The Influence of Postoperative Analgesia on Systemic Inflammatory Response and POCD After Femoral Fractures Surgery

The Influence of Postoperative Analgesia on Systemic Inflammatory Response and POCD After Femoral Fractures Surgery

The Influence of Postoperative Analgesia on Systemic Inflammatory Response and Postoperative Cognitive Disfunction in Elderly Patients After Surgical Repair of Femoral Fractures

The purpose of this study is to determine whether epidural levobupivacaine applied for the purpose of post-operative analgesia compared to systemic analgesia with morphine leads to better pain control, stronger suppression of the inflammatory response and the production of inflammatory mediators, faster recovery of patients and consequently less incidence of postoperative cognitive dysfunction (POCD) in elderly patients after surgical treatment of femoral fractures.

The research will be carried out at the Department of Surgery at Clinical Hospital Centre(CHC) Osijek after approval by the Ethics Committee of CHC Osijek and will be organized as a prospective randomized trial. Respecting the including and excluding criteria for participation in the study, the research will include 70 patients aged 65 years and over who are undergoing surgery for proximal femur fractures and will be operated with the same operating technique (osteosynthesis with nail). All participants will receive the same type of anesthesia and one of two forms of post-operative analgesia, so it will be divided into two groups (35 patients) depending on which form of post-operative analgesia receive. Randomization will be performed by drawing an envelope in which the specified one or other form of post-operative analgesia will be written. The study will be stopped in case of serious complications life-threatening (excessive sedation, respiratory insufficiency, hemodynamic instability and profound hypotension, heart rhythm disorders), which could possibly be related to the administration of drugs used for postoperative analgesia.

The patient-controlled intravenous analgesia with morphine (basal flow of 0.5-2 mg / h, bolus dose of 0.5 mg, lockout interval of 20 minutes, hour limit of 3 doses), which will be carried out 72 hours after the surgery

Upon completion of the operation for a period of 72 hours will be implemented continuous epidural local anesthetic through the Patient Controlled Analgesia (PCA) pump (Levobupivacaine 0.125%, basal flow of 6 ml / hour, a bolus dose of 2 ml, lockout interval of 20 minutes, hour limit of 3 doses).

Assessment of cognitive function will be done using the Mini-mental state examination (MMSE) rating scales before and 24,48,72,96 and 120 hours after the surgery at the same time every morning. Mini-Mental State Examination Scale: minimum score is 0 and maximum score is 30; the severity of cognitive impairment: no cognitive impairment=25-30; mild cognitive impairment=19-24; moderate cognitive impairment=10-18; and severe cognitive impairment<9. Higher scores mean a better and lower scores mean a worse outcome.

Assessment will be done using Numeric Rating Scale (NRS). During the first 72 hours after the surgery assessment will be done every 3 hours, after that assessment will be done 3 times daily. Median of 8 time points measurements during the first 24, 48 and 72 hours after the surgery will be reported. After that, median of 3 time points will be reported from the 4. to 6. postoperative day and on the day of discharge. Minimum score 0 and maximum score 10 ( 0-No Pain; 1-3 Mild Pain; 4-6 Moderate Pain; 7-10 Severe Pain ). Higher scores mean a worse and lower scores mean a better outcome.

During the first 72 hours after the surgery assessment will be done every 3 hours, after that assessment will be done 3 times daily until discharge

Inclusion Criteria: patients age 65 and over fracture of the proximal femur preoperative assessment American Society of Anesthesiologists(ASA) score I - ASA III a written consent of the patient to participate in research Exclusion Criteria: patient non-compliance ASA status IV and IV above patients younger than 65 years dementia, Parkinson's disease, cerebrovascular accident history; simultaneous head injuries,the use of opioids and benzodiazepines longer than a month before the surgery; alcoholism; serious liver disease (class C according to Child-Pugh's classification); severe kidney disease that require dialysis result of MMSE test (Mini-Mental State Examination) under 17 the existence of any contraindications for the implementation of regional anesthesia and one or other form of post-operative analgesia.

Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA. 2010 Jul 28;304(4):443-51. doi: 10.1001/jama.2010.1013.

Raats JW, van Eijsden WA, Crolla RM, Steyerberg EW, van der Laan L. Risk Factors and Outcomes for Postoperative Delirium after Major Surgery in Elderly Patients. PLoS One. 2015 Aug 20;10(8):e0136071. doi: 10.1371/journal.pone.0136071. eCollection 2015.

Wang W, Wang Y, Wu H, Lei L, Xu S, Shen X, Guo X, Shen R, Xia X, Liu Y, Wang F. Postoperative cognitive dysfunction: current developments in mechanism and prevention. Med Sci Monit. 2014 Oct 12;20:1908-12. doi: 10.12659/MSM.892485.

Vega P E, Nazar J C, Rattalino F M, Pedemonte T J, Carrasco G M. [Postoperative delirium among older people]. Rev Med Chil. 2014 Apr;142(4):481-93. doi: 10.4067/S0034-98872014000400010. Spanish.

Vacas S, Degos V, Feng X, Maze M. The neuroinflammatory response of postoperative cognitive decline. Br Med Bull. 2013;106(1):161-78. doi: 10.1093/bmb/ldt006. Epub 2013 Apr 4.

Zywiel MG, Prabhu A, Perruccio AV, Gandhi R. The influence of anesthesia and pain management on cognitive dysfunction after joint arthroplasty: a systematic review. Clin Orthop Relat Res. 2014 May;472(5):1453-66. doi: 10.1007/s11999-013-3363-2.

Kampe S, Weinreich G, Darr C, Eicker K, Stamatis G, Hachenberg T. The impact of epidural analgesia compared to systemic opioid-based analgesia with regard to length of hospital stay and recovery of bowel function: retrospective evaluation of 1555 patients undergoing thoracotomy. J Cardiothorac Surg. 2014 Nov 23;9:175. doi: 10.1186/s13019-014-0175-8.

Popping DM, Elia N, Van Aken HK, Marret E, Schug SA, Kranke P, Wenk M, Tramer MR. Impact of epidural analgesia on mortality and morbidity after surgery: systematic review and meta-analysis of randomized controlled trials. Ann Surg. 2014 Jun;259(6):1056-67. doi: 10.1097/SLA.0000000000000237.

Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012 Jul 5;367(1):30-9. doi: 10.1056/NEJMoa1112923.

Leslie DL, Marcantonio ER, Zhang Y, Leo-Summers L, Inouye SK. One-year health care costs associated with delirium in the elderly population. Arch Intern Med. 2008 Jan 14;168(1):27-32. doi: 10.1001/archinternmed.2007.4.

McDaniel M, Brudney C. Postoperative delirium: etiology and management. Curr Opin Crit Care. 2012 Aug;18(4):372-6. doi: 10.1097/MCC.0b013e3283557211.

Hansen MV. Chronobiology, cognitive function and depressive symptoms in surgical patients. Dan Med J. 2014 Sep;61(9):B4914.

Seitz DP, Adunuri N, Gill SS, Rochon PA. Prevalence of dementia and cognitive impairment among older adults with hip fractures. J Am Med Dir Assoc. 2011 Oct;12(8):556-564. doi: 10.1016/j.jamda.2010.12.001. Epub 2011 Mar 8.

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. Erratum In: Mayo Clin Proc. 2010 Apr;85(4):400. Dosage error in article text.

van Harten AE, Scheeren TW, Absalom AR. A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anaesthesia. Anaesthesia. 2012 Mar;67(3):280-93. doi: 10.1111/j.1365-2044.2011.07008.x.

Cunningham C. Systemic inflammation and delirium: important co-factors in the progression of dementia. Biochem Soc Trans. 2011 Aug;39(4):945-53. doi: 10.1042/BST0390945.

Steinman L. Modulation of postoperative cognitive decline via blockade of inflammatory cytokines outside the brain. Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20595-6. doi: 10.1073/pnas.1015282107. Epub 2010 Nov 22. No abstract available.

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.

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.

Morrison RS, Magaziner J, Gilbert M, Koval KJ, McLaughlin MA, Orosz G, Strauss E, Siu AL. Relationship between pain and opioid analgesics on the development of delirium following hip fracture. J Gerontol A Biol Sci Med Sci. 2003 Jan;58(1):76-81. doi: 10.1093/gerona/58.1.m76.

Wang Y, Sands LP, Vaurio L, Mullen EA, Leung JM. The effects of postoperative pain and its management on postoperative cognitive dysfunction. Am J Geriatr Psychiatry. 2007 Jan;15(1):50-9. doi: 10.1097/01.JGP.0000229792.31009.da.

Zura M, Kozmar A, Sakic K, Malenica B, Hrgovic Z. Effect of spinal and general anesthesia on serum concentration of pro-inflammatory and anti-inflammatory cytokines. Immunobiology. 2012 Jun;217(6):622-7. doi: 10.1016/j.imbio.2011.10.018. Epub 2011 Nov 3.

Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007 May;39(2):175-91. doi: 10.3758/bf03193146.

Kristek G, Rados I, Kristek D, Kapural L, Neskovic N, Skiljic S, Horvat V, Mandic S, Harsanji-Drenjancevic I. Influence of postoperative analgesia on systemic inflammatory response and postoperative cognitive dysfunction after femoral fractures surgery: a randomized controlled trial. Reg Anesth Pain Med. 2019 Jan;44(1):59-68. doi: 10.1136/rapm-2018-000023. Erratum In: Reg Anesth Pain Med. 2019 Oct;44(10):e2.