Effect of Low Dose Corticosteroids on Perioperative Markers of Thrombosis and Fibrinolysis in Total Knee Arthroplasty

Effect of Low Dose Corticosteroids on Perioperative Markers of Thrombosis and Fibrinolysis in Total Knee Arthroplasty

The Effect of Low Dose Corticosteroids on Perioperative Markers of Thrombosis and Fibrinolysis in Total Knee Arthroplasty

One postoperative complication following unilateral or bilateral total knee arthroplasty is thrombosis (blood clot formation). In this prospective, double-blinded randomized controlled clinical trial, researchers are investigating the effect of steroids on biochemical markers of thrombosis. Furthermore, elevated cellular markers of thrombosis (specifically IL-6) have been linked to postoperative depression following total knee arthroplasty surgery. Hence the investigators are also checking if use of hydrocortisone, a steroid, may help reduce the incidence of postoperative depression. Other studies have shown that surgery causes some reaction in the body that is consistent with inflammation. When the inflammation is extensive, it may affect different parts of the body. It may also lead to clotting disorders and result in blood clots. In a previous study by this principal investigator (see reference 22, "Use of low-dose steroids in decreasing cytokine release during bilateral total knee arthroplasty"), hydrocortisone was administered over 24 hours following surgery to patients who underwent bilateral total knee arthroplasty. The investigator found lower levels of cellular markers consistent with inflammation (specifically the protein, IL-6). Steroid use also showed additional benefits, such as decreased pain and better range of motion at the knee. In this study, investigators recruit patients undergoing total knee arthroplasty surgery. Patients are randomized to receive three 100 mg doses of hydrocortisone or three doses of a saline placebo. In addition to analyzing patients' blood samples for hydrocortisone's effect on clotting factors (i.e. IL-6), investigators record patients' pain scores and patients' oral analgesic use. To assess patients' well-being, patients are contacted one month and 3 months following their surgeries and administered the Patient Health Questionnaire (see reference 23, "The PHQ-9: validity of a brief depression severity measure.") arthroplasty.

Orthopedic Procedures, Prostheses and Implants, Joint Prosthesis, Knee Prosthesis, Arthroplasty, Knee, Thromboembolism, Inflammation, B-Cell Differentiation Factor-2, Differentiation Factor-2, B-Cell, B-Cell Stimulatory Factor-2, BSF-2, IFN-beta 2, MGI-2, Interleukin-6 (IL-6), Steroids, Pregnenediones, Hydrocortisone, Physiological Effects of Drugs, Therapeutic Uses

Patients receive a saline placebo before surgery, 8 hours after the first dose and 16 hours after the first dose.

Patients receive 3 100 mg of hydrocortisone: prior to surgery, 8 hours after the first dose and 16 hours after the first dose.

Patients randomized to treatment arm will three doses of 100 mg of hydrocortisone at the following times: prior to surgery, 8 hours after the first dose and 16 hours after the first dose.

Patients receive placebo prior to surgery, 8 hours after the first dose and 16 hours after the first dose.

Study patients received 100 mg of intravenous hydrocortisone 2 h prior to surgery, and controls received normal saline. Blood samples, drawn pre-incision and at 4 h post tourniquet release, were assayed for PF1.2 and PAP

Study patients received 100 mg of intravenous hydrocortisone 2 h prior to surgery, and controls received normal saline. Blood samples, drawn pre-incision and at 4 h post tourniquet release, were assayed for PF1.2 and PAP

Elevated IL-6 has been linked to post-operative depression following total knee replacement surgery. Patients will be administered the patient health questionnaire (PHQ-9) one month and 3 months following surgery to assess their well-being.

Pain scores (rated on a scale of 0-10) will be taken throughout study participation. We will also record analgesic use to see if patients who received hydrocortisone needed fewer pain killers to control their postoperative pain.

Throughout each patient's study participation, the patient and the data collector will be asked to guess their treatment status. This helps ascertain if there is an association between blinding status, treatment effect and the depression measure.

Inclusion Criteria: All patients undergoing unilateral or bilateral total knee replacement Age 50-90 Exclusion Criteria: All patients on steroid therapy regardless of dose or duration of treatment or those requiring stress-dose steroids preoperatively Patients who are smokers Patients under 50 years of age Patients over 90 years of age Patients with diabetes Patients with a prior history of corticosteroid intolerance Patients with previous complications of steroid use

Boermeester MA, van Leeuwen PA, Coyle SM, Wolbink GJ, Hack CE, Lowry SF. Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg. 1995 Jul;130(7):739-48. doi: 10.1001/archsurg.1995.01430070061012.

Busso N, Belin D, Failly-Crepin C, Vassalli JD. Plasminogen activators and their inhibitors in a human mammary cell line (HBL-100). Modulation by glucocorticoids. J Biol Chem. 1986 Jul 15;261(20):9309-15.

Collen D, Hoylaerts MF. Relationship between inflammation and venous thromboembolism as studied by microparticle assessment in plasma. J Am Coll Cardiol. 2005 May 3;45(9):1472-3. doi: 10.1016/j.jacc.2005.02.029. No abstract available.

Cremeans-Smith JK, Soehlen S, Greene K, Alexander T, Delahanty DL. In-hospital levels of C-reactive protein and IL-6 predict post-operative depressive symptoms among patients undergoing total knee replacement surgery. Brain Behav Immun. 2009 Nov;23(8):1096-103. doi: 10.1016/j.bbi.2009.06.148. Epub 2009 Jun 24.

Fox EA, Kahn SR. The relationship between inflammation and venous thrombosis. A systematic review of clinical studies. Thromb Haemost. 2005 Aug;94(2):362-5. doi: 10.1160/TH05-04-0266.

Hogevold HE, Hoiseth A, Reikeras O. Effect of high-dose corticosteroids on the incidence of deep vein thrombosis after total hip replacement. Arch Orthop Trauma Surg. 1991;111(1):29-31. doi: 10.1007/BF00390189.

Jansen NJ, van Oeveren W, van den Broek L, Oudemans-van Straaten HM, Stoutenbeek CP, Joen MC, Roozendaal KJ, Eysman L, Wildevuur CR. Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1991 Oct;102(4):515-25.

Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet. 1999 Dec 4;354(9194):1940-7. doi: 10.1016/S0140-6736(99)01264-7.

Levi M, van der Poll T. Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med. 2005 Oct;15(7):254-9. doi: 10.1016/j.tcm.2005.07.004.

Medcalf RL, Van den Berg E, Schleuning WD. Glucocorticoid-modulated gene expression of tissue- and urinary-type plasminogen activator and plasminogen activator inhibitor 1 and 2. J Cell Biol. 1988 Mar;106(3):971-8. doi: 10.1083/jcb.106.3.971.

Medcalf RL, Kruithof EK, Schleuning WD. Plasminogen activator inhibitor 1 and 2 are tumor necrosis factor/cachectin-responsive genes. J Exp Med. 1988 Aug 1;168(2):751-9. doi: 10.1084/jem.168.2.751.

Nilsson T, Carlsson J, Sundqvist G. Inactivation of key factors of the plasma proteinase cascade systems by Bacteroides gingivalis. Infect Immun. 1985 Nov;50(2):467-71. doi: 10.1128/iai.50.2.467-471.1985.

Parvizi J, Mui A, Purtill JJ, Sharkey PF, Hozack WJ, Rothman RH. Total joint arthroplasty: When do fatal or near-fatal complications occur? J Bone Joint Surg Am. 2007 Jan;89(1):27-32. doi: 10.2106/JBJS.E.01443.

Pulido L, Ghanem E, Joshi A, Purtill JJ, Parvizi J. Periprosthetic joint infection: the incidence, timing, and predisposing factors. Clin Orthop Relat Res. 2008 Jul;466(7):1710-5. doi: 10.1007/s11999-008-0209-4. Epub 2008 Apr 18.

Reikeras O, Clementsen T. Thrombosis markers in hip versus knee arthroplasty: a pilot study. J Orthop Surg (Hong Kong). 2009 Dec;17(3):291-5. doi: 10.1177/230949900901700309.

Sharrock NE, Go G, Sculco TP, Salvati EA, Westrich GH, Harpel PC. Dose response of intravenous heparin on markers of thrombosis during primary total hip replacement. Anesthesiology. 1999 Apr;90(4):981-7. doi: 10.1097/00000542-199904000-00009.

van der Poll T, Levi M, Hack CE, ten Cate H, van Deventer SJ, Eerenberg AJ, de Groot ER, Jansen J, Gallati H, Buller HR, et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med. 1994 Apr 1;179(4):1253-9. doi: 10.1084/jem.179.4.1253.

van Deventer SJ, Buller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood. 1990 Dec 15;76(12):2520-6.

van Giezen JJ, Chung-A-Hing JE, Vegter CB, Bouma BN, Jansen JW. Fibrinolytic activity in blood is distributed over a cellular and the plasma fraction which can be modulated separately. Thromb Haemost. 1994 Dec;72(6):887-92.

Voshaar RC, Banerjee S, Horan M, Baldwin R, Pendleton N, Proctor R, Tarrier N, Woodward Y, Burns A. Predictors of incident depression after hip fracture surgery. Am J Geriatr Psychiatry. 2007 Sep;15(9):807-14. doi: 10.1097/JGP.0b013e318098610c. Epub 2007 Aug 13.

Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol. 2003 Dec;23(12):2131-7. doi: 10.1161/01.ATV.0000095974.95122.EC. Epub 2003 Sep 18.

Jules-Elysee KM, Lipnitsky JY, Patel N, Anastasian G, Wilfred SE, Urban MK, Sculco TP. Use of low-dose steroids in decreasing cytokine release during bilateral total knee replacement. Reg Anesth Pain Med. 2011 Jan-Feb;36(1):36-40. doi: 10.1097/AAP.0b013e31820306c5.

Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16(9):606-13. doi: 10.1046/j.1525-1497.2001.016009606.x.

McLawhorn AS, Poultsides LA, Sakellariou VI, Kunze KN, Fields KG, Jules-Elysee K, Sculco TP. Low-Dose Perioperative Corticosteroids Can Be Administered Without Additional Morbidity in Patients Undergoing Bilateral Total Knee Replacement: A Retrospective Follow-up Study of a Randomized Controlled Trial. HSS J. 2022 Feb;18(1):48-56. doi: 10.1177/15563316211006098. Epub 2021 Apr 9.