Prospective Randomized Controlled Trials And Rats Experiment On Multimodal Cocktail Peri-articular Injection Analgesia For Total Joint Arthroplasty

Background and Aim:Multimodal cocktail periarticular injection(MCPI)analgesia has become the standard method for multimodal pain control regimens post total hip/knee arthroplasty.However,it is currently questionable for its role in multimodal analgesia after total knee arthroplasty(TKA).Also,extensive literature review found little information about standardization of periarticular cocktail ingredients and prospective randomized controlled trials were needed to compared various cocktail ingredients with one another;We aim to:①To evaluate additive efficacy of MCPI as part of a multimodal analgesia in patients undergoing unilateral TKA with respect to(a)pain;(b)narcotic use;(c)knee function;and(d)complications.②compares the safety and effectiveness of commonly used periarticular injection formulations with or without steriosis in patients undergoing simultaneous bilateralTKA.③test the hypothesis that the local injection of flurbiprofen ester microspheres significantly reduce pain score,inflammation and without side effects on systemic inflammatory model which was induced in Wistar rats.Methods:Two prospective randomized controlled trials were performed:①A multicenter randomized,controlled,double blind study were performed.101 patients undergoing unilateral TKA in two centers were randomly divided into two groups(A and B).Group A(50 cases)received a MCPI of ropivacaine,fentanyl and epinephrine at operation and Group B(51cases)did not.All patients received standardized general anesthesia and postoperative intravenous patient-controlled analgesia(PCA).The primary outcome was postoperative pain,on a 0 to 10 scale.Secondary outcomes were narcotic use,knee function,and complications.②to assess the local efficacy of adding betamethasone to intraoperative MCPI in patients undergoing simultaneous bilateral TKA.Sixty total knee arthroplasty patients(120 knees)were received periarticular injections in randomly selected one knee with added betamethasone(7 mg)and the other knee without.The periarticular injection was composed of ropivacaine,epinephrine,morphine,and flurbiprofen sodium.Visual analog scale pain scores at rest and on motion,range of motion(ROM),thigh swelling,thigh skin temperature,the HSS score,and adverse outcomes were compared between the 2 sides.③Systemic inflammatory model was induced in Wistar rats(45)by closed femoral shaft fracture;9 non-fractured rats were used as the blank control group(group A).The systemic inflammation model of 45 rats was divided into 5 groups(9 in each group);Group B:intramuscular injection of the same amount of normal saline as a control at different time points;Group C:intravenous injection of flurbiprofen ester microspheres at different time points(4.5 mg/kg);Group D:intramuscular injection of flurbiprofen ester microspheres(2.25 mg/kg)at different time points;Group E:intramuscular injection of flurbiprofen ester at different time points Microspheres(4.5 mg/kg);Group F:intramuscular injection of flurbiprofen ester microspheres(9 mg/kg)at different time points;The safety of local muscle necrosis at the injection site was evaluated by pathological section with HE staining;Evaluation of pain intensity score(PIS)were done by behavior observation.Determination of inflammation reduction by CRP,IL-6,COX-1,COX-2 and TNF-a in rats by ELISA test.Results:First trial:①At PACU the mean VAS in MCPI Group was lower than None-MCPI Group(P<0.05).The time of opening PCA in Group A was longer than Group B(P<0.05).The narcotic use in PCA in Group A Was less than Group B(P<0.05).There was no difference of mean VAS at the other times point,knee ROM,length of stay and side effects between two groups(P<0.05).Second trial:there were no statistically significant differences in the VAS score,ROM,thigh girth,thigh skin temperature,HSS score,and adverse events between the 2 sides.Patients were unable to detect a difference in the functional recovery between their knees on postoperative day 0,1,2,3 or 3 months follow-up.Rats experiment:③Pathological sections at 1,2,and 4 days post surgery did not show any local muscle necrosis on local injection site;Fracture rats with local injection of flurbiprofen ester microspheres showed lower inflammation level measured by CRP,IL-6 and COX-1 and PIS socre compared with the control.Conclusion:①Patients receiving MCPI had similar pain scores except at PACU,but less narcotic use compared with patients without it.They are both simple and safe to use.②Betamethasone peri-articular injection s is ineffective locally for relieving pain,reducing swelling,and improving the postoperative ROM.③Intramuscular injection of flurbiprofen ester microspheres significantly reduced the inflammatory response and PIS score in fracture rats,and did not increase the risk of muscle necrosis,suggesting its feasibility in local injection analgesia.