Non-opioid analgesic combinations following total hip arthroplasty (RECIPE): a randomised, placebo-controlled, blinded, multicentre trial.

BACKGROUND: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. METHODS: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. FINDINGS: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. INTERPRETATION: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. FUNDING: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.

Spinal anaesthesia versus general anaesthesia (SAGA) on recovery after hip and knee arthroplasty: A study protocol for three randomized, single-blinded, multi-centre, clinical trials.

Mobilisation difficulties, due to muscle weakness, and urinary retention are common reasons for prolonged admission following hip and knee arthroplasty procedures. Whether spinal anaesthesia is detrimental to early mobilisation is controversial. Previous studies have reported differences in post-operative recovery between spinal anaesthesia and general anaesthesia; however, up-to-date comparisons in fast-track setups are needed. Our randomized, single-blinded, multi-centre, clinical trials aim to compare the post-operative recovery after total hip (THA), total knee (TKA), and unicompartmental knee arthroplasties (UKA) respectively when using either spinal anaesthesia (SA) or general anaesthesia (GA) in a fast-track setup. Included patients (74 THA, 74 TKA, and 74 UKA patients) are randomized (1:1) to receive either SA (2 mL 0.5% Bupivacaine) or GA (Induction: Propofol 1.0-2.0 mg/kg iv with Remifentanil 3-5 mcg/kg iv. Infusion: Propofol 3-5 mg/kg/h and Remifentanil 0.5 mcg/kg/min iv). Patients undergo standard primary unilateral hip and knee arthroplasty procedures in an optimized fast-track setup with intraoperative local infiltrative analgesia in TKA and UKA, post-operative multimodal opioid sparing analgesia, immediate mobilisation with full weightbearing, no drains and in-hospital only thromboprophylaxis. Data will be collected on the day of surgery and until patients are discharged. The primary outcome is the ability to be safely mobilised during a 5-m walking test within 6 h of surgery. Secondary outcomes include fulfilment of discharge criteria, post-operative pain, dizziness, and nausea as well as patient reported recovery and opioid related side effects. Data will also be gathered on all hospital contacts within 30-days of surgery. This study will offer insights into advantages and disadvantages of anaesthetic methods used in fast-track arthroplasty surgery.

High dose dexamethasone in high pain responders undergoing total hip arthroplasty: A randomized controlled trial.

BACKGROUND: Postoperative pain after total hip arthroplasty (THA) may delay postoperative mobilization and discharge. Postoperative pain has been shown to be higher in pain catastrophisers and patients receiving opioids. A single dose of glucocorticoid reduces pain after THA, and an increased dose of glucocorticoids has been found to be effective in patients at high risk of postoperative pain after total knee arthroplasty (TKA), however, the ideal dose in THA remains unknown. OBJECTIVE: To evaluate the effect of a high dose (1 mg kg -1 ) vs. intermediate dose (0.3 mg kg -1 ) of dexamethasone on pain after THA. DESIGN: A randomized double-blind controlled study. SETTING: A two-centre study including two large arthroplasty sites in Denmark was conducted from February 2019 to August 2020. PATIENTS: A total of 160 patients undergoing THA by neuraxial block with multimodal analgesia, having a Pain Catastrophising Scale score >20 and/or preoperative opioid use were included. INTERVENTION: Patients were randomly assigned to receive dexamethasone 1 mg kg -1 or 0.3 mg kg -1 before THA. MAIN OUTCOME MEASURES: Primary outcome was percentage of patients experiencing moderate to severe pain (visual analogue scale, VAS > 30 mm on a 0 to 100 mm scale) on ambulating 24 h after surgery. Secondary outcomes included cumulated pain scores, C-reactive protein (CRP), opioid use, postoperative recovery scores, length of stay, complications, and re-admission within 30 and 90 days. RESULTS: No difference was found in percentage of VAS >30 mm 24 h after surgery in the 5-m walk test (VAS > 30/VAS ≤ 30%); 33/42 (44%) vs. 32/43 (43%), relative risk = 1.04 (95% confidence interval 0.72-1.51; P  = 0.814) in 1 mg kg -1vs. 0.3 mg kg -1 respectively. No differences were found in CRP and opioid use between groups. Also, no intergroup differences were found in recovery scores, re-admissions, or complications. CONCLUSION: 1 mg kg -1vs. 0.3 mg kg -1 dexamethasone improved neither postoperative pain nor recovery in THA in a cohort of predicted high pain responders. TRIAL REGISTRATION: ClinicalTrials.gov ID-number NCT03763760 and EudraCT-number 2018-2636-25.

Repeat dose steroid in high pain responders after total knee arthroplasty: A study protocol.

Pain after total knee arthroplasty (TKA) is a well-known clinical problem potentially delaying ambulation and recovery. Perioperative glucocorticoids reduce pain and facilitate early recovery, but the optimal timing and dose are still unknown. High pain catastrophizers have an increased risk of poorly controlled postoperative pain, and moderate to severe pain at 24 h is associated with a risk of pain relapse at 48 h. To evaluate the effect of a repeat moderate dose of glucocorticoids after TKA in high pain catastrophizers presenting with moderate to severe pain 24 h postoperatively, having received preoperative high-dose glucocorticoids. High pain catastrophizers (Pain Catastrophizing Scale > 20) undergoing TKA are screened 24 h postoperatively and are included if they experience moderate to severe pain (VAS > 30) during a 5 m walk test. The included patients will receive either oral 24 mg dexamethasone (n = 55) or placebo (n = 55) on the evening of Day 1 (~30-37 h) after surgery. In addition, patients receive a standard multimodal analgesic regimen, including paracetamol, celecoxib, local infiltration analgesia, and preoperative dexamethasone (1 mg/kg). Patients will fill out a pain diary for 7 days after surgery. The primary outcome is moderate to severe pain (VAS > 30) during a 5 m walk test on the morning of Day 2 after surgery. The secondary outcomes include cumulated pain at rest and during ambulation, cumulated use of rescue analgesics, quality of sleep, lethargy, dizziness, nausea, satisfaction with the analgesic regimen, length of stay, morbidity, mortality, and reasons for readmissions. Follow-up is at 8 and 30 days. The data from this study will provide evidence for the effect of a repeated dose of dexamethasone as an analgesic adjuvant in patients undergoing TKA with a high risk of postoperative pain.

High-dose dexamethasone in low pain responders undergoing total knee arthroplasty: a randomised double-blind trial.

BACKGROUND: Postoperative pain after total knee arthroplasty (TKA) is a continuing problem despite optimised multimodal analgesia. Previous studies have shown preoperative glucocorticoids to reduce postoperative pain, but knowledge about specific doses and effects in specific patient groups is lacking. METHODS: A two-centre, double-blind, two-arm study comparing preoperative dexamethasone (1 mg kg-1vs 0.3 mg kg-1 i.v.) on postoperative pain in 160 planned TKA subjects with low preoperative pain catastrophising and no opioid use. Subjects received multimodal analgesia with paracetamol, cyclooxygenase-2 inhibitors, local anaesthetic infiltration analgesia, and rescue opioids. The primary outcome was percentage of subjects experiencing moderate to severe pain (visual analogue scale >30 mm) upon ambulation at 24 h. Secondary outcomes included pain scores, postoperative inflammation (C-reactive protein), opioid and antiemetics use, and 'Quality of Recovery-15' and 'Opioid-Related Symptom Distress Scale', length of stay, readmissions, and complications up to Day 90. RESULTS: A total of 157 subjects (80 vs 77) were included. No difference was found between groups in the incidence of subjects experiencing visual analogue scale >30 on ambulation 24 h after surgery (56% vs 53%, relative risk =1.07, confidence interval: 0.8-1.4, P=0.65). No differences in other pain outcomes or use of rescue opioids and antiemetics, in Quality of Recovery-15 and Opioid-Related Symptom Distress Scale, length of stay, readmissions, or complications. C-reactive protein values were comparable at 24 h (13 [6-25] mg L-1vs 16 [9-38] mg L-1, P = 0.07), but lower at 48 h (26 [9-52] mg L-1vs 50 [30-72] mg L-1, P<0.01) in the high-dose group. CONCLUSION: Use of 1 mg kg-1vs 0.3 mg kg-1 i.v. dexamethasone in low pain responders after TKA did not improve early postoperative pain or other outcomes in contrast to benefits in a high pain responder population. CLINICAL TRIAL REGISTRATION: NCT03758170 (first registration 29-11-2018).

Pain treatment after total hip arthroplasty: Detailed statistical analysis plan for the RECIPE randomised clinical trial.

BACKGROUND: The RECIPE trial systematically investigates the effects of different combinations of paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty. To preserve transparency, minimise risk of bias and to prevent data-driven analysis, we present this detailed statistical analysis plan. METHODS: The RECIPE trial is a randomised, blinded, parallel four-group multicenter clinical trial for patients undergoing planned primary total hip arthroplasty. Interventions are initiated preoperatively and continued for 24 h postoperatively. Primary outcome is total opioid consumption 0-24 h after end of surgery. Primary analysis will be performed in the modified intention to treat population of all patients undergoing total hip arthroplasty, and all analyses will be stratified for site. We will perform pairwise comparisons between each of the four groups. The primary outcome will be analysed using the van Elteren test and we will present Hodges-Lehmann median differences and confidence intervals. Binary outcomes will be analysed using logistic regression. To preserve a family-wise error rate of <0.05, we will use a Bonferroni-adjusted alfa of 0.05/6 = 0.0083 for all six pairwise comparisons between groups when analysing the primary outcome. We will systematically assess the underlying statistical assumptions for each analysis. Data will be analysed by two blinded independent statisticians, and we will write abstracts covering all possible combinations of conclusions, before breaking the blind. DISCUSSION: The RECIPE trial will provide important information on benefit and harm of combinations of the most frequently used non-opioid analgesics for pain after primary hip arthroplasty.

High-dose steroids in high pain responders undergoing total knee arthroplasty: a randomised double-blind trial.

BACKGROUND: Total knee arthroplasty (TKA) is associated with moderate-to-severe postoperative pain despite multimodal opioid-sparing analgesia. Pain catastrophising or preoperative opioid therapy is associated with increased postoperative pain. Preoperative glucocorticoid improves pain after TKA, but dose-finding studies and benefit in high pain responders are lacking. METHODS: A randomised double-blind controlled trial with preoperative high-dose intravenous dexamethasone 1 mg kg-1 or intermediate-dose dexamethasone 0.3 mg kg-1 in 88 patients undergoing TKA with preoperative pain catastrophising score >20 or regular opioid use was designed. The primary outcome was the proportion of patients experiencing moderate-to-severe pain (VAS >30) during a 5 m walk 24 h postoperatively. Secondary outcomes included pain at rest during nights and at passive leg raise, C-reactive protein, opioid use, quality of sleep, Quality of Recovery-15 and Opioid-Related Symptom Distress Scale, readmission, and complications. RESULTS: Moderate-to-severe pain when walking 24 h postoperatively was reduced (high dose vs intermediate dose, 49% vs 79%; P<0.01), along with pain at leg raise at 24 and 48 h (14% vs 29%, P=0.02 and 12% vs 31%, P=0.03, respectively). C-reactive protein was reduced in the high-dose group at both 24 and 48 h (both P<0.01). Quality of Recovery-15 was also improved (P<0.01). CONCLUSIONS: When compared with preoperative dexamethasone 0.3 mg kg-1 i.v., dexamethasone 1 mg kg-1 reduced moderate-to-severe pain 24 h after TKA and improved recovery in high pain responders without apparent side-effects. CLINICAL TRIAL REGISTRATION: NCT03763734.

Lack of nephrotoxicity by 6% hydroxyethyl starch 130/0.4 during hip arthroplasty: a randomized controlled trial.

BACKGROUND: Hydroxyethyl starch (HES) is commonly used as plasma expander during surgery but may be nephrotoxic as seen in studies in patients with sepsis. The authors hypothesized that the possible nephrotoxicity of 6% HES 130/0.4 could be revealed by measurements of urinary excretion of neutrophil gelatinase-associated lipocalin (u-NGAL) in patients with normal renal function during hip arthroplasty. METHODS: In this randomized, double-blinded, placebo-controlled study, 40 patients referred for hip arthroplasty received either 6% HES 130/0.4 or isotonic saline 0.9%; 7.5 ml/kg during the first hour of surgery and 5 ml/kg during the following hours; 38 patients completed the study. U-NGAL, urine albumin, blood pressure, and plasma concentrations of creatinine, renin, NGAL, albumin, angiotensin-II, and aldosterone were measured before, during, and after surgery. U-NGAL was defined as primary outcome. RESULTS: There were no significant differences in U-NGAL (mean difference and 95% CI), plasma creatinine, and urine albumin during the study. U-NGAL and urine albumin increased significantly in both groups the morning after surgery but was normalized at follow-up after 10 to 12 days. Mean arterial pressure was significantly higher during the recovery period in the HES group compared with that in the control group (91 [13] and 83 [6] mmHg, mean [SD], P < 0.03). Plasma renin and angiotensin-II were nonsignificantly different in both groups, whereas plasma aldosterone was significantly lower in the HES group. Plasma albumin was reduced in both groups, but to a significantly lower level in the HES group. CONCLUSION: The study showed no evidence of a harmful effect of intraoperative infusion of 6% HES 130/0.4 on renal function in patients during hip arthroplasty.