We appreciate the points raised by Dr. Deem. Our manuscript addresses the differences in infusion duration. 1To briefly recapitulate: this was a double-blind, randomized study. Occasionally randomization fails to divide patient covariates evenly between groups. The smaller the study, and the more covariates considered, the more likely it is that not all covariates will be evenly divided between groups. Since randomization failed to provide similar durations of infusions, we used a model-based approach to draw clinical inference from the fundamental PK/PD characteristics. Those inferences support our conclusions. The half-lives reported for midazolam (10 h) and lorazepam (16 h) in our manuscript are consistent with the published PK of midazolam 2–7and lorazepam. 7–12
As explained in the manuscript, fentanyl was administered by target-controlled infusion, set to 1.5 ng/ml. Because this was a randomized study, the concept of “standardizing analgesic regimens between groups” is irrelevant. There was no difference in the fentanyl administered to the two groups, nor in the “success of the associated analgesic regimen.”
Swart et al . reported that 5 of 6 patients with delayed midazolam elimination had been treated with erythromycin for more than 2 days. 7Obviously such patients should be treated with drugs not metabolized by CYP 3A4, such as lorazepam. Absent those patients, the variability in midazolam and lorazepam reported by Swart was similar to what we observed in our patients, none of who received erythromycin. We cannot explain why Swart et al . were unable to achieve the desired level of sedation with midazolam, despite average infusions rates of 16 mg/hr. In our experience, adequate sedation, including complete unconsciousness, can be achieved with either drug, and at far lower doses of midazolam than reported by Swart.
As Dr. Deem notes, Swart et al report a 15-fold difference in infusion rates between midazolam and lorazepam. This is much higher than in our study or in other published comparisons of midazolam and lorazepam in the intensive care unit. 13,14Of note, the dosing differences for midazolam and lorazepam reported by Swart et al . correspond exactly with the concentration differences of drugs in their syringes: 0.33 mg/ml of lorazepam versus 5 mg/ml of midazolam. Swart et al . titrated to deep levels of sedation, where drug effect is difficult to assess precisely. In this study design, lack of precise titration to drug effect would be expected to produce a 15-fold potency difference by default. We believe this is the most likely explanation for their anomalous results.
Our manuscript documents that both midazolam and lorazepam are effective drugs for intensive care unit sedation, and provides guidelines in administering them to achieve comparable results. We did not address which drug was cheaper in the long run, which is a complex question involving far more than drug acquisition costs.