A recent study published in PLoS One found that s-ketamine maintained respiratory adaptability more effectively than midazolam during sedation procedures. The randomized controlled pilot trial examined the effects of these commonly used sedatives on respiratory variability, which reflects the respiratory system’s ability to adapt to changing physiological demands.
The investigation was conducted as part of a larger randomized controlled trial that originally assessed s-ketamine conditioning effects on pain sensitivity in fibromyalgia syndrome patients. A total of 57 experiments were performed across 28 participants who were randomly assigned to receive blinded infusions of either s-ketamine (0.3 mg kg-1 h-1), midazolam (0.05 mg kg-1 h-1), or saline control. The study revealed baseline median variabilities of respiratory rate and tidal volume were 0.19 (IQR: 0.16-0.25) and 0.23 (0.19-0.34), respectively. While neither sedative affected mean respiratory rate, midazolam produced significant reductions in both respiratory variability measures. Specifically, midazolam decreased VRR (ß = -0.071, 95% CI: -0.120 to -0.021) and VTV (ß = -0.117, 95% CI: -0.170 to -0.062), indicating reduced respiratory adaptability.
In contrast, s-ketamine demonstrated a more favorable respiratory profile. The agent produced only a minimal decrease in VTV (ß = -0.062, 95% CI: -0.118 to -0.003) while leaving VRR unaffected (ß = -0.036, 95% CI: -0.092 to 0.019). This preservation of respiratory variability suggested that s-ketamine maintained the respiratory system’s adaptive capacity during sedation. The findings indicated that midazolam’s reduction of respiratory variability resulted in more regular but less adaptable breathing patterns. This effect raised concerns for clinical scenarios where respiratory adaptability remained crucial, particularly in patients already at elevated risk for respiratory compromise. The study suggested that s-ketamine’s preservation of respiratory variability could offer clinical advantages in critically ill patients requiring sedation while maintaining spontaneous ventilation.
In anesthesiology, emergency medicine, and critical care, midazolam and s-ketamine are widely used but differ in their effects on respiration. Midazolam, a benzodiazepine that enhances GABA activity, can depress ventilation by lowering respiratory rate and tidal volume. In contrast, s-ketamine, an NMDA receptor antagonist, causes minimal respiratory depression and may even stimulate breathing under certain conditions. A systematic review conducted by Carvalho et al. evaluated the efficacy and safety of ketamine in treating fibromyalgia. The findings indicated that short-term studies reported significant reductions in pain scores on the visual analog scale. However, the only trial that followed participants for eight weeks did not show sustained benefits. While adverse effects were common, they were generally transient, occurring during the infusion and resolving shortly afterward. Overall, ketamine demonstrated short-term analgesic effectiveness with acceptable tolerability, but the evidence remains limited, and its long-term efficacy has not been confirmed.
The research highlighted important considerations for sedative selection in anesthesiology and intensive care settings. The differential effects on respiratory variability between these agents provided evidence that could influence clinical decision-making when choosing sedatives for patients with compromised respiratory function or those requiring prolonged sedation with preserved spontaneous breathing. The investigators concluded that further research was needed to evaluate these respiratory effects in critically ill patient populations and to better understand the clinical implications for sedative management protocols in intensive care and anesthesiology practice.
References
- van den Bosch OFC, van Lennep JPA, Alvarez-Jimenez R, van Middendorp H, Evers AWM, Steegers MAH, Schober P, Loer SA. Effects of s-ketamine and midazolam on respiratory variability: A randomized controlled pilot trial. PLoS One. 2025 Sep 4;20(9):e0331358.
- de Carvalho JF, de Sena EP. Ketamine in fibromyalgia: a systematic review. Adv Rheumatol. 2024 Jul 29;64(1):54.