Esketamine Infusion May Prevent Post-Surgery Sleep Disturbances

Intraoperative esketamine infusion may provide preventive benefit against sleep disturbances after operations, according to new data.

In new findings from a single-center, double-blind, placebo-controlled randomized trial in China, a team of investigators reported that the ketamine-based NMDAR antagonist therapy—commonly used for anesthesia in countries including China—is positively associated with reduced burden of insomnia-like symptoms in patients shortly after surgery.

The findings highlight a more possibly diverse utility of the investigative drug, particularly for preventing a condition generally driven by symptoms of pain in postoperative patients.

Led by Di Qiu, MD, of the department of anesthesiology, pain and perioperative medicine at The First Affiliated Hospital of Zhengzhou University in Henan, a team of Chinese and Japanese investigators sought to assess the impact of intraoperative esketamine on incident postoperative sleep disturbance in patients receiving gynecological laparoscopic surgery.

They noted that post-surgery sleep disturbance can impact anywhere from 15% to 72% of patients, and is commonly linked to factors including older age, female sex, and symptoms related to the operation including pain, anxiety, nausea and vomiting.

“Postoperative sleep disturbance could lead to postoperative delirium and cognitive impairment, exacerbate acute postoperative pain, and delay postoperative recovery,” they wrote. “Pharmacological interventions, such as short-acting non-benzodiazepine zolpidem and melatonin, have often been used to improve postoperative sleep quality.”

To their knowledge, this would be the first study assessing a prophylactic agent for postoperative sleep disturbance.

Qiu and colleagues conducted their clinical trial from August 2021 to April 2022 at the university hospital. Eligible patients were aged 18 - 65 years old, undergoing gynecological laparoscopic surgery, with an American Society of Anesthesiologist Physical Status classification from I - III. They were randomized 1:1 to either 0.3 mg/kg/h intraoperative esketamine infusion or a control equivalent volume of saline.

Investigators sought a primary outcome of incidence of postoperative sleep disturbance on postoperative days 1 and 3. They defined sleep disturbance as scores of ≥6 on the Athens Insomnia Scale. Key secondary outcomes included postoperative anxiety and depression scores per Hospital Anxiety and Depression Scale and postoperative pain per visual analog scales, among others.

The final trial included 183 female patients administered either esketamine infusion (n = 91) or control (n = 91). Among patients receiving the prophylactic treatment, median age was 43 years old. The treatment arms reported similarities in demographic data including age, body mass index, preexisting medical conditions, and smoking and drinking status.

Incidence of postoperative sleep disturbance was significantly lower among patients receiving esketamine on postoperative days 1 (22.8% vs 44.0%) and 3 (7.6% vs 19.8%), indicating odds ratios (ORs) of 0.38 (95% CI, 0.20 - 0.72; P = .002) and 0.33 (95% CI, 0.13 - 0.84; P = .02), respectively.

Though investigators observed no difference in incidence of postoperative depression and anxiety scores between the esketamine infusion and control groups, pain scores per analog visual scales were significantly improved in the treatment arm (3 [95% CI, 3 -4] vs 4 [95% CI, 3-5]; P <.001).

The team additionally observed 4 key risk factors linked to postoperative sleep disturbance via multivariable logistic regression analyses:

• Preoperative depression (OR, 1.31; 95% CI, 1.01 - 1.70)
• Anxiety (OR, 1.67; 95% CI, 1.04 - 1.80)
• Duration of anesthesia (OR, 1.04; 95% CI, 1.00 - 1.08)
• Postoperative pain score (OR, 1.92; 95% CI, 1.24 - 2.96)

Investigators did not observe significant differences in prevalence of key adverse events among the treatment arms, including vomiting, nausea, dizziness, itching and nightmare.

Qui and colleagues concluded that their findings suggest esketamine infusion may prevent poor postoperative sleep quality and disturbances in patients undergoing gynecological laparoscopic surgery.

“The underlying mechanisms of the prophylactic effect of esketamine on postoperative sleep quality and (disturbances) are currently unclear,” they wrote. “Nonetheless, further studies are needed to confirm the role of circadian rhythms in the prophylactic effect of esketamine on postoperative sleep disturbance.”

The study, “Effect of Intraoperative Esketamine Infusion on Postoperative Sleep Disturbance After Gynecological Laparoscopy,” was published online in JAMA Network Open.