Midazolam Reduces Breathing Flexibility, While S-Ketamine Preserves It: Pilot Trial Finds
Netherlands: Midazolam sedation can noticeably restrict the natural adaptability of breathing, while s-ketamine largely preserves it, a recent randomized controlled pilot study published in PLOS ONE has shown.
Researchers observed that midazolam significantly reduced the variability of both respiratory rate and tidal volume, resulting in a more uniform breathing pattern that may raise the risk of complications in patients with already fragile respiratory function. In contrast, s-ketamine showed only a minor effect on tidal volume variability and left respiratory rate variability largely unchanged, suggesting it could be the safer sedative when spontaneous breathing must be maintained.
The investigation was led by Oscar F. C. van den Bosch and colleagues from the Department of Anesthesiology at Amsterdam UMC, Vrije Universiteit, in the Netherlands. Their goal was to clarify how these commonly used sedatives influence the natural fluctuations in breathing—known as respiratory variability—which help the body adapt to changing demands.
The team enrolled 28 adults with fibromyalgia syndrome who were otherwise healthy. In a double-blind design, participants were randomly assigned to receive a continuous intravenous infusion of s-ketamine (0.3 mg kg⁻¹ h⁻¹), midazolam (0.05 mg kg⁻¹ h⁻¹), or saline as a control. Using a non-invasive bio-impedance method, the researchers continuously monitored mean respiratory rate along with two key indicators: variability of respiratory rate (VRR) and variability of tidal volume (VTV). Data from 57 experimental sessions were analyzed with a linear mixed model to account for repeated measures and missing data.
The study revealed the following findings:
- The average respiratory rate stayed stable across all groups.
- Midazolam caused a significant decrease in variability of respiratory rate (VRR) (β = −0.071).
- Midazolam also led to a marked reduction in variability of tidal volume (VTV) (β = −0.117), resulting in a more rigid breathing pattern.
- S-ketamine showed only a small decline in VTV (β = −0.062).
- S-ketamine left VRR statistically unaffected (β = −0.036).
- Overall, s-ketamine preserved much of the respiratory system’s natural variability and adaptability.
The authors cautioned that the pilot trial had limitations. Participants were fibromyalgia patients without significant lung disease, and respiratory data were incomplete for roughly one-fifth of sessions. Moreover, clinical sedation often involves multiple drugs or different dosing strategies. Despite these factors, the researchers believe the observed differences are relevant for broader patient populations, particularly those with compromised pulmonary function.
Overall, the study highlights a critical distinction between two frequently used sedatives. Midazolam’s tendency to dampen respiratory variability could pose added risks in settings such as intensive care or procedural sedation, where maintaining spontaneous, adaptable breathing is essential. S-ketamine, by preserving variability, may offer an advantage when clinicians require sedation without suppressing a patient’s natural respiratory responsiveness.
"Larger, multi-center trials are now needed to confirm these results and to explore their implications for anesthesiology and critical care practice," the authors concluded.
Reference:
Alvarez-Jimenez, R., M. Evers, A. W., H. Steegers, M. A., Schober, P., & Loer, S. A. (2025). Effects of s-ketamine and midazolam on respiratory variability: A randomized controlled pilot trial. PLOS ONE, 20(9), e0331358. https://doi.org/10.1371/journal.pone.0331358
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