Dexmedetomidine Supplemented Intravenous Analgesia in Elderly After Orthopedic Surgery

Impact of Dexmedetomidine Supplemented Intravenous Analgesia on Postoperative Delirium and Long-term Outcomes in Elderly After Orthopedic Surgery: A Multicenter, Double-blinded, Randomized Controlled Trial

Delirium is common in the elderly after orthopedic surgery and is associated with worse outcomes. The investigators hypothesize that, for elderly patients after orthopedic surgery, dexmedetomidine supplemented intravenous analgesia can reduce the incidence of delirium and improve the long-term outcomes.

Study Overview

• Status: Active, not recruiting
• Conditions: Analgesia; Postoperative Delirium; Elderly; Orthopedic Surgery; Dexmedetomidine; Long-term Outcome
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Placebo

Detailed Description

A growing number of elderly patients undergo orthopedic surgery each year. Delirium is a common complication in these patients after surgery and is associated with worse outcomes, including prolonged hospital stay, poor functional recovery, decreased cognitive function, increased health care costs, and elevated mortality rate. Previous studies showed that, for elderly patients admitted to the intensive care unit after non-cardiac surgery, low-dose dexmedetomidine infusion improved subjective sleep quality and reduced delirium early after surgery; it also increased survival up to 2 years and improved life quality in 3-year survivors. The investigators hypothesize that dexmedetomidine supplemented intravenous analgesia (in the form of patient-controlled analgesia) can also reduce delirium and improve long-term outcomes in elderly patients after orthopedic surgery.

• Study Type: Interventional
• Enrollment (Actual): 712
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Beijing Jishuitan Hospital
  • Beijing, China, 100034
    • Peking University First Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 89 years (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 65 years but < 90 years;
• Scheduled to undergo total knee/hip replacement surgery, or spinal surgery;
• Planned to use patient-controlled intravenous analgesia (PCIA) after surgery.

Exclusion Criteria:

• Refuse to participate in this study;
• Preoperative history of schizophrenia, epilepsy, Parkinsonism, or myasthenia gravis;
• Inability to communicate in the preoperative period because of coma, profound dementia or language barrier;
• Preoperative obstructive sleep apnea (diagnosed sleep apnea syndrome or a STOP-Bang score ≥3 combined with a serum bicarbonate ≥28 mmol/L);
• Sick sinus syndrome, severe sinus bradycardia (< 50 beats per minute), or second-degree or above atrioventricular block without pacemaker;
• Severe hepatic dysfunction (Child-Pugh class C);
• Severe renal dysfunction (requirement of renal replacement therapy before surgery);
• American Society of Anesthesiologists physical status >IV, or estimated survival ≤24 h.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine group; For patients in the dexmedetomidine group, postoperative analgesia is provided in the form of patient-controlled intravenous analgesia. The formula contains a mixture of sufentanil (1.25 ug/ml) and dexmedetomidine (1.25 ug/ml), diluted with normal saline to a total volume of 160 ml. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with a patient-controlled bolus of 2 ml each time and a lockout interval of 8 minutes.	Drug: Dexmedetomidine; Patients in this group receive patient-controlled intravenous analgesia for 1-3 days after surgery. The formula is a mixture of dexmedetomidine (1.25 ug/ml) and sufentanil (1.25 ug/ml), diluted with normal saline to 160 ml. 5-HT3 receptor antagonist is added when necessary. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with a bolus dose of 2 ml at each time and a lockout interval of 8 minutes.; Other Names: Sufentanil analgesia
Placebo Comparator: Control group; For patients in the control group, postoperative analgesia is provided in the form of patient-controlled intravenous analgesia. The formula contains a mixture of placebo and sufentanil (1.25 ug/ml), diluted with normal saline to a total volume of 160 ml. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with a patient-controlled bolus of 2 ml each time and a lockout interval of 8 minutes.	Drug: Placebo; Patients in this group receive patient-controlled intravenous analgesia for 1-3 days after surgery. The formula is a mixture of placebo and sufentanil (1.25 ug/m), diluted with normal saline to 160 ml. 5-HT3 receptor antagonist is added when necessary. The analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with a bolus dose of 2 ml at each time and a lockout interval of 8 minutes.; Other Names: Sufentanil analgesia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of delirium within the first 5 days after surgery	Incidence of delirium within the first 5 days after surgery	The first 5 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of stay in hospital after surgery	Length of stay in hospital after surgery	Up to 30 days after surgery
All-cause 30-day mortality	All-cause 30-day mortality	Up to 30 days after surgery
Cumulative sufentanil consumption within 5 postoperative days	Cumulative sufentanil consumption within 5 postoperative days	Up to 5 days after surgery
Daily prevalence of delirium during the first 5 days after surgery	Daily prevalence of delirium during the first 5 days after surgery	The first 5 days after surgery
Incidence of non-delirium complications with 30 days after surgery	Incidence of non-delirium complications with 30 days after surgery	Up to 30 days after surgery
Quality of life of 30-day survivors	Quality of life of 30-day survivors is assessed with World Health Organization Quality of Life brief version (WHOQOL-BREF), a 24-item questionnaire that provides assessments of the quality of life in physical, psychological, social relationship, and environmental domains. For each domain, the score ranges from 0 to 100, with higher score indicating better function.	At 30 days after surgery
Cognitive function of 30-day survivors	Cognitive function of 30-day survivors is assessed with the modified Telephone Interview for Cognitive Status (TICS-m), a 12-item questionnaire that provides an assessment of global cognitive function by verbal communication via telephone. The score ranges from 0 to 48, with higher score indicating better function.	At 30 days after surgery
Agitation or sedation level during postoperative days 1-5	Agitation or sedation level is assessed twice daily with the Richmond Agitation-Sedation Scale (RASS), of which the range is as follows: +4 (combative), +3 (very agitated), +2 (agitated), +1 (restless), 0 (alert and clam), -1 (drowsy), -2 (light sedation), -3 (moderate sedation), -4 (deep sedation), and -5 (unarousable).	The first 1-5 days after surgery
Pain severity during postoperative days 1-5	Pain severity is assessed with twice daily the Numeric Rating Scale (NRS), an 11 point scale where 0=no pain and 10=the worst possible pain.	The first 1-5 days after surgery
Subjective sleep quality during postoperative days 1-5	Subjective sleep quality is assessed once daily with the Numeric Rating Scale (NRS), an 11 point scale where 0=the best sleep and 10=the worst sleep.	The first 1-5 days after surgery
Overall survival for up to 3 years after surgery	Time from surgery to all-cause death for up to 3 years after surgery.	Up to 3 years after surgery
Event-free survival for up to 3 years after surgery	Time from surgery to new-onset diseases or all-cause death, whichever comes first. New-onset disease indicates those that required hospital admission and/or interventional procedure.	Up to 3 years after surgery
Quality of life in 1-，2- and 3-year survivors after surgery	Quality of life in 1-，2- and 3-year survivors is assessed with the WHOQOL-BREF, a 24-item questionnaire that provides assessments of the quality of life in physical, psychological, social relationship, and environmental domains. For each domain, the score ranges from 0 to 100, with higher score indicating better function.	At the end of the 1st, 2nd, and 3rd year after surgery
Cognitive function in 1-，2- and 3-year survivors after surgery	Cognitive function in 1-，2- and 3-year survivors is assessed with the TICS-m, a 12-item questionnaire that provides an assessment of global cognitive function by verbal communication via telephone. The score ranges from 0 to 48, with higher score indicating better function.	At the end of the 1st, 2nd, and 3rd year after surgery

Collaborators and Investigators

• Sponsor: Peking University First Hospital
• Collaborators: Beijing Jishuitan Hospital

Publications and helpful links

General Publications

• Dyer CB, Ashton CM, Teasdale TA. Postoperative delirium. A review of 80 primary data-collection studies. Arch Intern Med. 1995 Mar 13;155(5):461-5. doi: 10.1001/archinte.155.5.461.
• McDaniel M, Brudney C. Postoperative delirium: etiology and management. Curr Opin Crit Care. 2012 Aug;18(4):372-6. doi: 10.1097/MCC.0b013e3283557211.
• Mu DL, Wang DX, Li LH, Shan GJ, Li J, Yu QJ, Shi CX. High serum cortisol level is associated with increased risk of delirium after coronary artery bypass graft surgery: a prospective cohort study. Crit Care. 2010;14(6):R238. doi: 10.1186/cc9393. Epub 2010 Dec 30.
• Shi CM, Wang DX, Chen KS, Gu XE. Incidence and risk factors of delirium in critically ill patients after non-cardiac surgery. Chin Med J (Engl). 2010 Apr 20;123(8):993-9.
• Lat I, McMillian W, Taylor S, Janzen JM, Papadopoulos S, Korth L, Ehtisham A, Nold J, Agarwal S, Azocar R, Burke P. The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients. Crit Care Med. 2009 Jun;37(6):1898-905. doi: 10.1097/CCM.0b013e31819ffe38.
• Quinlan N, Rudolph JL. Postoperative delirium and functional decline after noncardiac surgery. J Am Geriatr Soc. 2011 Nov;59 Suppl 2:S301-4. doi: 10.1111/j.1532-5415.2011.03679.x.
• Lescot T, Karvellas CJ, Chaudhury P, Tchervenkov J, Paraskevas S, Barkun J, Metrakos P, Goldberg P, Magder S. Postoperative delirium in the intensive care unit predicts worse outcomes in liver transplant recipients. Can J Gastroenterol. 2013 Apr;27(4):207-12. doi: 10.1155/2013/289185.
• Abelha FJ, Luis C, Veiga D, Parente D, Fernandes V, Santos P, Botelho M, Santos A, Santos C. Outcome and quality of life in patients with postoperative delirium during an ICU stay following major surgery. Crit Care. 2013 Oct 29;17(5):R257. doi: 10.1186/cc13084.
• Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med. 2009 Dec 1;180(11):1092-7. doi: 10.1164/rccm.200904-0537OC. Epub 2009 Sep 10.
• Bickel H, Gradinger R, Kochs E, Forstl H. High risk of cognitive and functional decline after postoperative delirium. A three-year prospective study. Dement Geriatr Cogn Disord. 2008;26(1):26-31. doi: 10.1159/000140804. Epub 2008 Jun 24.
• Van Rompaey B, Schuurmans MJ, Shortridge-Baggett LM, Truijen S, Elseviers M, Bossaert L. Long term outcome after delirium in the intensive care unit. J Clin Nurs. 2009 Dec;18(23):3349-57. doi: 10.1111/j.1365-2702.2009.02933.x. Epub 2009 Sep 4.
• Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007 Jan;33(1):66-73. doi: 10.1007/s00134-006-0399-8. Epub 2006 Nov 11.
• Stuck A, Clark MJ, Connelly CD. Preventing intensive care unit delirium: a patient-centered approach to reducing sleep disruption. Dimens Crit Care Nurs. 2011 Nov-Dec;30(6):315-20. doi: 10.1097/DCC.0b013e31822fa97c.
• Siddiqi N, Harrison JK, Clegg A, Teale EA, Young J, Taylor J, Simpkins SA. Interventions for preventing delirium in hospitalised non-ICU patients. Cochrane Database Syst Rev. 2016 Mar 11;3:CD005563. doi: 10.1002/14651858.CD005563.pub3.
• Kosar CM, Tabloski PA, Travison TG, Jones RN, Schmitt EM, Puelle MR, Inloes JB, Saczynski JS, Marcantonio ER, Meagher D, Reid MC, Inouye SK. EFFECT OF PREOPERATIVE PAIN AND DEPRESSIVE SYMPTOMS ON THE DEVELOPMENT OF POSTOPERATIVE DELIRIUM. Lancet Psychiatry. 2014 Nov;1(6):431-436. doi: 10.1016/S2215-0366(14)00006-6.
• Halaszynski TM. Pain management in the elderly and cognitively impaired patient: the role of regional anesthesia and analgesia. Curr Opin Anaesthesiol. 2009 Oct;22(5):594-9. doi: 10.1097/ACO.0b013e32833020dc.
• Rudolph JL, Ramlawi B, Kuchel GA, McElhaney JE, Xie D, Sellke FW, Khabbaz K, Levkoff SE, Marcantonio ER. Chemokines are associated with delirium after cardiac surgery. J Gerontol A Biol Sci Med Sci. 2008 Feb;63(2):184-9. doi: 10.1093/gerona/63.2.184.
• Brummel NE, Girard TD. Preventing delirium in the intensive care unit. Crit Care Clin. 2013 Jan;29(1):51-65. doi: 10.1016/j.ccc.2012.10.007.
• Peng K, Liu HY, Wu SR, Cheng H, Ji FH. Effects of Combining Dexmedetomidine and Opioids for Postoperative Intravenous Patient-controlled Analgesia: A Systematic Review and Meta-analysis. Clin J Pain. 2015 Dec;31(12):1097-104. doi: 10.1097/AJP.0000000000000219.
• Su X, Meng ZT, Wu XH, Cui F, Li HL, Wang DX, Zhu X, Zhu SN, Maze M, Ma D. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016 Oct 15;388(10054):1893-1902. doi: 10.1016/S0140-6736(16)30580-3. Epub 2016 Aug 16.
• Zhang DF, Su X, Meng ZT, Li HL, Wang DX, Xue-Ying Li, Maze M, Ma D. Impact of Dexmedetomidine on Long-term Outcomes After Noncardiac Surgery in Elderly: 3-Year Follow-up of a Randomized Controlled Trial. Ann Surg. 2019 Aug;270(2):356-363. doi: 10.1097/SLA.0000000000002801.
• Mu DL, Zhang DZ, Wang DX, Wang G, Li CJ, Meng ZT, Li YW, Liu C, Li XY. Parecoxib Supplementation to Morphine Analgesia Decreases Incidence of Delirium in Elderly Patients After Hip or Knee Replacement Surgery: A Randomized Controlled Trial. Anesth Analg. 2017 Jun;124(6):1992-2000. doi: 10.1213/ANE.0000000000002095.
• Kalisvaart KJ, de Jonghe JF, Bogaards MJ, Vreeswijk R, Egberts TC, Burger BJ, Eikelenboom P, van Gool WA. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. J Am Geriatr Soc. 2005 Oct;53(10):1658-66. doi: 10.1111/j.1532-5415.2005.53503.x.
• Hong H, Zhang DZ, Li M, Wang G, Zhu SN, Zhang Y, Wang DX, Sessler DI. Impact of dexmedetomidine supplemented analgesia on delirium in patients recovering from orthopedic surgery: A randomized controlled trial. BMC Anesthesiol. 2021 Sep 13;21(1):223. doi: 10.1186/s12871-021-01441-3.

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2018
• Primary Completion (Actual): December 6, 2019
• Study Completion (Anticipated): December 7, 2022

Study Registration Dates

• First Submitted: August 8, 2018
• First Submitted That Met QC Criteria: August 13, 2018
• First Posted (Actual): August 14, 2018

Study Record Updates

• Last Update Posted (Actual): July 7, 2021
• Last Update Submitted That Met QC Criteria: July 5, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Elderly; Analgesia; Dexmedetomidine; Orthopedic Surgery; Postoperative Delirium; Long-term Outcome
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Analgesics, Opioid; Narcotics; Hypnotics and Sedatives; Adjuvants, Anesthesia; Dexmedetomidine; Sufentanil; Dsuvia
• Other Study ID Numbers: 2018-131; ChiCTR1800017182 (Registry Identifier: Chinese Clinical Trial Registry (www.chictr.org.cn))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No