Effects of s-ketamine and midazolam on respiratory variability: A randomized controlled pilot trial

S-ketamine and midazolam are frequently used to provide sedation while maintaining spontaneous respiration. However, the effects of these agents on respiratory variability, which reflects the adaptability of the respiratory system, have not been thoroughly explored. We evaluated these effects in a randomized controlled pilot trial. This study was conducted as part of a randomized controlled trial originally designed to assess the effects of s-ketamine conditioning on pain sensitivity in patients with fibromyalgia syndrome. Participants were randomly assigned to receive an infusion of either s-ketamine (0.3 mg kg-1 h-1), midazolam (0.05 mg kg-1 h-1), or saline in a blinded fashion. Mean respiratory rate, variability of respiratory rate (VRR), and variability of tidal volume (VTV) were measured continuously and non-invasively with a bio-impedance method. Changes during drug infusion were compared in a linear mixed model to assess the effects of s-ketamine and midazolam compared to saline. Data were analyzed for 57 experiments in 28 participants. Their median baseline variabilities of respiratory rate and tidal volume were 0.19 (IQR: 0.16-0.25) and 0.23 (0.19-0.34), respectively. While mean respiratory rate was not affected, midazolam resulted in a significant decrease in both VRR (ß = -0.071, 95% CI: -0.120 to -0.021) and VTV (ß = -0.117, 95% CI: -0.170 to -0.062). In contrast, s-ketamine appeared to produce a smaller decrease in VTV (ß = -0.062, 95% CI: -0.118 to -0.003) with VRR remaining unaffected (ß = -0.036, 95% CI: -0.092 to 0.019). In conclusion, our study demonstrates that midazolam reduces respiratory variability, potentially impairing the adaptability of the respiratory system. In contrast, s-ketamine largely preserved respiratory variability, suggesting it may be a safer alternative for sedation in patients with impaired spontaneous breathing. Further studies are needed to assess the clinical implications of these observations in patients undergoing sedation.