4 Oliceridine respiratory effects ˙V E55 versus Slope of the Hypercapnic Ventilatory Response We measured the non–steady-state ventilatory response to carbon dioxide according to Read,16 Rebuck,17 and Florianet al.18 Rather than using the slope of the response curve as our primary endpoint, we used ventilation at an end-tidal PCO2of 55 mmHg ( ˙VE55) calculated from the slope (S) and the x-axis intercept (B) as follows: ˙VE55= [S ×(55 – B)]; S and B are estimated from the regression of the breath-to-breath Pco2 ventilation data. As is apparent from the formula, ˙VE55 considers the slope and the position of the hypercapnic response curve. Opioids are known to decrease the slope and shift the response curve to the right, both of which are signs of respiratory depression. We and others earlier used ˙VE55 to reliably express opioid effects on ventilatory control. 18,20,23We chose a rebreathing rather than a steady-state technique to quantify the opioid effect on the hypercapnic ventilatory response to enable rapid and frequent testing over time. The steady-state technique is more cumbersome and takes 30 to 40 min to complete.20 We previously argued that, in contrast to the steady-state technique, the rebreathing technique causes a reduction of the response slope due to a decrease in the differences between end-tidal (and arterial) PCO2 and the content in the rebreathing balloon (7%) after opioid administration.45,46 However, the opioid-induced rise in end-tidal is due to the opioid respiratory effect, and, consequently, the reduced slope is a sign of respiratory depression that becomes apparent because of methodologic issues. A reduced slope is often not observed using a nonrebreathing steady-state technique.47 Interestingly, opioids cause a rightward shift of the steady-state hypercapnic response curve, but the effect of opioids on ˙VE55 seems independent of the method used to measure the hypercapnic ventilatory response.48 In conclusion, our population pharmacokinetic–pharmacodynamic analysis, performed in older individuals, shows that oliceridine has a more rapid onset/offset of respiratory depression, as defined by parameter t1/2ke0, combined with a 30% lesser potency for respiratory depression, as defined by parameter C50, than morphine. 91
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