We have prepared this protocol for our systematic reviews in accordance with the guideline of the Preferred Reporting Items for Systematic Review and Meta-Analyses-Protocols (PRISMA-P). A populated PRISMA-P checklist is provided (see Additional file 1).
Study selection
We will include studies in any language if they evaluate the aforementioned research questions and meet the following criteria.
Population
Adults undergoing elective or non-elective non-cardiac surgery, excluding cranial neurosurgery. We will include all studies in adults (i.e., ≥ 18 years old) but plan to report and summarize the evidence on the older population (i.e., ≥ 65 years old) whenever possible.
Intervention/exposure and comparator
For questions Q1 and Q3 (Table 1), studies will be included if they reported the incidence and/or severity of acute postsurgical pain and/or CPSP, measured by any scale including the visual analog scale, numeric pain rating scale, or brief pain inventory [29, 30]. We will consider acute postsurgical pain as pain occurring up to 7 days after surgery, and CPSP as “chronic pain that develops or increases in intensity after a surgical procedure and persists beyond the healing process, i.e., at least 3 months after the surgery” according to the definition of the International Association for the Study of Pain [31]. Studies reporting mild vs. moderate or severe postoperative pain without specifying the measurement tool will also be included. We will include studies evaluating chronic pain of different etiologies, as long as they specify that their population also included people who underwent surgery; we will extract relevant data on this subgroup whenever available. For questions Q2 and Q4 (Table 1), studies will be included if they examined pre-, intra-, or postoperative interventions for preventing or managing postsurgical pain, proven or intended to minimize opioid use (opioid-sparing), as compared to alternative interventions, or no active intervention/placebo/standard or usual care. This definition will comprise (1) pharmacological interventions, including different types or doses of opioids; (2) regional analgesic techniques including nerve blocks; and (3) non-pharmacological interventions, e.g., physiotherapy and psychotherapy [32]. We will consider single or multi-modal interventions.
Outcomes
Our primary outcomes of interest are POD (questions Q1 and Q2) and POCD (all questions). We expect to find variability in how different studies measured these outcomes. We will initially include studies regardless of the definition and instruments used, as long as the investigators intended to assess POD and POCD (i.e., based on face validity of their definitions). Secondarily, we will report and summarize the evidence only including studies in which (1) POD was defined in agreement with the Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) terminology and assessed by a validated tool, such as the Confusion Assessment Method [33] or the Memorial Delirium Assessment Scale [34], and (2) POCD was defined as a decline in cognitive function(s) occurring up to 12 months after surgery as compared to the preoperative performance, and as assessed by validated neuropsychological tests such as Montreal Cognitive Assessment [35]. Studies will be included whether POD and POCD are the primary outcomes in the eligible studies or not. For studies on interventions reporting results on our primary outcomes of interest, we will also collect data, when available, on the effects of those interventions on acute and persistent pain.
Study design
For Q1 and Q3, we will include cohort, case-control, and cross-sectional studies. For Q2 and Q4, we will include randomized controlled trials (RCTs) and non-randomized studies. We will not include cases series.
Search strategy for identification of relevant studies
The following electronic databases will be searched from their inception to date: MEDLINE (1946–date), EMBASE (1974–date), Cochrane Central Register for Controlled Trials (CENTRAL), CINAHL, and PSYCHINFO. In addition, national and international clinical trial registries (e.g., WHO ICTRP and ClinicalTrials.gov) will be checked for ongoing trials and corresponding researchers will be contacted for their data if trials are completed but not published. We will also search gray literature by targeted google searches (first 100 hits) and databases like Health Canada and Open Grey. Simultaneous to the electronic search, the reference list of relevant studies and systematic reviews will be manually checked. Field experts will be contacted in person or via email for other references. The most important concepts from our review questions (population and intervention) were used to build a list of words selected by scanning relevant studies as well as databases for text words, controlled vocabulary, and mesh terms which were used in the search. Search terms for the neurocognitive outcome were added when the primary search returned an enormous amount of hits that were mostly irrelevant to the objective of the review. The search strategy was revised by an expert librarian. An example of the detailed search strategy, used for the MEDLINE database, is outlined in an additional file (see Additional file 2).
Screening and data abstraction
Initial title and abstract screening will be done independently by pairs of reviewers. Any article that is clearly ineligible will be excluded at that stage. All full-text articles deemed eligible for inclusion from the previous step will then be independently screened by pairs of reviewers using specific eligibility criteria via a pretested screening form. Disagreements will be resolved by consensus or via third-reviewer adjudication if necessary. The number of articles included and excluded at the various stages will be documented.
Data abstraction will be conducted by pairs of reviewers, independently and in duplicate, using standardized pretested data extraction forms which will be piloted. The following information will be extracted: study characteristics (design, year, duration of follow-up, sample size per each study arm, setting, and country), participant characteristics (age, gender, type of surgery), intervention or exposure details (type of intervention, route of administration, dose, duration, frequency of administration, pain score, and opioid consumption), and results (risk statistics and their corresponding measures of variance for dichotomous outcomes and means and their corresponding measures of variance for continuous outcomes for each of the reported time-points). In the case of disagreement between pairs, reviewers will be asked to come to a consensus. If a consensus cannot be reached, a third reviewer will be consulted.
Risk of bias assessment and assessment of the level of evidence
For randomized trials, the risk of bias will be assessed using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) [36]. The following five domains of bias will be assessed: the randomization process (including sequence generation and allocation concealment), deviations from intended interventions, missing outcome data, measurement of the outcome, and selective outcome reporting. The RoB 2 algorithm for suggested judgment of risk of bias will be used as a guide to determine the judgment for each domain. For interventional non-randomized trials, the Risk Of Bias In Non-randomized Studies–of Interventions (ROBINS-I) assessment tool will be used to assess the risk of bias [37]. The following seven domains will be assessed for bias: confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, outcome measurement, and selective reporting. The ROBINS-I guide for judgment will also be used to determine the overall risk of bias as mild, moderate, serious, or critical. For observational studies addressing our questions Q1 and Q3, we will use the Newcastle-Ottawa Scale (NOS) [38] for cohort and case-control studies and the Joanna Briggs Institute (JBI) critical appraisal checklist for analytical cross-sectional studies [39]. The risk of bias assessment will be done in duplicate for each outcome (two reviewers will independently assess each outcome).
The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach will be used to assess the certainty of evidence for each of the prespecified outcomes. The five GRADE considerations (risk of bias, inconsistency, indirectness, imprecision, and publication bias) will be used to rate the quality as high, moderate, low, or very low. For RCTs, the evidence rating will be started as high and rated down if needed. For non-randomized trials, the level of evidence will be started at low and upgraded if there is a large effect, dose-response or plausible confounding opposing the effect. GRADE assessment will be done in duplicate for each outcome (2 reviewers will assess each outcome for GRADE). GRADEpro software will be used to prepare the summary of findings tables.
Data synthesis and analysis
Statistical analyses will be conducted in RevMan (version 5.3). Meta-analyses will be performed when deemed appropriate based on the level of homogeneity in the design of the original studies. We will primarily perform random effects models. We will assess and report heterogeneity quantitatively using the I2 statistic and performing a chi-square test. I2 statistics will be interpreted according to guidelines from the Cochrane Handbook. For all meta-analyses with at least 10 studies, potential for publication bias will be visually assessed by funnel plot symmetry.
Q2 and Q4: For studies reporting the effects of interventions on dichotomous outcomes (i.e., incidence of POD and POCD), we will calculate and meta-analyze odds ratios (OR) with 95% confidence intervals (CIs). For studies reporting the effects of interventions on continuous outcomes (e.g., severity of POD, changes in cognitive scores), we will calculate and meta-analyze the pooled weighted mean difference (WMD) and/or standardized mean difference (SMD) with corresponding 95% CIs. In the decision of the feasibility of a meta-analysis and the meta-analytic methods to use, careful considerations will be given to (1) whether effect sizes are measured upon different scales and (2) whether treatment effects are measured and reported as post-intervention measurements or changes from baseline. For non-randomized studies, adjusted and non-adjusted effect sizes will be extracted (collecting information about the covariates included in the original analyses); adjusted measurements of effects will be prioritized for inclusion in our meta-analyses.
Q1 and Q3: We expect variability with which relevant observational studies might address our research questions, including looking at changes in the risk of POD or POCD (dichotomous outcome) per each unit of change in acute or chronic pain score; looking at the association between the risk of POD or POCD (dichotomous outcome) and the presence of acute or persistent pain according to a certain cut-off; and looking at the severity of POD or changes in cognitive scores per each unit of change in acute or chronic pain score, or associated with the presence of acute or persistent pain according to a certain cut-off. Also, we expect to find observational studies that purely looked at an association, including cross-sectional studies, and studies with a more appropriate design to infer about an exposure-outcome type of relationship. We will decide on whether and how to pool and meta-analyze studies accounting for this variability and based on the available data.
We plan to perform the following secondary analyses:
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1)
Meta-analyses including only RCTs for Q2 and Q4
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2)
Meta-analyses including only prospective cohort studies for Q1 and Q3
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3)
Meta-analyses including only studies with low risk of bias
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4)
Meta-analyses including only studies using standardized definitions and validated methods of assessment for our primary outcomes
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5)
Separate meta-analyses for studies evaluating POCD based on the time of assessment