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.

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.

Paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty: protocol for the randomised, placebo-controlled, parallel 4-group, blinded, multicentre RECIPE trial.

INTRODUCTION: Multimodal analgesia with paracetamol, non-steroidal anti-inflammatory drug and glucocorticoid is recommended for hip arthroplasty, but with uncertain effects of the different combinations. We aim to investigate benefit and harm of different combinations of paracetamol, ibuprofen and dexamethasone following total hip arthroplasty. METHODS AND ANALYSIS: RECIPE is a randomised, placebo-controlled, parallel 4-group, blinded trial with 90-day and 1-year follow-up performed at nine Danish hospitals. Interventions are initiated preoperatively and continued for 24 hours postoperatively. Eligible participants undergoing total hip arthroplasty are randomised to:group A: oral paracetamol 1000 mg × 4+oral ibuprofen 400 mg × 4+intravenous placebo; group B: oral paracetamol 1000 mg × 4+intravenous dexamethasone 24 mg+oral placebo; group C: oral ibuprofen 400 mg × 4+intravenous dexamethasone 24 mg+oral placebo; group D: oral paracetamol 1000 mg × 4+oral ibuprofen 400 mg × 4+intravenous dexamethasone 24 mg.Primary outcome is cumulative opioid consumption at 0-24 hours. Secondary outcomes are pain at rest, during mobilisation and during a 5 m walk and adverse events. Follow-up includes serious adverse events and patient reported outcome measures at 90 days and 1 year. A total of 1060 participants are needed to demonstrate a difference of 8 mg in 24-hour morphine consumption assuming an SD of 24.5 mg, a risk of type I errors of 0.0083 and a risk of type 2 errors of 0.2. Primary analysis will be a modified intention-to-treat analysis.With this trial we aim to verify recommendations for pain treatment after total hip arthroplasty, and investigate the role of dexamethasone as an analgesic adjuvant to paracetamol and ibuprofen. ETHICS AND DISSEMINATION: This trial is approved by the Region Zealand Committee on Health Research Ethics (SJ-799). Plans for dissemination include publication in peer-reviewed journals and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: NCT04123873.

Adductor Canal Block With Continuous Infusion Versus Intermittent Boluses and Morphine Consumption: A Randomized, Blinded, Controlled Clinical Trial.

BACKGROUND: Based on the assumption that relatively large volumes of local anesthetic optimize an adductor canal block (ACB), we theorized that an ACB administered as repeated boluses would improve analgesia without compromising mobility, compared with a continuous infusion. METHODS: We performed a randomized, blinded, controlled study, including patients scheduled for total knee arthroplasty with spinal anesthesia. Patients received 0.2% ropivacaine via a catheter in the adductor canal administered as either repeated intermittent boluses (21 mL/3 h) or continuous infusion (7 mL/h). The primary outcome was total (postoperative day [POD], 0-2) opioid consumption (mg), administered as patient-controlled analgesia. Pain, ambulation, and quadriceps muscle strength were secondary outcomes. RESULTS: We randomized 110 patients, of whom 107 were analyzed. Total opioid consumption (POD, 0-2) was a median (range) of 23 mg (0-139) in the bolus group and 26 mg (3-120) in the infusion group (estimated median difference, 4 mg; 95% confidence interval [CI], -13 to 5; P = .29). Linear mixed-model analyses revealed no difference in pain during knee flexion (mean difference, 2.6 mm; 95% CI, -2.9 to 8.0) or at rest (mean difference, 1.7 mm; 95% CI, -1.5 to 4.9). Patients in the bolus group had improved quadriceps sparing on POD 2 (median difference, 7.4%; 95% CI, 0.5%-15.5%). However, this difference was not present on POD 1 or reflected in the ambulation tests (P > .05). CONCLUSIONS: Changing the mode of administration for an ACB from continuous infusion to repeated intermittent boluses did not decrease opioid consumption, pain, nor mobility.

Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial.

OBJECTIVE: To investigate the effect of a restricted intravenous fluid regimen versus a standard regimen on complications after colorectal resection. SUMMARY BACKGROUND DATA: Current fluid administration in major surgery causes a weight increase of 3-6 kg. Complications after colorectal surgery are reported in up to 68% of patients. Associations between postoperative weight gain and poor survival as well as fluid overload and complications have been shown. METHODS: We did a randomized observer-blinded multicenter trial. After informed consent was obtained, 172 patients were allocated to either a restricted or a standard intraoperative and postoperative intravenous fluid regimen. The restricted regimen aimed at maintaining preoperative body weight; the standard regimen resembled everyday practice. The primary outcome measures were complications; the secondary measures were death and adverse effects. RESULTS: The restricted intravenous fluid regimen significantly reduced postoperative complications both by intention-to-treat (33% versus 51%, P = 0.013) and per-protocol (30% versus 56%, P = 0.003) analyses. The numbers of both cardiopulmonary (7% versus 24%, P = 0.007) and tissue-healing complications (16% versus 31%, P = 0.04) were significantly reduced. No patients died in the restricted group compared with 4 deaths in the standard group (0% versus 4.7%, P = 0.12). No harmful adverse effects were observed. CONCLUSION: The restricted perioperative intravenous fluid regimen aiming at unchanged body weight reduces complications after elective colorectal resection.