidence of postoperative delirium in elderly patients undergoing major
      noncardiac surgery.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Single (Outcomes Assessor)
measure: Incidence of postoperative delirium
time frame: During the first 7 days after surgery.
description: Patients will be visited twice daily during the first seven days after surgery (between 08:00 h and 10:00 h, and between 18:00 h and 20:00 h). Delirium will be assessed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). The incidence is calculated as percentage of patients who develope any episode of delirium during that period.
measure: Intensive care unit (ICU) admission after surgery
time frame: During the day of surgery.
description: The proportion of patients admitted to the ICU after surgery
measure: APACHE II score at ICU admission
time frame: Within 24 hours after surgery.
description: For patients admitted to the ICU after surgery, the worst Acute Physiology and Chronic Health Evaluation II (APACHE II) score within 24 h will be recorded.
measure: The percentage of ICU admission with endotracheal intubation
time frame: During the day of surgery.
description: The percentage of ICU admission with endotracheal intubation.
measure: The duration of Mechanical Ventilation in ICU
time frame: Up to 30 days after surgery.
description: For patients admitted to the ICU after surgery, the duration of mechanical ventilation (for those with endotracheal tubes) will be recorded.
measure: The Length of ICU stay
time frame: Up to 30 days after surgery.
description: For patients admitted to the ICU after surgery, the length of ICU stay will be recorded.
measure: Time to the first onset of delirium
time frame: Up to 7 days after surgery.
description: Patients will be visited twice daily during the first seven days after surgery (between 08:00 h and 10:00 h, and between 18:00 h and 20:00 h). Delirium will be assessed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).
measure: Time to fluid/food intake
time frame: Up to 30 days after surgery.
description: Patients will be followed-up until 30 days after surgery and time to fluid and food intake after surgery will be recorded.
measure: Length of stay in hospital after surgery
time frame: Up to 30 days after surgery.
description: Patients will be followed-up until 30 days after surgery.
measure: All-cause 30-day mortality
time frame: Within the first 30 days after surgery.
description: All-cause 30-day mortality
measure: Non-delirium complications within 30 days after surgery surgery
time frame: Within the first 30 days after surgery.
description: Defined as newly occurred medical conditions other than delirium that are harmful to patients' postoperative recovery and required therapeutic intervention (i.e., grade II or higher on the Clavien-Dindo classification).
measure: The intensity of postoperative pain
time frame: During the first 3 postoperative days.
description: The intensity of postoperative pain both at rest and with movement will be evaluated twice daily at the same time of delirium assessment (between 08:00 h and 10:00 h, and between 18:00 h and 20:00 h) with the numeric rating scale (NRS, an 11-point scale where 0=no pain and 10=the worst pain).
measure: Serum cortisol concentration (substudy)
time frame: Blood samples will be collected from selected patients before surgery, and in the morning of the 1st and 3rd day after surgery.
description: Serum cortisol concentration (substudy)
measure: Serum IL-6 concentration (substudy)
time frame: Blood samples will be collected from selected patients before surgery, and in the morning of the 1st and 3rd day after surgery.
description: Serum IL-6 concentration (substudy)
measure: Serum IL-8 concentration (substudy)
time frame: Blood samples will be collected from selected patients before surgery, and in the morning of the 1st and 3rd day after surgery.
description: Serum IL-8 concentration (substudy)
arm group label: Combined Epi-GA/PCEA
arm group type: Experimental
description: Patients assigned to this group (experimental group) will receive combined epidural-general anesthesia (combined Epi-GA) and patient-controlled epidural analgesia (PCEA).
An epidural catheter will be placed before anesthesia induction. General anesthesia will be induced and maintained in the same manner as in the control group, with the addition of a continuous infusion or intermittent boluses of 0.375%-0.5% ropivacaine given through the epidural catheter for analgesia maintenance. Patient-controlled epidural analgesia will be provided for postoperative analgesia (established with 0.12% ropivacaine and 0.5 μg/mL sufentanil in 250 mL normal saline, programmed to deliver a 2-mL bolus with a lockout interval of 20 minutes and a background infusion of 4 mL/hr).
arm group label: GA/PCIA
arm group type: Active Comparator
description: Patients assigned to this group (control group) will receive general anesthesia (GA) and patient-controlled intravenous analgesia (PCIA).
General anesthesia will be induced with midazolam, sufentanil, propofol and rocuronium. Anesthesia will then be maintained by inhalation of sevoflurane with or without nitrous oxide, and/or continuous intravenous infusion of propofol. Sufentanil and rocuronium will be given when needed. Patient-controlled intravenous analgesia will be provided for postoperative analgesia (established with 50 mg morphine in 100 mL normal saline, programmed to deliver a 2-mL bolus with a 6-10 minutes lockout interval and a 1 mL/hr background infusion).
intervention type: Procedure
intervention name: Combined Epi-GA/PCEA
description: An epidural catheter will be placed before the induction of general anesthesia. General anesthesia will be induced and maintained as in the control group, with the addition of epidural anesthesia which will be maintained with the use of 0.375%-0.5% ropivacaine during surgery. Patient-controlled epidural analgesia will be provided after surgery.
arm group label: Combined Epi-GA/PCEA
intervention type: Procedure
intervention name: GA/PCIA
description: General anesthesia will be induced with midazolam, propofol, sufentanil and rocuronium. Anesthesia will be maintained with either intravenous (propofol), inhalational (sevoflurane with or without nitrous oxide), or combined intravenous-inhalational anesthetics. Additional opioids (remifentanil, sufentanil, fentanyl, or morphine) and muscle relaxant (rocuronium, atracurium, or cisatracurium) will be administered when deemed necessary by the attending anesthesiologists. Patient-controlled intravenous analgesia will be provided after surgery.
arm group label: GA/PCIA
criteria: 
gender: All
minimum age: 60 Years
maximum age: 90 Years
healthy volunteers: No
last name: Dong-Xin Wang, MD, PhD
role: Principal Investigator
affiliation: Peking University First Hopital
facility: 
country: China
citation: Dyer CB, Ashton CM, Teasdale TA. Postoperative delirium. A review of 80 primary data-collection studies. Arch Intern Med. 1995 Mar 13;155(5):461-5. doi: 10.1001/archinte.155.5.461.
PMID: 7864702
citation: Girard TD, Pandharipande PP, Ely EW. Delirium in the intensive care unit. Crit Care. 2008;12 Suppl 3(Suppl 3):S3. doi: 10.1186/cc6149. Epub 2008 May 14.
PMID: 18495054
citation: Mu DL, Wang DX, Li LH, Shan GJ, Li J, Yu QJ, Shi CX. High serum cortisol level is associated with increased risk of delirium after coronary artery bypass graft surgery: a prospective cohort study. Crit Care. 2010;14(6):R238. doi: 10.1186/cc9393. Epub 2010 Dec 30.
PMID: 21192800
citation: Shi CM, Wang DX, Chen KS, Gu XE. Incidence and risk factors of delirium in critically ill patients after non-cardiac surgery. Chin Med J (Engl). 2010 Apr 20;123(8):993-9.
PMID: 20497703
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citation: Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-62. doi: 10.1001/jama.291.14.1753.
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citation: Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med. 2009 Dec 1;180(11):1092-7. doi: 10.1164/rccm.200904-0537OC. Epub 2009 Sep 10.
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citation: Bickel H, Gradinger R, Kochs E, Forstl H. High risk of cognitive and functional decline after postoperative delirium. A three-year prospective study. Dement Geriatr Cogn Disord. 2008;26(1):26-31. doi: 10.1159/000140804. Epub 2008 Jun 24.
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citation: Van Rompaey B, Schuurmans MJ, Shortridge-Baggett LM, Truijen S, Elseviers M, Bossaert L. Long term outcome after delirium in the intensive care unit. J Clin Nurs. 2009 Dec;18(23):3349-57. doi: 10.1111/j.1365-2702.2009.02933.x. Epub 2009 Sep 4.
PMID: 19735334
citation: Inouye SK. Delirium in older persons. N Engl J Med. 2006 Mar 16;354(11):1157-65. doi: 10.1056/NEJMra052321. No abstract available. Erratum In: N Engl J Med. 2006 Apr 13;354(15):1655.
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citation: Milstein A, Pollack A, Kleinman G, Barak Y. Confusion/delirium following cataract surgery: an incidence study of 1-year duration. Int Psychogeriatr. 2002 Sep;14(3):301-6. doi: 10.1017/s1041610202008499.
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citation: Vaurio LE, Sands LP, Wang Y, Mullen EA, Leung JM. Postoperative delirium: the importance of pain and pain management. Anesth Analg. 2006 Apr;102(4):1267-73. doi: 10.1213/01.ane.0000199156.59226.af.
PMID: 16551935
citation: Halaszynski TM. Pain management in the elderly and cognitively impaired patient: the role of regional anesthesia and analgesia. Curr Opin Anaesthesiol. 2009 Oct;22(5):594-9. doi: 10.1097/ACO.0b013e32833020dc.
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citation: Hudek K. Emergence delirium: a nursing perspective. AORN J. 2009 Mar;89(3):509-16; quiz 517-9. doi: 10.1016/j.aorn.2008.12.026.
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citation: Rudolph JL, Ramlawi B, Kuchel GA, McElhaney JE, Xie D, Sellke FW, Khabbaz K, Levkoff SE, Marcantonio ER. Chemokines are associated with delirium after cardiac surgery. J Gerontol A Biol Sci Med Sci. 2008 Feb;63(2):184-9. doi: 10.1093/gerona/63.2.184.
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citation: de Rooij SE, van Munster BC, Korevaar JC, Levi M. Cytokines and acute phase response in delirium. J Psychosom Res. 2007 May;62(5):521-5. doi: 10.1016/j.jpsychores.2006.11.013.
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citation: van Munster BC, Korevaar JC, Zwinderman AH, Levi M, Wiersinga WJ, De Rooij SE. Time-course of cytokines during delirium in elderly patients with hip fractures. J Am Geriatr Soc. 2008 Sep;56(9):1704-9. doi: 10.1111/j.1532-5415.2008.01851.x. Epub 2008 Aug 4. Erratum In: J Am Geriatr Soc. 2009 Jan;57(1):190.
PMID: 18691278
citation: Li Y, Zhu S, Yan M. Combined general/epidural anesthesia (ropivacaine 0.375%) versus general anesthesia for upper abdominal surgery. Anesth Analg. 2008 May;106(5):1562-5, table of contents. doi: 10.1213/ane.0b013e31816d1976.
PMID: 18420877
citation: Ahlers O, Nachtigall I, Lenze J, Goldmann A, Schulte E, Hohne C, Fritz G, Keh D. Intraoperative thoracic epidural anaesthesia attenuates stress-induced immunosuppression in patients undergoing major abdominal surgery. Br J Anaesth. 2008 Dec;101(6):781-7. doi: 10.1093/bja/aen287. Epub 2008 Oct 15.
PMID: 18922851
citation: Pham-Marcou TA, Gentili M, Asehnoune K, Fletcher D, Mazoit JX. Effect of neurolytic nerve block on systemic carrageenan-induced inflammatory response in mice. Br J Anaesth. 2005 Aug;95(2):243-6. doi: 10.1093/bja/aei150. Epub 2005 Apr 29.
PMID: 15863437
citation: Behera BK, Puri GD, Ghai B. Patient-controlled epidural analgesia with fentanyl and bupivacaine provides better analgesia than intravenous morphine patient-controlled analgesia for early thoracotomy pain. J Postgrad Med. 2008 Apr-Jun;54(2):86-90. doi: 10.4103/0022-3859.40772.
PMID: 18480522
citation: Pisani MA, Murphy TE, Araujo KL, Slattum P, Van Ness PH, Inouye SK. Benzodiazepine and opioid use and the duration of intensive care unit delirium in an older population. Crit Care Med. 2009 Jan;37(1):177-83. doi: 10.1097/CCM.0b013e318192fcf9.
PMID: 19050611
citation: Saeki H, Ishimura H, Higashi H, Kitagawa D, Tanaka J, Maruyama R, Katoh H, Shimazoe H, Yamauchi K, Ayabe H, Kakeji Y, Morita M, Maehara Y. Postoperative management using intensive patient-controlled epidural analgesia and early rehabilitation after an esophagectomy. Surg Today. 2009;39(6):476-80. doi: 10.1007/s00595-008-3924-2. Epub 2009 May 27.
PMID: 19468802
citation: Ballantyne JC, Kupelnick B, McPeek B, Lau J. Does the evidence support the use of spinal and epidural anesthesia for surgery? J Clin Anesth. 2005 Aug;17(5):382-91. doi: 10.1016/j.jclinane.2004.10.005.
PMID: 16102692
citation: Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ, Parsons RW, Collins KS; MASTER Anaethesia Trial Study Group. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet. 2002 Apr 13;359(9314):1276-82. doi: 10.1016/S0140-6736(02)08266-1.
PMID: 11965272
citation: Park WY, Thompson JS, Lee KK. Effect of epidural anesthesia and analgesia on perioperative outcome: a randomized, controlled Veterans Affairs cooperative study. Ann Surg. 2001 Oct;234(4):560-9; discussion 569-71. doi: 10.1097/00000658-200110000-00015.
PMID: 11573049
citation: Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van Zundert A, Sage D, Futter M, Saville G, Clark T, MacMahon S. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ. 2000 Dec 16;321(7275):1493. doi: 10.1136/bmj.321.7275.1493.
PMID: 11118174
citation: Bryson GL, Wyand A. Evidence-based clinical update: general anesthesia and the risk of delirium and postoperative cognitive dysfunction. Can J Anaesth. 2006 Jul;53(7):669-77. doi: 10.1007/BF03021625.
PMID: 16803914
citation: Kamitani K, Higuchi A, Asahi T, Yoshida H. [Postoperative delirium after general anesthesia vs. spinal anesthesia in geriatric patients]. Masui. 2003 Sep;52(9):972-5. Japanese.
PMID: 14531256
citation: Papaioannou A, Fraidakis O, Michaloudis D, Balalis C, Askitopoulou H. The impact of the type of anaesthesia on cognitive status and delirium during the first postoperative days in elderly patients. Eur J Anaesthesiol. 2005 Jul;22(7):492-9. doi: 10.1017/s0265021505000840.
PMID: 16045136
responsible party type: Principal Investigator
investigator affiliation: Peking University First Hospital
investigator full name: Dong-Xin Wang
investigator title: Professor and Chairman, Department of Anesthesiology and Critical Care Medicine
mesh term: Delirium
mesh term: Emergence Delirium
sharing ipd: No
ipd description: Data will be provided on request.