Anterior cruciate ligament (ACL) injuries are a common orthopedic injury with isolated tears having an annual incidence of 69/100 000 person years.1 Little consensus exists concerning the optimal timing of ACL reconstruction (ACLR)2,3 or what constitutes “early” versus “late” surgery.4–8 Potential advantages of early reconstruction include a shorter rehabilitative period, quicker return to work/sport, as well as a decreased risk of exposure to secondary injury due to persistent instability.2 Proponents for a delayed ACLR argue that it will allow for optimal restoration of range of motion and strength before surgery and minimize the risk of arthrofibrosis.9 Initially, it was believed that early ACLR caused an increased rate of arthrofibrosis, resulting in diminished postoperative range of motion.3,10 However, this was challenged by subsequent studies that showed no loss of motion as well as improved outcomes with early reconstruction.11,12
Smith et al4 first performed a systematic review in 2010 that evaluated clinical outcomes in patients who underwent early versus delayed surgery. In this review, they found that there was no significant difference between those who underwent surgery <3 weeks from injury compared to those who had surgery performed >4 weeks from injury in regard to Tegner, Lysholm, International Knee Documentation Committee (IKDC), Hospital for Special Surgery scores, patient satisfaction, KT-1000, Lachman, pivot shift, range of motion, arthrofibrosis, chondral injury, patellofemoral pain, meniscal injury, patellofemoral joint crepitus, or strength. After this, Andernord et al2 performed a comprehensive review of randomized controlled trials and prospective cohort studies, also finding few or no significant differences in subjective and objective clinical outcomes due to timing of the ACLR. In addition, the authors also noted the large variability in the classification of early and late reconstruction, ranging from 2 days to 7 months and 3 weeks to 24 years, respectively. In 2017, Larrson et al13 analyzed the synovial fluid contents of knees that underwent ACLR early (<10 weeks), delayed (>10 weeks to 5 years), and with rehabilitation alone. By synovial analysis, they determined that an ACLR acted much like a secondary trauma to the knee regardless of the timing with those in the rehabilitation group showing the lowest levels of inflammatory markers at follow-up. One of the primary concerns and rationale for restoring the knee to its anatomical state in a nondemanding population is to prevent the development of osteoarthritis (OA) after ACL injury. In a 2017 review, Paschos14 concluded that ACLR restored knee stability, which could potentially reduce the risk of OA, although it was difficult to conclude due to the high incidence of OA in both groups, which was concluded to be likely from the initial trauma of the injury.15 This led Paschos to suggest investigating factors outside of stability and whether these factors increase the risk of OA.16–19
Several studies have identified additional pathology, outside of the torn ACL, as contributors to degeneration, with cartilage lesions and meniscal tears being determined as important predictors of OA. This led Krutsch et al20 to perform a prospective study investigating the effect of delay in ACLR and the incidence of cartilage and meniscal lesions. They found that although there was no difference in the amount of cartilage lesions, a delay in surgery resulted in significantly more irreparable meniscal lesions. Past studies have shown a substantial increase in knee OA in relation to amount of meniscus resected, with the highest rates found in complete meniscectomies.21,22 Further studies have supported this notion with a general understanding that increasing the amount of meniscus resected increases the likelihood for future degenerative change.21,23
The objective of this systematic review was to identify, critically appraise, and meta-analyze data from randomized controlled trials (RCTs) to determine the effect of timing of ACLR on the incidence of meniscal and chondral lesions at the time of arthroscopic surgery.
An a priori protocol was created and is available from the authors on request. We conducted a systematic review adherent to the Methodological Expectations of Cochrane Intervention Reviews framework.24 Reporting was consistent with the criteria outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.25 Ethics approval was not required for this meta-analysis.
We performed a systematic review and meta-analysis to answer the question “In skeletally mature patients, does early reconstruction of the ACL result in fewer meniscal and chondral lesions at the time of surgery compared with a delayed ACLR?” Our primary outcome measure was the incidence of cartilage and meniscal injuries at the time of ACLR per group (early vs delayed). Secondary outcomes included activity level (Tegner activity score), knee-specific outcome scores (IKDC), knee range of motion (flexion deficit >5 degrees and extension deficit >5 degrees), and knee stability (KT-1000) measurement. Safety outcomes included the proportion of individuals who suffered a graft rupture as well as the proportion of individuals who suffered a postoperative infection in each group.
Search Strategy and Study Selection
A systematic literature search was completed and is up to date as of March 20, 2018. The databases MEDLINE (Ovid), EMBASE (Ovid), and Scopus were searched using engine-specific strategies unique to each database to maximize sensitivity (see Appendix A, Supplemental Digital Content 1, http://links.lww.com/JSM/A211). Abstract and conference proceedings from the following societies were searched (2016-2018): American Academy of Orthopedic Surgeons, Canadian Orthopedic Association, American Orthopedic Society for Sports Medicine, and the Arthroscopic Association of North America. In addition, the reference lists of relevant systematic reviews, meta-analyses, and included trials were hand searched for relevant citations.
All search results were then compiled in EndNote (X7; Thomson Reuters, Philadelphia, Pennsylvania). Two reviewers (G.M. and S.K.) independently reviewed the title and abstract of each citation to determine eligibility based on prespecified criteria. Studies were then screened based on title and abstract for eligibility. Any discrepancies were agreed upon mutually between reviewers. Studies that were believed to be eligible then underwent full-text review, after which only primary articles, which met all the inclusion and exclusion criteria, were included in the systematic review. A meta-analysis and systematic review was planned for any randomized controlled trials identified. For the purposes of the meta-analysis, early ACLR was defined as <3 weeks and that of delayed ACLR was defined as >4 weeks.
We included RCTs involving ACLR on skeletally mature (100% radiographic physeal closure) patients in which the groups were randomized according to the timing of ACLR (early vs delayed), as well as trials which, at minimum, reported on the primary outcome measure. In addition, included trials must have used an arthroscopic or arthroscopically assisted surgical technique and included human participants. If a study had multiple published interim results, only the most recent published data were included. Studies were excluded if ACLR was performed as a revision procedure, case reports/series, review articles and narratives, cohort studies (prospective or retrospective), quasi-randomized, crossover or cluster trials as well as studies not published in English because research has shown that the quality of systematic reviews, particularly conventional medicine, is not impacted by this exclusion; however, there still remains some controversy.26–29
Data Extraction Form
Two reviewers (G.M. and S.K.) independently extracted data from the included trials using piloted data extraction forms. Discrepancies were resolved through mutual consensus. The following data were extracted from each study: study demographics (author, year of publication, randomization form, sample size-total and number per patient group, minimum follow-up time, number, number of patients who dropped out of the study, definition of surgical timing into “early” or “delayed” categories, graft type used for ACLR, physiotherapy type, and duration); patient characteristics (average age of the participants, male-to-female ratio, percentage of patients who suffered an athletic injury, and average time from injury to surgery); primary outcomes measures (incidence of meniscal and chondral lesions); secondary outcome measures (number of participants with a flexion or extension deficit >5 degrees, knee stability outcome scores—KT 1000, and knee functional outcomes scores—IKDC); and safety outcomes (incidence of postoperative graft rupture and postoperative infection). The data were input into a Microsoft Excel database (Microsoft Corp, Redmond, Washington).
Internal Validity Assessments
The internal validity of the trials was assessed using the Cochrane Collaboration Risk of Bias tool.30 This tool consists of 6 domains (sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias) and a categorization of the overall risk of bias. Each separate domain was rated low risk, unclear risk, or high risk. The overall assessment was based on the responses to individual domains. If one or more individual domains were assessed as having a high risk of bias, the overall trial was rated as having a high risk of bias. The overall risk of bias will be considered low only if all components were rated as having a low risk of bias. In addition, the Detsky scale was used to classify the studies for methodologic quality31 (see Appendix B, Supplemental Digital Content 1,http://links.lww.com/JSM/A211). The Detsky scale is a 20-point scale used for studies with a statistically significant result (hereafter referred to as “positive studies”) and a 21-point scale for studies without a statistically significant result (hereafter referred to as “negative studies”). It measures the methodological quality based on the description of 5 parameters: randomization, outcomes measures, inclusion/exclusion criteria, intervention, and statistics.
Meta-analysis was performed using Cochrane's Review Manager (RevMan, version 5.3.5, 2014; The Cochrane Collaboration, Copenhagen, Denmark). Count data were expressed as log (risk ratios) and standard error, with 95% confidence intervals (CIs) using the inverse variance method, and dichotomous outcomes as number of events and odds ratio (OR) with 95% CIs using the Mantel–Haenszel method. A random-effects model was used for all analysis. Heterogeneity was assessed initially by visual inspection of the forest plots. In addition, an I2 statistic was used to quantify risk of heterogeneity between studies. When data could not be compared in a similar manner for outcomes of interest, the results were summarized and presented as best evidence available. Publication bias was not assessed using funnel plot techniques because the number of studies was much too low.32 The Detsky scores were converted to a score out of 100 to facilitate comparison between studies. The proportion of studies meeting the standard of acceptability (> 75%) was then calculated.
Unfortunately, we could not perform an a priori defined subgroup analyses on patient age, rehabilitation type and duration or other concomitant surgeries performed due to lack of reported data in the included trials.
Of the 1887 citations identified from electronic and hand searches, we included 4 unique trial reports (303 patients; range 31-104)33–36 (Table 1 and Figure 1). Publication year ranged from 2003 to 2017. The mean age of enrolled patients in included trials ranged from 21 to 31.2 years with the majority of patients being male (73%). Definition of early ACLR ranged from <1 to <3 weeks, and that of delayed ranged from >4 weeks to 8 to 12 weeks. The mechanism of injury was mostly athletic injuries (41%-100%), and the minimum time to follow-up was an average of 12.5 months (6-26 months) and a maximum follow-up time of 5 years. Most outcome measures were recorded between 12 weeks postoperatively to 1 year. Three trials used a hamstring autograft for ACLR,whereas one trial used patellar bone. In regard to rehabilitation, none of the trials reported the compliance rate and only 2 trials reported the duration of physiotherapy (3 and 6 months). Two articles described the type of physiotherapy and both focused on early weight-bearing range of motion from 0 to 90 degrees (within a few days after operation), followed by early strengthening (3 weeks) and return to sporting activities (6 months).
TABLE 1. -
Demographics of Studies
||N = (Early/Delayed)
||Average Age (Early/Delayed)
||Athletic Injury (%) (Early/Delayed)
|Meighan et al34
|Bottoni et al33
|Raviraj et al36
|Manandhar et al35
||Definition Early (wk)
||Average Time to Surgery (d)-Early
||Average Time to Surgery (d)-Delayed
||Minimum Follow Up (mo)
|Meighan et al34
|Bottoni et al33
|Raviraj et al36
|Manandhar et al35
BTB, bone tendon bone; HS, hamstring; NR, not recorded.
Risk of Bias and Methodologic Quality
One trial was considered to be at high risk of bias,35 whereas 2 trials were deemed unclear risk of bias33,34 and one trial was considered at low risk of bias36 (Figure 2) (see Appendix C, Supplemental Digital Content 1,http://links.lww.com/JSM/A211, for risk stratification). Of note, under risk of bias for blinding, we did not consider the lack of blinding of the patient or the surgeon as high risk because it would be difficult to achieve in a surgical study, and we feel that it would not impact the results of the outcomes of the trial. The Detsky score was calculated in all trials and only one trial did not meet a value of 75%34 suggesting lower-quality methodology (Table 2). The main reason for this was due to the lack of details regarding data analysis, sample size calculation, and description of the interventions.
||Detsky Score (21)
|Manandhar et al35
The incidence of meniscal lesions was reported in all 4 trials at the time of arthroscopic surgery.33–36 We pooled the data from the 4 trials to generate a rate ratio, which was converted to a log (risk ratio) and standard error (Figure 3). The results of this analysis showed there to be no evidence of a difference between groups [relative risk (RR), 0.98; CI, 0.74-1.29; P = 0.87]. The incidence of chondral lesions were reported in 3 out of 4 studies33,35,36 and these data were pooled as above (Figure 4). The results of this analysis also showed no significant difference between groups (RR, 0.88; CI, 0.59-1.29; P = 0.50). No subgroup analysis could be performed on the primary outcomes.
Tegner activity level was measured in 3 out of 4 studies33–36; however, these data were not able to be pooled. One trial reported the mean score without a measure of variance,33 another reported the mean score with the SD,35 whereas the last trial reported the median score.36 All trials reported no significant difference between groups in Tegner activity score at the latest follow-up. In regard to knee-specific outcome scores, only one trial reported the IKDC score,35 which showed no difference between groups. Range of motion was reported in 3 trials,33,34,36 with one reporting average flexion and extension deficit33 and the others reporting extension and flexion deficits >5 degrees34,36 with all authors reporting no difference between groups at final follow-up. In regard to knee instability, only one trial recorded KT-1000 results33 and found no difference between groups.
Three trials reported the incidence of postoperative infection33,34,36 (Figure 5), with no evidence of a significant difference found between groups (OR, 4.13; 95% CI, 0.66-26.02; P = 0.13). Two trials reported the incidence of graft rupture33,34 (Figure 6); however, no evidence of significant difference was found (OR, 0.71; CI, 0.08-6.03; P = 0.76).
In our systematic review of patients who have undergone an ACLR, the timing of the surgery did not show a significant difference in the incidence of meniscal or chondral lesions. As previous studies have shown an increase in the number of chondral and meniscal lesions, the reason our review did not show this could be 2-fold. First, 2 out of 4 studies35,36 excluded meniscal lesions requiring a repair or chondral lesions that required more than simple debridement from the study population due to the alteration in rehabilitation protocol they would have to undergo. These studies excluded any meniscal injuries that required a repair, or the more severe chondral lesions, classified as outerbridge grades III and IV. These were also the studies that explicitly stated what the rehabilitation protocol was, showing good transparency in methods. As shown by Leiter et al,37 these lesions are of interest, particularly medial meniscal lesions, because those requiring repair or excision were the only predictors identified for future degenerative change in their study (P = 0.012). Second, the time frame used for these studies is quite short and does not reflect regular practice; particularly, in our institution (publicly funded), the average time to ACLR is well over 4 weeks. Previous retrospective cohort studies have shown significant differences between early and delayed reconstruction when using an end point of >3,38–40 >6,6,41 and >12 months42–45 for delayed reconstruction, in regard to the incidence of meniscal and chondral lesions. The main reason of concern for the increased incidence of meniscal and chondral injuries is due to the eventual development of posttraumatic OA. In their retrospective study, Church and Keating44 was able to document the increased incidence of degenerative change at the time of surgery in knees that had greater than a year from the time of injury to surgery, adding further support to the correlation between meniscal/chondral damage and the onset of OA. In a study performed by Frobell et al,46 they compared early ACLR defined as <10 weeks and the optional late reconstruction group occurring at an average of 347 ± 124 days, giving a range of roughly 8 to 13 months. In their study, they found no significant differences in Knee Injury and Osteoarthritis Outcome Score, SF-36 score, or Tegner activity score. In addition, in their 5-year follow-up study47, they continued to find no difference in the above scores, as well as incidence of radiographic arthritis. They concluded that it is acceptable to wait up to 3 months from the time of injury to ACLR during which conservative treatment is initiated. However, the numbers in each group were quite skewed because only 23 patients in the optional delayed reconstruction group underwent ACLR compared with 60 patients in the early reconstruction group. In addition, this study did not document the number of chondral lesions, which as mentioned above, is a significant contributor to the development of OA. In the follow-up study reporting on incidence of radiographic OA, unfortunately, radiographic analysis of cartilage degeneration does not accurately reflect actual degenerative change found on arthroscopy. In a study by Brandt et al48 of 17 patients reported to have no signs of radiographic arthritis, 7 (41%) were found to have advanced tibiofemoral or patellofemoral OA seen on arthroscopy. In addition, radiographic change was only moderately strong in its correlation with actual articular degeneration found on arthroscopy as reported by Kijowski et al49. These findings of inaccuracy between arthroscopic and radiographic signs of degeneration has been supported previously as well50,51.
Unfortunately, we were unable to pool any of the secondary outcome measures; however, the individual studies reported no significant differences in any of the outcomes recorded. This reflects the conclusions of previous systematic reviews2,8,46 where no differences were found in outcomes or postoperative stiffness between the 2 groups.
The internal validity of the included trials was variable with only one trial being rated as having a high risk of bias35 and only one study ranking <75% on the Detsky score.34 Interestingly, the trial with high risk of bias was also the only study to report a significant difference in meniscal and chondral injuries, favoring the early reconstruction group.
Our meta-analysis adds to the existing literature by objectively evaluating and pooling data to answer the question regarding timing of surgery and the incidence of chondral lesions from 0 to 4 weeks after injury. Strengths of our review include our comprehensive search strategy, utilization of multiple electronic database searches, hand searches, and searching of conference abstracts. We strictly adhered to the recommended guidelines for conducting and reporting systematic reviews and provided a comprehensive evaluation of the literature's methodological quality as well as risk of bias.
Limitations of this study include the small number of included studies, the short duration of the delayed reconstruction group, the lack of reported secondary outcome measures, and the smaller sample sizes.
There is a paucity of randomized controlled trials that measure outcomes and the rate of meniscal and chondral injuries secondary to the timing of ACLR. In patients receiving an ACLR, there is no evidence of a significant difference in the incidence of meniscal or chondral pathology between those operated on <3 weeks from injury and those that were >4 weeks from injury. Future randomized controls trials should address larger periods between early and delayed reconstruction because most studies in the past have shown significant differences with a delay of 3 months or greater. A future meta-analysis that takes into account the lower quality studies (level II and level III) may be performed to get a more accurate description of secondary pathology using these longer periods.
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