Osteoarthritis, the most common type of arthritis, is estimated to affect more than 40 million people across Europe1 and has a lifetime risk of 45% for knee osteoarthritis.2 Symptomatic knee osteoarthritis has a prevalence of 16.7% in subjects over the age of 45 years, and more than 500 000 knee replacements are performed annually in the USA.3,4 This number was projected to grow by 673% from 2005 to 2030.4 Total knee arthroplasty (TKA) is widely performed to improve mobility and quality of life. TKA is a very painful surgical procedure.5 Effective analgesia in the immediate postoperative phase is essential to allow the patient to exercise and regain mobility, thereby facilitating recovery and decreasing the length of hospital stay. Several techniques of regional analgesia (RA) have been developed for postoperative pain relief. RA has been widely evaluated and several systematic reviews have shown its benefit for pain relief after TKA.6–13 However, the impacts on functional recovery and adverse effects are less well known. We undertook a systematic review of randomised controlled trials that compared RA with systemic analgesia in adults undergoing major knee surgery for osteoarthritis. We assessed length of hospital stay, range of motion (ROM), global function and severe adverse effects.
The systematic review of randomised controlled trials (RCTs) was reported in accordance with the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the current recommendations of the Cochrane Collaboration.14,15 The study was registered at PROSPERO (CRD42014013995).
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and LILACS, from the inception of each database to January 2017. The search equation is available in Supplementary data 1, http://links.lww.com/EJA/A194. The articles identified had to be published in English. We also searched the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects for previous relevant systematic reviews. We hand-searched the annual conference proceedings of the American Society of Anesthesiologists and the European Society of Anaesthesiology from June 2013 to June 2017 and searched for completed trials in ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. We identified randomised trials with the highly sensitive search strategy of the Cochrane Collaboration.16
We included all RCTs on adults undergoing TKA for osteoarthritis. For trials on mixed populations, we considered only those in which more than 50% of the patients were suffering from osteoarthritis. The interventions of interest were: epidural analgesia, peripheral nerve block, local infiltration analgesia (LIA), regardless of the anaesthetic drug, volume administered, type of block or type of local infiltration (peri-articular tissue and/or intra-articular space). The control group of interests was either a group with a sham technique with saline administration or a group with no RA. In either case, systemic analgesia had to be clearly defined. We excluded trials in which functional outcomes were not provided. Two authors (TO and SB) independently screened titles, abstracts and full texts for the inclusion criteria. Any disagreement between these two authors was settled by discussion with a third author (VM) until a consensus was reached.
The primary outcomes assessed were length of stay (LOS) in hospital in days, and knee flexion ROM in degrees on day 4 after surgery (if this value was not provided, we used the ROM recorded for the week closest to this time point). The secondary outcomes were: time to first ambulation (in days), knee flexion ROM at least 1 month after surgery, number of patients achieving active straight leg raising (SLR), patient satisfaction and functional score [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Oxford Score, knee society score] in the first week and at least 1 month after surgery. We assessed the incidence of severe adverse events (SAEs) corresponding to the definition of Food and Drug Administration (FDA).17 We expected only small total numbers of SAEs to be reported. We therefore analysed specific adverse effects corresponding to the FDA definition and reported in the trials included in the meta-analysis. Three experts independently predetermined which adverse effects frequently reported in previous studies corresponded to SAEs. Following discussion to resolve any conflicts/disagreements, we classified the following adverse effects as SAEs: haemodynamic instability, respiratory depression, venous thrombosis, wound infection or necrosis (whatever the site), arrhythmia or bradycardia, syncope, knee infection, falls, pneumonia, cerebral stroke, myocardial infarction or death.
Pairs of authors independently reviewed and extracted data from each study. Disagreements were resolved by consensus with a third author. We extracted information about the general characteristics of the study (first author, number of arms in the study, country, sponsorship), participants [age, BMI, American Society of Anesthesiologists’ (ASA) physical status, characteristics of the population, population randomised and analysed], experimental intervention (local anaesthetic used, administration route, timing of administration and doses), the use of discharge criteria, the existence of an enhanced recovery programme and all functional outcomes evaluated. Dichotomous outcomes were extracted as the presence or absence of an effect. For continuous data, we calculated mean and SD. If necessary, means and measures of dispersion were approximated from figures generated with dedicated software (http://www.datathief.org/). If not reported, the SDs were obtained from the confidence intervals (CIs) or P values for the differences between the means of two groups.16,18 If medians with ranges were reported, we obtained the mean and SD as described by Hozo.19 If only means were reported, we contacted the authors. We followed the recommendations of the Cochrane group to manage multiple groups.20 First, we selected only interventions of interest in our meta-analysis. Second when possible, we combined groups to create a single pair-wise comparison. Third, when we needed to include each pair-wise comparison separately, we split the ‘shared’ group into two groups with smaller sample size, and include two comparisons. For dichotomous outcomes, both the number of events and the total number of patients were recorded.
Two of the authors (TO, SB) independently assessed the methodological quality of the trials with the Cochrane Risk of Bias tool, with any discrepancies resolved by consensus.21 We documented the methods used for generating allocation sequences, allocation concealment, the blinding of investigators and participants, the blinding of outcome assessors, and for dealing with incomplete outcome data. Each item was classified as having a low, unclear or high risk of bias. The overall risk of bias was defined as the highest risk of bias documented.
Data synthesis and analysis
We calculated risk ratios with 95% CIs for dichotomous data and mean differences with 95% CI for continuous data. We expected there to be heterogeneity (because of the diverse populations included), and we therefore used the Dersimonian and Lairs random effects meta-analysis modules. We used the Wells calculator to obtain the number needed to treat for an additional beneficial outcome for continuous measures (available at the Cochrane Musculoskeletal Group editorial office https://musculoskeletal.cochrane.org/). We assumed a minimal clinically importance difference (MCID) of 1 day for LOS and 10° for ROM to interpret the clinical importance of our results.22 We assessed statistical heterogeneity by a visual inspection of graphs and by using the I2 statistic, which describes the proportion of variability in effect estimates due to heterogeneity rather than sampling error (I2 > 50% indicates substantial heterogeneity).23 The software RevMan 5.30 (Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used for the meta-analysis. We rated the quality of evidence for each outcome following the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group system.24 sufficient evidence had been accrued. We rated the quality of evidence for each outcome following the GRADE Working Group system.24
There were 463 potentially eligible reports. We examined 65 full-text articles, and we selected 23 studies on a total of 1246 patients (Fig. 1). All the studies involved single sites. The median target sample size was 60 (range 16 to 210) patients. The median publication date was 2009 (range 1990 to 2015). Participants were adults with ASA physical status classes 1 or 2. The characteristics of the selected trials are reported in Supplemental data Table 1, http://links.lww.com/EJA/A194.
Seven trials (30%) were classified as being at low risk of bias, eight (33%) at an unclear risk of bias and eight (33%) at high risk of bias. The randomisation procedure was adequately described in 16 trials (66%) and the concealment of treatment allocation was described in 12 trials (50%). Eleven (48%) were double-blind. Four studies (17%) had an unclear or high risk of incomplete data outcomes (Fig. 2 details the risk of bias for each trial).
Thirteen studies,27–39 including 872 patients, reported data for LOS, which was found to be shorter for RA than for systemic analgesia by 0.9 days (range 0.36 to 1.45, I2 = 82%). Subgroup analysis by type of RA showed that this small but significant difference concerned only the LIA group [1.05 days (range 0.46 to 1.64, I2 = 60%)]. Sixteen studies,29–32,34–36,39–47 including 958 patients, reported data for range of flexion on day 4 after surgery. ROM was significantly higher for patients given RA than for those receiving systemic analgesia, regardless of the type of RA [9.2° (range 4.7 to 13.7, I2 = 95%)]. The effect estimates for both outcomes met our criteria for MCID (i.e. 1 day for LOS and 10° for ROM) and were statistically significant (P < 0.05). The number needed to treat for a beneficial outcome was four (range 2.5 to 10) for LOS and two (range 1.5 to 3.7) for ROM. The level of quality of evidence was downgraded twice for both outcomes due to inconsistency (I2 > 50%) and insufficient quality of data, so the quality of evidence is low (Fig. 3).
Three studies,33,34,48 including 155 patients, reported data for time to first ambulation. There was no significant global difference in this time between LIA and systemic analgesia [−0.29 days (range −0.82 to 0.2), I2 = 73%]. Only one study reported a significant difference in the time to ambulation between epidural analgesia and systemic analgesia [0.80 (range 0.08 to 1.52), P = 0.03].34 Three studies45,46,49 comparing LIA and systemic analgesia, including 261 patients, evaluated the time until the patient could perform SLR after surgery. The time to first SLR was significantly shorter for LIA than for systemic analgesia [20.6 h (range 17.7 to 23.5), I2 = 91%]. Four studies35,45,46,50 comparing LIA and systemic analgesia, including 310 patients, reported data for ROM in the longer term. No difference in median ROM was found between LIA and systemic analgesia 3 months after surgery [1.5° (range −1.1 to 4.2)], with a median ROM for the control group of 108° at this time point. Two studies41,51 indicated no difference in long-term WOMAC score between femoral nerve block and systemic analgesia. Three studies41,48,52 showed no difference in long-term Knee Society Score (KSS) between femoral nerve block and systemic analgesia. One study showed no difference in long-term KSS and WOMAC scores between LIA and systemic analgesia.27 Three33,41,48 of five33,41,48,53,54 studies reported higher satisfaction in the peripheral nerve block group than in the systemic analgesia group. Two studies compared patient satisfaction between LIA and systemic analgesia and reported conflicting results.27,29 Fifteen studies27,30–34,36,39–41,45,46,49,50,53,55 including 1221 patients, compared the occurrence of SAEs between systemic analgesia and RA groups. The incidence of SAEs tended to be smaller in the RA group but failed to achieve significance with a risk ratios of 0.75 (range 0.52 to 1.08, I2 = 11%) (Fig. 3). The level of quality of evidence was downgraded for imprecision because the optimal information size was not reached. The quality of evidence was moderate (Fig. 3). Falls were not reported in the included studies.
The systematic review summarises the available evidence concerning the impact of regional analgesia on functional recovery after TKA. It shows that all RA techniques provide a similar transient improvement in knee ROM in the first week over that observed in patients receiving systemic analgesia. However, none of the regional analgesia techniques influenced global postoperative function or the recovery process in the long term after surgery.
Overall, the randomised clinical trials reported that all RA techniques slightly increased ROM in the early postoperative period but had no impact on long-term function. It has been suggested that peripheral nerve blocks provide better pain control, particularly for pain on movement, than systemic analgesia alone.7,10 Better pain management probably improves mobility, as indicated by the greater ROM recorded in the early postoperative period. However, this benefit does not seem to be systematically sustained beyond the period covered by the peripheral nerve block, with conflicting results reported for functional outcomes after discharge35,45,46,50 and no impact on long-term functional recovery.56 Although, the decrease in LOS was very small, it reached the minimal clinical importance difference and was similar to that reported in other systematic reviews.11,12 However, this decrease in LOS is much lower than the 2 to 3 days reported in cohort studies including an enhanced recovery programme.55,57,58 It could be explained by the lack of standardised discharge criteria in more than two-third of trials included.
Our systematic review was based on numerous small single-site trials. There was therefore a risk of overestimation of treatment effects and underreporting of relevant severe adverse effects. We observed a significant imbalance in terms of the amount of evidence available for individual types of intervention, with an underrepresentation of epidural analgesia. In addition, the included trials reported many different nonstandardised endpoints, precluding the comparison of trial results and the pooling of data from independent studies. The retrieved trials dealt with highly diverse drug regimens (volume, dose, timing and molecule administered), and the limited functional outcome data reported made it impossible to carry out more detailed subgroup analyses.
Our study has several strengths. First, we conducted a rigorous and extensive literature search, including registry searches, contact with the authors of the studies considered and searches of the abstract proceedings for the two main congresses in the field for up to 5 years. Second, our meta-analysis provides a complete overview of current scientific knowledge concerning the contribution of regional analgesic techniques to functional recovery after knee arthroplasty compared with systemic analgesia. This analysis could therefore be used to develop a rational basis for future research. Based both on the frequency of outcomes reported in this systematic review and on the unmet needs for which future clinical research is required, we suggest the following evaluation of function after TKA. Global function should be evaluated before surgery and in the longer term after surgery, by calculating the WOMAC score. Maximal flexion of the knee and SLR tests could be used as intermediate functional outcomes in the immediate postoperative period. The lack of standardised criteria of discharge is an issue and precludes the evaluation of the LOS based on a combination of criteria used in the studies included in this review and cohort studies regarding the addition of an enhanced recovery program for TKA55,57 could be proposed. We suggest that the following criteria should be considered; to standardise LOS endpoint in trials independently mobile with sticks or elbow crutches, ability to climb or descend a single flight of stairs safely, 90° knee flexion, satisfactory analgesia (maximum 30 mm on a visual analogue scale) and good quadriceps strength (able to stand up from a sitting position and to maintain knee extension while weight-bearing).55 The achievement of discharge criteria should be the gold standard in all studies evaluating analgesia approaches in postoperative care.
There is an urgent need to standardise functional evaluation after knee arthroplasty. Nevertheless, we can confirm with confidence that all RA techniques are superior to systemic analgesia in terms of the ROM achieved in the early postoperative period. However, no impact of regional analgesia techniques on global function in the longer term has been demonstrated.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
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