Impact of Dexmedetomidine Supplemented Analgesia on Delirium in Patients Recovering From Orthopedic Surgery

A Randomized Controlled Trial

Hong Hong; Da-Zhi Zhang; Mo Li; Geng Wang; Sai-Nan Zhu; Yue Zhang; Dong-Xin Wang; Daniel I. Sessler


BMC Anesthesiol. 2021;21(223) 

In This Article


The trial started on October 28, 2018. From that time to December 6, 2019, 2,817 patients were screened for eligibility, among whom 712 patients were enrolled and randomly assigned to receive either dexmedetomidine (n = 356) or placebo (n = 356). Surgeries were cancelled in 2 patients, protocol deviation occurred in 12 patients. Specifically, study drug administration was modified in 9 patients, age was < 65 years in 2 patients, the surgical procedure changed in 1 patient. There was never need to unmask the study drug, and no assessment was aborted due to deep sedation. A total of 710 patients who were randomized and underwent surgeries were included in the intention-to-treat analysis. Per-protocol analysis included 698 patients who completed the study according to the established protocol (Figure 1). Thirty-day follow-up of the last participant finished on January 5, 2020.

Figure 1.

Trial diagram. OSAS, obstructive sleep apnea syndrome; PCA, patient-controlled analgesia

The two groups were well balanced on baseline characteristics (Table 1). Intra-operative variables were similar in each group, as were postoperative sufentanil use and use of supplemental analgesics, hypnotics, and antiemetics over the initial 5 postoperative days. In patients assigned to dexmedetomidine, the mean infusion rate was 0.026 μg·kg−1·h−1 (Table 2).

Postoperative delirium occurred in 26 of 354 (7.3%) of patients given placebo and in 17 of 356 (4.8%) of those given dexmedetomidine: relative risk 0.65, 95% CI 0.36 to 1.18, P = 0.151. In the per-protocol analysis, 26 of 347 (7.5%) of the patients given placebo and 17 of 351 (4.8%) of those given dexmedetomidine: relative risk 0.65, 95% CI 0.36 to 1.17, P = 0.145. Hypoactive delirium was most common in both groups (Table 3). In a post-hoc analysis, the prevalence of delirium was slightly lower in patients given dexmedetomidine [12 of 356 (3.4%)] than in those given placebos on the first postoperative day [23 of 354 (6.5%)], but the difference was not statistically significant (relative risk 0.519, 95% CI 0.262 to 1.026, P = 0.054; Supplemental Figure S1). Pre-defined sub-group analyses are presented in Supplemental Figure S2. No sub-group interactions were statistically significant.

Pain severity at rest was lower in the dexmedetomidine group than in the placebo group across the first 5 postoperative days, with the median difference being -1 to 0 points, P ≤ 0·001; among these, the differences were clinically significant at 3 time-points, i.e., day 1 afternoon, day 2 morning, and day 2 afternoon. Pain severity during movement was also lower in the dexmedetomidine group across the first 5 postoperative days, with a median difference -1 points, P < 0·001; the differences were clinically significant at all 10 time-points. Subjective sleep quality was better in patients given dexmedetomidine than placebo during the initial 3 postoperative days (day 1: median difference -1, 95% CI -1 to 0 points, P = 0.007; day 2: median difference 0, 95% CI -1 to 0 points, P = 0.010; day 3: median difference 0, 95% CI -1 to 0 points, P = 0.003); among these, the improvement on day 1 was clinically significant. RAAS scores were similar in dexmedetomidine and placebo patients throughout the first 5 postoperative days (Figure 2, Supplemental Table S1).

Figure 2.

Comparison of the NRS pain score at rest (A) and with movement (B), and the NRS of subjective sleep quality (C) between groups. The box and whiskers plots show medians, interquartile ranges and outer ranges, and individual points mean mild outliers (○, which are outside 1.5 times of interquartile range) and extreme outliers (▽, which are outside 3 times of interquartile range). NRS, numeric rating scale. DEX, dexmedetomidine

Regarding other secondary outcomes after surgery, sufentanil equivalent dose within 5 days, use of non-steroidal anti-inflammatory drugs within 5 days, length of hospital stays, and non-delirium complications within 30 days did not differ between the two groups. No patient died within 30 days. At 30 days after surgery, physical (mean difference 3.8, 95% CI 1.6 to 5.9, P = 0.001) and psychological (mean difference 2.8, 95% CI 1.0 to 4.7, P = 0.002) components of the WHOQOL-BREF were both better in dexmedetomidine than placebo patients, but the differences were too small to be clinically important. The social and environment domains of the WHOQOL-BREF and the TICS-m score did not differ significantly (Table 3, Supplemental Table S2). The incidence of adverse events was similar in the two groups. No severe adverse events occurred during the study period (Table 4).