Efficacy and Safety of Intravenous Esketamine in Elderly Patients Undergoing Laparoscopic Radical Prostatectomy

Summary

This study assesses the efficacy and safety of intravenous esketamine administration in elderly prostate cancer patients undergoing laparoscopic radical prostatectomy, focusing on hemodynamic stability, postoperative recovery, and adverse events.

Abstract

While perioperative esketamine use has grown increasingly prevalent, evidence supporting its efficacy and safety in elderly patients undergoing laparoscopic prostate cancer surgery remains limited. This retrospective study evaluated intravenous esketamine's performance in this population by analyzing 186 elderly patients treated between 2021 and 2024, divided into a control group (n = 91; conventional anesthesia) and an esketamine group (n = 95; conventional anesthesia plus esketamine). Esketamine infusion was discontinued 30 min before surgery completion. Hemodynamic parameters-heart rate (HR) and mean arterial pressure (MAP)-were recorded at five time points: pre intubation (T1), 1 min post intubation (T2), 1 h intraoperatively (T3), skin closure (T4), and 5 min post extubation (T5). Secondary outcomes included anesthesia duration, extubation time, awakening time, analgesic use, Riker Sedation-Agitation Scale scores, visual analog scale (VAS) pain scores (immediately, and at 6 and 24 h postoperatively), Mini-Mental State Examination (MMSE) scores, postoperative cognitive dysfunction (POCD), and adverse events.

Compared with the control group, the esketamine group required significantly less remifentanil, propofol, and muscle relaxant (P < 0.05). Hemodynamically, HR and MAP were higher at T2 and lower at T3 in the esketamine group (P < 0.05). Postoperatively, esketamine prolonged awakening time slightly but reduced agitation and severe coughing (P < 0.05), shortened postanesthesia care unit (PACU) stay (P < 0.05), and improved VAS pain scores (P < 0.05). MMSE scores at 1 and 7 days post surgery were higher, and POCD incidence was lower (P < 0.05). The only notable adverse event difference was a higher rate of mild drowsiness (P < 0.05); other adverse events did not differ.

These findings suggest that esketamine may help maintain hemodynamic stability and enhance postoperative recovery in elderly patients undergoing laparoscopic radical prostatectomy, reducing anesthetic requirements and improving cognitive outcomes with minimal additional risk.

Introduction

Prostate cancer is a common malignancy of the male genitourinary system¹, predominantly affecting elderly men. Its incidence rises with age, ranking second only to lung cancer among cancers in this population². In recent years, advances in medical technology have improved diagnostic and therapeutic approaches, with transperitoneal laparoscopic surgery emerging as a key clinical intervention that significantly enhances surgical outcomes and accelerates postoperative recovery³. However, elderly patients undergoing this surgery face unique anesthesia-related challenges. During the anesthetic awakening period, they are prone to agitated behavior, driven by multiple factors: a high prevalence of preexisting chronic diseases and concurrent medications, as well as postoperative stimuli such as incision pain and catheter-related discomfort^4,5. Beyond agitation, elderly patients also face risks of postoperative cognitive dysfunction (POCD) and perioperative hemodynamic instability, which can complicate surgical outcomes and prolong hospital stays⁶. Addressing these challenges is critical to optimizing perioperative care for elderly prostate cancer patients.

To mitigate these issues, perioperative analgesics and anesthetic adjuvants play a pivotal role, but traditional agents have limitations. Racemic ketamine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors⁷, is widely used for intraoperative anesthesia and perioperative adjunctive analgesia, yet it is associated with a relatively high incidence of adverse events (e.g., hallucinations, dizziness) and modest potency⁸. Opioids, another mainstay of perioperative analgesia, carry risks of respiratory depression, constipation, and opioid-induced hyperalgesia-risks that are amplified in elderly patients with comorbidities⁹. Dexmedetomidine, an α₂-adrenergic agonist used to reduce agitation, may cause bradycardia and hypotension, which are particularly concerning in patients with cardiovascular dysfunction¹⁰. Esketamine, the S(+) enantiomer of racemic ketamine, has emerged as a promising alternative to these agents, with pharmacologic properties that address the limitations of traditional therapies. Compared to racemic ketamine, esketamine exhibits two- to four-fold greater potency, faster and more efficient metabolism, and a significantly lower incidence of adverse events¹¹. It also acts as a potent analgesic, with studies demonstrating its ability to reduce opioid requirements in thoracic surgery while maintaining perioperative hemodynamic homeostasis¹². Additionally, preclinical and early clinical data suggest that esketamine may have neuroprotective effects, potentially lowering the risk of POCD-a key concern in elderly patients¹³. These attributes make esketamine a compelling candidate for improving perioperative care in elderly patients undergoing laparoscopic radical prostatectomy.

Despite growing interest in esketamine, evidence of its efficacy and safety in elderly patients undergoing laparoscopic prostate cancer surgery remains limited. While previous studies have explored perioperative esketamine use^14,15, its specific impact on this patient population-with their unique physiological vulnerabilities and surgical stressors-has not been confirmed. This retrospective study, therefore, aims to compare the effectiveness and safety of intravenous esketamine versus conventional anesthesia in elderly patients undergoing laparoscopic radical prostatectomy. By evaluating hemodynamic stability, anesthesia drug requirements, emergence agitation, POCD, and adverse events, this research seeks to optimize anesthetic management and improve postoperative recovery quality for this high-risk group. Notably, the study focuses on patients with American Society of Anesthesiologists (ASA) grades I-II, as those with ASA III or severe organ dysfunction (e.g., advanced cardiac or renal disease) were excluded due to potential confounding effects on hemodynamics and recovery.

Protocol

This study was conducted in accordance with institutional human research ethics guidelines and was approved by the Ethics Committee of the First People's Hospital of Yongkang City, Zhejiang Province (Approval ID: YZ--20200657). We secured a signed informed consent form from every participant.

Study design

This retrospective clinical study analyzed the efficacy and safety of intravenous esketamine infusion in elderly patients undergoing laparoscopic prostate cancer surgery. A total of 186 elderly patients admitted between 2021 and 2024 were divided into an esketamine group (n = 95) and a control group (n = 91) according to the intervention method. The control group received conventional anesthesia throughout the surgical process, whereas the esketamine group received intravenous esketamine in addition to the same anesthesia regimen. This design ensured consistency in the anesthetic framework while isolating the effect of esketamine (Figure 1).

Inclusion and exclusion criteria

The inclusion criteria were: (1) age ≥ 65 years, meeting the WHO definition of elderly; (2) undergoing laparoscopic prostate cancer surgery; (3) American Society of Anesthesiologists (ASA) physical status classification I-II; (4) normal mental status and effective communication ability; and (5) complete clinical data.

Exclusion criteria included: (1) allergy to the study drug; (2) presence of other organ tumors or abnormal vital organ function; (3) history of alcoholism, long-term antidepressant use, or related conditions; (4) severe cardiac arrhythmia or uncontrolled hypertension; and (5) cardiopulmonary dysfunction.

Sample size calculation

An independent-samples t-test was used for data analysis and the sample size estimated. Based on previous studies on postoperative pain scores¹⁶, the effect size was set at 0.5, the significance level (α) at 0.05 (two-tailed), and the statistical power (1 - β) at 0.8. The calculated minimum required sample size per group was 64 participants. A total of 186 patients were ultimately enrolled, satisfying the statistical requirements of the study.

Anesthesia protocol

All surgical and anesthetic procedures were performed by a fixed, standardized team consisting of two attending anesthesiologists (each with at least 5 years of experience in urological laparoscopic anesthesia) and one specialized nursing team. This ensured consistency in intraoperative monitoring, drug administration, and response to adverse events.

All patients underwent standardized fasting before surgery, with no solid food for 8 h and no clear liquids for 2 h. No premedication was administered. Upon entering the operating room, patients were connected to a multi-parameter monitor to continuously record non-invasive blood pressure (NIBP), electrocardiogram (ECG), pulse oxygen saturation (SpO₂), end-tidal carbon dioxide (ETCO₂), and bispectral index (BIS).

In the esketamine group, patients received intravenous esketamine (25 mg/mL) at a dose of 0.2 mg/kg, followed by propofol (10 mg/mL, Fresenius) at 1.5 mg/kg, sufentanil (50 µg/mL) at 0.3 µg/kg, and cis-atracurium (5 mg/vial) at 0.2 mg/kg. The control group received the same doses of propofol, sufentanil, and cis-atracurium without esketamine.

Anesthesia was maintained with propofol infusion adjusted in real time to maintain a BIS value between 40 and 60 (4-8 mg/(kg·h)). Remifentanil (1 mg/vial) was infused at 6-12 µg/(kg·h) to maintain the spectral entropy index (SPI) between 20 and 50. Sufentanil (0.15 µg/kg) was administered intravenously 5 min before skin incision and again 30 minutes before the end of surgery. Cis-atracurium (0.1 mg/kg) was supplemented intravenously if intraoperative muscle relaxation was insufficient, as assessed by train-of-four stimulation.

In the esketamine group, esketamine was continuously infused at 0.2 mg/(kg·h) using an intravenous pump during surgery, and the infusion was discontinued 30 min before completion of the procedure. In the control group, all maintenance drugs (except cis-atracurium supplements) were discontinued 30 minutes before the end of surgery.

Postoperative patient-controlled analgesia (PCA) was implemented using a pump containing sufentanil (2 µg/kg) and granisetron (0.15 mg/kg; 1 mg/mL). The background infusion rate was set at 2 mL/h, and patients could administer a 0.5 mL bolus with a 15 min lockout interval.

For patients with mild renal impairment [estimated glomerular filtration rate (eGFR) 60-89 mL/min/1.73 m²], the cis-atracurium dose was reduced by 20% to avoid prolonged muscle relaxation. No dose adjustments were made for esketamine, propofol, sufentanil, or remifentanil. For patients aged ≥ 75 years, the initial dose of propofol during induction was reduced by 10% (from 1.5 mg/kg to 1.35 mg/kg) to minimize the risk of hypotension.

Esketamine handling was performed in a well-ventilated area, with gloves worn at all times. Any spills were wiped immediately with 0.5% sodium hypochlorite solution. Sharps were discarded into puncture-proof containers, and residual drugs or blood-contaminated materials were disposed of according to institutional protocols for cytotoxic and infectious waste.

Observation indicators

The primary outcomes included heart rate (HR) and mean arterial pressure (MAP) measured at pre intubation (T1), 1 min post intubation (T2), 1 h intraoperatively (T3), skin closure (T4), and 5 min post extubation (T5). Additional parameters included surgical duration, blood loss, anesthesia duration, awakening time, extubation time, and the dosages of remifentanil, propofol, sufentanil, and muscle relaxants.

Secondary outcomes included the incidence of agitation, severe coughing, and recovery of spontaneous respiration. Visual analog scale (VAS) pain scores were recorded immediately after surgery and at 6 and 24 h postoperatively (0 = no pain, 10 = worst pain)¹⁷. Mini-Mental State Examination (MMSE) and postoperative cognitive dysfunction (POCD) scores were evaluated, along with the incidence of adverse events such as nausea, chills, and respiratory depression.

Statistical analysis

Continuous variables that followed a normal distribution were expressed as mean ± SD and compared between groups using two-tailed Student's t-tests after verifying normality with the Shapiro-Wilk test and homogeneity of variance with Levene's test. Non-normally distributed data were presented as median (Q₁, Q₃) and compared using the Mann-Whitney U test. Categorical variables were expressed as n (%) and compared using the χ² test. Repeated hemodynamic measurements were analyzed using two-way repeated-measures ANOVA, with Bonferroni post hoc tests and Mauchly's test of sphericity. Statistical significance was set at P < 0.05.

Results

Table 1 presents a comparison of baseline characteristics and preoperative data between the esketamine group (n = 95) and the control group (n = 91). The variables included age, body mass index (BMI), TNM cancer stage, American Society of Anesthesiologists (ASA) physical status classification, and the prevalence of comorbidities such as hypertension, tobacco and alcohol history, diabetes, coronary heart disease, asthma, and abnormal liver or kidney function. Original data for both groups are also shown i...

Discussion

Prostate cancer is a prevalent urological malignancy among middle-aged and elderly men, with a high incidence rate. In China, both the incidence and mortality of prostate cancer have continued to rise annually¹⁸. For early-stage cases, surgical resection remains the primary approach to extend patients' lifespan. Laparoscopic radical prostatectomy is widely used clinically due to its minimal invasiveness, fewer complications, faster recovery, and lower pain levels¹⁹. Des...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
BIS Vista Monitor	Medtronic	185-0151	Used to monitor BIS, guiding propofol infusion rate to maintain BIS at 40-60
Cis-atracurium	Hengrui Pharmaceutical	0594502	Used in both groups for induction (0.2 mg/kg); 0.1 mg/kg added if necessary during operation
Esketamine	Hengrui Medicine	KH080601	Used in the experimental group: 0.2 mg/kg for induction; 0.2 mg/(kg·h) via intravenous pump for maintenance (stopped 30 min before surgery end)
G*Power			software for sample size estimation
Patient Monitoring Machine	Heal Force Bio-meditech Holdings Limited	ZD120	Monitor blood pressure, electrocardiogram, blood oxygen saturation and end-expiratory carbon dioxide, etc
Propofol	Fresenius	4463021	Used in both groups for induction (1.5 mg/kg) and maintenance. Maintenance rate adjusted by BIS (4-8 mg/(kg·h)), maintaining BIS at 40-60
Remifentanil	Yichang Renfu	H20030197	Used in both groups for maintenance at 6-12 μg/(kg·h), maintaining SPI at 20-50
SPSS 26.0	IBM Corp., Armonk, NY, USA
Sufentanil	Yichang Renfu	1170118	Used in both groups for induction (0.3 μg/kg). Additional 0.15 μg/kg given 5 min before skinning and 30 min before surgery end. Included in analgesic pump (2 μg/kg)
Tolansetron	Hengrui Pharmaceuticals	H20061193	Included in analgesic pump (0.15 mg/kg)