Combination of N-methyl-D-aspartate receptor antagonists and propofol for procedural sedation

BACKGROUND Propofol is widely considered for procedural sedation and analgesia across medical facilities. It is associated with dose-dependent hypotension, respiratory depression, and lack of analgesia. These limitations can be managed by combining propofol with N-methyl-D-aspartate (NMDA) receptor antagonists (ketamine/esketamine); however, previous reviews have not fully synthesized the data on both agents. AIM To investigate the safety and efficacy of combining NMDA receptor antagonists (ketamine or esketamine) with propofol compared to propofol monotherapy for procedural sedation. METHODS Randomized controlled trials comparing NMDA antagonist-propofol combinations with propofol monotherapy were searched across PubMed, EMBASE, and ClinicalTrials.gov through June 2025. A random-effects model pooled risk ratios (RRs) and mean differences with 95% confidence intervals (CIs), and I2 statistics quantified heterogeneity, which was reduced through sensitivity, subgroup, and meta-regression analyses. RESULTS Nineteen randomized controlled trials (n = 8400+) were included, from which 13 assessed ketamine-propofol, while 6 assessed esketamine-propofol. Combination therapy significantly reduced hypotension (RR = 0.40; 95%CI: 0.26-0.60) and the need for respiratory interventions (RR = 0.73; 95%CI: 0.58-0.93), whereas hallucinations were significantly more frequent in the intervention cohort (RR = 2.24; 95%CI: 1.65-3.03). No significant differences were observed for desaturation, apnea, recovery time, systolic/diastolic blood pressure, mean arterial pressure, or heart rate. Patient satisfaction was comparable across groups. Sensitivity and subgroup analyses confirmed the strength of the key findings, and meta-regression revealed an increased risk of hypotension with higher propofol dosing, which was reduced with higher ketamine dosing. CONCLUSION NMDA antagonist-propofol regimen improves hemodynamic safety and reduces respiratory interventions in procedural sedation and analgesia compared to propofol, but is associated with a higher risk of hallucinations. These findings support the selective use of this approach, with dosing strategies justifying further modifications.