Br J Anaesth. 2016;116(2):163-176.
Authors: R. L. Johnson et al
A Systematic Review of Comparative-Effectiveness Research
Background: This systematic review evaluated the evidence comparing patient-important outcomes in spinal or epidural vs general anaesthesia for total hip and total knee arthroplasty.
Methods: MEDLINE, Ovid EMBASE, EBSCO CINAHL, Thomson Reuters Web of Science, and the Cochrane Central Register of Controlled Trials from inception until March 2015 were searched. Eligible randomized controlled trials or prospective comparative studies investigating mortality, major morbidity, and patient-experience outcomes directly comparing neuraxial (spinal or epidural) with general anaesthesia for total hip arthroplasty, total knee arthroplasty, or both were included. Independent reviewers working in duplicate extracted study characteristics, validity, and outcomes data. Meta-analysis was conducted using the random-effects model.
Results: We included 29 studies involving 10 488 patients. Compared with general anaesthesia, neuraxial anaesthesia significantly reduced length of stay (weighted mean difference −0.40 days; 95% confidence interval −0.76 to −0.03; P=0.03; I2 73%; 12 studies). No statistically significant differences were found between neuraxial and general anaesthesia for mortality, surgical duration, surgical site or chest infections, nerve palsies, postoperative nausea and vomiting, or thromboembolic disease when antithrombotic prophylaxis was used. Subgroup analyses failed to find statistically significant interactions (P>0.05) based on risk of bias, type of surgery, or type of neuraxial anaesthesia.
Conclusion: Neuraxial anaesthesia for total hip or total knee arthroplasty, or both appears equally effective without increased morbidity when compared with general anaesthesia. There is limited quantitative evidence to suggest that neuraxial anaesthesia is associated with improved perioperative outcomes. Future investigations should compare intermediate and long-term outcome differences to better inform anaesthesiologists, surgeons, and patients on importance of anaesthetic selection.
Systematic evaluation of patient-important perioperative outcomes and economics is needed to assist patients and providers alike in making optimal decisions regarding the choice of anaesthesia for major orthopaedic surgery. The frequency of major hip and knee surgeries is forecasted to increase dramatically during the next 20 yr,[1,2] and anaesthetic options have become increasingly more complex and costly. Unlike major abdominal or cardiac surgeries that require general anaesthesia, major lower extremity orthopaedic surgeries can be performed with either neuraxial or general anaesthesia. Several previous studies addressing possible differences in perioperative morbidity and mortality with neuraxial and general anaesthesia for total joint arthroplasty suggest largely equivalent results.[3,4]
Value in health-care delivery is directly proportional to perioperative outcomes and inversely proportional to cost. Determining evidence-based practice for orthopaedic anaesthesia has been hindered by previous experimental and observational studies showing conflicting data on differences in major morbidity and mortality outcomes by anaesthesia type.[3,4,6–13] These studies were, however, limited in the ability to evaluate patient-important outcomes fully, largely because of the following factors: (i) there were few small studies specifically evaluating spinal or epidural anaesthesia vs general anaesthesia; and (ii) the low incidence of major complications, such as death, cardiovascular events, or permanent neurological injury cannot be investigated properly in small randomized controlled trials. Recently, Memtsoudis and colleagues, in a large observational study of more than 500 000 patients, found that major morbidity and mortality may be significantly reduced among patients receiving neuraxial anaesthesia or neuraxial anaesthesia combined with general anaesthesia for total hip and knee arthroplasty when compared with general anaesthesia alone. However, retrospective studies based on large administrative databases are subject to bias because of lack of randomization; thus, such studies have limited internal validity and rarely accommodate straightforward comparisons between anaesthetic techniques. The aim of the present systematic review with meta-analysis, therefore, was to investigate differences in patient-important perioperative outcome between neuraxial and general anaesthesia in patients undergoing elective total hip arthroplasty (THA) or total knee arthroplasty (TKA) through qualitative and quantitative analysis of all available observational and experimental results, randomized and non-randomized, to guide an evidence-based recommendation more directly.
This protocol-driven systematic review addressing the intervention neuraxial (spinal or epidural) anaesthesia adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Eligible studies included comparative studies, either randomized controlled (Level I) trials (RCTs) or prospective observational (Level II) studies, enrolling adult patients undergoing elective THA, TKA, or both. Only studies comparing neuraxial anaesthesia directly with general anaesthesia for primary anaesthesia type were eligible (combined general and regional anaesthesia was excluded). Only studies where outcome and exposure ascertainment was done using the clinical record were included, whereas studies in which outcome or exposure ascertainment was determined exclusively using administrative billing data were excluded. For the purposes of this review, neuraxial anaesthesia was differentiated from use of regional techniques (e.g. epidural or peripheral nerve infusions) for postoperative analgesia. Specific patient-important outcomes of interest included mortality, major morbidity [vascular events (e.g. deep vein thrombosis, cerebral vascular accidents, and myocardial infarction), infection (e.g. chest and wound), and nerve palsies] and any patient-centred/patient-experience outcomes available, including postoperative nausea and vomiting (PONV), postoperative pain persisting beyond 3 months, changes in mental status, and hospital length of stay. The duration of surgery and anaesthesia drug and supply costs were additional resource utilization outcomes of interest. All eligible studies were included regardless of size, language constraints, or quality assessment ratings. Strictly descriptive articles (e.g. reviews, commentaries, or letters) were excluded.
Both electronic and hand-searching techniques were used to identify studies. Ovid MEDLINE, Ovid EMBASE, EBSCO CINAHL, Thomson Reuters Web of Science, and the Cochrane Central Register of Controlled Trials were all queried from database inception until March 2015. The search cross-referenced keywords and controlled vocabulary for each of the following areas of interest: arthroplasty, replacement, hip plus THA; arthroplasty, replacement, knee plus TKA; spinal, neuraxial, epidural, regional anaesthesia; and postoperative complications and outcomes, including specific problems, such as infection, nausea, transfusion, stroke, and paresthesias, in addition to the economic ramifications of complications, including cost and length of stay. The search yielded 1345 studies. A summary of the search strategies is available as Supplementary Appendix S1 https://bja.oxfordjournals.org/content/116/2/163/suppl/DC1. Additional studies were identified by review of the reference sections of all eligible studies and review of previously published systematic reviews.[8–11,13,15–18]
Decisions for inclusion were based on independent review of each of the abstracts by four study investigators (R.L.J., C.M.D., C.M.B., and A.K.J.). Eligibility of potential studies (as determined by either reviewer) underwent full-text review by two reviewers working independently and in duplicate. Studies were excluded if the full-text review identified that they: (i) did not contain the population of interest (e.g. non-elective surgery for hip fractures was excluded); (ii) were not a direct comparative evaluation of spinal or epidural anaesthesia vs general anaesthesia (intervention); (iii) did not contain a patient-important outcome of interest; (iv) were not an original study; or (v) were a conference abstract without follow-up publication.
Four reviewers (R.L.J., C.M.D., C.M.B., and A.K.J.) working independently and using replicate electronic data-collection tools extracted all data from the full-text versions of eligible studies. Study characteristics included author, publication year, sample size, study population (age), outcome data, primary anaesthesia type, type of major lower extremity surgery, study design, and quality ratings. Discrepancies in data collection between the two reviewers were resolved by consensus first, followed by verification by a third investigator (C.B.M.) not involved with the initial data-extraction process.
Risk of bias of the included studies was independently assessed by two reviewers (R.L.J. and S.L.K.). The Cochrane Collaboration Risk Assessment Tool was adapted and used to evaluate risk of bias for RCT evidence. Allocation concealment, blinding of outcome assessors, incomplete outcome data, and loss to follow-up were critically assessed on included RCTs when determining the overall risk of bias as either high or low rating. The Newcastle–Ottawa quality assessment tool was used to evaluate risk of bias amongst the observational studies. A study was rated overall as high risk for bias if there were important imbalances at baseline, if there was failure of blinding of outcome assessors, or if there was significant (>15%) loss to follow-up.
A qualitative synthesis was performed for studies that reported data not comparable by formal meta-analysis. To facilitate meta-analysis, standard deviations were imputed from reported ranges using guidelines outlined by Hozo and colleagues. Forest plots were used to show point estimates and confidence intervals (CI) of individual included studies. Data analysis abided by the guidelines set out by the Cochrane Collaboration regarding statistical methods. In all instances, two-tailed P-values <0.05 were considered significant. Relative risks (RRs) and the weighted mean difference (WMD) for binary and continuous outcomes were also calculated. Considering the expected heterogeneity across studies, we decided a priori to use a random-effects model to evaluate outcomes. We conducted subgroup analysis based on the risk of bias (high vs low), type of surgery (TKA, THA, or both) and type of anaesthesia (spinal, epidural, combined spinal and epidural anaesthesia, or general anaesthesia), and to address the influence of modern surgical and anaesthesia practice we analysed subgroups of articles published in 2006 or more recently compared with publications before 2006. Interaction testing between subgroups was conducted to determine whether differences between the effect sizes of subgroups was statistically significant. Heterogeneity was assessed using the I2 statistics, where values >50% are consistent with large heterogeneity. Sensitivity analyses were performed on the results of the meta-analyses. Funnel plots were constructed to detect publication bias and statistically test for publication bias by using the Egger regression test. All analyses were conducted (by M.H.M.) using Comprehensive Meta-analysis V 2.0 (Biostat, Englewood, NJ, USA).
After screening, 126 full-text articles were assessed for eligibility. The majority were excluded because of an inappropriate study design (19 studies),[3,4,18,25–40] population (seven studies),[16,41–46] intervention (44 studies),[47–90] or outcome measure (19 studies).[91–109] Nine conference abstracts were also excluded.[110–118] One study was screened and added after review of the reference section. Another study was published in Czech and was translated with the assistance of electronic translation software. In total, 29 studies published up to March 2015 met inclusion criteria.[6,7,12,104,119–143] Included studies date from 1989 to 2015. Neuraxial anaesthesia (epidural or spinal anaesthesia) was provided to 2776 patients (median age 68 yr), whereas 7712 patients (median age 67 yr) underwent general anaesthesia for total hip arthroplasty, total knee arthroplasty, or both. Supplementary Appendix S2 https://bja.oxfordjournals.org/content/116/2/163/suppl/DC1 illustrates the process of study selection.
Nineteen studies[6,7,12,119,123,125,127–129,131–135,137,139–141,143] were RCTs, and 10 studies[104,120–122,124,126,130,136,138,142] were observational studies. Surgical data for THA was included in 14 studies[6,118,119,124–126,130,136–142] [median study size 78 patients (range 22–140)] and for TKA in 10 studies[7,122,123,127,128,131–134,144] [median study size 68 patients (range 20–377)]. Two studies[120,129] provided separate outcomes data from THA and TKA populations. Three studies [median study size 146 patients (range 40–7704)][12,121,135] provided data on a mixed total hip and knee arthroplasty population.
A majority of included studies, 16, used epidural anaesthesia as the primary type of neuraxial anaesthesia.[104,119,125–134,139–143] Spinal anaesthesia was used in 10 studies[6,7,12,121,122,124,133,135,137,138] and combined spinal and epidural anaesthesia (CSE) in two studies.[120,123] One study reported data on both spinal and epidural anaesthesia use together. Epidural infusions were reported to be continued for postoperative analgesia in 10 included studies.[119–123,125,132–134,139–141] There was a noticeable change in preferences for neuraxial anaesthesia over time. Recent studies (from 2003 to the present)[6,7,12,120–124] reported use of spinal or CSE anaesthesia (eight of eight studies), whereas studies from 1980 to 2003 reported mainly epidural anaesthesia usage (15 of 20 studies).
Qualitative Synthesis: Comparative Effectiveness of Spinal or Epidural vs General Anaesthesia
Each study reported one or more patient-important perioperative outcome (Table 1). Assorted differences relating to short-term, within-hospital, patient-centred/patient-experience perioperative outcome were available among the included studies (Table 1), such as pain at rest and with movement at various time points, opioid consumption, PONV, ambulation distance/rehabilitation goals, use of urinary catheters, patient satisfaction, postdural puncture headache, and inpatient falls. Differences in perioperative outcome relating to short-term resource allocation were examined in a few studies, including postoperative anaesthesia care unit (PACU) length of stay, hospital length of stay, and anaesthesia drug and supply costs. No study reported on postoperative pain persistent beyond 3 months, measures of health-related quality of life, functional capacity, resource utilization, or long-term outcomes after hospital discharge. Differences in short- and long-term cognitive outcome were discussed within five studies (Table 2).[128,133,135,138,143]
Assessment of Risk of Bias
Thirteen of the included RCTs were rated with overall low risk of bias,[6,7,12,119,123,124,127,131,135,137,140,141,143] and seven as high risk of bias[125,128,129,132–134,139] (Supplementary Appendix S3 https://bja.oxfordjournals.org/content/116/2/163/suppl/DC1) based on criteria adapted from the Cochrane ‘Risk of Bias’ assessment tool. There were no important imbalances at baseline in any trial. None of the RCTs reported loss to follow-up >15%. Overall ratings were decided as low risk of bias primarily as a result of ‘blinding of outcome assessors’, the presence of ‘incomplete outcome data’ within the included trials, or both.
Supplementary Appendix S4 https://bja.oxfordjournals.org/content/116/2/163/suppl/DC1 presents the quality ratings of the nine cohort studies, as determined using the Newcastle–Ottawa Assessment Scale. Four cohort studies were rated low risk of bias[77,121,122,126] and the remaining five studies were judged high risk of bias based on imbalances between neuraxial and general anaesthesia groups at baseline, failure to blind outcome assessors, inadequate follow-up of patients, or a combination of these factors.[39,120,130,138,142]
Meta-analysis: Effectiveness of Neuraxial Anaesthesia Compared With General Anaesthesia
Compared with general anaesthesia, neuraxial anaesthesia was associated with lower risk of deep vein thrombosis (RR 0.51; 95% CI 0.41–0.62, nine studies) and pulmonary embolism (RR 0.36; 95% CI 0.22–0.60, seven studies) in patients who did not receive chemical antithrombotic prophylaxis. However, in those studies that included chemical antithrombotic prophylaxis in patient-care protocols, there were no statistically significant differences in either deep vein thrombosis or pulmonary embolism rates. Figure 1 shows that patients who received neuraxial anaesthesia had statistically significant shorter hospital stay (WMD −0.40 days; 95% CI −0.76 to −0.03; I2 min shorter operative time (WMD −5.13 73%; 12 studies, 1240 patients). Although neuraxial anaesthesia resulted in up to a 10 min; 95% CI −10.96 to −0.70; I2 94%; 21 studies, 9382 patients; Fig. 2), overall this difference in outcome failed to achieve statistical significance (P=0.08). There was no statistically significant difference in other outcomes, including mortality, chest infection, surgical site infection, nerve palsies, or PONV. The results of meta-analysis of all outcomes are contained in Table 3. All subgroup analyses failed to show statistically significant interactions (P>0.05) based on risk of bias, type of surgery, year of publication (2006 and newer vs publication before 2006), and type of neuraxial anaesthesia. Sensitivity analysis for mortality was performed by adding 378 patients from three trials with no events,[6,7,137] which resulted in no meaningful change in mortality results (RR 0.85; 95% CI 0.30–2.46; I 2 0%; seven studies). We were unable to detect a statistically significant publication bias; however, the number of studies included in each analysis was small, making tests for publication bias unreliable.
This systematic review and meta-analysis confirms that neuraxial anaesthesia was either equivalent or favoured over general anaesthesia for patient-important outcomes of total hip or total knee arthroplasty. Surgical durations were not lengthened, yet hospital length of stay was reduced when neuraxial techniques were used. Although the evidence is limited to suggest that use of neuraxial anaesthesia is associated with improved perioperative outcomes, there are no meta-analysis results supporting that outcomes are better when general anaesthesia is used.
Comparison With Previous Literature
There are previous systematic reviews and meta-analyses[8–11,18] and recent population-based studies using administrative billing data[3,4,27,30,35,145] that have analysed differences in mortality and major morbidity outcomes by anaesthesia type. Not unlike our review, previous literature on this topic also reports results for a superior anaesthesia technique (e.g. neuraxial) for some, but often not all included outcomes. In the last several years, administrative billing data studies have dominated the literature on this topic, and despite larger sample sizes within these papers, the results have yet to be definitive enough to transform clinical practice to default to neuraxial anaesthesia. The most recent population-based studies are summarized in Table 4. Additionally, past studies have been indirect for anaesthesia comparisons, lacking head-to-head examination, and imprecise in the estimation of the effect size. For instance, Rodgers and colleagues were among the first to synthesize the evidence for benefits of neuraxial techniques, yet their systematic review was highly criticized for its wide confidence intervals among outcomes, which probably resulted from inclusion of a broad range of surgical populations. In contrast to most previous studies, we focused our systematic review and meta-analysis to compare directly the primary types of anaesthesia specifically used for total hip and knee arthroplasty.
Total hip and knee arthroplasty rarely require the combination of both general and neuraxial anaesthesia during the same procedure. Previous studies using administrative billing data are often restricted by coding limitations and thus include both neuraxial and general anaesthesia interventions during analysis. Consequently, results from this research, in particular for orthopaedic procedures that do not require combined anaesthesia techniques, do little to inform decisions. For instance, Memtsoudis and colleagues grouped patients undergoing orthopaedic procedures under broad categories of anaesthesia type that included neuraxial, general plus neuraxial, and general alone. As our investigation was not restricted to billing data, we were able to make a more direct comparison of neuraxial and general anaesthesia types.
Unfortunately, disparities exist in the availability of neuraxial anaesthesia and anaesthesia practice utilization has been understudied. An analysis from the Anaesthesia Quality Institute found that neuraxial anaesthesia was accessible disproportionately less often (31.3 vs 57.9%) than general anaesthesia to patients undergoing TKA. Neuraxial anaesthesia, in this study by Fleischut and colleagues, was provided less often, and despite this, appears to be preferentially more available to older patients and those with more co-morbidities (higher ASA physical class score ≥III). Likewise, our review found disproportionate use of anaesthesia types even in randomized trials such that neuraxial anaesthesia was provided to only about one-third of the overall sample. Regardless, meta-analysis indicates equivalent results when neuraxial anaesthesia is used. Future research should focus study on patient, surgeon, and anaesthetist preferences in choosing neuraxial techniques, including use in specific subpopulations, such as the elderly and sick, where the benefits may be more apparent.
Current expert opinions on the overall importance of primary anaesthesia choice on differences in outcome are varied. The results from our review do support choosing neuraxial anaesthesia over general anaesthesia for the outcome of hospital stay. However, as with other retrospective studies, we are unable to draw a causal link between the choice of anaesthetic and the differences in outcome. Systematic reviews are also retrospective in design and inherently limited by the quality of the available literature. It is possible that our protocol may have missed eligible studies, our inclusion criteria could have been too narrow, or exclusion of articles may have affected our results. We emphasize that our review directly compared spinal or epidural anaesthesia with general anaesthesia rather than evaluating the effects of multimodal analgesia protocols that include regional anaesthesia for postoperative analgesia. As such, the present review does not elucidate possible effects of regional analgesia techniques, including neuraxial or peripheral nerve block, on perioperative outcomes. Nevertheless, the strengths of our study relate to the thoroughness of our rigorous protocol determined a priori with sensitivity analyses performed to test the robustness of the results. Consequently, this systematic review and meta-analysis summarizes the best available evidence to inform providers on the comparative effectiveness of neuraxial block compared with general anaesthesia for total hip and total knee arthroplasty.
The most significant confounder or effect modifier of outcome results may still be unknown. Depth of sedation, for instance, is once such variable. The fact that depth of sedation was unknown in all studies leaves us to wonder whether a deep sedation with spinal anaesthesia compared with general anaesthesia is different enough for comparison. With a majority of our patients requesting to ‘hear nothing’, practitioners often ‘over-‘ rather than ‘undersedate’ a patient. This may further disambiguate relationships between anaesthesia type and outcome measurement. Also, the use of an enhanced recovery programme needs to be considered in isolation because influences of multimodal analgesia apart from the choice of primary anaesthesia type still require study. Without an ability to control for confounding variables, solid conclusions comparing anaesthetic options for total hip and knee arthroplasty may never be made through retrospective study. In the end, only a valid randomized trial may control adequately for these observed inequities in the use of anaesthesia type and control for the resultant confounding effects. Our systematic review results suggest that it may be of economic interest to pursue a large, multicentre randomized trial based on the evidence of length-of-stay reduction alone. Even the reported half-day difference on a population level makes significant argument for funding such a costly trial.
We intended to report on major differences in morbidity and mortality and on variation in patient-experience outcome between neuraxial and general anaesthesia for total joint arthroplasty. However, our efforts were limited by the lack of comparative-effectiveness research evaluating most patient-important outcomes. Intermediate-term outcomes for pain, including persistent pain beyond the immediate postoperative period or conversion from acute to chronic pain syndromes, are also lacking. Scoring of subjective pain rating (at rest or with movement) and opioid consumption were the lone descriptors of pain outcomes, and for a majority of studies were used as a primary outcome to achieve individual study power calculations. Likewise, we were unable to comment directly on differences in either patient satisfaction or rehabilitation milestones (e.g. ambulation) between neuraxial and general anaesthesia because too few studies included these patient-important outcomes. Lastly, differences in long-term outcome in activities of daily living and quality of life according to type of anaesthesia are unavailable for synthesis. Considering the emerging importance of ‘the patient experience’ within health-care delivery, future researchers may wish to consider including more patient-experience outcomes, intermediate and long-term outcome assessments, or both in future study designs.
Neuraxial anaesthesia appears equally effective with no more adverse events compared with general anaesthesia among the comparative-effectiveness research studies to date on patients undergoing total hip arthroplasty, total knee arthroplasty, or both. We did, however, find that patients receiving neuraxial anaesthesia have a shorter hospital length of stay than patients undergoing general anaesthesia. There is evidence to suggest that neuraxial anaesthesia takes no more time to perform and may even be responsible for shorter surgical durations (up to 11 min less), although these time differences have indeterminate clinical significance. Genuine uncertainty, clinical equipoise, remains when it comes to differences in patient-important outcome by anaesthesia type for total hip and knee arthroplasty amongst studies directly comparing neuraxial with general anaesthesia. It is thus essential to conduct prospective studies on differences in patient-important perioperative outcome of anaesthetic choice for total hip and total knee arthroplasty. We call for the funding of a large, multicentre study that directly compares general anaesthesia with neuraxial anaesthesia, barring contraindications, while controlling for depth of sedation in order to inform shared decision-making between patients, anaesthetists, and surgeons.
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