ED50 and ED90 of intravenous hydromorphone in ICU patient without mechanical ventilation: A Prospective Dose-Finding Study Using Up-and- Down Sequential Allocation Method

Background The primary objective of this study was to determine the effective dose of intravenous hydromorphone for analgesia in 50% and 90% of non-mechanically ventilated patients (ED50 and ED90) and identify the optimal dose. Patients and Methods: Consenting participants were randomized to receive hydromorphone infusion with doses titrated hourly using the up-and-down method (for ED50) or a biased coin design up-and-down method (for ED90). The starting dose was 0.2 mg/h, with increments of 0.05 mg/h. Effective analgesia was defined as numeric rating scores ≤ 3 without rescue hydromorphone within 24 hours. Probit and isotonic regression were employed to estimate ED50 and ED90. Results Data from 60 patients were analyzed (22 in ED50 group, 38 in ED90 group). Vital signs remained stable within 30 minutes of loading dose administration. The ED50 and ED90 of hydromorphone infusion were 0.106 mg/h (95% CI, 0.058–0.136 mg/h) and 0.153 mg/h (95% CI, 0.128–0.260 mg/h) via probit regression, and 0.107 mg/h (95% CI, 0.075–0.147 mg/h) and 0.175 mg/h (95% CI, 0.148–0.240 mg/h) via isotonic regression. No adverse events occurred. Hydromorphone blood concentration correlated with analgesia efficacy (P < 0.05), but metabolites did not differ between groups. Conclusion For safe and effective analgesia in non-mechanically ventilated critically ill patients, the ED50 and ED90 of hydromorphone were 0.106 mg/h and 0.175 mg/h, respectively. The recommended dose is 0.175 mg/h. Trial registration: NCT04436224 (registered June 12, 2020)