Clinical trial NCT03120442: Postoperative Delirium After Total Knee Arthroplasty Under Regional Anesthesia
Official title: Postoperative Delirium After Total Knee Arthroplasty Under Regional Anesthesia: a Comparison Between Intraoperative Sedation With Fentanyl, Fentanyl-dexmedetomidine and Fentanyl-propofol
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Postoperative Delirium
Keywords: postoperative delirium
total knee arthroplasty
propofol
dexmedetomidine
fentanyl
inflammatory response
interleukins
CAM-ICU
Lead sponsor: Mahidol University
Sponsor class: OTHER
First posted: 2017-04-19
Enrollment: 600
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Postoperative delirium after total knee replacement surgery has been related to significant morbidity and mortality among high risk patients. Anesthetic care might play a role in the development of postoperative delirium.

The purpose of this study is to compare the incidence of postoperative delirium between different intraoperative sedation regimen. Delirium assessment using standardized screening tools will be done every 8 hours after surgery.

Detailed description: * In this randomized controlled trial, the investigator will compare the incidence of postoperative delirium after total knee arthroplasty between 3 intraoperative sedation regimens including (1) propofol-fentanyl (2) dexmedetomidine -fentanyl (3) fentanyl alone
* Anesthesia techniques include spinal anesthesia and adductor canal block for postoperative analgesia. Sedation will be provide per group assignment.
* After performance of regional anesthesia, sedation protocols will be used as followed: (1) target-controlled infusion of Propofol to achieve MOAA/S of 3-4 (2) incremental titration of Dexmedetomidine to achieve MOAA/S of 3-4 (3) supplemental fentanyl for anxiolysis.
* Delirium will be screened by trained physicians, registered nurses every 8 hours postoperatively with validated Thai-version CAM-ICU (Confusion Assessment Method-Intensive Care Unit) until patient discharge.
* Serum Interleukins (IL-1, IL-6) Tumor necrosis factor-Alpha and S100B protein from preoperative period will be compared with serum from postoperative period between delirium and non-delirium group. The level of serum biomarkers will be acquired in a 6-hour interval for 5 measurement points during the first postoperative day in the first 12 participants. The subsequent participants will have 1 measurement of serum biomarker during the first postoperative day.
* Genetic profile for ApolipoproteinE genotype will be acquired and compared between delirium and non-delirium group.

Eligibility criteria: Inclusion Criteria:

* Age 65 year or older
* Scheduled for elective primary total knee arthroplasty

Exclusion Criteria:

* Contraindication for spinal anesthesia
* Contraindication for adductor canal block
* Allergy to fentanyl or propofol or dexmedetomidine or bupivacaine
* Cognitive impairment
* NSQIP database risk calculator \> 10% overall complication
* Unable to communicate in Thai language
* Significant visual and hearing impairment

Primary outcomes:
measure: Incidence of postoperative delirium
timeFrame: Up to 7 days
Secondary outcomes:
measure: The effect of age on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: Apolipoprotein genotype
timeFrame: 1 days
measure: The effect of Apolipoprotein genotype on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: Inflammatory biomarker
timeFrame: 2 days
measure: The effect of delirium on inflammatory biomarker levels
timeFrame: Up to 7 days
measure: The effect of gender on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of ASA-physical status on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of alcohol consumption on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of cognitive inpairment on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of coronary artery disease on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of cerebrovascular disease on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of chronic kidney disease on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of liver disease on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of hypertension on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of diabetes mellitus on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of postoperative pain on the incidence of postoperative delirium
timeFrame: Up to 7 days
measure: The effect of intraoperative BIS value on the incidence of postoperative delirium
timeFrame: 7 days
measure: The effect of intraoperative blood transfusion and blood loss on the incidence of postoperative delirium
timeFrame: 7 days
measure: The effect of delirium on hospital length of stay
timeFrame: 7 days
measure: The effect of delirium on postoperative rehabilitation
timeFrame: 7 days
measure: The effect of delirium on postoperative complications.
timeFrame: 7 days
Other outcomes:
Locations:
city: Bangkok noi
country: Thailand
facility: Siriraj Hospital
state: Bangkok
Study officials:
References:
citation: Gleason LJ, Schmitt EM, Kosar CM, Tabloski P, Saczynski JS, Robinson T, Cooper Z, Rogers SO Jr, Jones RN, Marcantonio ER, Inouye SK. Effect of Delirium and Other Major Complications on Outcomes After Elective Surgery in Older Adults. JAMA Surg. 2015 Dec;150(12):1134-40. doi: 10.1001/jamasurg.2015.2606.
citation: da Silva RR, Santos AA, de Sampaio Carvalho Junior J, Matos MA. Quality of life after total knee arthroplasty: systematic review. Rev Bras Ortop. 2014 Sep 19;49(5):520-7. doi: 10.1016/j.rboe.2014.09.007. eCollection 2014 Sep-Oct.
citation: Rade MC, Yadeau JT, Ford C, Reid MC. Postoperative delirium in elderly patients after elective hip or knee arthroplasty performed under regional anesthesia. HSS J. 2011 Jul;7(2):151-6. doi: 10.1007/s11420-011-9195-2. Epub 2011 Feb 11.
citation: Kinjo S, Lim E, Sands LP, Bozic KJ, Leung JM. Does using a femoral nerve block for total knee replacement decrease postoperative delirium? BMC Anesthesiol. 2012 Mar 10;12:4. doi: 10.1186/1471-2253-12-4.
citation: Yen TE, Allen JC, Rivelli SK, Patterson SC, Metcalf MR, Flink BJ, Mirrakhimov AE, Lagoo SA, Vail TP, Young CC, Moon RE, Trzepacz PT, Kwatra MM. Association between Serum IGF-I levels and Postoperative Delirium in Elderly Subjects Undergoing Elective Knee Arthroplasty. Sci Rep. 2016 Feb 5;6:20736. doi: 10.1038/srep20736.
citation: Liang CK, Chu CL, Chou MY, Lin YT, Lu T, Hsu CJ, Chen LK. Interrelationship of postoperative delirium and cognitive impairment and their impact on the functional status in older patients undergoing orthopaedic surgery: a prospective cohort study. PLoS One. 2014 Nov 17;9(11):e110339. doi: 10.1371/journal.pone.0110339. eCollection 2014.
citation: Liang CK, Chu CL, Chou MY, Lin YT, Lu T, Hsu CJ, Lam HC, Chen LK. Developing a Prediction Model for Post-Operative Delirium and Long-Term Outcomes Among Older Patients Receiving Elective Orthopedic Surgery: A Prospective Cohort Study in Taiwan. Rejuvenation Res. 2015 Aug;18(4):347-55. doi: 10.1089/rej.2014.1645.
citation: Nandi S, Harvey WF, Saillant J, Kazakin A, Talmo C, Bono J. Pharmacologic risk factors for post-operative delirium in total joint arthroplasty patients: a case-control study. J Arthroplasty. 2014 Feb;29(2):268-71. doi: 10.1016/j.arth.2013.06.004. Epub 2013 Jul 5.
citation: Scott JE, Mathias JL, Kneebone AC. Incidence of delirium following total joint replacement in older adults: a meta-analysis. Gen Hosp Psychiatry. 2015 May-Jun;37(3):223-9. doi: 10.1016/j.genhosppsych.2015.02.004. Epub 2015 Feb 23.
citation: Vasunilashorn SM, Ngo L, Inouye SK, Libermann TA, Jones RN, Alsop DC, Guess J, Jastrzebski S, McElhaney JE, Kuchel GA, Marcantonio ER. Cytokines and Postoperative Delirium in Older Patients Undergoing Major Elective Surgery. J Gerontol A Biol Sci Med Sci. 2015 Oct;70(10):1289-95. doi: 10.1093/gerona/glv083. Epub 2015 Jul 27.
citation: Fournier A, Krause R, Winterer G, Schneider R. Biomarkers of postoperative delirium and cognitive dysfunction. Front Aging Neurosci. 2015 Jun 9;7:112. doi: 10.3389/fnagi.2015.00112. eCollection 2015.
citation: Peng L, Xu L, Ouyang W. Role of peripheral inflammatory markers in postoperative cognitive dysfunction (POCD): a meta-analysis. PLoS One. 2013 Nov 13;8(11):e79624. doi: 10.1371/journal.pone.0079624. eCollection 2013.
citation: Tomaszewski D. Biomarkers of Brain Damage and Postoperative Cognitive Disorders in Orthopedic Patients: An Update. Biomed Res Int. 2015;2015:402959. doi: 10.1155/2015/402959. Epub 2015 Aug 31.
citation: Hirsch J, Vacas S, Terrando N, Yuan M, Sands LP, Kramer J, Bozic K, Maze MM, Leung JM. Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery. J Neuroinflammation. 2016 Aug 30;13(1):211. doi: 10.1186/s12974-016-0681-9.
citation: Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet. 2014 Mar 8;383(9920):911-22. doi: 10.1016/S0140-6736(13)60688-1. Epub 2013 Aug 28.
citation: van Munster BC, Bisschop PH, Zwinderman AH, Korevaar JC, Endert E, Wiersinga WJ, van Oosten HE, Goslings JC, de Rooij SE. Cortisol, interleukins and S100B in delirium in the elderly. Brain Cogn. 2010 Oct;74(1):18-23. doi: 10.1016/j.bandc.2010.05.010. Epub 2010 Jun 26.
citation: Krenk L, Rasmussen LS, Hansen TB, Bogo S, Soballe K, Kehlet H. Delirium after fast-track hip and knee arthroplasty. Br J Anaesth. 2012 Apr;108(4):607-11. doi: 10.1093/bja/aer493. Epub 2012 Jan 24.
citation: Krenk L, Kehlet H, Baek Hansen T, Solgaard S, Soballe K, Rasmussen LS. Cognitive dysfunction after fast-track hip and knee replacement. Anesth Analg. 2014 May;118(5):1034-40. doi: 10.1213/ANE.0000000000000194.
citation: Orena EF, King AB, Hughes CG. The role of anesthesia in the prevention of postoperative delirium: a systematic review. Minerva Anestesiol. 2016 Jun;82(6):669-83. Epub 2016 Jan 28.
citation: Djaiani G, Silverton N, Fedorko L, Carroll J, Styra R, Rao V, Katznelson R. Dexmedetomidine versus Propofol Sedation Reduces Delirium after Cardiac Surgery: A Randomized Controlled Trial. Anesthesiology. 2016 Feb;124(2):362-8. doi: 10.1097/ALN.0000000000000951.
citation: 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.
citation: Liu Y, Ma L, Gao M, Guo W, Ma Y. Dexmedetomidine reduces postoperative delirium after joint replacement in elderly patients with mild cognitive impairment. Aging Clin Exp Res. 2016 Aug;28(4):729-36. doi: 10.1007/s40520-015-0492-3. Epub 2015 Nov 11.
citation: Sieber FE, Zakriya KJ, Gottschalk A, Blute MR, Lee HB, Rosenberg PB, Mears SC. Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair. Mayo Clin Proc. 2010 Jan;85(1):18-26. doi: 10.4065/mcp.2009.0469.
citation: Chan MT, Cheng BC, Lee TM, Gin T; CODA Trial Group. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol. 2013 Jan;25(1):33-42. doi: 10.1097/ANA.0b013e3182712fba.
citation: Radtke FM, Franck M, Lendner J, Kruger S, Wernecke KD, Spies CD. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction. Br J Anaesth. 2013 Jun;110 Suppl 1:i98-105. doi: 10.1093/bja/aet055. Epub 2013 Mar 28.
citation: Ely EW, Girard TD, Shintani AK, Jackson JC, Gordon SM, Thomason JW, Pun BT, Canonico AE, Light RW, Pandharipande P, Laskowitz DT. Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients. Crit Care Med. 2007 Jan;35(1):112-7. doi: 10.1097/01.CCM.0000251925.18961.CA.
citation: Leung JM, Sands LP, Wang Y, Poon A, Kwok PY, Kane JP, Pullinger CR. Apolipoprotein E e4 allele increases the risk of early postoperative delirium in older patients undergoing noncardiac surgery. Anesthesiology. 2007 Sep;107(3):406-11. doi: 10.1097/01.anes.0000278905.07899.df.
citation: Cai Y, Hu H, Liu P, Feng G, Dong W, Yu B, Zhu Y, Song J, Zhao M. Association between the apolipoprotein E4 and postoperative cognitive dysfunction in elderly patients undergoing intravenous anesthesia and inhalation anesthesia. Anesthesiology. 2012 Jan;116(1):84-93. doi: 10.1097/ALN.0b013e31823da7a2.
citation: Ward A, Crean S, Mercaldi CJ, Collins JM, Boyd D, Cook MN, Arrighi HM. Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer's disease: a systematic review and meta-analysis. Neuroepidemiology. 2012;38(1):1-17. doi: 10.1159/000334607. Epub 2011 Dec 17.
citation: Gusmao-Flores D, Salluh JI, Chalhub RA, Quarantini LC. The confusion assessment method for the intensive care unit (CAM-ICU) and intensive care delirium screening checklist (ICDSC) for the diagnosis of delirium: a systematic review and meta-analysis of clinical studies. Crit Care. 2012 Jul 3;16(4):R115. doi: 10.1186/cc11407.
citation: Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, Speroff T, Gautam S, Bernard GR, Inouye SK. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001 Jul;29(7):1370-9. doi: 10.1097/00003246-200107000-00012.
citation: Pipanmekaporn T, Wongpakaran N, Mueankwan S, Dendumrongkul P, Chittawatanarat K, Khongpheng N, Duangsoy N. Validity and reliability of the Thai version of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Clin Interv Aging. 2014 May 29;9:879-85. doi: 10.2147/CIA.S62660. eCollection 2014.