DEX-2-TKA

DEXamethasone twice for pain treatment of Total Knee Arthroplasty (DEX-2-TKA)

A randomized blinded placebo-controlled clinical trial

Background

Effective postoperative pain management is essential for the well-being and rehabilitation of the surgical patient. No “gold standard” exists for pain treatment after total knee arthroplasty (TKA) since combinations of different analgesic treatments are used with nearly no evidence for combined analgesic efficacy. A single perioperative dose of glucocorticoid (GCC) (i.e. dexamethasone) has well established effects on postoperative nausea and vomiting, and may be beneficial for postoperative pain. A recent trial suggested that an additional postoperative dose of GCC improved postoperative pain treatment. Recent systematic reviews, sub-studies of RCTs and cohort studies of perioperative GCC raised no concern regarding serious adverse events of a single dose GCC for non-cardiac surgery. However, optimal dose, combination and regimen of perioperative GCC remains unsettled.

Objectives

To establish the analgesic effect and safety of one and two consecutive days of a single dose of dexamethasone after TKA. GCC will be administered in combination with paracetamol, NSAID (ibuprofen), and local infiltration analgesia.

Intervention

The participants will be randomised in three groups: A) 24 mg dexamethasone i.v. perioperatively (POD0) and 24 mg dexamethasone i.v. on the first postoperative day (POD1); B) 24 mg dexamethasone i.v. POD0 and placebo (isotonic saline) i.v. on POD1; and C) placebo i.v. on POD0 and POD1.

Design and trial size

Placebo-controlled, randomised, parallel 3-group multicentre trial with adequate centralised computer-generated allocation sequence and allocation concealment with unknown block size. Assessor, investigator, caregivers and participants will all be blinded. A total of 423 eligible participants are needed to detect a difference of 10 mg morphine for the first 48 hours postoperatively with a standard deviation of 22.7 mg, an overall familywise type 1 error rate of 0.05 and a type 2 error rate of 0.10. To compensate for uncertainty of the distribution a surplus of 15 % is added, thus a total of 486 patients will be included.

Inclusion and exclusion criteria

Patients scheduled for unilateral TKA; Age ≥ 18 years; ASA 1-3; BMI ≥ 18 and ≤ 40; informed consent; negative HCG for women in the fertile age.

Patients will be excluded, who cannot cooperate with the trial; participation in another medicine trial; patients who cannot understand or speak Danish; daily use of high dose opioid (equivalent of oral morphine 30 mg/day), methadone or systemic glucocorticoid; allergy against trial medication; contraindications against ibuprofen and dexamethasone; dysregulated diabetes; alcohol and/or drug abuse.

Primary outcome

Cumulative usage of intravenous morphine (eqv) the first 48 hours postoperatively. Administered both as patient-controlled analgesia (PCA) i.v. morphine 0-24 hours and oral morphine on demand 24-48 hours, and any other supplemental morphine administered postoperatively.

Secondary and exploratory outcome

Serious adverse events within 90 days after surgery. Total need of i.v. morphine the first 24 hours postoperatively; total need of oral morphine the following 24-48 hours. Visual analogue scale (VAS) pain scores at rest and with active 45 degrees flexion of the knee at 6, 24 and 48 hours postoperatively, and both highest and average pain score in the periods 0-24 h and 24-48 hours postoperatively. Timed up and go test at 24 and 48 hours postoperatively, including maximum pain during the test. Adverse event from intervention start to 48 hours as well as levels of nausea, vomiting, dizziness, and sedation at 6, 24, and 48 hours. Consumption of antiemetic in the periods 0-24 and 24-48 hours postoperatively. Quality of sleep and level of fatigue at 24 hours and 48 hours. Questionnaire on pain, sleep, satisfaction and use of medication for POD 3-7. 90-day follow-up with EQ-5D-5L and Oxford-Knee-Score at 90 days postoperatively and the need for medical attention and/or intervention including need for antibiotics and/or re-operation.

Time schedule:

The study recruitet the first patient october 2018 and expect to finish 31. december 2019. Follwow up period 90 days after last patient. Data analyses april to august 2020 and manuscript submission winter 2020.

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