Postoperative epidural analgesia versus systemic analgesia for thoraco‐lumbar spine surgery in children

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of epidural analgesia compared with systemic analgesia for acute postoperative pain control after thoraco‐lumbar spine surgery in children.

Background

Description of the condition

Idiopathic scoliosis is the most common spinal deformity encountered by general orthopaedic surgeons (Sud 2013). Scoliosis is a disease in which the spine is curved in three dimensions. Although the condition may have various causes (i.e. congenital, neurological, or musculoskeletal disorders), in children (defined as ≤ 18 years old for the purpose of this review), idiopathic scoliosis is the most common form (approximately 70% to 80% of all cases) (McNicol 2016; Negrini 2015). The prevalence of idiopathic scoliosis is estimated to be between 0.9% and 12% of the population, with up to 0.1% at risk of requiring a surgical intervention (Negrini 2015). A severe form is more commonly found in female adolescents (80% to 90%) (Negrini 2015). Problems related to scoliosis include reduced quality of life, disability, pain, cosmetic deformity, functional limitations, and pulmonary problems (Negrini 2015). For idiopathic scoliosis, most surgeons agree that surgical treatment should be considered in skeletally mature patients with curves > 50° (thoracic Cobb curve angle as measured on x‐rays) because of the risk of progression into adulthood (Agabegi 2015). Surgical treatment includes decompression, instrumented fusion, and deformity correction. In children, spinal fusion (with or without thoracotomy) is common and expensive. In the USA, the average cost of each procedure is USD 28,696, and total annual expenses for spinal fusions in children was estimated to be about USD 600 million in 2013 (Center for Disease Control and Prevention 2015).

Spinal surgery may also be required for treatment of traumatic injuries and infectious, inflammatory, or neoplastic diseases. Around the world, the incidence of traumatic spinal cord injuries varies from 3.6 to 195.4 per million population (Jazayeri 2015). Females are at greatest risk in adolescence (World Health Organization 2013).

Orthopaedic surgeries, including spine surgery, are among the most painful surgical procedures and are frequently associated with severe acute postoperative pain (Borgeat 2008; Gramke 2007). Adequate treatment of acute postoperative pain is considered a human fundamental right (White 2007). Treatment of acute postoperative pain in patients undergoing spine surgery may be complicated by the fact that some of these patients are suffering from chronic pain and may be opioid tolerant. Modalities that have been proposed to treat acute postoperative pain after spine surgery include systemic opioids, non‐steroidal anti‐inflammatory drugs, gabapentinoids, N‐methyl‐D‐aspartate (NMDA) antagonists, and neuraxial blocks (Sharma 2012). Systemic opioids for acute postoperative pain may increase postoperative nausea and vomiting and gastrointestinal ileus and may prolong hospitalization, potentially increasing hospital costs (Guay 2016). Pulmonary function may also be affected in children with scoliosis deformity, particularly among children with non‐idiopathic scoliosis or those with idiopathic scoliosis and a thoracic deformity (Chua 2016; Ran 2016), making them more susceptible to respiratory depression from systemic opioids. Non‐steroidal anti‐inflammatory drugs, gabapentinoids, and NMDA antagonists, although useful, are usually considered as co‐analgesic drugs (added to systemic opioids or neuraxial blocks) that are insufficient to be used alone. Neuraxial blocks, including single‐injection intrathecal opioids or continuous epidural analgesia with one or two catheters, have been proposed as an alternative.

Description of the intervention

Epidural analgesia, which consists of injection of a solution into the spine outside the dura mater, can be used for surgery as the sole anaesthetic or as a supplement to general anaesthesia for postoperative analgesia (De Rojas 2014). The solution may contain a local anaesthetic alone or an opioid alone or may be used in combination. Various adjuvants may be added to improve efficacy or prolong duration of the solution. The solution may be administered as a single injection (single shot block) or as a loading dose followed by a continuous infusion (through an epidural catheter) to control postoperative pain for the first few days after surgery, when pain is most intense. For this specific surgery of the spine, the surgeon usually provides a single injection or epidural catheter insertion at the end of surgery. Injection of a local anaesthetic before surgical incision or at the start of surgery could potentially interfere with the neurological spinal cord monitoring required during this type of surgery (Loughman 1995). In children, epidural analgesia for spine surgery has been used mainly to treat postoperative pain after scoliosis surgery (Blumenthal 2005; Cassady 2000; Gauger 2009; Klatt 2013; O'Hara 2004). Investigators have infused the local anaesthetic ropivacaine or bupivacaine (Blumenthal 2005; Cassady 2000; Gauger 2009; Klatt 2013; O'Hara 2004). These investigators have added fentanyl, hydromorphone, or no adjuvant to the epidural solution (Blumenthal 2005; Cassady 2000; Gauger 2009; Klatt 2013; O'Hara 2004). Researchers have administered epidural analgesia through one or two catheters (Blumenthal 2005; Cassady 2000; Gauger 2009; Klatt 2013; O'Hara 2004). Investigators have compared epidural analgesia versus a continuous morphine infusion or versus intravenous patient‐controlled analgesia (Blumenthal 2005; Cassady 2000; Gauger 2009; Klatt 2013).

How the intervention might work

When compared with a systemic opioid‐based regimen, epidural analgesia with local anaesthetics has been reported to decrease postoperative pain, hasten gastrointestinal transit return, and decrease hospital length of stay for open abdominal surgery (Guay 2016). It has been postulated that faster return of gastrointestinal transit may be due to sympathetic blockade by the epidural, reduced opioid requirements, or local anaesthetics themselves (Guay 2016). Specifically for scoliosis surgery, a non‐Cochrane review suggests that epidural analgesia may improve pain control, hasten gastrointestinal transit return, and improve patient satisfaction (Borgeat 2008).

Why it is important to do this review

It is unknown whether epidural analgesia improves pain control, accelerates return of gastrointestinal transit, or reduces risk of respiratory depression, length of hospitalization, and costs of care among children. Epidural analgesia is more complex to administer than systemic analgesia and is associated with rare but serious adverse events such as epidural haematoma or abscess. it is important to justify epidural use with clear documentation of superiority compared with systemic opioid‐based postoperative analgesia. This protocol will be followed by the lone Cochrane Review comparing epidural analgesia versus systemic analgesia (opioids or others) for postoperative pain after thoraco‐lumbar spine surgery in children.

Objectives

To assess the effects of epidural analgesia compared with systemic analgesia for acute postoperative pain control after thoraco‐lumbar spine surgery in children.

Methods

Criteria for considering studies for this review

Types of studies

We will include only randomized controlled trials (RCTs) evaluating epidural analgesia for postoperative pain, and will compare epidural analgesia with any form of systemic analgesia by any route. We will exclude observational studies, quasi‐randomized trials, cross‐over trials, and cluster‐randomized trials (Higgins 2011a). We will not exclude studies on the basis of language of publication or publication status.

Types of participants

We will include studies performed on children (0 to 18 years included) undergoing thoracic, lumbar, or thoraco‐lumbar spine surgery for any condition while under general anaesthesia. We will include studies using any surgical approach: minimally invasive or not, posterior or anterior or both, and located at the thoracic or lumbar or thoraco‐lumbar level.

Types of interventions

We will include studies comparing a group of participants with epidural analgesia used for postoperative analgesia versus a group of participants receiving systemic analgesia (opioid based or others) used for postoperative analgesia. We will include studies in which investigators administered epidural analgesia as a single shot block or as a continuous infusion for any duration and containing a local anaesthetic alone (extended duration or not) or in combination with an opioid (extended duration or not) or an opioid alone. We will also include studies in which trialists added an adjuvant to the solution. We will exclude studies in which investigators added substances directly in the epidural space without the use of an epidural needle/catheter, such as steroids or other substances (gelfoam soaked or microfibrillar collagen or other). We will exclude studies in which researchers administered the local anaesthetic or the opioid intrathecally. We will not include trials comparing nerve blocks versus systemic analgesia. For the comparator, we will include all forms of systemic analgesia (opioid‐based regimen or other) regardless of the route of administration (intravenous (with or without a proxy‐ or self‐administered patient‐controlled device), intramuscular or oral analgesia, or other).

Types of outcome measures

Primary outcomes

1. Pain (at rest and on movement up to 72 hours after surgery). We will include pain measured on any ascending or descending scale as provided by study authors

2. Vomiting up to 48 hours after surgery (if possible, we will extract data on this outcome as the number of participants who experienced vomiting episodes)

3. Return of gastrointestinal function measured as:

3a. Time to first flatus in hours (hours)

3b. Time to first bowel movement (hours)

3c. Time to first liquid ingestion (hours)

3d. Time to first solid food ingestion (hours)

For the 'Summary of findings' table for this outcome, we will retain time to first flatus in hours.

Secondary outcomes

1. Time to first mobilization (hours)

2. Hospital length of stay (days). If we find enough data, we will replace this with time to readiness for discharge

3. Satisfaction with postoperative analgesia regimen (any ascending or descending scale as provided by study authors):

3a. Participant satisfaction

3b. Parent satisfaction

For the 'Summary of findings' table for this outcome, we will retain parent satisfaction. If a trial reports satisfaction at more than one time point, we will take the scores that best reflect overall satisfaction.

4. Complications (related to analgesic techniques (epidural or systemic analgesia), including respiratory depression, hospital in‐patient falls, and infections (e.g. wound infection, epidural abscess) within 30 days of surgery) and neurological complications

We will report this outcome as a narrative review and will provide an additional table.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (latest issue); MEDLINE Ovid: Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (from 1946 onwards); Embase Ovid (from 1974 onwards); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (from 1981 onwards). We have devised a draft search strategy for RCTs in Medline, which is displayed in Appendix 1. We will use this as the basis for search strategies for the other databases listed. When appropriate, we will combine these with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying RCTs and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, 6.4.11 (Higgins 2011a)).

Searching other resources

We will look at the World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch) and ClinicalTrials.gov (http://www.clinicaltrials.gov) to identify trials in progress.

We will scan the reference lists and citations of all included trials and of any relevant systematic reviews identified to obtain further references to additional trials. We will screen the conference proceedings of anaesthesiology societies for the past five years, as published in three major anaesthesiology journals: British Journal of Anaesthesiology,European Journal of Anaesthesiology, and Regional Anesthesia and Pain Medicine. We will also look for abstracts on the website of the American Society of Anesthesiologists for the same years. When necessary, we will contact trial authors for additional information.

Data collection and analysis

Selection of studies

Two review authors (JG and RLJ) will independently screen the list of all titles and abstracts identified by the search above. We will retrieve and independently read potential articles to determine their eligibility for inclusion. We will resolve discrepancies by discussion or with the help of a third review author (SK) when required. We will document the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009). We will list all reasons for exclusion in a 'Characteristics of excluded studies' table.

Data extraction and management

Two review authors (JG and SK) will independently extract data. If necessary, we will seek the help of a third review author (RLJ) to resolve discrepancies. For selected studies, we will enter the following parameters onto our data extraction form: risk of bias as measured with the Cochrane tool; and outcomes and factors chosen a priori for assessment of heterogeneity (Higgins 2011b). We will extract dichotomous data as the number of participants experiencing the event and the total number of participants in each treatment group. We will extract continuous data as means, standard deviations, and total numbers of participants. When data are not available in these formats, we will extract data as P values, numbers of participants, and direction of effect. We will not consider medians as equivalent to means and will not estimate standard deviations from quartiles or ranges. We will enter first the site where the study was performed and the date of data collection (to facilitate exclusion of duplicate publications), then whether the study is included in the review or the reason for exclusion. After we reach agreement, one review author will enter into the comprehensive meta‐analysis the data and moderators for heterogeneity exploration (Comprehensive Meta‐Analysis 2007). Also, after we reach agreement, we will enter the risk of bias evaluation into Review Manager 5 (RevMan 5.3). We will resolve disagreements by discussion or with the help of a third review author and will contact study authors to request additional information when required. We will transfer data for analysis to Review Manager in the format required to include the maximal number of studies (events and total numbers of participants for each group; means, standard deviations, and numbers of participants included in each group; or generic inverse variance, if necessary). When possible, we will enter the data into an intention‐to‐treat (ITT) analysis.

Assessment of risk of bias in included studies

We will assess the quality of included studies by using the Cochrane 'Risk of bias' tool found in RevMan 5.3 (Higgins 2011b) to examine random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. We will resolve disagreements by discussion or with the help of a third review author. We will assess risk of bias on the basis of information presented in the reports, while making no assumptions.

Measures of treatment effect

We will report results as risk ratios (RRs) and 95% confidence intervals (95% CIs) for dichotomous data (vomiting and complications) (McColl 1998). We will report results as mean differences (MDs) and 95% CIs for continuous data (pain scores, hospital length of stay, participant and/or parent satisfaction) as much as feasible. If some of the continuous data are extracted from different scales (pain scores), or if only P values are extractable, we will present results as standardized mean differences (SMDs) and 95% CIs and will give equivalence on a clinical scale. For SMDs, we will consider 0.2 a small effect, 0.5 a medium effect, and 0.8 a large effect (Pace 2011). For time‐to‐event data (time to return of gastrointestinal transit, time to first mobilization), we will contact trial authors to try to obtain data as hazard ratios for analysis. If this proves impossible, we will analyse these data in the format provided by trial authors in their reports and will treat them as other continuous data reported as MDs with 95% CIs. When an effect will be noted, we will calculate from the odds ratio a number needed to treat for an additional beneficial outcome (NNTB) or a number needed to treat for an additional harmful outcome (NNTH) (Cates 2016; Deeks 2002). When we are not able to demonstrate an effect, we will calculate the optimal information size to make sure that enough participants were included in the retained studies to justify a conclusion on the absence of effect (Brant R; Pogue 1998). We will consider a difference of 15% (increase or decrease) as the minimal clinically relevant difference.

Unit of analysis issues

We will include only parallel‐group trials. If a study contains more than two groups, we will fuse two groups (by using the appropriate formula for adding standard deviations when required) if we think they are equivalent according to the criteria of our protocol (taking our factors for heterogeneity exploration into account), or we will separate them and split the control group in half if we think they are different.

Dealing with missing data

We will contact study authors for additional information when published articles do not provide enough information for extraction of data. We will not make any imputation.

Assessment of heterogeneity

We will consider clinical heterogeneity before pooling results and will examine statistical heterogeneity before carrying out any meta‐analysis. We will quantify statistical heterogeneity by using the I² statistic while entering data in the way (benefit or harm) that yields the least heterogeneity. We will quantify the amount of heterogeneity as low (I²< 25%), moderate (I² 50%), or high (I² 75%), depending on the value obtained for the I² statistic (Higgins 2003).

Assessment of reporting biases

We will assess publication bias by using a funnel plot, followed by Duval and Tweedie's trim and fill technique (Borenstein 2009; Duval 2000a; Duval 2000b). This technique not only assesses whether publication bias is likely, it also yields an estimate of effect size after correction for the possibility of publication bias when such bias is suspected.

Data synthesis

We will analyse data using Review Manager 5 and Comprehensive Meta‐Analysis Version 2.2.044 via a random‐effects models (Comprehensive Meta‐Analysis 2007; RevMan 5.3). For dichotomous data, we will provide results as risk ratios (values best understood by clinicians; McColl 1998). For continuous data, if some analyses cannot be entered in our favoured format (means, standard deviations (SDs), and numbers of participants), we will not consider a median as equivalent to a mean and will not estimate SDs from quartiles. Instead we will enter data as P values, numbers of participants, and direction of effect (using the RevMan calculator). In such cases, mean differences cannot be obtained. We will then present our results as standardized mean differences (SMDs). For results provided as SMDs, we will give clinical equivalents calculated as follows: SMD multiplied by the SD of a study at low risk of bias, and for which a typical SD on a clinical scale was provided (Higgins 2011b). For results in which the intervention produces an effect, we will calculate the NNTB or the NNTH by using the odds ratio (Cates 2016). If an effect cannot be demonstrated, we will also calculate optimal information size to ensure that enough participants were included in the retained studies to justify a conclusion based on absence of effect (Brant R; Pogue 1998).

Subgroup analysis and investigation of heterogeneity

We will explore any amount of heterogeneity > 25% by using Egger's regression intercept (comprehensive meta‐analysis; to eliminate a small‐study effect), sensitivity analysis, subgrouping, or meta‐regression (comprehensive meta‐analysis) as appropriate. A priori factors for heterogeneity will include the following.

1. Cause of the condition (scoliosis (idiopathic or other) vs traumatic vs other).

2. Elective versus urgent.

3. Surgical approach (open posterior only vs open anterior and open posterior vs other techniques).

4. Site of surgery (thoracic vs lumbar vs thoraco‐lumbar).

5. Number of fused vertebrae.

6. Epidural technique: number of catheters (one vs two).

7. Solution used in the catheter (local anaesthetics vs local anaesthetics plus opioids vs opioids only vs local anaesthetic plus opioids and other adjuvants).

8. Single shot versus continuous infusion (and duration).

9. Comparator (route, substance used, proxy‐patient‐controlled device vs continuous infusion vs intermittent administration (mandatory or on request)).

10. Mean age of participants.

11. Sex distribution.

Although we will examine forest plots for all outcomes with studies placed in order for all potential heterogeneity factors, to avoid multiple comparisons, we will perform analysis (sensitivity, subgrouping, or meta‐regression) only when forest plots suggest a statistically significant effect. We will analyse subgroup differences using Review Manager (Chi²) and will consider a P value < 0.05 significant for subgroup differences.

Sensitivity analysis

We will perform sensitivity analysis (defined as excluding a study on the basis of its risk of bias (allocation concealment and/or blinding of outcome assessors) or because it appeared as an outlier on a forest plot).

'Summary of findings' table and GRADE

We will judge the quality of the body of evidence according to the GRADE system and will present this assessment in a 'Summary of findings' table for all of our primary outcomes (GRADE Working Group 2011; Schünemann 2013). For risk of bias, we will judge the quality of evidence as high when we derive most information from studies at low risk of bias, and we will downgrade quality by one level when we obtain most information from studies at high or unclear risk of bias (allocation concealment and blinding of outcome assessors), or by two levels when the proportion of information obtained from studies at high risk of bias was sufficient to affect interpretation of results. For inconsistency, we will downgrade the quality of evidence by one when the I² statistic is 50% or higher without satisfactory explanation, and by two levels when the I² statistic is 75% or higher without explanation. We will not downgrade the quality of evidence for indirectness, if outcomes are based on direct comparisons performed on the population of interest and are not surrogate markers. For imprecision, we will downgrade the quality of evidence by one level when the confidence interval around the effect size is large or overlaps an absence of effect and fails to exclude an important benefit or harm, or when the number of participants is less than the optimal information size; and we will downgrade the quality by two levels when the confidence interval is very wide and includes both appreciable benefit and harm. For publication bias, we will downgrade the quality of evidence by one level when correcting for the possibility of publication bias as assessed by Duval and Tweedie’s fill and trim analysis changes the conclusion. When the quality of the body of evidence is high, further research is very unlikely to change our confidence in the estimate of effect. When quality is moderate, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. When quality is low, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. When the quality is very low, any estimate of effect is very uncertain. If data need to be treated as more than one comparison (not expected from known trials on this topic), we will create a 'Summary of findings' table for each comparison.

Appendices

Appendix 1. Search terms for MEDLINE

Database: Ovid MEDLINE(R) Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present>

Search strategy:

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

1 ((Spine* or spinal or lumbar) adj3 surg*).mp. or Spinal Diseases/su or Spinal Fusion/ or scoliosis/ or scolios*.mp. or thoracolumbar.mp. or (thoraco adj3 lumbar).mp. or (thoracic adj3 (lumbar or spine)).mp. (65651)

2 Analgesia, Epidural/ or Anesthetics, Local/ or Analgesics, Opioid/ or ((epidural or local or systemic) adj4 (analg* or an?esth*)).mp. or opioid*.mp. (174607)

3 Postoperative Period/ or Pain, Postoperative/ or Postoperative Care/ or post?operative.mp. or post operative.mp. (700189)

4 ((randomized controlled trial or controlled clinical trial).pt. or randomi?ed.ab. or placebo.ab. or drug therapy.fs. or randomly.ab. or trial.ab. or groups.ab.) not (exp animals/ not humans.sh.) (3452341)

5 1 and 2 and 3 and 4 (564)

[mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

Appendix 2. Data collection form

Data collection form

Intervention review – RCTs only

Review title

Postoperative epidural analgesia vs systemic analgesia for thoraco‐lumbar spine surgery in children and adolescents

Study ID(surname of first author and year first full report of study was published, e.g. Smith 2001)

Report IDs of other reports of this study(e.g. duplicate publications, follow‐up studies)

Notes:

1. General information

Date form completed(dd/mm/yyyy)
Name/ID of person extracting data
Report title (title of paper/abstract/report that data are extracted from)
Report ID (ID for this paper/abstract/report)
Reference details
Report author contact details
Publication type (e.g. full report, abstract, letter)
Study funding sources (including role of funders)
Possible conflicts of interest (for study authors)
Notes:

2. Study eligibility

Study characteristics	Eligibility criteria (Insert eligibility criteria for each characteristic as defined in the Protocol)		Yes	No	Unclear	Location in text (pg & ¶/fig/table)
Type of study	Randomized controlled trial
	Controlled clinical trial (quasi‐randomized trial)
Participants
Types of interventions
Types of outcome measures	Primary outcomes 1. Pain (at rest and on movement up to 72 hours after surgery) 2. Vomiting up to 48 hours after surgery 3. Return of gastrointestinal transit time measured as: 3a. Time to first flatus in hours (hours) 3b. Time to first bowel movement (hours) 3c. Time to first liquid ingestion (hours) 3d. Time to first solid food ingestion (hours) Secondary outcomes 1. Time to first mobilization (hours) 2. Hospital length of stay (days) 3. Satisfaction with postoperative analgesia regimen (any ascending or descending scale as provided by study authors): 3a. Participant satisfaction 3b. Parent satisfaction 4. Complications (related to analgesic techniques (epidural or systemic analgesia) including respiratory depression, hospital in‐patient falls, and infections (e.g. wound infection, epidural abscess) within 30 days of surgery) and neurological complications
INCLUDE		EXCLUDE
Reason for exclusion
Notes:

DO NOT PROCEED IF STUDY EXCLUDED FROM REVIEW

3. Population and setting

	Description Include comparative information for each group (i.e. intervention and controls) if available		Location in text (pg & ¶/fig/table)
Population description (from which study participants are drawn)
Setting (including location and social context)
Inclusion criteria
Exclusion criteria
Method/s of recruitment of participants
Informed consent obtained	Yes No Unclear
Notes:

4. Methods

	Descriptions as stated in report/paper		Location in text (pg & ¶/fig/table)
Aim of study
Design(e.g. parallel, cross‐over, cluster)
Unit of allocation (by individuals, clusters/groups, or body parts)
Start date
End date
Total study duration
Ethical approval needed/obtained for study	Yes No Unclear
Notes:

5. Risk of bias assessment

See Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions.

Domain	Risk of bias			Support for judgement	Location in text (pg & ¶/fig/table)
	Low risk	High risk	Unclear risk
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)				Outcome group: all/
(if required)				Outcome group:
Blinding of outcome assessment (detection bias)				Outcome group: all/
(if required)				Outcome group:
Incomplete outcome data (attrition bias)
Selective outcome reporting? (reporting bias)
Other bias
Notes:

6. Participants

Provide overall data and, if available, comparative data for each intervention or comparison group.

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Total no. randomized (or total pop. at start of study for NRCTs)
Baseline imbalances
Withdrawals and exclusions (if not provided below by outcome)
Age
Sex
Severity of illness
Co‐morbidities
Other treatment received(additional to study intervention)
Other relevant sociodemographics
Subgroups measured
Subgroups reported
Notes:

7. Intervention groups

Copy and paste table for each intervention and comparison group.

Intervention group 1

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Group name
No. randomized to group (specify whether no. people or clusters)
Theoretical basis(include key references)
Description(include sufficient detail for replication, e.g. content, dose, components)
Duration of treatment period
Timing(e.g. frequency, duration of each episode)
Delivery(e.g. mechanism, medium, intensity, fidelity)
Providers (e.g. no., profession, training, ethnicity, etc., if relevant)
Co‐interventions
Notes:

8. Outcomes

Copy and paste table for each outcome.

Outcome 1

	Description as stated in report/paper		Location in text (pg & ¶/fig/table)
Outcome name
Time points measured
Time points reported
Outcome definition(with diagnostic criteria if relevant)
Person measuring/reporting
Unit of measurement (if relevant)
Scales: upper and lower limits(indicate whether high or low score is good)
Is outcome/tool validated?	Yes No Unclear
Imputation of missing data (e.g. assumptions made for ITT analysis)
Assumed risk estimate (e.g. baseline or population risk noted in Background)
Power
Notes:

9. Results

Copy and paste the appropriate table for each outcome, including additional tables for each time point and subgroup as required.

Dichotomous outcome

	Description as stated in report/paper					Location in text (pg & ¶/fig/table)
Comparison
Outcome
Subgroup
Time point (specify whether from start or end of intervention)
Results	Intervention			Comparison
	No. events	No. participants		No. events	No. participants
No. missing participants and reasons
No. participants moved from other group and reasons
Any other results reported
Unit of analysis(by individuals, clusters/groups, or body parts)
Statistical methods used and appropriateness of these methods(e.g. adjustment for correlation)
Reanalysis required?(specify)	Yes No Unclear
Reanalysis possible?	Yes No Unclear
Reanalysed results
Notes:

Continuous outcome

		Description as stated in report/paper							Location in text (pg & ¶/fig/table)
Comparison
Outcome
Subgroup
Time point (specify whether from start or end of intervention)
Post intervention or change from baseline?
Results	Intervention					Comparison
	Mean		SD (or other variance)	No. participants		Mean	SD (or other variance)	No. participants
No. missing participants and reasons
No. participants moved from other group and reasons
Any other results reported
Unit of analysis (individuals, clusters/groups, or body parts)
Statistical methods used and appropriateness of these methods(e.g. adjustment for correlation)
Reanalysis required?(specify)		Yes No Unclear
Reanalysis possible?		Yes No Unclear
Reanalysed results
Notes:

Other outcome

	Description as stated in report/paper					Location in text (pg & ¶/fig/table)
Comparison
Outcome
Subgroup
Time point (specify whether from start or end of intervention)
Results	Intervention result	SD (or other variance)		Control result	SD (or other variance)
	Overall results			SE (or other variance)
No. participants	Intervention			Control
No. missing participants and reasons
No. participants moved from other group and reasons
Any other results reported
Unit of analysis(by individuals, clusters/groups, or body parts)
Statistical methods used and appropriateness of these methods
Reanalysis required?(specify)	Yes No Unclear
Reanalysis possible?	Yes No Unclear
Reanalysed results
Notes:

10. Applicability

Have important populations been excluded from the study?(consider disadvantaged populations and possible differences in the intervention effect)	Yes No Unclear
Is the intervention likely to be aimed at disadvantaged groups?(e.g. lower socioeconomic groups)	Yes No Unclear
Does the study directly address the review question? (any issues of partial or indirect applicability)	Yes No Unclear
Notes:

11. Other information

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Key conclusions of study authors
References to other relevant studies
Correspondence required for further study information(from whom, what, and when)
Notes:

12. Factors that will be considered in the heterogeneity exploration

	Treatment	Control	Remarks
Year of publication
Age
Sex distribution
Condition
Elective/Urgent
Surgical approach
Site of surgery
Number of fused vertebrae
Epidural technique
Solution in the epidural
Single injection vs continuous
Co‐analgesia
Comparator (route, substance, and method of administration)

Adapted from the ACE data collection form.

Contributions of authors

Joanne Guay (JG), Santhanam Suresh (SS), Sandra Kopp (SK), Rebecca L Johnson (RLJ).

Conceiving the review: JG, SS, SK, and RLJ.

Co‐ordinating the review: JG.

Undertaking manual searches: JG and RLJ.

Screening search results: JG and RLJ.

Organizing retrieval of papers: JG.

Screening retrieved papers against inclusion criteria: JG and RLJ.

Appraising quality of papers: JG and SK.

Abstracting data from papers: JG and SK.

Writing to authors of papers for additional information: JG.

Obtaining and screening data on unpublished studies: JG and RLJ.

Managing data for the review: JG.

Entering data into Review Manager: JG.

Analysing RevMan statistical data: JG.

Performing other statistical analysis not using RevMan: JG.

Interpreting data: JG, SS, SK, and RLJ.

Making statistical inferences: JG.

Writing the review: JG, SS, SK, and RLJ.

Securing funding for the review: departmental resources only.

Performing previous work that was the foundation of the present review: JG, SS, SK, and RLJ.

Serving as guarantor for the review (one review author): JG.

Taking responsibility for reading and checking the review before submission: JG, SS, SK, and RLJ.

Sources of support

Internal sources

• University of Sherbrooke, Canada.

  University of Sherbrooke provided access to some databases and some articles

• University of Quebec en Abitibi Temiscamingue (UQAT), Canada.

  University of Quebec en Abitibi Temiscamingue (UQAT) provided access to some articles

• Cochrane Anaesthesia, Critical and Emergency Care Group, Denmark.

  The review authors wish to thank Janne Vendt, Cochrane Information Specialist, who designed the search strategy

External sources

• No sources of support supplied

Declarations of interest

Joanne Guay: I have had no direct relationship with any pharmaceutical company or equipment manufacturer in the past five years. I have not acted as a witness expert in the past five years. I am not an author of any of the included or excluded studies. I do not hold stock other than mutual funds. I am the editor of a multi‐author textbook on anaesthesia (including notions on general and regional anaesthesia). I receive fees as Associate Professor from University of Quebec in Abitibi‐Temiscamingue for a course on airway management.

Santhanam Suresh: no conflicts of interest.

Sandra Kopp: no conflicts of interest.

Rebecca L Johnson: no conflicts of interest.

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