Description of the condition
Major knee surgery includes operations such as total knee arthroplasty, arthrolysis (Capdevila 1999) and anterior cruciate ligament reconstruction (ACLR) (Fowler 2008). Patients with end-stage knee disease or trauma can regain mobility and have improved quality of life after undergoing these procedures. Major knee surgery is becoming increasingly common; the annual number of total knee arthroplasties performed in the United States has doubled in the last decade (Weinstein 2013). Despite advances in surgical techniques, poorly controlled pain immediately after surgery is still a key issue that affects patients (Chan 2013). The incidence of moderate-to-severe pain after total knee arthroplasty is reported to be about 50%, greater than that reported for all surgeries in a general population or for total hip arthroplasty (Grosu 2013). Thus, an effective analgesic strategy is required. Patients are advised to undergo physical therapy after surgery to restore their ability to carry out daily activities. Physical therapy can include passive and active knee flexion and extension exercises. Postoperative muscle spasm is an obstacle to these exercises as well as a major source of pain. Therefore, efficacious muscle relaxation should be considered so as to optimize pain relief (Sakai 2013).
Description of the intervention
There are several analgesic options for major knee surgery, such as systemic, local infiltration, epidural and spinal analgesia. Systemic analgesia with opioids may cause various adverse effects, including nausea, vomiting, pruritus, sedation and drowsiness (Chan 2013). Local infiltration analgesia has been proven to be most effective when the patient is at rest, and may be less effective when they are walking or engaging in continuous passive movement (Yadeau 2013). There are many adverse effects associated with epidural and spinal analgesia, such as perioperative hypotension, urinary retention, nausea, vomiting, and sensory and motor blockade of the non-operated leg. To some extent, these adverse effects may cause harm to patients and interfere with early ambulation (Mugabure Bujedo 2012; Teng 2012). Moreover, the co-administration of anticoagulant drugs, used to prevent thromboembolic events, increases the potential risk of spinal epidural hematoma (Choi 2003).
Peripheral nerve blocks are localized and site-specific. Their history dates back to 1930, when the technique was first reported to relieve the pain in obliterative vascular disease of the lower leg (Smithwick 1930). In 1980, Rosenblatt reported the first use of peripheral nerve blocks as the sole means of postoperative analgesia after a knee operation (Rosenblatt 1980).
For decades, the accurate performance of peripheral nerve blocks has been supported by peripheral nerve stimulation techniques. In 1989, ultrasonography was first utilized to confirm the location of the needle and observe the spread of local anesthetic while performing peripheral nerve blocks (Ting 1989). Subsequently, ultrasound-guided blocks have become increasingly popular with clinicians owing to the precise action and faster onset of the block (Sala-Blanch 2012).
Bupivacaine and ropivacaine are the most commonly used local anesthetics for peripheral nerve blocks. In addition, drugs such as opioids, epinephrine and clonidine are utilized as adjuvants to increase the duration of the analgesic effect, but there are no reports of their safety or efficacy (Aguirre 2012).
There are several types of peripheral nerve block that aim to relieve lower extremity pain, including femoral nerve, sciatic nerve and lumbar plexus blocks. Among them, the femoral nerve block is considered one of the primary options following major knee surgery. The femoral nerve is the largest branch of the lumbar plexus and provides sensation to the anterior aspect of the knee, whereas the sciatic nerve innervates the posterior aspect. Therefore, one method of ensuring complete reduction of pain transmission in the knee is to perform a sciatic nerve block in combination with a femoral nerve block (Tantry 2012). Another combination of peripheral nerve blocks used to ensure optimum pain relief is the three-in-one technique, which blocks three branches of the lumbar plexus: the femoral nerve (L2-L4), the obturator nerve (L2-L4), and the lateral femoral cutaneous nerve (L2-L3) (Hogan 2009).
Peripheral nerve blocks can be administered as a single shot or continuously via a catheter and a pump. Continuous peripheral nerve blocks (CPNBs) were introduced by Ansbro in 1946, later than single-shot peripheral nerve blocks (SSPNBs), to increase the duration of the effect of the brachial plexus block (Ansbro 1946). Since then, continuous peripheral nerve blocks have evolved into reliable analgesic techniques that are widely used in the postoperative period. Continuous peripheral nerve blocks take approximately one and a half to four times longer than single shots, but the duration of the analgesic effect is increased (Chan 2013). Furthermore, the well-designed instrumentation used for a continuous peripheral nerve block provides patients with adequate and continuous analgesia after discharge (Dervin 2012).
How the intervention might work
Peripheral nerve blocks following major knee surgery reduce local pain transmission by blocking one or more major nerves supplying the lower limb. Clinical trials have also shown that they may reduce the postoperative inflammatory response (Bagry 2008; Martin 2008).
Peripheral nerve blocks offer a number of advantages for postoperative analgesia following major knee surgery. It has been reported that they result in better analgesic control, fewer opioid-related side effects, earlier improvements in knee flexion, and less pain during rehabilitation (Chan 2013; Sakai 2013). Additionally, they avoid motor blockade to the non-operated leg, thereby encouraging early ambulation and relieving psychological stress to some degree.
It is worth noting that performing a peripheral nerve block is limited by certain factors such as the position of the patient. In addition, safety factors, such as the potential infection risk and the risk of exceeding the safe dose of local anesthetic, may even potentially become life-threatening (Tantry 2012).
Why it is important to do this review
Peripheral nerve blocks may be effective for postoperative pain after major knee surgery. Most randomized controlled trials (RCTs) conclude that they relieve postoperative pain and decrease consumption of opioids, although studies have included a relatively small number of patients.
A number of meta-analyses have been conducted on related topics in recent years. However, most of them focus on specific types of peripheral nerve block, such as the femoral nerve (Paul 2010), sciatic nerve (Abdallah 2011) and continuous peripheral nerve block (Richman 2006), and the surgical procedures studied have mainly been limited to total knee arthroplasty. It is important to evaluate the effect of peripheral nerve blocks after major knee surgery.
To examine the efficacy and safety of peripheral nerve blocks for postoperative pain control following major knee surgery using methods that permit comparison with systemic, local infiltration, epidural and spinal analgesia.
Criteria for considering studies for this review
Types of studies
We will include prospective, randomized controlled clinical trials. We will exclude concurrent cohort studies and observational studies, as well as case series and case reports without a control group.
In order to maintain participant blinding, placebo catheters normally need to be inserted, which may cause unnecessary discomfort and raise the risk of infection (Chan 2013). Therefore, this insertion is not obligatory but studies should ensure that patients have the same expectations of treatment throughout the entire treatment process. For example, all procedures could be performed behind a drape to block the patient's view, dressings could be placed on injection sites and blocks could be performed by anesthetists who are not involved with data collection (Allen 1998).
Types of participants
We will include studies of adult participants (> 15 years) who underwent major knee surgery. The procedure could be either total knee arthroplasty, arthrolysis, anterior cruciate ligament reconstruction or any other major surgeries performed on the knee.
Types of interventions
We will include studies that compare the analgesic effect of peripheral nerve block versus systemic, local infiltration, epidural or spinal analgesia following major knee surgery. All subtypes of peripheral nerve block will be included.
Types of outcome measures
We will consider pain intensity measured as greater than 30 mm on a 100 mm visual analogue scale (VAS) to equate to 'at least moderate pain'. To clarify, we will consider an intensity of less than or equal to 30 mm to be 'no worse than mild pain' (Collins 1997; Moore 2013).
- Pain intensity assessed on a 100 mm VAS on the day of surgery and within the following 72 hours after surgery (divided into three time intervals: zero to 23 hours, 24 to 47 hours, 48 to 72 hours) at rest or on movement. We will normalize pain intensity data described by other means than a 100 mm VAS to such a scale.
- Proportion of patients with 'no worse than mild pain' (pain intensity of less than or equal to 30 mm of 100 mm VAS).
- Additional analgesic consumption within 72 hours after surgery (divided into three time intervals: zero to 23 hours, 24 to 47 hours, 48 to 72 hours) and median time to remedication.
- Adverse events within 72 hours after surgery (divided into three time intervals: zero to 23 hours, 24 to 47 hours, 48 to 72 hours).
- Knee range of motion within 72 hours after surgery (divided into three time intervals: zero to 23 hours, 24 to 47 hours, 48 to 72 hours) and median time to ambulation.
- Length of hospital stay and hospital costs.
- Patient satisfaction.
Search methods for identification of studies
We will search the following electronic databases from the date of inception: the Cochrane Central Register of Controlled Trial (CENTRAL, in The Cochrane Library), MEDLINE and EMBASE.
See Appendix 1 for the MEDLINE search strategy. We will apply no language restrictions.
Searching other resources
We will carry out handsearching of the reference lists of retrieved articles for relevant trials not identified by the electronic searches. We will identify any ongoing trials by searching trial registries, including the metaRegister of controlled trials (mRCT), clinicaltrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP).
Data collection and analysis
Selection of studies
We will initially determine eligibility by reading the titles retrieved from each search. We will then screen all remaining articles by reading each abstract. Two review authors (JX, XC) will evaluate the studies independently. Disagreement will be resolved by discussion or, if necessary, by a third review author (XW). We will document the selection process in sufficient detail to complete a PRISMA flowchart (Liberati 2009). We will create a table of 'Characteristics of included studies' in the full review.
Data extraction and management
We will extract data from the included trials (JX, XC). Disagreements will be resolved through a third review author (XW). We will use a standard data extraction form to tabulate the extracted data. This form will include:
- patient characteristics (total numbers of patients, age and gender of each patient);
- type of knee surgery;
- type of analgesia and related details;
- pain intensity (both at rest and on movement, from the day of surgery to 72 hours after surgery);
- additional analgesic requirements (name and amount of analgesic consumed, median time to remedication);
- safety (incidence and degree of adverse events);
- rehabilitation indices (median time to ambulation and knee range of motion);
- length of hospital stay and hospital costs;
- patient satisfaction.
Assessment of risk of bias in included studies
We intend to use the Oxford quality and validity scales to assess the risk of bias in included studies (Jadad 1996). Two review authors (JX, XC) will assess each study independently and resolve any disagreement through discussion, with a third review author (XW) if necessary.
The scales are as follows.
- Is the study randomized? If yes add one point.
- Is the randomization procedure reported and is it appropriate? If yes add one point, if no deduct one point.
- Is the study double-blind? If yes add one point.
- Is the double-blind method reported and is it appropriate? If yes add one point, if no deduct one point.
- Are the reasons for patient withdrawals and drop-outs described? If yes add one point.
We will also use the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess the risk of bias further.
The criteria are as follows:
Sequence generation (checking for possible selection bias)
We will assess the method used in each included study to generate the allocation sequence. The judgement will be as follows: low risk of bias (a random component was described in the process, e.g. random number table; computer random number generator; coin tossing); high risk of bias (a non-random component is described in the process, e.g. odd or even date of birth; date of admission; hospital or clinical record number); unclear risk of bias.
Allocation concealment (checking for possible selection bias)
We will assess the method used in each included study to conceal the allocation sequence. The judgement will be as follows: low risk of bias (assignment could not be foreseen, e.g. central allocation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes); high risk of bias (assignment could possibly be foreseen, e.g. using an open random allocation schedule; assignment envelopes were used without appropriate safeguards; alternation or rotation); unclear risk of bias.
Blinding of participants and personnel (checking for possible performance bias)
We will assess the method used in each included study to blind study participants and personnel from knowledge of which intervention a participant received. The judgement will be as follows: low risk of bias (no blinding or incomplete blinding, but the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken); high risk of bias (no blinding or incomplete blinding, or blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding); unclear risk of bias.
Blinding of outcome assessment (checking for possible detection bias)
We will assess the method used in each included study to blind outcome assessors from knowledge of which intervention a participant received. The judgement will be as follows: low risk of bias (no blinding of outcome assessment, but the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken); high risk of bias (no blinding of outcome assessment, or blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding); unclear risk of bias.
Incomplete outcome data (checking for possible attrition bias)
We will assess the completeness of outcome data in each included study. The judgement will be as follows: low risk of bias (e.g. no missing outcome data; reasons for missing outcome data unlikely to be related to true outcome; missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups); high risk of bias (e.g. reasons for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups); unclear risk of bias.
Selective reporting (checking for possible reporting bias)
We will state how the possibility of selective outcome reporting is examined and what is found. The judgement will be as follows: low risk of bias (the study protocol is available and all of the prespecified outcomes that are of interest in the review are reported in the prespecified way; the study protocol is not available but the published report includes all expected outcomes); high risk of bias (e.g. not all of the prespecified primary outcomes are reported; one or more primary outcomes are reported using measurements, analysis methods or subsets of the data that were not prespecified; one or more reported primary outcomes are not prespecified); unclear risk of bias.
Size of study (checking for possible biases related to small size)
We will assess studies as follows: low risk of bias (more than or equal to 200 participants per treatment arm); high risk of bias (fewer than 50 participants per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm).
Other sources of bias
We will state any important concerns about bias that are not addressed by the other domains in the tool. The judgement will be as follows: low risk of bias (the study appears to be free of other sources of bias); high risk of bias (at least one important risk of bias due to problems not covered elsewhere in the criteria above); unclear risk of bias.
Measures of treatment effect
We will carry out statistical analysis of treatment effects using the Review Manager software (RevMan 2012) where two or more studies investigate the same outcome.
For dichotomous data, we will present results as summary risk ratio (RR) and 95% confidence interval (95% CI). Where possible, we will calculate numbers needed to treat to benefit (NNTB) or numbers needed to treat to harm (NNTH), together with 95% CIs. For continuous data, we will use the mean difference (MD) and 95% CI for similar outcome measures. We will report individual study results if pooling of data is not possible.
Unit of analysis issues
We will describe special issues in the analysis of studies with non-standard designs.
Dealing with missing data
If some data are not reported or not clearly reported for some outcomes or groups, we will attempt to contact the study authors for further information.
We will conduct an intention-to-treat (ITT) analysis to estimate whether the intervention effect is biased if some participants are excluded from analysis in the randomized trials or they are lost to follow-up. We will analyze available data on all participants in each arm, regardless of what happened subsequently (Newell 1992).
We will use the baseline observation carried forward (BOCF) approach to avoid the analgesic effect calculation of the original intervention being affected by the effect of remedication. After remedication, pain intensity will be reverted to its initial value and pain relief will become zero for all subsequent time points (Moore 2005).
Assessment of heterogeneity
We will use the I
Assessment of reporting biases
The methods of assessing the risk of reporting bias are described above in 'Selective reporting (checking for possible reporting bias)' (Assessment of risk of bias in included studies). When reporting bias is suspected, we will perform a sensitivity analysis to explore whether the related studies cause severe bias. We will use funnel plots to explore publication bias (Higgins 2011).
We will use a fixed-effect model to conduct meta-analysis if data are homogeneous, otherwise we will use a random-effects model. Where the data are unsuitable for meta-analysis, we will attempt to describe the findings of multiple studies separately.
Subgroup analysis and investigation of heterogeneity
We will take into consideration several potential sources of heterogeneity. Firstly, the types and doses of analgesics applied in each intervention will not be standardized between studies. Secondly, peripheral nerve blocks may be administered as single-shot or continuous doses, and continuous peripheral nerve blocks increase the duration of the analgesic effect beyond that of single-shot peripheral nerve blocks. Thirdly, applying the intervention to different locations, such as femoral nerve block only, or combining a femoral with a sciatic or obturator nerve block, may have different analgesic effects. Therefore, if there is sufficient information (a minimum of two studies and 200 participants) (Moore 1998) we will carry out subgroup analysis to check whether these differences affect the results.
We will perform sensitivity analyses to explore the effect of quality score (two versus three or more) and trial size (39 or fewer versus 40 or more per treatment arm) for important outcomes in the review.
The authors wish to thank Dr. Annette Swinkels and Miss Yi-jing Lu for their helpful suggestions on this protocol.
Appendix 1. Search strategy for MEDLINE (via Ovid)
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
5. clinical trials as topic.sh.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. exp animals/ not humans.sh.
10. 8 not 9
11. exp arthroplasty, replacement, knee/
12. exp knee prosthesis/
13. exp anterior cruciate ligament reconstruction/
15. 11 or 12 or 13 or 14 or 15
16. exp pain, postoperative/
17. exp analgesia/
18. exp pain management/
19. exp analgesia, patient-controlled/
20. ((postoperat* or post-operat* or "after operat*" or "follow* operat*" or postsurg* or post-surg* or "after surg*" or "follow* surg*") abj6 (pain* or analgesi*)).mp.
21. 17 or 18 or 19 or 20 or 21
22. exp nerve block/
23. ("nerve adj3 block*" or chemodenervation or "chemical adj1 neurolys?s").mp.
24. 23 or 24
25. 10 AND 16 AND 22 AND 25
Contributions of authors
Jin Xu wrote the protocol. Xue-mei Chen and Chen-kai Ma designed the search strategy. Xiang-rui Wang conceived and provided general advice on the protocol.
Declarations of interest