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Patients undergoing lower limb revascularization surgery for peripheral artery disease (PAD) have a high risk of perioperative morbidity and mortality and often have long hospital stays. Use of neuraxial or regional anesthesia instead of general anesthesia may represent one approach to improving outcomes and reducing resource use among these patients.
The aim is to conduct a systematic review and meta-analysis to determine whether receipt of neuraxial or regional anesthesia instead of general anesthesia in adults undergoing lower limb revascularization surgery for PAD results in improved health outcomes and costs and a shorter length of hospitalization.
We will search electronic bibliographic databases (MEDLINE, EMBASE, the seven databases in Evidence-Based Medicine Reviews, medRxiv, bioRxiv, and Google Scholar), review papers identified during the search, and included article bibliographies. We will include randomized and nonrandomized studies comparing the use of neuraxial or regional anesthesia instead of general anesthesia in adults undergoing lower limb revascularization surgery for PAD. Two investigators will independently evaluate the risk of bias. The primary outcome will be short-term (in-hospital or 30-day) mortality. Secondary outcomes will include longer-term mortality; major adverse cardiovascular, pulmonary, renal, and limb events; delirium; deep vein thrombosis or pulmonary embolism; neuraxial or regional anesthesia–related complications; graft-related outcomes; length of operation and hospital stay; costs; and patient-reported or functional outcomes. We will calculate summary odds ratios (ORs) and standardized mean differences (SMDs) using random-effects models. Heterogeneity will be explored using stratified meta-analyses and meta-regression. We will assess for publication bias using the Begg and Egger tests and use the trim-and-fill method to estimate the potential influence of this bias on summary estimates. Finally, we will use Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology to make an overall rating of the quality of evidence in our effect estimates.
The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO). We executed the peer-reviewed search strategy on March 2, 2021. We completed the review of titles and abstracts on July 30, 2021, and plan to complete the review of full-text papers by September 30, 2021. We will complete full-text study data extraction and the risk-of-bias assessment by November 15, 2021, and conduct qualitative and then quantitative data synthesis and GRADE assessment of results by January 1, 2022, before drafting the manuscript. We anticipate that we will be able to submit the manuscript for peer review by the end of February 2022.
This study will synthesize existing evidence regarding whether receipt of neuraxial or regional anesthesia instead of general anesthesia in adults undergoing lower limb revascularization surgery for PAD results in improved health outcomes, graft patency, and costs and a shorter length of hospital stay. Study results will be used to inform practice and future research, including creation of a pilot and then multicenter randomized controlled trial.
Prospero CRD42021237060; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=237060
PRR1-10.2196/32170
Lower limb revascularization surgeries (ie, endarterectomy, patch angioplasty, and arterial bypass) are commonly performed across North America [
Patients undergoing lower limb revascularization surgery for PAD are typically older (average age of approximately 70 years), are current or past cigarette smokers, and have several comorbidities that place them at high risk for perioperative morbidity and mortality [
Use of neuraxial (spinal or epidural) or regional (peripheral nerve block) anesthesia instead of general anesthesia may represent one approach to improving postoperative health outcomes and reducing resource use among patients undergoing lower limb revascularization surgery for PAD [
We propose to conduct a systematic review and meta-analysis of randomized and nonrandomized comparative studies to determine whether receipt of neuraxial or regional anesthesia instead of general anesthesia in adults undergoing lower limb revascularization surgery for PAD results in improved health outcomes, graft patency, and costs and a shorter length of hospital stay. We will also determine whether results of these studies vary by differences in study design, included patient populations, or risk of bias.
This systematic review protocol was developed and reported according to the Preferred Reporting Items in Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [
We formulated the focused clinical question for the study according to the patient, intervention (or exposure, for nonrandomized studies), comparison, outcome, and design (PI[E]COD) method of designing clinical questions for systematic reviews. Our focused clinical question was:
P: for adults (≥18 years of age) undergoing lower limb revascularization surgery for PAD
I(E): does receipt of neuraxial (spinal or epidural) or regional (peripheral nerve block) anesthesia (as the primary anesthetic technique)
C: compared with general anesthesia (as the primary anesthetic technique), including general anesthesia combined with other anesthesia techniques
O: Result in improved outcomes, including (1) primary outcome (short-term [in-hospital or 30-day] mortality) and (2) secondary outcomes (longer-term mortality; major adverse cardiovascular, pulmonary, renal, and limb events; delirium; deep vein thrombosis or pulmonary embolism; neuraxial or regional anesthesia–related complications; graft-related outcomes; length of operation and hospital stay; costs; and patient-reported or functional outcomes [see below for definitions of these outcomes])
D: in randomized and nonrandomized comparative studies?
We will search MEDLINE; MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations; EMBASE; the seven databases contained within Evidence-Based Medicine Reviews (American College of Physicians [ACP] Journal Club®; the Cochrane Central Register of Controlled Trials, the Database of Systematic Reviews, and the Methodology Register Database; the Database of Abstracts of Reviews of Effects; the Health Technology Assessment Database; and the National Health Service Economic Evaluation Database); and medRxiv, bioRxiv, and Google Scholar from their first available date until study initiation without language, publication date, or other restrictions. To identify additional citations, we will also use the PubMed “related articles” feature and search bibliographies of included studies and relevant review papers identified during the search.
A vascular surgeon and epidemiologist with graduate training in information science and evidence synthesis methods (author DJR) created the initial MEDLINE search strategy. Using a combination of Medical Subject Heading (MeSH) terms and keywords, search filters were constructed covering the themes
Ovid MEDLINE database search strategies.
Search theme | MeSHa search terms | Search term text words |
Lower limb revascularization surgery | arterial occlusive disease/surgery OR blood vessel prosthesis OR blood vessel prosthesis implantation OR endarterectomy OR ischemia/surgery OR lower extremity/surgery OR |
((iliofemoral OR femoral OR femoral artery*) adj3 (endarterectom* OR patch* OR repair*)) OR ((femoral-distal OR femoral distal OR femoral-popliteal OR femoral popliteal OR femoral-tibial OR femoral tibial OR infrageniculate OR suprageniculate OR infrainguinal OR lower extremity OR lower limb OR peripheral vascular) adj3 (arterial surg* OR arterial bypass* OR bypass* OR bypass graft* OR bypass surg* OR graft* OR intervention* OR revascularization* OR revascularization procedure* OR vascular bypass* OR vascular bypass surg* OR vascular graft* OR vein graft* OR prosthetic graft*)) |
Anesthetic type | Anesthesia OR anesthesia, endotracheal OR anesthesia, epidural* OR anesthesia, spinal* OR anesthesia, local* OR anesthesia, general* OR nerve block | ((general OR regional OR neuraxial OR epidural OR spinal) adj3 (anesthe*)) OR epidural* OR nerve block* OR peripheral nerve block* OR spinal* |
aMeSH: Medical Subject Heading.
Ovid EMBASE database search strategies.
Search theme | Emtree search terms | Search term text words |
Lower limb revascularization surgery | artery bypass OR blood vessel graft OR bypass surgery OR critical limb ischemia/surgery OR endarterectomy OR limb ischemia/surgery OR peripheral artery occlusive disease/surgery OR prosthetic vascular graft OR vascular surgery OR vein bypass |
((iliofemoral OR femoral OR femoral artery*) adj3 (endarterectom* OR patch* OR repair*)) OR ((femoral-distal OR femoral distal OR femoral-popliteal OR femoral popliteal OR femoral-tibial OR femoral tibial OR infrageniculate OR suprageniculate OR infrainguinal OR lower extremity OR lower limb OR peripheral vascular) adj3 (arterial surg* OR arterial bypass* OR bypass* OR bypass graft* OR bypass surg* OR graft* OR intervention* OR revascularization* OR revascularization procedure* OR vascular bypass* OR vascular bypass surg* OR vascular graft* OR vein graft* OR prosthetic graft*)) |
Anesthetic type | Anesthesia OR general anesthesia OR epidural anesthesia OR nerve block OR regional anesthesia OR spinal anesthesia | ((general OR regional OR neuraxial OR epidural OR spinal) adj3 (anesthe*)) OR epidural* OR nerve block* OR peripheral nerve block* OR spinal* |
The titles and abstracts of citations identified during the search will be exported into EndNote X9 reference management software (Clarivate, Thomson Reuters Corporation, Fairfax, VA, USA). This software will then be used to remove identical duplicates from the citation list. Two investigators will subsequently independently review the titles and abstracts of all identified citations and select any paper deemed potentially relevant by either investigator for full-text review using Covidence (Covidence, Melbourne, Australia). Finally, these two investigators will review the full text of all potentially relevant citations and select studies for inclusion in the systematic review. Disagreements regarding study inclusion will be resolved via consensus or arbitration by a third investigator (DJR).
We will include studies where participants were adults (≥18 years of age) undergoing lower limb revascularization surgery for PAD. Lower limb revascularization surgery will be considered to include iliofemoral or femoral endarterectomy or patch angioplasty and iliofemoral or infrainguinal bypass (eg, femoral-popliteal or femoral-tibial bypass) [
The intervention (for randomized studies) or exposure (for nonrandomized comparative studies) of interest will include neuraxial or regional anesthesia as the primary anesthesia technique. Neuraxial anesthesia will be defined as spinal, epidural, or combined spinal-epidural anesthesia without general anesthesia, while regional anesthesia will be defined as use of a peripheral nerve block without general anesthesia. The comparison of interest will be general anesthesia (including general anesthesia in combination with neuraxial or regional anesthesia).
The primary outcome will be short-term (in-hospital or 30-day) mortality. Secondary outcomes will include (1) longer-term mortality (mortality beyond 30 days); (2) major adverse cardiovascular events (cardiovascular death, stroke, or myocardial infarction) [
The included studies must be randomized or nonrandomized (ie, cohort, case–control, or comparative effectiveness) comparative (ie, with a comparator group) studies of the above interventions [
There will be no restrictions regarding the setting or language of the study.
The same two investigators will independently extract data using an electronic data extraction spreadsheet and tables piloted on a representative sample of three randomized and three nonrandomized studies. We will extract the following data from included studies (where applicable or reported): (1) year of publication, design, data source, and study country or setting; (2) patient recruitment period; (3) inclusion and exclusion criteria; (4) patient and procedural characteristics, including the types of lower limb revascularization surgeries performed and the urgency of and indication(s) for these procedures; (5) characteristics of the anesthetics provided to the intervention and comparison groups (ie, percentage of spinal and epidural anesthesia, types of medications administered into the spinal or epidural space, and types of peripheral nerve blocks and medications used for these blocks); (6) follow-up duration; and (7) study outcomes and their definitions (as reported by study authors). For reported study outcomes, we will extract event rates or odds ratios (ORs), with 95% confidence intervals (CIs); group means (with SDs), for continuous differences; and other relative or absolute effect measures describing one or more outcomes of interest between the groups (or we will calculate them from the data provided). For nonrandomized comparative studies, we will extract the most thoroughly adjusted effect estimates (and which confounding factors were adjusted for) when variably adjusted outcomes were reported [
Two investigators will independently judge the risk of bias among the included RCTs using the Cochrane Collaboration tool [
The same two investigators will also judge the risk of bias among the included nonrandomized studies using the Risk of Bias in Non-randomised Studies – of Interventions (ROBINS-I) tool [
Discrepancies between investigators in study-level risk-of-bias assessments will be resolved by discussion and consensus between the investigators or arbitration by a third investigator (DJR).
Characteristics of the included studies (including year of publication, country of origin, patient recruitment periods, inclusion and exclusion criteria, interventions and comparisons, and follow-up durations) and their included patient populations (mean/median ages and types of lower limb revascularization surgeries performed) will be tabulated by study design (randomized or nonrandomized comparative) and types of comparisons (ie, neuraxial or regional anesthesia compared with general anesthesia). This will allow us to compare recruitment periods and determine whether potentially overlapping data may have been reported before performing randomized and nonrandomized comparative study meta-analyses. We will also tabulate results of risk-of-bias assessments by study design (randomized or nonrandomized).
We will use the OR (for dichotomous outcomes) and the standardized mean difference (SMD) (for continuous outcomes) as the summary measures of association when combining results of randomized and nonrandomized studies, respectively. When risk ratios (RRs) or hazard ratios (HRs) were reported instead of ORs by study authors, we will pool these measures of association separately by estimate type, as has been suggested [
Results of randomized and nonrandomized studies will be pooled separately by comparison type (ie, by whether neuraxial or regional anesthesia was compared to general anesthesia) in primary analyses using the method of restricted maximum likelihood (REML) [
In the presence of low or greater interstudy heterogeneity, we will conduct prespecified subgroup analyses using random-effects models and meta-regression, with the summary OR for in-hospital mortality as the dependent variable. We will use the following predictor variables in an attempt to explain heterogeneity in these stratified analyses or meta-regressions: (1) study design (randomized vs nonrandomized comparative), (2) publication status (abstract vs full-text publication), (3) whether there was a low versus higher risk of bias related to random sequence generation or allocation concealment in randomized studies, (4) whether nonrandomized studies reported an OR or other measure of association that was adjusted using the minimum confounder set (to determine whether better-adjusted estimates more closely agree with those obtained from randomized studies) [
We will evaluate for the presence of small study effects potentially due to publication bias for each outcome by visually inspecting produced funnel plots and using Begg and Egger tests (
Statistical analyses will be performed using Stata MP version 13.1 (Stata Corporation, College Station, TX, USA) by a trained meta-analyst [
We will use the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology to make an overall rating of the quality of evidence in our effect estimates for the primary and secondary outcomes (ie, confidence that our effect estimates are correct) [
We will provide the raw data included in meta-analyses at the point of publication.
We executed the peer-reviewed search strategy on March 2, 2021. We completed the review of titles and abstracts on July 30, 2021, and plan to complete the review of full-text papers by September 30, 2021. We will complete full-text study data extraction and the risk-of-bias assessment by November 15, 2021. Subsequently, we will conduct qualitative and then quantitative data synthesis and the GRADE assessment of the results by January 1, 2022, before drafting the manuscript. We anticipate that we will be able to submit the manuscript for peer review by the end of February 2022.
Patients undergoing lower limb revascularization surgery for PAD are at high risk of serious postoperative adverse events and consume substantial health care resources. We hypothesize that avoidance of general anesthesia may represent an efficacious approach to improving their health outcomes and reducing resource use [
By evaluating a variety of relevant primary and secondary outcomes, our systematic review will help to identify which outcomes (if any) are likely to be improved after receipt of neuraxial or regional anesthesia instead of general anesthesia in patients undergoing lower limb revascularization surgery. After synthesizing the available evidence, we will use the GRADE methodology to assess the risk of bias, consistency, directness, precision, and publication bias associated with the evidence for each outcome. We will then use these assessments to rate the overall confidence in the cumulative evidence for each of these outcomes to inform current lower limb revascularization surgery practice. We will also identify important knowledge gaps not addressed by the current literature on this topic. These may include a lack of patient-reported, functional, and longer-term outcomes after use of different types of anesthesia in patients undergoing lower limb revascularization surgery.
To the best of our knowledge, no multicenter RCTs comparing neuraxial or regional anesthesia and general anesthesia in adults undergoing lower limb revascularization surgery have been reported. If none are identified and future RCTs comparing neuraxial or regional anesthesia and general anesthesia are required, the findings of our systematic review will inform their design. For example, patients undergoing these surgeries often have multiple and sometimes life-threatening comorbidities and take a number of different medications, including antiplatelets and anticoagulants, some of which contraindicate the use of neuraxial anesthesia [
In summary, we propose to synthesize existing evidence regarding whether receipt of neuraxial or regional anesthesia instead of general anesthesia in adults undergoing lower limb revascularization surgery results in improved health outcomes, graft patency, and costs and a shorter length of hospital stay. Study results will be used to inform practice and future research, including creation of a pilot and then multicenter RCTs comparing neuraxial and general anesthesia in this patient population.
PRISMA-P (Preferred Reporting Items in Systematic Reviews and Meta-Analyses Protocols) checklist.
chronic limb-threatening ischemia
Grading of Recommendations, Assessment, Development, and Evaluation
hazard ratio
Medical Subject Heading
odds ratio
peripheral artery disease
patient, intervention (or exposure), comparison, outcome, and design
Preferred Reporting Items in Systematic Reviews and Meta-Analyses
Preferred Reporting Items in Systematic Reviews and Meta-Analyses Protocols
randomized controlled trial
restricted maximum likelihood
Risk of Bias in Non-randomised Studies – of Interventions
risk ratio
DJR is the guarantor. DJR conceived and DJR, HD, SKN, AL, JPL, TB, PJ, LD, HTS, and DIM designed the study. DJR and DIM designed the quantitative and statistical analysis plan. DJR designed the search strategy, which was refined by HD, SKN, AL, JPL, TB, PJ, LD, HTS, and DIM. DJR wrote the first draft of the protocol, which was critically revised by HD, SKN, AL, JPL, TB, PJ, LD, HTS, and DIM. DJR submitted the protocol to PROSPERO. DJR, HD, SKN, AL, JPL, TB, PJ, LD, HTS, and DIM read and approved the final protocol.
The authors declare that they have no competing interests.