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

Study Overview
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Brief Summary
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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.

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

Conditions
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Total Knee Arthroplasty

Intervention / Treatment
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* Drug: Hydrocortisone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Patients receive a saline placebo before surgery, 8 hours after the first dose and 16 hours after the first dose. | Drug: Placebo<br>* Patients receive placebo prior to surgery, 8 hours after the first dose and 16 hours after the first dose.<br>|
| Active Comparator: Treatment<br>Patients receive 3 100 mg of hydrocortisone: prior to surgery, 8 hours after the first dose and 16 hours after the first dose. | Drug: Hydrocortisone<br>* 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.<br>* Other names: Corta-Cap;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prothrombin Fragment (PF1.2), a Marker of Thrombin Generation | 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 | Baseline and up to 4 hours following surgery | 
| Plasmin-alpha-2-antiplasmin Complex (PAP), a Marker of Fibrinolysis | 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 | Baseline and up to 4 hours following surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hydrocortisone's Effect on Depression | 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. | one month and up to 3 months following surgery | 
| Pain Scores and Opioid Consumption | 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. | one month and up to 3 months following surgery | 
| Blinding Assessment | 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. | one month and up to 3 months following surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Differentiation Factor-2, B-Cell, B-Cell Stimulatory Factor-2, IFN-beta 2, MGI-2, Interleukin-6 (IL-6), Steroids, Pregnenediones, Hydrocortisone, Physiological Effects of Drugs, Therapeutic Uses, Orthopedic Procedures, Prostheses and Implants, Joint Prosthesis, Knee Prosthesis, Arthroplasty, Knee, Thromboembolism, Inflammation, B-Cell Differentiation Factor-2, BSF-2