Dexmedetomidine-esketamine Combined Nasal Administration and Emergence Delirium

July 28, 2025 updated by: Dong-Xin Wang, Peking University First Hospital

Effect of Dexmedetomidine-esketamine Combined Nasal Administration on Emergence Delirium in Elderly Patients After Surgery: a Randomized, Double-blind, Placebo-controlled Trial

Emergence delirium is common in older patients after surgery and associated with worse perioperative outcomes, including increased postoperative delirium. Nasal administrations of both dexmedetomidine and esketamine are approved for medical purposes. Combination of low-dose dexmedetomidine and esketamine has shown some synergic effects in analgesia and anxiolysis. In a recent randomized trial, combined nasal administration of dexmedetomidine and esketamine was more effective in reducing pre-dental anxiety in pediatric patients. The investigators hypothesize that perioperative nasal administration of dexmedetomidine-esketamine combination can reduce the incidence of emergence delirium in older patients after surgery.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Delirium is a common brain dysfunction syndrome in older patients after major surgery. Delirium that occurs after surgery includes emergence delirium and postoperative delirium. Emergence delirium occurred in 17.5% to 37.0% of patients following general anesthesia. The reported incidence of postoperative delirium ranged from 12.0% to 32.9% in older patients after noncardiac surgery. It is well known that the occurrence of postoperative delirium is associated with adverse outcomes. Recent studies found that emergence delirium is also associated with adverse perioperative outcomes, including increased postoperative delirium, more non-delirium complications, longer hospital stay, and higher healthcare costs.

Dexmedetomidine is a highly selective alpha 2-adrenoceptor agonist with sedative, anxiolytic, and analgesic effects. Prophylactic administration of dexmedetomidine preoperatively or intraoperatively has also been shown to reduce the incidence of postoperative delirium. Dexmedetomidine via nasal administration is now widely used for pediatric preoperative sedation. Nasal administration of dexmedetomidine is also used in adults. In a retrospective study, postoperative nasal administration of dexmedetomidine (100 μg) to elderly orthopedic surgical patients improved analgesia and reduced symptoms of agitation. A recent study of patients undergoing gynecologic laparoscopic surgery, night-time dexmedetomidine (1.5 µg/kg) administration by nasal drops from preoperative day 1 to postoperative day 5 improved sleep quality and reduced the incidence of postoperative delirium.

Esketamine is a N-methyl-D-aspartic acid receptor antagonist and has been used as an anesthetic and analgesic. Low-dose intravenous infusion of ketamine is recommended for postoperative analgesia. Esketamine is s-enantiomer of ketamine and twice as potent as ketamine in analgesic potency. Nasal administration of esketamine is approved by FDA for intractable depression in adults. A randomized trial showed that nasal application of esketamine was effective in relieving post-thoracic puncture pain in adult patients without significant adverse effects. And postoperative pain is a common risk factor of emergence delirium and postoperative delirium.

This randomized trial is designed to test the hypothesis that combined nasal administration of dexmedetomidine-esketamine combination may reduce the incidence of emergence delirium in older patients after surgery.

Study Type

Interventional

Enrollment (Actual)

340

Phase

  • Phase 4

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
      • Beijing, Beijing, China, 100034
        • 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

  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Aged ≥ 65 years;
  2. Scheduled for inpatient elective or semi-elective surgery under general anesthesia, with an expected surgical duration of ≤2 hours;
  3. Planned to stay in hospital for at least 1 day after surgery.

Exclusion Criteria:

  1. Not suitable for intranasal drug administration due to nasal disease (e.g., rhinitis, nasal polyps, or nasal congestion due to any cause);
  2. Preoperative schizophrenia, epilepsy, Parkinson's disease, myasthenia gravis, or delirium;
  3. Inability to communicate due to coma, severe dementia, or language barrier before surgery;
  4. Brain trauma or neurosurgery;
  5. Use of sedatives or hypnotics at bedtime during the last month;
  6. History of hyperthyroidism or pheochromocytoma;
  7. Preoperative left ventricular ejection fraction <30%, or sick sinus node syndrome, severe sinus bradycardia (heart rate <50 beats per minute), or atrioventricular block of degree II or higher without pacemaker, or systolic blood pressure <90 mmHg before enrollment;
  8. Severe hepatic dysfunction (Child-Pugh class C), severe renal dysfunction (receiving dialysis before surgery), or American Society of Anesthesiologists classification ≥ IV;
  9. Planned admission to the intensive care unit after surgery;
  10. Allergic to dexmedetomidine and/or esketamine, or any other conditions that are 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: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Combined dexmedetomidine-esketamine
A mixture of dexmedetomidine 0.5 µg/kg and esketamine 0.2 mg/kg is administered via nasal spray at 20:30 pm the day before surgery and at 07:30 am and 20:30 pm the day of surgery.
Drug: Dexmedetomidine
Dexmedetomidine 0.5 µg/kg is administered via nasal spray at 20:30 pm the day before surgery and at 07:30 am and 20:30 pm the day of surgery.
Drug: Esketamine
Esketamine 0.2 mg/kg is administered via nasal spray at 20:30 pm the day before surgery and at 07:30 am and 20:30 pm the day of surgery.
Placebo Comparator: Normal saline
Placebo (normal saline) at the same volume is administered via nasal spray at 20:30 pm the day before surgery and at 07:30 am and 20:30 pm the day of surgery.
Drug: Normal saline
Normal saline at the same volume is administered via nasal spray at 20:30 pm the day before surgery and at 07:30 am and 20:30 pm the day of surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of emergence delirium after surgery
Time Frame: During stay in the post-anesthesia care unit
Emergence delirium is assessed with the Richmond Agitation Sedation Scale (RASS; scores range from -5 [unarousable] to +4 [combative] and 0 indicates alert and calm) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) at 5 and 30 minutes after admission to the post-anesthesia care unit.
During stay in the post-anesthesia care unit

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of emergence agitation
Time Frame: During anesthesia emergence in the operating room
Emergence agitation is assessed with the RASS after surgery from cessation of general anesthesia to leaving operating room. A RASS score ≥+2 at any time is defined as having emergence agitation.
During anesthesia emergence in the operating room
Subjective sleep quality score
Time Frame: The night before surgery and the night of surgery
Subjective sleep quality is assessed with the Richards-Campbell Sleep Questionnaire (RCSQ). The RCSQ is a self-reported measure that evaluates perception of nighttime sleep in five items, including sleep depth, sleep latency, number of awakenings, returning to sleep, and overall sleep quality. Each item is assessed with a 100 millimeter visual analog scale (score ranges from 0 to 100, with higher scores indicating better sleep quality). The mean score of the five items represents the overall sleep quality.
The night before surgery and the night of surgery
Incidence of delayed neurocognitive recovery
Time Frame: At 5 days after surgery
Cognition is assessed with the telephone-Montreal Cognitive Assessment (T-MoCA; score ranges from 0 to 22, with higher score indicating better function). A reducation of T-MoCA score of ≥1 standard deviation (SD) from baseline is defined as having delayed neurocognitive recovery.
At 5 days after surgery

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pain intensity within 24 hours after surgery
Time Frame: Up to 24 hours after surgery
Pain intensity is assessed with the numeric rating scale (NRS, an 11-point scale where 0=no pain and 10=the worst pain) at 5 and 30 minutes on the day of surgery and between 8 and 10 am and 18 and 20 pm on the first day after surgery.
Up to 24 hours after surgery
Analgesic use within 24 hours after surgery
Time Frame: Up to 24 hours after surgery
Includes opioids and non-opioid analgesics.
Up to 24 hours after surgery
Incidence of postoperative delirium within 3 days after surgery
Time Frame: Up to 3 days after surgery
Postoperative delirium is assessed twice daily (8-10 am and 18-20 pm) with the 3-minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) for non-intubated patients or the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) for intubated patients.
Up to 3 days after surgery
Length of hospital stay after surgery
Time Frame: Up to 30 days after surgery
Length of hospital stay after surgery.
Up to 30 days after surgery
Subjective sleep quality at 30 day after surgery
Time Frame: At 30 days after surgery
Subjective sleep quality at 30 days is assessed with the Pittsburgh Sleep Quality Index (PSQI). PSQI is a 7-item questionnaire consisting 19 self-rated questions that assesses sleep quality over the last month, each weighted equally on a 0-3 scale; higher scores indicate worse sleep quality
At 30 days after surgery
Incidence of postoperative complications within 30 days after surgery
Time Frame: Up to 30 days after surgery
Postoperative complications are defined as new-onset medical events that are deemed harmful and required therapeutic intervention, that is grade II or higher on the Clavien-Dindo classification.
Up to 30 days after surgery

Collaborators and Investigators

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

Sponsor

Peking University First Hospital

Investigators

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

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)

September 2, 2024

Primary Completion (Actual)

March 28, 2025

Study Completion (Actual)

May 1, 2025

Study Registration Dates

First Submitted

August 20, 2024

First Submitted That Met QC Criteria

August 20, 2024

First Posted (Actual)

August 22, 2024

Study Record Updates

Last Update Posted (Actual)

July 31, 2025

Last Update Submitted That Met QC Criteria

July 28, 2025

Last Verified

July 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2024-405

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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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