Anesthesia-analgesia Methods and Postoperative Delirium

July 6, 2020 updated by: Dong-Xin Wang, Peking University First Hospital

Effects of Two Different Anesthesia-analgesia Methods on the Incidence of Postoperative Delirium: a Multicenter, Randomized Controlled Trial

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

1800

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
      • Beijing, China, 100034
        • Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

60 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion criteria:

  1. elderly patients (age range 60-90 years);
  2. scheduled to undergo noncardiac thoracic or abdominal surgery with an expected duration of 2 hours or longer. For those who undergo thoracoscopic or laparoscopic surgery, the expected length of incision must be 5 centimeters or more;
  3. agree to receive patient-controlled postoperative analgesia.

Exclusion criteria (patients who meet any of the following criteria will be excluded):

  1. previous history of schizophrenia, epilepsy or Parkinson disease, or unable to complete preoperative assessment due to severe dementia, language barrier or end-stage disease;
  2. history of myocardial infarction within 3 months before surgery;
  3. any contraindication to epidural anesthesia and analgesia, including abnormal vertebral anatomy, previous spinal trauma or surgery, severe chronic back pain, coagulation disorder (prothrombin time or activated partial prothrombin time longer than 1.5 times of the upper limit of normal, or platelet count of less than 80 × 10^9/L), local infection near the site of puncture, and severe sepsis;
  4. severe heart dysfunction (New York Heart Association functional classification 3 or above), hepatic insufficiency (Child-Pugh grades C), or renal insufficiency (serum creatinine of 442 μmol/L or above, with or without serum potassium of 6.5 mmol/L or above, or requirement of renal replacement therapy); or
  5. any other conditions that were considered unsuitable for study participation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Combined Epi-GA/PCEA

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).
Procedure: Combined Epi-GA/PCEA
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.
Active Comparator: GA/PCIA

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).
Procedure: GA/PCIA
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of postoperative delirium
Time Frame: During the first 7 days after surgery.
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.
During the first 7 days after surgery.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intensive care unit (ICU) admission after surgery
Time Frame: During the day of surgery.
The proportion of patients admitted to the ICU after surgery
During the day of surgery.
APACHE II score at ICU admission
Time Frame: Within 24 hours after surgery.
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.
Within 24 hours after surgery.
The percentage of ICU admission with endotracheal intubation
Time Frame: During the day of surgery.
The percentage of ICU admission with endotracheal intubation.
During the day of surgery.
The duration of Mechanical Ventilation in ICU
Time Frame: Up to 30 days after surgery.
For patients admitted to the ICU after surgery, the duration of mechanical ventilation (for those with endotracheal tubes) will be recorded.
Up to 30 days after surgery.
The Length of ICU stay
Time Frame: Up to 30 days after surgery.
For patients admitted to the ICU after surgery, the length of ICU stay will be recorded.
Up to 30 days after surgery.
Time to the first onset of delirium
Time Frame: Up to 7 days after surgery.
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).
Up to 7 days after surgery.
Time to fluid/food intake
Time Frame: Up to 30 days after surgery.
Patients will be followed-up until 30 days after surgery and time to fluid and food intake after surgery will be recorded.
Up to 30 days after surgery.
Length of stay in hospital after surgery
Time Frame: Up to 30 days after surgery.
Patients will be followed-up until 30 days after surgery.
Up to 30 days after surgery.
All-cause 30-day mortality
Time Frame: Within the first 30 days after surgery.
All-cause 30-day mortality
Within the first 30 days after surgery.
Non-delirium complications within 30 days after surgery surgery
Time Frame: Within the first 30 days after surgery.
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).
Within the first 30 days after surgery.
The intensity of postoperative pain
Time Frame: During the first 3 postoperative days.
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).
During the first 3 postoperative days.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Serum cortisol concentration (substudy)
Blood samples will be collected from selected patients before surgery, and in the morning of the 1st and 3rd day after surgery.
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.
Serum IL-6 concentration (substudy)
Blood samples will be collected from selected patients before surgery, and in the morning of the 1st and 3rd day after surgery.
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.
Serum IL-8 concentration (substudy)
Blood samples will be collected from selected patients before surgery, and in the morning of the 1st and 3rd day after surgery.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Peking University First Hospital

Collaborators

Peking University People's Hospital
Peking University Third Hospital
Beijing Hospital
Beijing Shijitan Hospital, Capital Medical University

Investigators

  • Principal Investigator: Dong-Xin Wang, MD, PhD, Peking University First Hopital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 21, 2011

Primary Completion (Actual)

May 25, 2015

Study Completion (Actual)

June 24, 2015

Study Registration Dates

First Submitted

August 2, 2012

First Submitted That Met QC Criteria

August 7, 2012

First Posted (Estimate)

August 10, 2012

Study Record Updates

Last Update Posted (Actual)

July 8, 2020

Last Update Submitted That Met QC Criteria

July 6, 2020

Last Verified

July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PUCRP201101
  • ChiCTR-TRC-09000543 (Registry Identifier: Chinese Clinical Trial Registry (www.chictr.org.cn))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Data will be provided on request.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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