Authors: van Lemmen, Maarten et al.
Anesthesiology, September 12, 2025. DOI: 10.1097/ALN.0000000000005710
This study explored how fentanyl affects ventilatory control when used alone—isolated from other anesthetics—to better understand its respiratory depressant effects in clinical settings. Despite widespread use of opioids in anesthesia, their direct influence on ventilation when not confounded by other agents is incompletely defined.
Twelve healthy volunteers received a series of intravenous fentanyl doses totaling 350 μg over 120 minutes, followed by continuous respiratory monitoring for an additional hour. Researchers measured minute ventilation, end-tidal CO₂, and arterial fentanyl levels while applying three pharmacokinetic–pharmacodynamic (PK-PD) modeling approaches: one focused on ventilation alone, one on end-tidal CO₂, and a physiologic “closed-loop” model integrating both variables along with CO₂ kinetics.
The physiologic model yielded a markedly lower and more realistic estimate of fentanyl potency—a 50% reduction in ventilation at a plasma concentration of 2.3 ± 0.5 ng/mL—compared to 7.5 ± 1.3 ng/mL in the simpler models. This discrepancy underscores how accounting for CO₂ feedback and ventilatory control dynamics enhances accuracy. The physiologic model also provided insight into the gain and timing of ventilatory response to hypercapnia, revealing a feedback time constant of approximately 2.4 minutes.
These findings suggest that traditional single-variable models likely overestimate the concentration of fentanyl required to cause ventilatory depression, which has implications for dosing safety, postoperative monitoring, and opioid titration.
What You Should Know:
Fentanyl’s ventilatory depressant effect is stronger than previously estimated when analyzed under physiologic modeling that accounts for CO₂ regulation. This refined approach may better reflect real-world anesthetic conditions and inform safer opioid dosing practices.
Thank you to Anesthesiology for publishing this detailed exploration of opioid pharmacodynamics and ventilatory control modeling.