Comparative safety of esketamine in procedural sedation and analgesia: a systematic review and network meta-analysis

The safety of esketamine relative to other sedatives in procedural sedation remains incompletely elucidated. This systematic review and network meta-analysis evaluated the comparative safety of esketamine against commonly used sedative and analgesic agents across a range of respiratory, hemodynamic, and recovery outcomes. A systematic search of PubMed/MEDLINE, Scopus, Cochrane CENTRAL, and Web of Science was conducted from 2000 to 2025 for randomized controlled trials (RCTs) comparing esketamine with other sedatives or placebo in patients undergoing procedural sedation. Primary outcomes included respiratory events (hypoxia) and hemodynamic stability (hypotension, bradycardia, vasoactive drug use). Secondary outcomes included recovery parameters (PACU discharge time) and drug consumption. A frequentist network meta-analysis was performed, and treatments were ranked using Surface Under the Cumulative Ranking Curve (SUCRA) values. Thirty-nine RCTs involving 5,885 participants were included. Esketamine demonstrated a significantly lower risk of hypoxia compared to propofol (RR 6.11, 95% CI 1.91–19.57), sufentanil (RR 2.72, 95% CI 1.48–4.98), and fentanyl (RR 2.26, 95% CI 1.34–3.82). In terms of hemodynamic safety, esketamine was superior to propofol (RR 5.24, 95% CI 2.48–11.09), sufentanil (RR 3.05, 95% CI 1.84–5.06), and fentanyl (RR 2.18, 95% CI 1.54–3.08) in preventing hypotension. Propofol was also associated with the highest risk of requiring vasoactive drugs (RR 7.17 versus esketamine). Regarding recovery, opioid-free anesthesia (OFA) significantly reduced PACU discharge time compared to esketamine (MD -4.96 min), whereas propofol and remifentanil prolonged it. Esketamine exhibits a favorable safety profile in procedural sedation, characterized by superior hemodynamic stability and a reduced risk of respiratory depression compared to conventional opioids and propofol. These findings support its utility as a valuable component in balanced sedation and opioid-sparing protocols, particularly for patients at risk of hemodynamic instability.