Anesthesia-analgesia Methods and Postoperative Delirium

This study has been completed.
Sponsor:
Collaborators:
Peking University People's Hospital
Peking University Third Hospital
Beijing Hospital
Beijing Shijitan Hospital
Information provided by (Responsible Party):
Dong-Xin Wang, Peking University First Hospital
ClinicalTrials.gov Identifier:
NCT01661907
First received: August 2, 2012
Last updated: October 28, 2015
Last verified: October 2015
  Purpose
Postoperative delirium is a common complication in critically ill patients after surgery. Its occurrence is associated with worse outcomes of the patients. The pathophysiology of delirium remains poorly understood. A universal phenomenon is that delirium was frequently identified in elderly patients after major complicated surgery, but was rarely noted after minor ambulatory surgery (such as cataract surgery). This indicated 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 anesthesia 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 lengthy complicated operations without any awareness. The investigators hypothesize that combined epidural-general anesthesia and postoperative epidural analgesia can decrease the incidence of postoperative delirium and, thus, improve the prognosis of critically ill elderly patients undergoing major surgery. The purpose of this 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 surgery.

Condition Intervention
Delirium
Postoperative Complications
Procedure: Combined Epi-GA/PCEA
Procedure: GA/PCIA

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Effects of Two Different Anesthesia-analgesia Methods on the Incidence of Postoperative Delirium: a Multicenter, Randomized Controlled Trial

Resource links provided by NLM:


Further study details as provided by Peking University First Hospital:

Primary Outcome Measures:
  • Incidence of postoperative delirium [ Time Frame: During the first 7 days after surgery. ] [ Designated as safety issue: Yes ]
    Patients will be visited twice daily during the first seven days after surgery. 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.


Secondary Outcome Measures:
  • Incidence of postoperative complications [ Time Frame: During the first 30 days after surgery. ] [ Designated as safety issue: Yes ]
    Patients will be visited twice daily during the first seven days after surgery for monitoring of non-delirium complications. They will then be followed up weekly until 30 days after surgery for monitoring of non-delirium complications. Non-delirium complications are defined as medical conditions other than delirium that required therapeutic intervention.

  • All-cause 30-day mortality [ Time Frame: Within the first 30 days after surgery. ] [ Designated as safety issue: Yes ]
  • NRS pain score [ Time Frame: During the first 3 postoperative days. ] [ Designated as safety issue: No ]
    The intensity of postoperative pain both at rest and with coughing will be evaluated twice daily at the same time of delirium assessment (i.e., from 8 to 10 a.m. and from 6 to 8 p.m.) with the numeric rating scale (NRS, a 11-point scale where 0 indicates no pain and 10 indicates the worst pain).

  • Length of stay in hospital after surgery [ Time Frame: From end of surgery until hospital discharge or 30 days after surgery. ] [ Designated as safety issue: Yes ]
    Patients will be followed-up until 30 days after surgery.

  • Daily prevalence of postoperative delirium [ Time Frame: During the first 7 postoperative days. ] [ Designated as safety issue: Yes ]
    Calculated as percentage of patients who develope any episode of delirium during that day.

  • Duration of delirium [ Time Frame: During the first 7 postoperative days. ] [ Designated as safety issue: Yes ]
    Calculated as the summary of days during which time any episode of delirium occurres.


Other Outcome Measures:
  • Serum cortisol concentration [ Time Frame: Blood samples will be drawn before anesthesia, and on the 1st and 3rd day after surgery. ] [ Designated as safety issue: No ]
  • Serum IL-6 concentration [ Time Frame: Blood samples will be drawn before anesthesia, and on the 1st and 3rd day after surgery. ] [ Designated as safety issue: No ]
  • Serum IL-8 concentration [ Time Frame: Blood samples will be drawn before anesthesia, and on the 1st and 3rd day after surgery. ] [ Designated as safety issue: No ]

Enrollment: 1800
Study Start Date: November 2011
Study Completion Date: June 2015
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 0.5%-0.75% ropivacaine given through the epidural catheter for analgesia maintenance. Patient controlled epidural analgesia will be used for postoperative analgesia (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 0.5%-0.75% 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 oxygen-nitrous oxide mixture (1:1-2) and sevoflurane, and/or continuous intravenous infusing of propofol. Sufentanil and rocuronium will be given when needed. If necessary, other types of opioids and muscle relaxants are also allowed. Patient controlled intravenous analgesia will be used for postoperative analgesia (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.

Detailed Description:

Delirium is a transient mental syndrome of acute onset 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 critically ill 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 occurred in up to 80% of patients in the ICU. Our recent studies found that the incidence of postoperative delirium occurring in patients at the SICU was 51.0% after cardiac surgery and 44.5% after non-cardiac surgery.

The occurrence of postoperative delirium is associated with worse outcomes of the patients. Studies showed that delirious patients had 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 malignant tumors, etc, the occurrence of postoperative delirium still remained an independent predictor of long-term mortality in patients.

The pathophysiology of delirium remains poorly understood. A universal phenomenon is that delirium was frequently identified in elderly patients after major complicated surgery, but was rarely noted after minor ambulatory surgery (such as cataract surgery). Studies also found that postoperative pain was an independent risk factor of delirium, and effective pain relief may help to reduce the incidence of delirium. Our recent studies of patients undergoing cardiac or non-cardiac surgeries both showed that high serum cortisol level was an independent predictor 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 attenuated the hypersecretion of cortisol, and decreased the intensity of inflammatory response more effectively after surgery. And epidural analgesia provided better postoperative pain relief than intravenous analgesia. It was also reported that, when compared with general anesthesia and 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, and is performed in about 1/4 of patients undergoing surgery in the applicant's hospital. Theoretically, this anesthesia 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 lengthy complicated operations without any awareness. However, there is no evidence whether combined epidural-general anesthesia/postoperative epidural analgesia can decrease the incidence of postoperative delirium and, thus, improve the outcomes of 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 surgery.

  Eligibility

Ages Eligible for Study:   60 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

(1) elderly patients (age range 60-90 years), (2) scheduled to undergo open thoracic or open 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, and (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 × 109/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.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01661907

Locations
China
Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital
Beijing, China, 100034
Sponsors and Collaborators
Peking University First Hospital
Peking University People's Hospital
Peking University Third Hospital
Beijing Hospital
Beijing Shijitan Hospital
Investigators
Principal Investigator: Dong-Xin Wang, MD, PhD Peking University First Hopital
  More Information

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Dong-Xin Wang, Professor and Chairman, Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital
ClinicalTrials.gov Identifier: NCT01661907     History of Changes
Other Study ID Numbers: PUCRP201101 
Study First Received: August 2, 2012
Last Updated: October 28, 2015
Health Authority: China: National Health and Family Planning Commission

Keywords provided by Peking University First Hospital:
Elderly
Anesthesia and postoperative analgesia
Postoperative period
Delirium
Postoperative complications

Additional relevant MeSH terms:
Delirium
Postoperative Complications
Confusion
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Nervous System Diseases
Neurobehavioral Manifestations
Neurologic Manifestations
Pathologic Processes
Signs and Symptoms
Anesthetics
Central Nervous System Agents
Central Nervous System Depressants
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on April 27, 2016