Effect of Acetaminophen vs Placebo and Propofol vs Dexmedetomidine on Delirium After Cardiac Surgery | Anesthesiology | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

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

Educational Objective
To learn the effect of postoperative intravenous (IV) acetaminophen, combined with propofol or dexmedetomidine, on postoperative delirium among older adults following cardiac surgery.
1 Credit CME
Key Points

Question  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?

Findings  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).

Meaning  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.

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, 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.

Trial Registration  ClinicalTrials.gov Identifier: NCT02546765

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Author: Balachundhar Subramaniam, MD, MPH, Beth Israel Deaconess Medical Center, 375 Longwood Ave, W/MS-414, Boston, MA 02215 (bsubrama@bidmc.harvard.edu).

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.

References
1.
Rudolph  JL, Marcantonio  ER.  Review articles: postoperative delirium: acute change with long-term implications.  Anesth Analg. 2011;112(5):1202-1211. doi:10.1213/ANE.0b013e3182147f6dPubMedGoogle ScholarCrossref
2.
Inouye  SK, Westendorp  RG, Saczynski  JS.  Delirium in elderly people.  Lancet. 2014;383(9920):911-922. doi:10.1016/S0140-6736(13)60688-1PubMedGoogle ScholarCrossref
3.
Saczynski  JS, Marcantonio  ER, Quach  L,  et al.  Cognitive trajectories after postoperative delirium.  N Engl J Med. 2012;367(1):30-39. doi:10.1056/NEJMoa1112923PubMedGoogle ScholarCrossref
4.
Brown  CH.  Delirium in the cardiac surgical ICU.  Curr Opin Anaesthesiol. 2014;27(2):117-122. doi:10.1097/ACO.0000000000000061PubMedGoogle ScholarCrossref
5.
Morrison  RS, Magaziner  J, Gilbert  M,  et al.  Relationship between pain and opioid analgesics on the development of delirium following hip fracture.  J Gerontol A Biol Sci Med Sci. 2003;58(1):76-81. doi:10.1093/gerona/58.1.M76PubMedGoogle ScholarCrossref
6.
Gallagher  R.  Opioid-induced neurotoxicity.  Can Fam Physician. 2007;53(3):426-427.PubMedGoogle Scholar
7.
Santos  FS, Velasco  IT, Fráguas  R  Jr.  Risk factors for delirium in the elderly after coronary artery bypass graft surgery.  Int Psychogeriatr. 2004;16(2):175-193. doi:10.1017/S1041610204000365PubMedGoogle ScholarCrossref
8.
Graham  GG, Scott  KF.  Mechanism of action of paracetamol.  Am J Ther. 2005;12(1):46-55. doi:10.1097/00045391-200501000-00008PubMedGoogle ScholarCrossref
9.
O’Neal  JB.  The utility of intravenous acetaminophen in the perioperative period.  Front Public Health. 2013;1:25.PubMedGoogle ScholarCrossref
10.
Song  J, Ji  Q, Sun  Q, Gao  T, Liu  K, Li  L.  The opioid-sparing effect of intraoperative dexmedetomidine infusion after craniotomy.  J Neurosurg Anesthesiol. 2016;28(1):14-20. doi:10.1097/ANA.0000000000000190PubMedGoogle ScholarCrossref
11.
Li  B, Li  Y, Tian  S,  et al.  Anti-inflammatory effects of perioperative dexmedetomidine administered as an adjunct to general anesthesia: a meta-analysis.  Sci Rep. 2015;5:12342. doi:10.1038/srep12342PubMedGoogle ScholarCrossref
12.
Li  X, Yang  J, Nie  XL,  et al.  Impact of dexmedetomidine on the incidence of delirium in elderly patients after cardiac surgery: a randomized controlled trial.  PLoS One. 2017;12(2):e0170757. doi:10.1371/journal.pone.0170757PubMedGoogle ScholarCrossref
13.
Deiner  S, Luo  X, Lin  HM,  et al; Dexlirium Writing Group.  Intraoperative infusion of dexmedetomidine for prevention of postoperative delirium and cognitive dysfunction in elderly patients undergoing major elective noncardiac surgery: a randomized clinical trial.  JAMA Surg. 2017;152(8):e171505. doi:10.1001/jamasurg.2017.1505PubMedGoogle ScholarCrossref
14.
Su  X, Meng  ZT, Wu  XH,  et al.  Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial.  Lancet. 2016;388(10054):1893-1902. doi:10.1016/S0140-6736(16)30580-3PubMedGoogle ScholarCrossref
15.
Shankar  P, Mueller  A, Packiasabapathy  S,  et al.  Dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium following cardiac surgery (DEXACET trial): protocol for a prospective randomized controlled trial.  Trials. 2018;19(1):326. doi:10.1186/s13063-018-2718-0PubMedGoogle ScholarCrossref
16.
Alcántara Montero  A, Sánchez Carnerero  CI, Ibor Vidal  PJ, Alonso Verdugo  A.  CDC guidelines for prescribing opioids for chronic pain [in Spanish].  Semergen. 2017;43(4):e53-e54.PubMedGoogle ScholarCrossref
17.
Wong  GKC, Mak  JSY, Wong  A,  et al.  Minimum clinically important difference of Montreal Cognitive Assessment in aneurysmal subarachnoid hemorrhage patients.  J Clin Neurosci. 2017;46:41-44. doi:10.1016/j.jocn.2017.08.039PubMedGoogle ScholarCrossref
18.
Vasunilashorn  SM, Fong  TG, Albuquerque  A,  et al.  Delirium severity post-surgery and its relationship with long-term cognitive decline in a cohort of patients without dementia.  J Alzheimers Dis. 2018;61(1):347-358. doi:10.3233/JAD-170288PubMedGoogle ScholarCrossref
19.
Myles  PS, Myles  DB, Galagher  W,  et al.  Measuring acute postoperative pain using the visual analog scale: the minimal clinically important difference and patient acceptable symptom state.  Br J Anaesth. 2017;118(3):424-429. doi:10.1093/bja/aew466PubMedGoogle ScholarCrossref
20.
Susheela  AT, Packiasabapathy  S, Gasangwa  DV,  et al.  The use of dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium in cardiac surgery patients over 60 years of age: a pilot study.  F1000Res. 2017;6:1842. doi:10.12688/f1000research.12552.1PubMedGoogle ScholarCrossref
21.
Inouye  SK, Bogardus  ST  Jr, Charpentier  PA,  et al.  A multicomponent intervention to prevent delirium in hospitalized older patients.  N Engl J Med. 1999;340(9):669-676. doi:10.1056/NEJM199903043400901PubMedGoogle ScholarCrossref
22.
Mamoun  NF, Lin  P, Zimmerman  NM,  et al.  Intravenous acetaminophen analgesia after cardiac surgery: a randomized, blinded, controlled superiority trial.  J Thorac Cardiovasc Surg. 2016;152(3):881-889.e1. doi:10.1016/j.jtcvs.2016.04.078PubMedGoogle ScholarCrossref
23.
Jelacic  S, Bollag  L, Bowdle  A, Rivat  C, Cain  KC, Richebe  P.  Intravenous acetaminophen as an adjunct analgesic in cardiac surgery reduces opioid consumption but not opioid-related adverse effects: a randomized controlled trial.  J Cardiothorac Vasc Anesth. 2016;30(4):997-1004. doi:10.1053/j.jvca.2016.02.010PubMedGoogle ScholarCrossref
24.
Eremenko  AA, Kuslieva  EV.  Analgesic and opioid-sparing effects of intravenous paracetamol in the early period after aortocoronary bypass surgery [in Russian].  Anesteziol Reanimatol. 2008;(5):11-14.PubMedGoogle Scholar
25.
Pettersson  PH, Jakobsson  J, Owall  A.  Intravenous acetaminophen reduced the use of opioids compared with oral administration after coronary artery bypass grafting.  J Cardiothorac Vasc Anesth. 2005;19(3):306-309. doi:10.1053/j.jvca.2005.03.006PubMedGoogle ScholarCrossref
26.
Macario  A, Royal  MA.  A literature review of randomized clinical trials of intravenous acetaminophen (paracetamol) for acute postoperative pain.  Pain Pract. 2011;11(3):290-296. doi:10.1111/j.1533-2500.2010.00426.xPubMedGoogle ScholarCrossref
27.
Salluh  JI, Wang  H, Schneider  EB,  et al.  Outcome of delirium in critically ill patients: systematic review and meta-analysis.  BMJ. 2015;350:h2538. doi:10.1136/bmj.h2538PubMedGoogle ScholarCrossref
28.
Vaughns  JD, Martin  C, Nelson  J, Nadler  E, Quezado  ZM.  Dexmedetomidine as an adjuvant for perioperative pain management in adolescents undergoing bariatric surgery: an observational cohort study.  J Pediatr Surg. 2017;52(11):1787-1790. doi:10.1016/j.jpedsurg.2017.04.007PubMedGoogle ScholarCrossref
29.
Tufanogullari  B, White  PF, Peixoto  MP,  et al.  Dexmedetomidine infusion during laparoscopic bariatric surgery: the effect on recovery outcome variables.  Anesth Analg. 2008;106(6):1741-1748. doi:10.1213/ane.0b013e318172c47cPubMedGoogle ScholarCrossref
30.
Djaiani  G, Silverton  N, Fedorko  L,  et al.  Dexmedetomidine versus propofol sedation reduces delirium after cardiac surgery: a randomized controlled trial.  Anesthesiology. 2016;124(2):362-368. doi:10.1097/ALN.0000000000000951PubMedGoogle ScholarCrossref
31.
Dasta  JF, Jacobi  J, Sesti  AM, McLaughlin  TP.  Addition of dexmedetomidine to standard sedation regimens after cardiac surgery: an outcomes analysis.  Pharmacotherapy. 2006;26(6):798-805. doi:10.1592/phco.26.6.798PubMedGoogle ScholarCrossref
32.
Evered  L, Silbert  B, Knopman  DS,  et al; Nomenclature Consensus Working Group.  Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery—2018.  Br J Anaesth. 2018;121(5):1005-1012. doi:10.1016/j.bja.2017.11.087PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close