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Does postoperative use of scheduled intravenous acetaminophen (paracetamol), combined with intravenous propofol or dexmedetomidine, reduce the risk of postoperative delirium among older patients undergoing cardiac surgery?
In this randomized clinical trial that included 120 patients undergoing cardiac surgery, scheduled intravenous acetaminophen administered postoperatively for 48 hours, combined with intravenous propofol or dexmedetomidine as a sedative, significantly reduced in-hospital delirium compared with placebo (10% vs 28%, respectively).
In older patients undergoing cardiac surgery, postoperative use of scheduled intravenous acetaminophen, combined with intravenous propofol or dexmedetomidine, may be considered to reduce the incidence of postoperative delirium, although additional research is needed.
Postoperative delirium is common following cardiac surgery and may be affected by choice of analgesic and sedative.
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.
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.
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, 10 082.5 vs 12 609.0 µg morphine equivalents; difference, −2530 [95% CI, −5064 to −22]). For dexmedetomidine vs propofol, only breakthrough analgesia was significantly different (median, 10 110.0 vs 12 612.5 µg; difference, −2567 [95% CI, −5094 to −26]; P = .03). 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.
ClinicalTrials.gov Identifier: NCT02546765
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Corresponding Author: Balachundhar Subramaniam, MD, MPH, Beth Israel Deaconess Medical Center, 375 Longwood Ave, W/MS-414, Boston, MA 02215 (firstname.lastname@example.org).
Accepted for Publication: January 16, 2019.
Correction: This article was corrected on July 16, 2019, for incorrect data in the Abstract, Results, Tables, and eFigures due to an incorrect conversion factor.
Author Contributions: Dr Subramaniam had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Subramaniam, Banner-Goodspeed, Gallagher, Talmor, Marcantonio.
Acquisition, analysis, or interpretation of data: Subramaniam, Shankar, Shaefi, Mueller, O’Gara, Banner-Goodspeed, Gasangwa, Patxot, Packiasabapathy, Mathur, Eikermann, Marcantonio.
Drafting of the manuscript: Subramaniam, Shankar, Shaefi, Mueller, O’Gara, Packiasabapathy, Mathur, Eikermann.
Critical revision of the manuscript for important intellectual content: Subramaniam, Shaefi, Mueller, O’Gara, Banner-Goodspeed, Gallagher, Gasangwa, Patxot, Packiasabapathy, Eikermann, Talmor, Marcantonio.
Statistical analysis: Mueller, Eikermann.
Obtained funding: Subramaniam, Banner-Goodspeed, Marcantonio.
Administrative, technical, or material support: Subramaniam, Shankar, Shaefi, Mueller, Banner-Goodspeed, Gasangwa, Patxot, Mathur, Talmor, Marcantonio.
Supervision: Subramaniam, Shaefi, O’Gara, Banner-Goodspeed, Gallagher, Talmor, Marcantonio.
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.
Funding/Support: The study was funded by Mallinckrodt Pharmaceuticals: funds were allotted to support time and effort of study personnel, sample acquisition, processing, storage, and regulatory compliance and to assist in paying for the study drugs and placebo.
Role of the Funder/Sponsor: Mallinckrodt Pharmaceuticals had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The authors had sole authority for the data, analysis, write-up, and submission.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the cardiothoracic surgeons for their support to help complete this study and members of the Center for Anesthesia Research Excellence within the Department of Anesthesia at Beth Israel Deaconess Medical Center (BIDMC), who supported protocol implementation, compliance, and adherence throughout this clinical trial. We also thank the nurses from the cardiovascular ICU and cardiac surgical floors at BIDMC, as well as the BIDMC Society for Thoracic Surgeons Database Outcomes Manager.
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