Dexmedetomidine-Esketamine Combination on Depression and Anxiety After Laparoscopic Ureteral Reconstruction

Phase 4Not Yet RecruitingNCT07753772

Peking University First Hospital658 enrolled

Overview

Anxiety and depressive symptoms are prevalent in patients undergoing surgical repair for ureteral stricture, driven by chronic pain, renal function concerns, and surgical uncertainty. Dexmedetomidine has anxiolytic and antidepressant effects but may increase bradycardia and hypotension; esketamine provides rapid antidepressant efficacy but may cause psychiatric side effects. Preliminary studies showed that combined use of low-dose dexmedetomidine and esketamine reduced the prevalence of postoperative depressive symptoms without increasing adverse events. This study is designed to test the hypothesis that perioperative use of low-dose dexmedetomidine-esketamine combination may relieve postoperative depressive symptoms and anxiety in patients undergoing laparoscopic ureteral reconstruction.

Ureteral stricture (US) is characterized by narrowing of the ureteral lumen, which can lead to upper urinary tract obstruction and subsequent renal impairment. The primary therapeutic goal of US is to relieve obstruction and preserve renal function. Current treatment methods include endoscopic balloon dilation, endoureterotomy, ureteral dilation, and ureteral reconstruction surgery. Among these, ureteral reconstruction surgery is highly effective, especially for complex strictures exceeding 2 cm in length. Patients with US often endure prolonged symptom burden and substantial medical costs, and are prone to emotional disturbances such as anxiety and depression. A multicenter prospective study reported that the preoperative prevalence of anxiety and depressive syndromes in US patients scheduled for surgery was 31.3% and 20.7%, respectively, with iatrogenic US and urinary symptoms being the strongest predictors of increased levels of anxiety and depression. Perioperative stress may further exacerbate the severity of anxiety and depressive symptoms, leading to increased intraoperative anesthetic and analgesic requirements, delayed emergence from anesthesia, and higher risks of postoperative delirium and sleep disturbances. Dexmedetomidine is a highly selective α2-adrenergic receptor agonist with sedative, analgesic, and anxiolytic properties. It also exerts antidepressant effects through multiple mechanisms. Clinical studies have confirmed its efficacy in alleviating postoperative anxiety and depression across various surgical populations. Esketamine, the S-enantiomer of ketamine, is an N-methyl-D-aspartate (NMDA) receptor antagonist with anesthetic, analgesic, and rapid-onset antidepressant effects. Perioperative studies also confirmed the efficacy of esketamine in relieving postoperative depressive symptoms. Routine dose esketamine may cause psychiatric side effects such as dissociative symptoms and hallucinations; administration of low-dose esketamine attenuates these side effects but may weaken the antidepressant efficacy. The sedative properties of dexmedetomidine can mitigate the side effects of esketamine. Furthermore, the combined use of low-dose dexmedetomidine and esketamine may offer synergistic anxiolytic and antidepressant effects with a favorable safety profile. This study is designed to test the hypothesis that perioperative administration of low-dose dexmedetomidine-esketamine combination may relieve postoperative depressive and anxiety symptoms in patients undergoing laparoscopic ureteral reconstruction for US.

Interventions

Combined dexmedetomidine-esketamine administrationDRUG

During anesthesia, a loading dose (0.8 ml/kg/h) of dexmedetomidine-esketamine (DEX-ESK) combination (DEX 1 ug/ml; ESK 0.5 mg/ml) will be infused after anesthesia induction for 30 min (DEX 0.4 ug/kg; ESK 0.2 mg/kg), followed by a continuous infusion at 0.1 ml/kg/h (DEX 0.1 ug/kg/h; ESK 0.05 mg/kg/h) until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with dexmedetomidine (DEX 1.5 ug/ml), esketamine (ESK 0.25 mg/ml), and sufentanil (1.0 ug/ml), programmed to deliver 2-ml boluses (DEX 3.0 ug, ESK 0.5 mg, and sufentanil 2.0 ug) with an 8-minute lockout interval and a 1-ml/h (DEX 1.5 ug/h, ESK 0.25 mg/h, and sufentanil 1.0 ug/h) background infusion, and used for up to 48 hours.

Placebo administrationDRUG

During anesthesia, a loading dose (0.8 ml/kg/h) of normal saline will be infused after anesthesia induction for 30 min, followed by a continuous infusion at 0.1 ml/kg/h until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with sufentanil (1.0 ug/ml), programmed to deliver 2-ml boluses (sufentanil 2.0 ug) with an 8-minute lockout interval and a 1-ml/h (sufentanil 1.0 ug/h) background infusion, and used for up to 48 hours.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Aged ≥ 18 years; 2. Diagnosed with ureteral stricture and scheduled for elective laparoscopic ureteral reconstruction under general anesthesia; 3. Requiring patient-controlled intravenous analgesia after surgery. Exclusion Criteria: 1. Preoperative inability to communicate due to coma, delirium, severe dementia, or language barrier; 2. History of schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis; 3. Presence of preexisting left ventricular ejection fraction (LVEF) \< 30%, sick sinus syndrome, severe sinus bradycardia (heart rate \< 50 beats/min), or atrioventricular block above grade II without pacemaker implanted; 4. Uncontrolled hyperthyroidism or history of pheochromocytoma; 5. Severe hepatic insufficiency (Child-Pugh Class C), severe renal insufficiency (required preoperative dialysis), or American Society of Anesthesiologists (ASA) physical status classification ≥ IV; 6. Allergy to dexmedetomidine and/or esketamine; 7. Other conditions deemed unsuitable for study participation by the investigators.

Outcomes

Primary Outcomes

Prevalence of depressive symptoms on postoperative day 7

Depressive symptoms will be screened using the Patient Health Questionnaire-9 (PHQ-9; total scores range from 0 to 27, with higher scores indicating more severe symptoms). A PHQ-9 score ≥5 is defined as presence of depressive symptoms.

Time frame: On postoperative day 7.

Secondary Outcomes

Incidence of moderate-to-severe catheter-related bladder discomfort (CRBD) within 24 hours after surgery

CRBD is defined as a strong desire to urinate or discomfort in the pubic region that occurs after awakening from anesthesia. The occurrence of CRBD will be assessed at 10 minutes, 30 minutes, 60 minutes, 2 hours, and 6 hours after surgery, and twice daily during the first postoperative day (8:00-10:00 am, or 6:00-8:00 pm). The severity of CRBD is divided into four levels: 1- None, even when asked, no discomfort is reported; 2- Mild, only report discomfort during questioning; 3-Moderate, reported discomfort without inquiry, but without behavioral reactions; 4-Severe, with the patient actively reporting discomfort and behavioral reactions (observable behavioral reactions include limb movement, strong vocal reactions, or attempts to remove the catheter).

Time frame: Up to 24 hours after surgery.

Prevalence of anxiety symptoms on postoperative day 7

Anxiety symptoms will be screened using the Generalized Anxiety Disorder-7 (GAD-7; total scores range from 0 to 21, with higher scores indicating more severe anxiety). A GAD-7 score ≥5 is defined as presence of anxiety symptoms.

Time frame: On postoperative day 7.

Prevalence of depressive symptoms 30 days after surgery

Time frame: At 30 days postoperatively.