Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial

Abstract

Importance: Postoperative delirium is common following cardiac surgery and may be affected by choice of analgesic and sedative.

Objective: To evaluate the effect of postoperative intravenous (IV) acetaminophen (paracetamol) vs placebo combined with IV propofol vs dexmedetomidine on postoperative delirium among older patients undergoing cardiac surgery.

Design, setting, and participants: Randomized, placebo-controlled, factorial clinical trial among 120 patients aged 60 years or older undergoing on-pump coronary artery bypass graft (CABG) surgery or combined CABG/valve surgeries at a US center. Enrollment was September 2015 to April 2018, with follow-up ending in April 2019.

Interventions: Patients were randomized to 1 of 4 groups receiving postoperative analgesia with IV acetaminophen or placebo every 6 hours for 48 hours and postoperative sedation with dexmedetomidine or propofol starting at chest closure and continued for up to 6 hours (acetaminophen and dexmedetomidine: n = 29; placebo and dexmedetomidine: n = 30; acetaminophen and propofol: n = 31; placebo and propofol: n = 30).

Main outcomes and measures: The primary outcome was incidence of postoperative in-hospital delirium by the Confusion Assessment Method. Secondary outcomes included delirium duration, cognitive decline, breakthrough analgesia within the first 48 hours, and ICU and hospital length of stay.

Results: Among 121 patients randomized (median age, 69 years; 19 women [15.8%]), 120 completed the trial. Patients treated with IV acetaminophen had a significant reduction in delirium (10% vs 28% placebo; difference, -18% [95% CI, -32% to -5%]; P = .01; HR, 2.8 [95% CI, 1.1-7.8]). Patients receiving dexmedetomidine vs propofol had no significant difference in delirium (17% vs 21%; difference, -4% [95% CI, -18% to 10%]; P = .54; HR, 0.8 [95% CI, 0.4-1.9]). There were significant differences favoring acetaminophen vs placebo for 3 prespecified secondary outcomes: delirium duration (median, 1 vs 2 days; difference, -1 [95% CI, -2 to 0]), ICU length of stay (median, 29.5 vs 46.7 hours; difference, -16.7 [95% CI, -20.3 to -0.8]), and breakthrough analgesia (median, 322.5 vs 405.3 µg morphine equivalents; difference, -83 [95% CI, -154 to -14]). For dexmedetomidine vs propofol, only breakthrough analgesia was significantly different (median, 328.8 vs 397.5 µg; difference, -69 [95% CI, -155 to -4]; P = .04). Fourteen patients in both the placebo-dexmedetomidine and acetaminophen-propofol groups (46% and 45%) and 7 in the acetaminophen-dexmedetomidine and placebo-propofol groups (24% and 23%) had hypotension.

Conclusions and relevance: Among older patients undergoing cardiac surgery, postoperative scheduled IV acetaminophen, combined with IV propofol or dexmedetomidine, reduced in-hospital delirium vs placebo. Additional research, including comparison of IV vs oral acetaminophen and other potentially opioid-sparing analgesics, on the incidence of postoperative delirium is warranted.

Trial registration: ClinicalTrials.gov Identifier: NCT02546765.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Subramaniam, Ms Banner-Goodspeed, and Dr Marcantonio reported receiving grant support from Mallinckrodt Pharmaceuticals for salary support during the conduct of the trial. Drs Subramaniam, Shaefi, Talmor, and Marcantonio reported receiving funds from the National Institutes of Health for unrelated work. Drs Shaefi and O’Gara reported receiving funding from the Foundation for Anesthesia and Education Research. No other disclosures were reported.

Figures

Figure 1.. Participant Flow in the DEXACET Randomized Clinical Trial

CABG indicates coronary artery bypass graft. To convert creatinine values to micromoles per liter, multiply by 88.4. aNumbers of participants who did not meet inclusion or exclusion criteria are nonexclusive.

Figure 2.. Post Hoc Pain Scores Stratified by Study Group

Median and worst daily pain scores are reported on a scale from 0 (best) to 10 (worst). Top and bottom of boxes indicate interquartile ranges; center lines indicate medians. Tukey error bars are shown, which extend to the farthest points that are not outliers. Outliers (black circles) were defined as values greater than 1.5 times the interquartile range.

Figure 3.. Post Hoc Kaplan-Meier Analysis for Time to Delirium

Patients in the acetaminophen-dexmedetomidine, placebo-dexmedetomidine, acetaminophen-propofol, and placebo-propofol groups were assessed for delirium on a median of 4 (interquartile range [IQR], 4-4) days, 4 (IQR, 4-5) days, 4 (IQR, 4-5) days, and 4 (IQR, 4-5) days, respectively.