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• Volume 28, Issue 6
• Rapid reviews methods series: Guidance on literature search
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• http://orcid.org/0000-0001-6644-9845 Irma Klerings 1 ,
• Shannon Robalino 2 ,
• http://orcid.org/0000-0003-4808-3880 Andrew Booth 3 ,
• http://orcid.org/0000-0002-2903-6870 Camila Micaela Escobar-Liquitay 4 ,
• Isolde Sommer 1 ,
• http://orcid.org/0000-0001-5531-3678 Gerald Gartlehner 1 , 5 ,
• Declan Devane 6 , 7 ,
• Siw Waffenschmidt 8
• On behalf of the Cochrane Rapid Reviews Methods Group
• 1 Department for Evidence-Based Medicine and Evaluation , University of Krems (Danube University Krems) , Krems , Niederösterreich , Austria
• 2 Center for Evidence-based Policy , Oregon Health & Science University , Portland , Oregon , USA
• 3 School of Health and Related Research (ScHARR) , The University of Sheffield , Sheffield , UK
• 4 Research Department, Associate Cochrane Centre , Instituto Universitario Escuela de Medicina del Hospital Italiano de Buenos Aires , Buenos Aires , Argentina
• 5 RTI-UNC Evidence-based Practice Center , RTI International , Research Triangle Park , North Carolina , USA
• 6 School of Nursing & Midwifery, HRB TMRN , National University of Ireland Galway , Galway , Ireland
• 7 Evidence Synthesis Ireland & Cochrane Ireland , University of Galway , Galway , Ireland
• 8 Information Management Department , Institute for Quality and Efficiency in Healthcare , Cologne , Germany
• Correspondence to Irma Klerings, Department for Evidence-based Medicine and Evaluation, Danube University Krems, Krems, Niederösterreich, Austria; irma.klerings{at}donau-uni.ac.at

This paper is part of a series of methodological guidance from the Cochrane Rapid Reviews Methods Group. Rapid reviews (RR) use modified systematic review methods to accelerate the review process while maintaining systematic, transparent and reproducible methods. In this paper, we address considerations for RR searches. We cover the main areas relevant to the search process: preparation and planning, information sources and search methods, search strategy development, quality assurance, reporting, and record management. Two options exist for abbreviating the search process: (1) reducing time spent on conducting searches and (2) reducing the size of the search result. Because screening search results is usually more resource-intensive than conducting the search, we suggest investing time upfront in planning and optimising the search to save time by reducing the literature screening workload. To achieve this goal, RR teams should work with an information specialist. They should select a small number of relevant information sources (eg, databases) and use search methods that are highly likely to identify relevant literature for their topic. Database search strategies should aim to optimise both precision and sensitivity, and quality assurance measures (peer review and validation of search strategies) should be applied to minimise errors.

• Evidence-Based Practice
• Systematic Reviews as Topic
• Information Science

Data availability statement

No data are available.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

http://dx.doi.org/10.1136/bmjebm-2022-112079

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Compared with systematic reviews, rapid reviews (RR) often abbreviate or limit the literature search in some way to accelerate review production. However, RR guidance rarely specifies how to select topic-appropriate search approaches.

WHAT THIS STUDY ADDS

This paper presents an overview of considerations and recommendations for RR searching, covering the complete search process from the planning stage to record management. We also provide extensive appendices with practical examples, useful sources and a glossary of terms.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

There is no one-size-fits-all solution for RR literature searching: review teams should consider what search approaches best fit their RR project.

Introduction

This paper is part of a series from the Cochrane Rapid Reviews Methods Group (RRMG) providing methodological guidance for rapid reviews (RRs). 1–3 While the RRMG’s guidance 4 5 on Cochrane RR production includes brief advice on literature searching, we aim to provide in-depth recommendations for the entire search process.

Literature searching is the foundation for all reviews; therefore, it is important to understand the goals of a specific RR. The scope of RRs varies considerably (from focused questions to overviews of broad topics). 6 As with conventional systematic reviews (SRs), there is not a one-size-fits-all approach for RR literature searches. We aim to support RR teams in choosing methods that best fit their project while understanding the limitations of modified search methods. Our recommendations derive from current systematic search guidance, evidence on modified search methods and practical experience conducting RRs.

This paper presents considerations and recommendations, described briefly in table 1 . The table also includes a comparison to the SR search process based on common recommendations. 7–10 We provide supplemental materials, including a list of additional resources, further details of our recommendations, practical examples, and a glossary (explaining the terms written in italics) in online supplemental appendices A–C .

Supplemental material

• View inline

Recommendations for rapid review literature searching

Preparation and planning

Given that the results of systematic literature searches underpin a review, planning the searches is integral to the overall RR preparation. The RR search process follows the same steps as an SR search; therefore, RR teams must be familiar with the general standards of systematic searching . Templates (see online supplemental appendix B ) and reporting guidance 11 for SR searches can also be adapted to structure the RR search process.

Developing a plan for the literature search forms part of protocol development and should involve an information specialist (eg, librarian). Information specialists can assist in refining the research question, selecting appropriate search methods and resources, designing and executing search strategies, and reporting the search methods. At minimum, specialist input should include assessing information sources and methods and providing feedback on the primary database search strategy.

Two options exist for abbreviating the search process: (1) reducing time spent on conducting searches (eg, using automation tools, reusing existing search strategies, omitting planning or quality assurance steps) and (2) reducing the size of the search result (eg, limiting the number of information sources, increasing the precision of search strategies, using study design filters). Study selection (ie, screening search results) is usually more resource-intensive than searching, 12 particularly for topics with complex or broad concepts or diffuse terminology; thus, the second option may be more efficient for the entire RR. Investing time upfront in optimising search sensitivity (ie, completeness) and precision (ie, positive predictive value) can save time in the long run by reducing the screening and selection workload.

Preliminary or scoping searches are critical to this process. They inform the choice of search methods and identify potentially relevant literature. Texts identified through preliminary searching serve as known relevant records that can be used throughout the search development process (see sections on database selection, development and validation of search strategies).

In addition to planning the search itself, the review team should factor in time for quality assurance steps (eg, search strategy peer review) and the management of search results (eg, deduplication, full-text retrieval).

Information sources and methods

To optimise the balance of search sensitivity and precision, RR teams should prioritise the most relevant information sources for the topic and the type of evidence required. These can include bibliographic databases (eg, MEDLINE/PubMed), grey literature sources and targeted supplementary search methods. Note that this approach differs from the Methodological Expectations of Cochrane Intervention Reviews Standards 9 where the same core set of information sources is required for every review and further supplemented by additional topic-specific and evidence-specific sources.

Choosing bibliographic databases

For many review topics, most evidence is found in peer-reviewed journal articles, making bibliographic databases the main resource of systematic searching. Limiting the number of databases searched can be a viable option in RRs, but it is important to prioritise topic-appropriate databases.

MEDLINE has been found to have high coverage for studies included in SRs 13 14 and is an appealing database choice because access is free via PubMed. However, coverage varies depending on topics and relevant study designs. 15 16 Additionally, even if all eligible studies for a topic were available in MEDLINE, search strategies will usually miss some eligible studies because search sensitivity is lower than database coverage. 13 17 This means searching MEDLINE alone is not a viable option, and additional information sources or search methods are required. Known relevant records can be used to help assess the coverage of selected databases (see also online supplemental appendix C ).

Further information sources and search techniques

Supplementary systematic search methods have three main goals, to identify (1) grey literature, (2) published literature not covered by the selected bibliographic databases and (3) database-covered literature that was not retrieved by the database searches.

When RRs search only a small number of databases, supplementary searches can be particularly important to pick up eligible studies not identified via database searching. While supplementary methods might increase the time spent on searching, they sometimes better optimise search sensitivity and precision, saving time in the long run. 18 Depending on the topic and relevant evidence, such methods can offer an alternative to adding additional specialised database searches. To decide if and what supplementary searches are helpful, it is important to evaluate what literature might be missed by the database searches and how this might affect the specific RR.

Study registries and other grey literature

Some studies indicate that the omission of grey literature searches rarely affects review conclusions. 17 19 However, the relevance of study registries and other grey literature sources is topic-dependent. 16 19–21 For example, randomised controlled trials (RCTs) on newly approved drugs are typically identified in ClinicalTrials.gov. 20 For rapidly evolving topics such as COVID-19, preprints are an important source. 21 For public health interventions, various types of grey literature may be important (eg, evaluations conducted by local public health agencies). 22

Further supplementary search methods

Other supplementary techniques (eg, checking reference lists, reviewing specific websites or electronic table of contents, contacting experts) may identify additional studies not retrieved by database searches. 23 One of the most common approaches involves checking reference lists of included studies and relevant reviews. This method may identify studies missed by limited database searches. 12 Another promising citation-based approach is using the ‘similar articles’ option in PubMed, although research has focused on updating existing SRs. 24 25

Considerations for RRs of RCTs

Databases and search methods to identify RCTs have been particularly well researched. 17 20 24 26 27 For this reason, it is possible to give more precise recommendations for RRs based on RCTs than for other types of review. Table 2 provides an overview of the most important considerations; additional information can be found in online supplemental appendix C .

Information sources for identification of randomised controlled trials (RCTs)

Search strategies

We define ‘search strategy’ as a Boolean search query in a specific database (eg, MEDLINE) using a specific interface (eg, Ovid). When several databases are searched, this query is usually developed in a primary database and interface (eg, Ovid MEDLINE) and translated to other databases.

Developing search strategies

Optimising search strategy precision while aiming for high sensitivity is critical in reducing the number of records retrieved. Preliminary searches provide crucial information to aid efficient search strategy development. Reviewing the abstracts and subject headings used in known relevant records will assist in identifying appropriate search terms. Text analysis tools can also be used to support this process, 28 29 for example, to develop ‘objectively derived’ search strategies. 30

Reusing or adapting complete search strategies (eg, from SRs identified by the preliminary searches) or selecting elements of search strategies for reuse can accelerate search strategy development. Additionally, validated search filters (eg, for study design) can be used to reduce the size of the search result without compromising the sensitivity of a search strategy. 31 However, quality assurance measures are necessary whether the search strategy is purpose-built, reused or adapted (see the ‘Quality assurance’ section.)

Database-specific and interface-specific functionalities can also be used to improve searches’ precision and reduce the search result’s size. Some options are: restricting to records where subject terms have been assigned as the major focus of an article (eg, major descriptors in MeSH), using proximity operators (ie, terms adjacent or within a set number of words), frequency operators (ie, terms have to appear a minimum number of times in an abstract) or restricting search terms to the article title. 32–34

Automated syntax translation can save time and reduce errors when translating a primary search strategy to different databases. 35 36 However, manual adjustments will usually be necessary.

The time taken to learn how to use supporting technologies (eg, text analysis, syntax translation) proficiently should not be underestimated. The time investment is most likely to pay off for frequent searchers. A later paper in this series will address supporting software for the entire review process.

Limits and restrictions

Limits and restrictions (eg, publication dates, language) are another way to reduce the number of records retrieved but should be tailored to the topic and applied with caution. For example, if most studies about an intervention were published 10 years ago, then an arbitrary cut-off of ‘the last 5 years’ will miss many relevant studies. 37 Similarly, limiting to ‘English only’ is acceptable for most cases, but early in the COVID-19 pandemic, a quarter of available research articles were written in Chinese. 38 Depending on the RR topic, certain document types (eg, conference abstracts, dissertations) might be excluded if not considered relevant to the research question.

Note also that preset limiting functions in search interfaces (eg, limit to humans) often rely on subject headings (eg, MeSH) alone. They will miss eligible studies that lack or have incomplete subject indexing. Using (validated) search filters 31 is preferable.

Updating existing reviews

One approach to RR production involves updating an existing SR. In this case, preliminary searches should be used to check if new evidence is available. If the review team decide to update the review, they should assess the original search methods and adapt these as necessary.

One option is to identify the minimum set of databases required to retrieve all the original included studies. 39 Any reused search strategies should be validated and peer-reviewed (see below) and optimised for precision and/or sensitivity.

Additionally, it is important to assess whether the topic terminology or the relevant databases have changed since the original SR search.

In some cases, designing a new search process may be more efficient than reproducing the original search.

Quality assurance and search strategy peer review

Errors in search strategies are common and can impact the sensitivity and comprehensiveness of the search result. 40 If an RR search uses a small number of information sources, such errors could affect the identification of relevant studies.

Validation of search strategies

The primary database search strategy should be validated using known relevant records (if available). This means testing if the primary search strategy retrieves eligible studies found through preliminary searching. If some known studies are not identified, the searcher assesses the reasons and decides if revisions are necessary. Even a precision-focused systematic search should identify the majority—we suggest at least 80%–90%—of known studies. This is based on benchmarks for sensitivity-precision-maximising search filters 41 and assumes that the set of known studies is representative of the whole of relevant studies.

Peer review of search strategies

Ideally, an information specialist should review the planned information sources and search methods and use the PRESS (Peer Review of Electronic Search Strategies) checklist 42 to assess the primary search strategy. Turnaround time has to be factored into the process from the outset (eg, waiting for feedback, revising the search strategy). PRESS recommends a maximum turnaround time of five working days for feedback, but in-house peer review often takes only a few hours.

If the overall RR time plan does not allow for a full peer review of the search strategy, a review team member with search experience should check the search strategy for spelling errors and correct use of Boolean operators (AND, OR, NOT) at a minimum.

Reporting and record management

Record management requirements of RRs are largely identical to SRs and have to be factored into the time plan. Teams should develop a data management plan and review the relevant reporting standards at the project’s outset. PRISMA-S (Preferred Reporting Items for Systematic Reviews and Meta-Analyses literature search extension) 11 is a reporting standard for SR searches that can be adapted for RRs.

Reference management software (eg, EndNote, 43 Zotero 44 ) should be used to track search results, including deduplication. Note that record management for database searches is less time-consuming than for many supplementary or grey literature searches, which often require manual entry into reference management software. 12

Additionally, software platforms for SR production (eg, Covidence, 45 EPPI-Reviewer, 46 Systematic Review Data Repository Plus 47 ) can provide a unified way to keep track of records throughout the whole review process, which can improve management and save time. These platforms and other dedicated tools (eg, SRA Deduplicator) 48 also offer automated deduplication. However, the time and cost investment necessary to appropriately use these tools have to be considered.

Decisions about search methods for an RR need to consider where time can be most usefully invested and processes accelerated. The literature search should be considered in the context of the entire review process, for example, protocol development and literature screening: Findings of preliminary searches often affect the development and refinement of the research question and the review’s eligibility criteria . In turn, they affect the number of records retrieved by the searches and therefore the time needed for literature selection.

For this reason, focusing only on reducing time spent on designing and conducting searches can be a false economy when seeking to speed up review production. While some approaches (eg, text analysis, automated syntax translation) may save time without negatively affecting search validity, others (eg, skipping quality assurance steps, using convenient information sources without considering their topic appropriateness) may harm the entire review. Information specialists can provide crucial aid concerning the appropriate design of search strategies, choice of methods and information sources.

For this reason, we consider that investing time at the outset of the review to carefully choose a small number of highly appropriate search methods and optimise search sensitivity and precision likely leads to better and more manageable results.

Ethics statements

Patient consent for publication.

Not applicable.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

Twitter @micaelaescb

Collaborators On behalf of the Cochrane Rapid Reviews Methods Group: Declan Devane, Gerald Gartlehner, Isolde Sommer.

Contributors IK, SR, AB, CME-L and SW contributed to the conceptualisation of this paper. IK, AB and CME-L wrote the first draft of the manuscript. All authors critically reviewed and revised the manuscript. IK is responsible for the overall content.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests AB is co-convenor of the Cochrane Qualitative and Implementation Methods Group. In the last 36 months, he received royalties from Systematic Approaches To a Successful Literature Review (Sage 3rd edn), payment or honoraria form the Agency for Healthcare Research and Quality, and travel support from the WHO. DD works part time for Cochrane Ireland and Evidence Synthesis Ireland, which are funded within the University of Ireland Galway (Ireland) by the Health Research Board (HRB) and the Health and Social Care, Research and Development (HSC R&D) Division of the Public Health Agency in Northern Ireland.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Linked Articles

• Research methods and reporting Rapid reviews methods series: Guidance on assessing the certainty of evidence Gerald Gartlehner Barbara Nussbaumer-Streit Declan Devane Leila Kahwati Meera Viswanathan Valerie J King Amir Qaseem Elie Akl Holger J Schuenemann BMJ Evidence-Based Medicine 2023; - Published Online First: 19 Apr 2023. doi: 10.1136/bmjebm-2022-112111
• Research methods and reporting Rapid reviews methods series: Guidance on team considerations, study selection, data extraction and risk of bias assessment Barbara Nussbaumer-Streit Isolde Sommer Candyce Hamel Declan Devane Anna Noel-Storr Livia Puljak Marialena Trivella Gerald Gartlehner BMJ Evidence-Based Medicine 2023; 28 418-423 Published Online First: 19 Apr 2023. doi: 10.1136/bmjebm-2022-112185
• Research methods and reporting Rapid Reviews Methods Series: Involving patient and public partners, healthcare providers and policymakers as knowledge users Chantelle Garritty Andrea C Tricco Maureen Smith Danielle Pollock Chris Kamel Valerie J King BMJ Evidence-Based Medicine 2023; - Published Online First: 19 Apr 2023. doi: 10.1136/bmjebm-2022-112070

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Hypnosis for pain management during labour and childbirth

Affiliation.

• 1 St Helen's Private Hospital, 186 Macquarie Street, Hobart, Tasmania, Australia, 7000.
• PMID: 27192949
• PMCID: PMC7120324
• DOI: 10.1002/14651858.CD009356.pub3

Background: This review is one in a series of Cochrane reviews investigating pain management for childbirth. These reviews all contribute to an overview of systematic reviews of pain management for women in labour, and share a generic protocol. This review updates an earlier version of the review of the same title.

Objectives: To examine the effectiveness and safety of hypnosis for pain management during labour and childbirth.

Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2015) and the reference lists of primary studies and review articles.

Selection criteria: Randomised controlled trials (RCTs) and quasi-RCTS comparing preparation for labour using hypnosis and/or use of hypnosis during labour, with or without concurrent use of pharmacological or non-pharmacological pain relief methods versus placebo, no treatment or any analgesic drug or technique.

Data collection and analysis: Two review authors independently extracted data and assessed trial quality. Where possible we contacted study authors seeking additional information about data and methodology.

Main results: We included nine trials randomising a total of 2954 women. The risk of bias in trials was variable, there were several well-designed large trials and some trials where little was reported about trial design. Although eight of the nine trials assessed antenatal hypnotherapy, there were considerable differences between these trials in timing and technique. One trial provided hypnotherapy during labour. In this updated review we compared hypnosis interventions with all control groups (main comparison) and also with specific control conditions: standard care (nine RCTs), supportive counselling (two RCTs) and relaxation training (two RCTs).In the main comparison, women in the hypnosis group were less likely to use pharmacological pain relief or analgesia than those in the control groups, (average risk ratio (RR) 0.73, 95% CI 0.57 to 0.94, eight studies, 2916 women; very low-quality evidence; random-effects model). There were no clear differences between women in the hypnosis group and those in the control groups for most of the other primary outcomes. There were no clear differences for sense of coping with labour (MD 0.22, 95% CI -0.14 to 0.58, one study, 420 women; low-quality evidence) or spontaneous vaginal birth (average RR 1.12, 95% CI 0.96 to 1.32, six studies, 2361 women; low-quality evidence; random-effects model). There were no clear differences for satisfaction with pain relief (measured on a seven-point scale two weeks postnatally) for women in the hypnosis group who also received pethidine (MD 0.41, 95% CI -0.45 to 1.27; one study, 72 women), Entonox (MD 0.19, 95% CI -0.19 to 0.57; one study, 357 women), self-hypnosis (MD 0.28, 95% CI -0.32 to 0.88; one study, 160 women), or epidural (MD -0.03, 95% CI -0.40 to 0.34; one study, 127 women), but a slight benefit in favour of hypnosis was seen for women who received water immersion (MD 0.52, 95% CI 0.04 to 1.00; one study, 174 women (all low-quality evidence). There were no clear differences for satisfaction with pain relief when it was measured as the number of women who reported they had adequate pain relief (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.94 to 1.20, one study, 264 women; low-quality evidence). It should be noted that for pharmacological pain relief and spontaneous vaginal birth, there was evidence of considerable statistical heterogeneity, which could not be fully explained by subgroup analysis.For this review's secondary outcomes, no clear differences were found between women in the hypnosis group and women in the control groups for most outcomes where data were available. There was mixed evidence regarding benefits for women in the hypnosis group compared with all control groups for pain intensity, satisfaction with childbirth experience and postnatal depression. For each of these outcomes, data from more than one trial were available for analysis but could not be combined due to differences in measurement methods. There was evidence that fewer women in the hypnosis group stayed in hospital for more than two days after the birth but this finding was based on one small study (RR 0.11, 95% CI 0.02 to 0.83). No clear differences between women in the hypnosis group and the control groups were found for the other secondary outcomes where data were available.In the comparisons of hypnosis with specific types of control conditions: standard care, supportive counselling and relaxation training, there were no clear differences found between women in the hypnosis group and those in the standard care control groups or the relaxation control groups for the primary outcomes. Compared with the women in the supportive counselling control group, women in the hypnosis group were less likely to use pharmacological analgesia (average RR 0.48, 95% CI 0.32 to 0.73, two studies, 562 women). They were also more likely to have a spontaneous vaginal birth (RR 2.42, 95% CI 1.43 to 4.07), although this finding was based on the results of one small study. Overall these new comparisons displayed much less statistical heterogeneity than the comparison including all control groups.

Authors' conclusions: There are still only a relatively small number of studies assessing the use of hypnosis for labour and childbirth. Hypnosis may reduce the overall use of analgesia during labour, but not epidural use. No clear differences were found between women in the hypnosis group and those in the control groups for satisfaction with pain relief, sense of coping with labour or spontaneous vaginal birth. Not enough evidence currently exists regarding satisfaction with pain relief or sense of coping with labour and we would encourage any future research to prioritise the measurement of these outcomes. The evidence for the main comparison was assessed using GRADE as being of low quality for all the primary outcomes with downgrading decisions due to concerns regarding inconsistency of the evidence, limitations in design and imprecision. Further research is needed in the form of large, well-designed randomised controlled trials to assess whether hypnosis is of value for pain management during labour and childbirth.

Publication types

• Meta-Analysis
• Research Support, Non-U.S. Gov't
• Systematic Review
• Analgesia, Obstetrical / methods*
• Hypnosis / methods*
• Labor Pain / psychology
• Labor Pain / therapy*
• Labor, Obstetric / psychology
• Length of Stay
• Patient Satisfaction
• Randomized Controlled Trials as Topic
• Time Factors

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--> Cochrane 30 years of evidence

Acupuncture for preventing migraine attacks.

Bottom line

The available evidence suggests that a course of acupuncture consisting of at least six treatment sessions can be a valuable option for people with migraine.

Individuals with migraine have repeated attacks of severe headache, usually just on one side and often with vomiting. Acupuncture is a therapy in which thin needles are inserted into the skin at particular points. It originated in China, and is now used in many countries to treat people with migraine. We evaluated whether acupuncture reduces the number of episodes of migraine. We looked at the number of people in whom the number of migraine days per month was reduced by half or more than half.

Key results

For this update, we reviewed 22 trials with 4985 people, published up to January 2016. We omitted five trials from the original review because they included people who had had migraine for less than 12 months. We included five new trials in this update.

In four trials, acupuncture added to usual care or treatment of migraine on onset only (usually with pain-killers) resulted in 41 in 100 people having the frequency of headaches at least halved, compared to 17 of 100 people given usual care only.

In 15 trials, acupuncture was compared with 'fake' acupuncture, where needles are inserted at incorrect points or do not penetrate the skin. The frequency of headaches halved in 50 of 100 people receiving true acupuncture, compared with 41 of 100 people receiving 'fake' acupuncture. The results were dominated by three good quality large trials (with about 1200 people) showing that the effect of true acupuncture was still present after six months. There were no differences in the number of side effects of real and 'fake' acupuncture, or the numbers dropping out because of side effects.

In five trials, acupuncture was compared to a drug proven to reduce the frequency of migraine attacks, but only three trials provided useful information. At three months, headache frequency halved in 57 of 100 people receiving acupuncture, compared with 46 of 100 people taking the drug. After six months, headache frequency halved in 59 of 100 people receiving acupuncture, compared with 54 of 100 people taking the drug. People receiving acupuncture reported side effects less often than people receiving drugs, and were less likely to drop out of the trial.

Our findings about the number of days with migraine per month can be summarized as follows. If people have six days with migraine per month on average before starting treatment, this would be reduced to five days in people receiving only usual care, to four days in those receiving fake acupuncture or a prophylactic drug, and to three and a half days in those receiving true acupuncture.

Quality of the evidence

Overall the quality of the evidence was moderate.

The available evidence suggests that adding acupuncture to symptomatic treatment of attacks reduces the frequency of headaches. Contrary to the previous findings, the updated evidence also suggests that there is an effect over sham, but this effect is small. The available trials also suggest that acupuncture may be at least similarly effective as treatment with prophylactic drugs. Acupuncture can be considered a treatment option for patients willing to undergo this treatment. As for other migraine treatments, long-term studies, more than one year in duration, are lacking.

Acupuncture is often used for migraine prevention but its effectiveness is still controversial. We present an update of our Cochrane review from 2009.

To investigate whether acupuncture is a) more effective than no prophylactic treatment/routine care only; b) more effective than sham (placebo) acupuncture; and c) as effective as prophylactic treatment with drugs in reducing headache frequency in adults with episodic migraine.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL: 2016, issue 1); MEDLINE (via Ovid, 2008 to January 2016); Ovid EMBASE (2008 to January 2016); and Ovid AMED (1985 to January 2016). We checked PubMed for recent publications to April 2016. We searched the World Health Organization (WHO) Clinical Trials Registry Platform to February 2016 for ongoing and unpublished trials.

We included randomized trials at least eight weeks in duration that compared an acupuncture intervention with a no-acupuncture control (no prophylactic treatment or routine care only), a sham-acupuncture intervention, or prophylactic drug in participants with episodic migraine.

Two reviewers checked eligibility; extracted information on participants, interventions, methods and results, and assessed risk of bias and quality of the acupuncture intervention. The primary outcome was migraine frequency (preferably migraine days, attacks or headache days if migraine days not measured/reported) after treatment and at follow-up. The secondary outcome was response (at least 50% frequency reduction). Safety outcomes were number of participants dropping out due to adverse effects and number of participants reporting at least one adverse effect. We calculated pooled effect size estimates using a fixed-effect model. We assessed the evidence using GRADE and created 'Summary of findings' tables.

Twenty-two trials including 4985 participants in total (median 71, range 30 to 1715) met our updated selection criteria. We excluded five previously included trials from this update because they included people who had had migraine for less than 12 months, and included five new trials. Five trials had a no-acupuncture control group (either treatment of attacks only or non-regulated routine care), 15 a sham-acupuncture control group, and five a comparator group receiving prophylactic drug treatment. In comparisons with no-acupuncture control groups and groups receiving prophylactic drug treatment, there was risk of performance and detection bias as blinding was not possible. Overall the quality of the evidence was moderate.

Comparison with no acupuncture

Acupuncture was associated with a moderate reduction of headache frequency over no acupuncture after treatment (four trials, 2199 participants; standardised mean difference (SMD) -0.56; 95% CI -0.65 to -0.48); findings were statistically heterogeneous (I² = 57%; moderate quality evidence). After treatment headache frequency at least halved in 41% of participants receiving acupuncture and 17% receiving no acupuncture (pooled risk ratio (RR) 2.40; 95% CI 2.08 to 2.76; 4 studies, 2519 participants) with a corresponding number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 6); there was no indication of statistical heterogeneity (I² = 7%; moderate quality evidence). The only trial with post-treatment follow-up found a small but significant benefit 12 months after randomisation (RR 2.16; 95% CI 1.35 to 3.45; NNT 7; 95% 4 to 25; 377 participants, low quality evidence).

Comparison with sham acupuncture

Both after treatment (12 trials, 1646 participants) and at follow-up (10 trials, 1534 participants), acupuncture was associated with a small but statistically significant frequency reduction over sham (moderate quality evidence). The SMD was -0.18 (95% CI -0.28 to -0.08; I² = 47%) after treatment and -0.19 (95% CI -0.30 to -0.09; I² = 59%) at follow-up. After treatment headache frequency at least halved in 50% of participants receiving true acupuncture and 41% receiving sham acupuncture (pooled RR 1.23, 95% CI 1.11 to 1.36; I² = 48%; 14 trials, 1825 participants) and at follow-up in 53% and 42%, respectively (pooled RR 1.25, 95% CI 1.13 to 1.39; I² = 61%; 11 trials, 1683 participants; moderate quality evidence). The corresponding NNTBs are 11 (95% CI 7.00 to 20.00) and 10 (95% CI 6.00 to 18.00), respectively. The number of participants dropping out due to adverse effects (odds ratio (OR) 2.84; 95% CI 0.43 to 18.71; 7 trials, 931 participants; low quality evidence) and the number of participants reporting adverse effects (OR 1.15; 95% CI 0.85 to 1.56; 4 trials, 1414 participants; moderate quality evidence) did not differ significantly between acupuncture and sham groups.

Comparison with prophylactic drug treatment

Acupuncture reduced migraine frequency significantly more than drug prophylaxis after treatment ( SMD -0.25; 95% CI -0.39 to -0.10; 3 trials, 739 participants), but the significance was not maintained at follow-up (SMD -0.13; 95% CI -0.28 to 0.01; 3 trials, 744 participants; moderate quality evidence). After three months headache frequency at least halved in 57% of participants receiving acupuncture and 46% receiving prophylactic drugs (pooled RR 1.24; 95% CI 1.08 to 1.44) and after six months in 59% and 54%, respectively (pooled RR 1.11; 95% CI 0.97 to 1.26; moderate quality evidence). Findings were consistent among trials with I² being 0% in all analyses. Trial participants receiving acupuncture were less likely to drop out due to adverse effects (OR 0.27; 95% CI 0.08 to 0.86; 4 trials, 451 participants) and to report adverse effects (OR 0.25; 95% CI 0.10 to 0.62; 5 trials 931 participants) than participants receiving prophylactic drugs (moderate quality evidence).

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Cochrane Training

Chapter iv: updating a review.

Miranda Cumpston and Ella Flemyng

Key Points:

• As new studies are completed, the results of reviews may become out of date and thereby provide misleading information to decision makers.
• Cochrane Reviews should be assessed periodically to determine whether an update is needed. The decision to update should be based on the continuing importance of the review question to decision makers and the availability of new data or new methods that would have a meaningful impact on the review findings.
• A review update provides an opportunity for the scope, eligibility criteria and methods used in the review to be revised.
• An update should be conducted according to the standards required for any review, with some additional requirements to ensure that any changes are managed appropriately and reported clearly to readers.

This chapter should be cited as: Cumpston M, Flemyng E. Chapter IV: Updating a review. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023. Available from www.training.cochrane.org/handbook .

IV.1 Introduction

Since its inception, Cochrane has sought to maintain its reviews to ensure they are updated to include the most recent evidence. Reviews that are out of date and do not incorporate all the available evidence risk providing misleading information to decision makers and other stakeholders.

Garner and colleagues define an update as “a new edition of a published systematic review with changes that can include new data, new methods, or new analyses to the previous edition” (Garner et al 2016). Adding new studies and new data can substantively change the findings of the review. Even where the new studies observe results consistent with the existing data, increasing the number of studies can improve precision of effect estimates, demonstrate wider applicability of the effect, or enable additional comparisons or subgroup analyses to be performed. The introduction of new review methods, such as updated risk of bias assessment tools or improved statistical analysis methods, can also change both the results and the certainty of the review’s findings. Examples of the impact of incorporating new information and methods are illustrated in Box IV.1.a .

All Cochrane Reviews should be assessed periodically to determine whether an update is needed. Some areas of research evolve rapidly, whereas others are more stable, and some research questions stop being relevant to decision makers. A report assessing 100 systematic reviews published between 1995 and 2005 concluded the median time to require an update was 5.5 years, although 23% of reviews were out of date within two years, 15% within one year, and 7% were already out of date at the time of publication (Shojania et al 2007). Authors of Cochrane Reviews should therefore consider both whether an update is warranted, and when it will be most beneficial for each specific review (see Section IV.2 ).

In some areas, authors are establishing ‘living’ systematic reviews that adopt a continual updating process, such as monthly searching followed by rapid incorporation of new evidence into the published review. Living systematic reviews are most likely to be appropriate for questions that are of high importance to decision makers, and for which new evidence is likely to be frequently published and to have an important impact on the review’s findings (Elliott et al 2017). Considerable resources are required to support such an ongoing process. Further discussion of living systematic reviews is presented in Chapter 22, Section 22.2.3 .

Cochrane’s Methodological Expectations of Cochrane Intervention Reviews (MECIR) , which guide the conduct of Cochrane Reviews, include expectations for updating reviews. See the online MECIR Manual for the 11 expectations specifically relevant to updates, although updated reviews should also meet the expectations that apply to all reviews. This chapter elaborates on the recommendations for the planning, conduct and reporting of Cochrane Review updates.

Box IV.1.a Examples of what factors might change in an updated systematic review (Garner et al 2016). Reproduced from Garner P, Hopewell S, Chandler J, MacLehose H, Akl EA, Beyene J, et al. When and how to update systematic reviews: consensus and checklist. BMJ 2016; 354: i3507 licensed under CC BY 3.0 .

IV.2 Deciding whether and when to update

The decision to undertake an update of a review requires consideration of a number of different factors. Garner and colleagues conducted an international consensus process to establish good practice guidance for determining when a systematic review should be updated (Garner et al 2016). Their published framework and checklist can assist authors in thinking through these issues in a structured way (see Figure IV.2.a ).

Figure IV.2.a Decision framework to assess systematic reviews for updating, with standard terms to report such decisions (Garner et al 2016). Reproduced from Garner P, Hopewell S, Chandler J, MacLehose H, Akl EA, Beyene J, et al. When and how to update systematic reviews: consensus and checklist. BMJ 2016; 354: i3507 licensed under CC BY 3.0 .

When deciding whether to update a particular review, the first consideration should be to determine whether the review question remains relevant to decision makers, and is well-targeted to answer current questions in policy and practice. Knowledge of the particular field will be required to answer this question. Checking whether the existing review is frequently accessed or cited can also be useful to indicate whether there is a need to update. A second aspect to this question is whether the original review was conducted well and used appropriate methods (Garner et al 2016). If the review question remains fundamentally of interest, additions and improvements may be possible to enhance the review’s methods (see Section IV.3.4 ). Depending on the changes required, it may be more appropriate to conduct a new review from scratch meeting current standards. A comparison between currently recommended methods and the methods used in the review can identify any important changes required.

If the review remains important and is of a sufficient standard, then the next step is to consider whether there are any new studies, newly available information, or newly recommended methods that could be incorporated into the review. The existing version of the review may include details of ongoing studies identified at the time of its publication, for example through searches of trials registers, and these trials may now be complete. Some authors may choose to monitor the literature continually for new studies (e.g. through automated alerts), or may conduct a rapid scoping search for this purpose.

If either new information or new methodology is available, a critical next step is to evaluate whether incorporating these into the review would be likely to impact on its findings (Garner et al 2016). In some cases, this decision can be very straightforward, for example when the existing reviews findings are considered very uncertain (for example, using the GRADE approach to assessment, see Chapter 14 ). For some reviews, the findings are of very high certainty, and it is unlikely that new information will meaningfully impact the conclusions. In some cases, maintaining credibility through the incorporation of additional information and new methods is sufficient in itself to warrant updating (Garner et al 2016).

In some cases, although the main findings of the review may be unaffected, additional information may shed light on more nuanced effects of different variations on the intervention, different settings, additional outcomes, or population subgroups. In other cases, it may not be clear whether the extent of new information available will be enough to impact meaningfully on the results (Garner et al 2016).

To date there is no consensus on when to update a review (Tsertsvadze et al 2011), although several methods have been proposed (e.g. Sampson et al (2008), Shekelle et al (2011), Tovey et al (2011), Ahmadzai et al (2013), Takwoingi et al (2013)). These methods use signals to indicate the need for an update and the likely impact of new studies on existing conclusions. They include surveillance searches, contact with experts, and quantitative or qualitative assessments, or both. Chapter 22, Section 22.2 , outlines a range of methods for surveillance of the literature and the interpretation of signals for updating, including statistical methods based on sample size calculations or the application of prediction equations to assess the impact of new evidence. Garner and colleagues also summarize a series of available methods (Garner et al 2016). Ultimately, review authors should make a judgement based on an individual assessment and their knowledge of the field covered by the review.

IV.3 Planning an update

Before embarking on an updated review, it is important to take the time to plan the process. Any proposed modifications or additions to the existing review should be planned in detail, and on occasion may require drafting a new protocol for the review. In addition, there are several issues unique to updates that should be considered.

Many of the approaches using new technologies designed to facilitate the review process are intended to support easier and more frequent updates. Further information is available in Chapter 4 , Section 4.6.6 , and Chapter 22 , Section 22.2.4 .

See the online MECIR Manual for expectations relevant to planning an update.

IV.3.1 Reconsidering review questions and eligibility criteria

Even when the overall review question has been agreed to remain relevant, an update is an opportunity to consider changes to the question and its scope. Authors should reconsider all elements of the review question (PICO), the eligibility criteria, comparisons and outcomes of interest. For example, evolving understanding of the problem may lead to the inclusion of a new comparison, an additional category of patients (e.g. children in addition to adults) or an important new outcome (e.g. adverse effects) that may not have been adequately addressed in the original review. Review authors may also wish to include additional objectives, such as addressing the economic aspects of the intervention or its implementation. Additional engagement with stakeholders may reveal current issues around which there is uncertainty (see Chapter 2 ).

Irrespective of whether the review question(s) change, there may be reason to amend the eligibility criteria for the review (see Chapter 3 ). For example, new intervention options may have become available since the publication of the original review. As the number of available studies increases over time, this may also affect decisions about eligibility. For example, if the original review included both randomized trials and non-randomized studies, and the former provide sufficient evidence to answer the review questions, it may be reasonable to decide to exclude non-randomized studies from subsequent updates of the review. Conversely, it may be reasonable to add non-randomized studies to a review that was previously restricted to randomized trials, to widen the evidence base, making use of methodological developments in critical evaluation of the validity of non-randomized studies (see Chapter 24 ).

IV.3.2 Splitting and merging reviews

As the body of evidence accumulates over time, a review may become too large for authors to manage (some of the largest Cochrane Reviews include hundreds of studies across multiple comparisons). It is sometimes appropriate to consider splitting the review into two or more reviews with more narrowly defined questions. For example, an early Cochrane Review investigated all interventions for shoulder pain. As this review became large and unwieldy over time, it was split into multiple separate reviews, each looking at an intervention category. One of these reviews looked at physiotherapy interventions for shoulder pain (Green et al 2003). As time went on, this review also became too large to manage, and was split into a number of reviews examining different physiotherapy interventions and specific types of shoulder pain (e.g. Page et al (2014a), Page et al (2014b), Page et al (2016a), Page et al (2016b)).

Narrower reviews may allow deeper investigation of specific intervention types, and more focused information for stakeholders, and may distribute the updating burden between several review author teams. On the other hand, narrower reviews can sometimes prevent readers from considering findings across all the interventions relevant to a decision (see Chapter 2, Section 2.3 ). Overviews of Reviews are an alternative option, allowing authors to summarize several more narrowly defined reviews that may have been split from a larger review (see Chapter V ).

It is also possible for one or more narrower Cochrane Reviews to be merged into a larger review, where agreed by all authors that this would present a more useful synthesis for decision makers. For example, it might be concluded that a network meta-analysis to compare multiple intervention options for a particular condition would be more useful than an existing series of separate reviews of specific interventions (see Chapter 11 ).

IV.3.3 Planning the search strategy for an update

Once the scope and eligibility criteria for the update have been agreed, authors will prepare for an update by deciding on the appropriate search process and strategy.

A starting point for identifying new studies for inclusion may be those already identified as ongoing studies at the time of the existing version of the review. Following this, in some cases, the search strategy can be re-run as specified in the existing review, with the addition of date limits set to the period following the most recent search. However, an information specialist or healthcare librarian should be consulted to ensure the strategy remains appropriate. Changes to electronic databases, their access mechanisms and controlled vocabulary can require expert amendments to the search strategies. In addition, informed by the experience of the search for the original review, a decision may be made to modify the list of sources to be searched or search terms to be used (Garner et al 2016).

If important changes to the PICO for the review or the eligibility criteria have been made since the original search, or developments in the field have led to the emergence of new terms to be added to the search, it may be necessary to re-run parts of the search back to the earliest records, to ensure that any records relevant to new search terms were not missed in the original search.

IV.3.4 Planning the methods for an update

Methodological advances in systematic review conduct since publication of the original review may result in a need to revise or extend the methods of the review update (Shea et al 2006). Authors are encouraged to consult current guidance on review methods and compare these with the methods used in the existing review to identify important changes.

Examples of situations in which review methodology might be updated include:

• incorporating updated guidance on risk of bias assessment (see Chapter 7 and Chapter 8 );
• using a new synthesis strategy, such as an improved method to perform a random-effects meta-analysis (see Chapter 10 ), or alternative methods for synthesis where meta-analysis is not possible (see Chapter 12 ).
• incorporating GRADE assessments and ‘Summary of findings’ tables if not already included (see Chapter 14 ); and
• adopting new guidance on the structure and presentation of findings, such as structured tabulation of results or alternative methods for visual presentation of results in reviews where meta-analysis is not used (see Chapter 12 ).

Changes to the scope of the review, such as expansion to include different study designs or outcome data, will require planning for new methods appropriate to the data expected.

Where changes to the review methods are substantive, authors are encouraged to write a complete, updated protocol to guide the conduct of the review update . In some cases, it may be more appropriate to consider the work as a new review, rather than an update.

Specific methods developed for systematic reviews that conduct ongoing and prospective approaches to accumulating evidence to maintain review currency are outlined in Chapter 22 . Formal sequential statistical methods that aim to address errors associated with repeating meta-analyses over time have been developed. However, such approaches are explicitly discouraged for updated meta-analyses in Cochrane Reviews, except in the context of a prospectively planned series of primary research studies (see Chapter 22, Section 22.4 ).

IV.3.5 Incorporating feedback and comments

Updating a published review provides an opportunity to consider any feedback or comments submitted to Cochrane or directly to the authors. Review authors are expected to be responsive to comments on their reviews, in the spirit of the scientific process and publication ethics. Comments may represent valid concerns and can usefully identify additional studies that were overlooked by the review authors.

IV.4 Conducting an update

An update of a review should be conducted according to the protocol, as closely as possible to the methods of the existing review while incorporating any planned changes (see Section IV.3 ). All steps should be conducted in accordance with the guidance presented throughout this Handbook .

A systematic search should be conducted for new studies (see Chapter 4 ), and the date of the search should be within 12 months of publication of the update. If new, potentially relevant studies are found, they should be assessed for inclusion in the review according to the eligibility criteria. If the existing review included records of any ongoing studies that are now complete, or studies for which classification as included or excluded was pending, newly available information should be sought and, where possible, final inclusion decisions made.

If new studies are to be included in the updated review, data should be collected (see Chapter 5 ) and risk of bias assessments completed for all new studies (see Chapter 7 ). On a practical note, when changes have been made to the scope or PICO of the review, tools such as the original data collection forms may need to be altered or extended and piloted again to ensure they are fit for purpose. This may also be needed if new software tools are to be used for data collection, or if a new author team has taken on the review, although existing templates and forms may be available from the original review authors or repositories such as the Systematic Review Data Repository ( https://srdr.ahrq.gov/ ).

The findings of any new studies should be integrated into the synthesis of the review (see Chapter 10 , Chapter 11 , and Chapter 12 ), and GRADE assessments completed (or revised), taking full account of the new body of evidence (see Chapter 14 ).

If no new studies are found to be included in the review, authors should complete and publish the updated review (see Section IV.5 ). While not modifying the findings, including the details of an updated search will reassure readers and decision makers of the currency of the review.

See the online MECIR Manual for expectations relevant to conducting an update.

IV.4.1 Updating data from previously included studies

Since the time of publication, additional information may be available about one or more studies included in the existing review. For example, additional outcome data measured at later time points may now be available, or the study may have been corrected or retracted due to errors, fraud or a range of other reasons. It is important to search online journals or databases such as MEDLINE (if the study is indexed there) for any notifications, corrections or retractions.

Any additions or corrections should be incorporated into the information contained in the review, if relevant. The reasons for retraction of any included studies should be considered. In addition to the publication record, this information may be available in reports of investigations, such as by the authors’ institutions or funders. In those cases where data appear to be incorrect or possibly fabricated, they should be removed from the review analysis and this decision should be reported in the review. Other studies by the same author(s) which would also be eligible for inclusion should be checked for similar issues, and a decision made as to whether they should similarly be removed. Further guidance on identifying corrected or retracted studies is provided in Chapter 4, section 4.4.6 , and in the Cochrane policy for managing potentially problematic studies .

If a new comparison or a new outcome has been added to the review, it may be necessary to go back to the original included studies and check whether they included any information not previously collected that would be relevant to the update.

IV.5 Reporting an updated review

An updated review should meet the same standards of reporting as any review (see Chapter III ), while ensuring that all updated information and changes made to the scope and methods of the review are reported clearly. The details of any changes, including justifications for the decisions made, can be briefly documented at the beginning of the Methods section of the review and elaborated on additional supplementary material if they are significant. Authors should clearly alert readers that this is an update of an earlier version, including statements in the Abstract, Background and Protocol and registration sections of the review.

Appearing at the beginning of the review, the Background section is not directly impacted by an update, but authors may wish to review the content of the Background to ensure that it remains fit for purpose. Discussions of the prevalence or incidence of a condition, new insights into the mechanism of action or impact on populations, or descriptions of current practice or policy options may be updated. Up-to-date references should be supplied to support this information. Any references to time, such as words like ‘recently’ or ‘in the next five years’, should be amended or, if possible, removed.

Reporting the details of the updated search alongside the search information in the existing review can become quite complex, especially if there have been several updates to the review over time. Detailed information on search strategies will be reported in Cochrane Reviews as supplementary material, so does not need to be described at length in the text of the review. There are several approaches to reporting the results of an updated search:

1. An integrated approach describes all searches together, which may be most feasible if the same search was repeated.

2. An incremental approach adds information at each update to describe explicitly which searches were done for the update, retaining all information about previous searches.

3. A replacement approach describes only the searches done for the update, using the previous review as one source of studies.

If any of the sources originally searched were not searched for the update, this should be explained and justified.

The updated search should also be presented in a PRISMA-type flow diagram (see Chapter 4, Section 4.5 ). Again, there are options as to how to present the results of multiple searches coherently in the diagram. Authors can retain the results of previous searches in the review and supplement with information about studies identified in the update or, alternatively, present only information about searches in the current update, with the previous version of the review serving as one particular source of studies. If taking the latter approach, the flow diagram should show one box for the number of studies included in the original review or previous update and an additional box for the new studies retrieved for the current update. If multiple searches have been conducted for the current update, the results of all the searches should be added together. It may be helpful to consider the clarity of the diagram as a summary for readers when selecting an approach.

The methods and results described throughout the review and its summaries (including the ‘Summary of findings’ table, Abstract and Plain Language Summaries) should be checked to ensure they still reflect the methods used accurately. Where the review is considered a ‘living’ systematic review, and regular updates are planned, additional methods should be included to describe the timing and nature of this process (see Chapter 22, Section 22.2 ).

The extent of revision to the Results of the review will depend on the influence of the new data on the results of the review. Examples include:

• the addition of small studies bringing about no change in the results or conclusions of the review (and so requiring very little revision of the text);
• increased certainty of pre-existing results and conclusions (requiring some modification of the text); and
• a change in the conclusion of a review (requiring a major rewrite of the Results, Discussion, Conclusion, ‘Summary of findings’ table, Abstract and Plain Language Summary).

When reporting the results, it is more helpful to readers to present an integrated picture of the overall results, rather than sequential or separate results for the update (especially where there has been more than one update), although any particularly notable changes to the review’s conclusions may be of interest to discuss when interpreting the results.

Authors should check that nothing else in the review requires editing, such as references to other Cochrane Reviews that may have been updated, or additions to the Acknowledgements. The ‘Declarations of interest’ sections of the review should be updated.

Finally, to inform returning readers, authors should summarize key changes in the ‘What’s new’ section. This should include the number of new studies and participants in those studies, and the nature of any changes in findings, the certainty of the evidence (e.g. using GRADE) and in the implications for practice.

IV.5.1 Changes in authorship

If there is a change in the authorship of the review, such as new authors joining the team, or an entirely new team of authors updating the review, the by-line (list of authors) may need to be changed. The decision regarding who is named in the by-line of an updated review, and in what order, should be assessed in terms of contributions to content in the updated version of the review (which will include historical content), and responsibility for approving the final content of the manuscript. If an author is no longer actively contributing to or involved in the approval of an updated review, the author should not be listed in the by-line of the new version and should be named in the Acknowledgements section. In addition, the contributions of all authors to both the update and earlier versions of the review should be described in the ‘Contributions of authors’ section.

See Cochrane’s policy on authorship and contributorship for Cochrane Reviews for more information.

IV.6 Chapter information

Authors: Miranda Cumpston and Ella Flemyng

Acknowledgements : This chapter builds on earlier versions of the Handbook . Contributors to earlier versions include Jacqueline Chandler, Julian Higgins, Rachel Marshall, Ruth Foxlee and members of the former Updating Working Group (Mike Clarke, Mark Davies, Davina Ghersi, Sally Green, Sonja Henderson, Harriet MacLehose, Jessie McGowan, David Moher, Rob Scholten (convenor) and Phil Wiffen). David Tovey, Carol Lefebvre and Sally Hopewell provided comments on earlier versions. Rachel Marshall re-drafted version 5.1 on which this version was based with input from Harriet MacLehose. Mona Nasser contributed to section IV.2.1. Rachel Churchill contributed to the re-structuring of this version. The work of Garner and colleagues (Garner et al 2016), a key reference used throughout, was based on a consensus meeting of experts funded by Cochrane.

IV.7 References

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• Published: 23 February 2018

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Summaries of Cochrane Systematic Reviews: making high-quality evidence accessible

• L. A. Harvey 1  

Spinal Cord volume  56 ,  page 185 ( 2018 ) Cite this article

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It is useful to summarise Cochrane Systematic Reviews because Cochrane Systematic Reviews can be technical, lengthy and difficult to read—some are over 100 pages long. In addition, evidence of the effects of the treatment options for a problem such as pressure ulcers are dispersed across many different reviews. For these reasons, summaries of related Cochrane Systematic Reviews are becoming increasingly popular. The Cochrane Handbook contains a chapter devoted to this topic titled—“Overviews of Reviews” [ 2 ]. These types of summaries of systematic reviews are also called “Umbrella Reviews” [ 3 ].

Cochrane Systematic Reviews are generally considered reliable summaries of the evidence. They have earnt this badge of honour because The Cochrane Collaboration has developed stringent methodologies to reduce bias and ensure trustworthy interpretation of the evidence. The level of evidence for a treatment is rated using the GRADE methodology which takes into account more than merely whether the evidence comes from a clinical trial which reports a few significant p values [ 4 ]. A typical Cochrane Systematic Review is preceded by a detailed protocol. Both the protocol and the review undergo meticulous scrutiny by methodological experts. In addition, authors of Cochrane Systematic Reviews are provided with training and support.

Often Cochrane Systematic Reviews span several conditions—they do not solely focus on one pathology. For example the Cochrane Systematic Reviews on management of pressure ulcers include treatment options for people who are elderly, in a coma, as well as people with SCI. There are advantages and disadvantages to including people with different pathologies in one review. The obvious advantage is the increase in the pool and quality of available data. The disadvantage is that treatments that are applicable and effective for one group of patients may not be so for another group of patients. However, a lot of what clinicians do and have accepted as normal practice in SCI is based on what we know about the response of people without SCI to various interventions and care.

Despite the obvious need to look further afield there is still a tendency to ignore what is known from studies conducted on people who do not have SCI, and rely solely on the results of studies involving people with SCI. This may be a mistake, particularly for those interventions that have only been tested on people with SCI in studies that are highly vulnerable to bias. In some situations, we may do better to look at higher quality evidence involving non-SCI populations. The limitations of relying on non-SCI-specific evidence can be captured in the Cochrane GRADE system for evaluating evidence by downgrading evidence for “indirectness” [ 5 ].

With this vision for the future, I welcome the current paper which summarises Cochrane Systematic Reviews and other types of reviews which deal with pressure ulcer management. It draws our attention to what is known about pressure ulcer management from patients with a range of pathologies and emphasises the need for more SCI-specific research on this important topic.

Atkinson RA, Cullum NA. Interventions for pressure ulcers: a summary of evidence for prevention and treatment. Spinal Cord. 2018;56:186–98.

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Harvey, L.A. Summaries of Cochrane Systematic Reviews: making high-quality evidence accessible. Spinal Cord 56 , 185 (2018). https://doi.org/10.1038/s41393-018-0071-5

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WHAT IS A COCHRANE REVIEW?

Pamela c. sieving.

Informationist, National Institutes of Health Library, Bethesda, MD, USA

In this era of evidence-based practice, it is important for nurses in all settings to understand and have access to high-quality systematic reviews of published evidence. This paper introduces a premier resource, the Cochrane Collaboration, and reviews mechanisms for accessing its published systematic reviews from any practice setting.

The international non-profit Cochrane Collaboration promotes and disseminates information on healthcare interventions. The Collaboration’s major product is a database of systematic reviews. Reviewers systematically search for all evidence related to clinical questions; reports of randomized controlled trials involving human subjects are critically evaluated to enable the reader to quickly determine if the findings apply to a particular patient. Reviews have included such topics as:

• Nursing interventions for smoking cessation
• Continuous positive airway pressure delivery interfaces for obstructive sleep apnoea
• The timing of tracheotomy
• Antibiotics to reduce post-tonsillectomy pain and morbidity
• Antibiotics for the prevention of acute and chronic suppurative otitis media in children

Cochrane also produces general reviews of such organizational, educational, and administrative questions as:

• Organisational infrastructures to promote evidence-based nursing practice
• Communication skills training for healthcare professionals working with cancer patients, their families and/or carers
• Interventions to promote collaboration between nurses and doctors

There are also reviews on topics of a broader health intervention nature:

• Powered toothbrushes for oral health
• Red-light cameras for the prevention of road traffic crashes

The first step in a Cochrane review is the registration of the proposed topic followed by the creation and approval of a protocol for the review. A review protocol is similar to a protocol for a clinical research project. Protocols are published to elicit commentary and input by other researchers. The published reviews, which are regularly reviewed and updated, appear in the Cochrane Library , and are indexed by Medline (PubMed), CINAHL, Web of Knowledge, Scopus, and other indexing services.

Academic and medical libraries may make Cochrane reviews available by a subscription to the Cochrane Library from Wiley InterScience, with access online or on quarterly CD-Rom discs, or in a suite of evidence-based medicine products, Evidence-Based Medicine Reviews , from Ovid. Individuals, clinics, and private offices may also subscribe to the Cochrane Library or acquire copies of individual reviews on a pay-per-use basis from Wiley. The Cochrane Library is free in some countries, including developing countries, and throughout Central and Latin America and the Caribbean. Subscription costs vary, but start at $285 per year USD for an individual subscription. Pay-per-view is $25 per article USD. Individual reviews are also available via standard interlibrary loan procedures through public, academic and medical libraries.

For Further information: The Cochrane Collaboration Website: www.cochrane.org

The U.S. Cochrane Center Website: www.cochrane.us .

Cochrane Methods

2016 cochrane methods symposium living systematic reviews.

Living Systematic Reviews are systematic reviews that are continually updated, incorporating new, relevant data as it becomes available. 1 By retaining currency, and maintaining methodological rigor, they offer a tantalising opportunity to realise the original vision for Cochrane, to ‘include a library of trial overviews which will be updated when new data become available’. 2

A number of Living Systematic Review approaches are being piloted internationally and Cochrane is at the forefront of these efforts. Living systematic reviews differ from traditional systematic reviews in several ways that have important implications for review methods and processes, affecting authors, editors and publishers. 

The purpose of this Methods Symposium was to introduce the concept of Living Systematic Reviews and when it might be appropriate to do them, and to present work to date on the methodological, production and publication implications and enablers of Living Systematic Reviews. After a series of presentations on these topics, we described the proposed model for the Cochrane Living Systematic Review pilots that are currently underway and the possible intersections of this work with living guidelines.

A list of the speakers, with a brief description of their presentation, and a link to their slides, is available . If you would like any further information, please contact Annie Synnot .

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• ROB-ME: a tool for...

ROB-ME: a tool for assessing risk of bias due to missing evidence in systematic reviews with meta-analysis

Linked editorial.

Will the ROB-ME checklist prevent omission bias in meta-analyses?

• Related content
• Peer review
• Matthew J Page , senior research fellow 1 ,
• Jonathan A C Sterne , professor 2 3 4 ,
• Isabelle Boutron , professor 5 ,
• Asbjørn Hróbjartsson , professor 6 7 ,
• Jamie J Kirkham , professor 8 ,
• Tianjing Li , associate professor 9 ,
• Andreas Lundh , associate professor 6 7 10 ,
• Evan Mayo-Wilson , associate professor 11 ,
• Joanne E McKenzie , professor 1 ,
• Lesley A Stewart , professor 12 ,
• Alex J Sutton , professor 13 ,
• Lisa Bero , professor 14 ,
• Adam G Dunn , professor 15 ,
• Kerry Dwan , senior lecturer 16 ,
• Roy G Elbers , senior researcher 17 ,
• Raju Kanukula , doctoral student 1 ,
• Joerg J Meerpohl , professor 18 19 ,
• Erick H Turner , professor 20 21 ,
• Julian P T Higgins , professor 2 3
• 1 Methods in Evidence Synthesis Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia
• 2 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
• 3 National Institute for Health and Care Research Bristol Biomedical Research Centre, Bristol, UK
• 4 Health Data Research UK South-West, Bristol, UK
• 5 Université de Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Paris, France
• 6 Centre for Evidence-Based Medicine Odense and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
• 7 Open Patient data Exploratory Network, Odense University Hospital, Odense, Denmark
• 8 Centre for Biostatistics, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
• 9 Department of Ophthalmology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
• 10 Department of Respiratory Medicine and Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
• 11 Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA
• 12 Centre for Reviews and Dissemination, University of York, York, UK
• 13 Department of Population Health Sciences, University of Leicester, Leicester, UK
• 14 Center for Bioethics and Humanities, University of Colorado, Aurora, CO, USA
• 15 Biomedical Informatics and Digital Health, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia
• 16 Liverpool School of Tropical Medicine, Liverpool, UK
• 17 Department of General Practice, Intellectual Disability Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, Netherlands
• 18 Institute for Evidence in Medicine, Medical Centre and Faculty of Medicine, University of Freiburg, Freiburg, Germany
• 19 Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany
• 20 Department of Psychiatry, Oregon Health and Science University, Portland, OR, USA
• 21 Behavioral Health and Neurosciences Division, Veterans Affairs Portland Health Care System, Portland, OR, USA
• Correspondence to: M Page matthew.page{at}monash.edu
• Accepted 13 September 2023

Various methods are available to help users assess whether selective non-publication of studies or selective non-reporting of study results has occurred, but not its impact on a meta-analysis. This limitation of existing methods leaves users to decide their own approach for judging the risk of bias in a meta-analysis result. In this paper, Page and colleagues describe the ROB-ME (risk of bias due to missing evidence) tool, a structured approach for assessing the risk of bias that arises when entire studies, or particular results within studies, are missing from a meta-analysis because of the P value, magnitude, or direction of the study results. The tool is anticipated to help authors and users of systematic reviews identify meta-analyses at high risk of bias and interpret results appropriately.

A key feature of systematic reviews of quantitative research is the attempt to identify all studies that meet the review inclusion criteria and to include relevant data from all such studies in meta-analyses. This goal is compromised when reporting of primary studies is influenced by the P value, magnitude, or direction of study results. 1 These factors might influence whether a study is published at all (selective non-publication of studies or publication bias), 2 3 the speed at which a study report is published (time lag bias), 4 or type of journal (indexed or not) in which a study report is published (location bias), 5 each of which can lead to studies missing from meta-analyses. The P value, magnitude, or direction of the study results might also influence whether, or how completely, particular results are reported (selective non-reporting of study results or outcome reporting bias), 6 leading to results missing from meta-analyses even when the study has been identified. The term “reporting bias” has often been used to describe such selective dissemination of evidence, but here we use the term “non-reporting bias” to emphasise the non-availability of evidence. 7

We present some examples of non-reporting bias to explain the concepts above. Suppose that after conducting a randomised trial comparing glucocorticoid injection with placebo for shoulder pain, investigators find higher shoulder strength in participants receiving glucocorticoid injections, but find no difference in pain intensity and function between groups. The investigators might never submit a study report for publication, because the observed results conflict with their prior hypotheses about the benefits of glucocorticoid injection, or because they assume that journal editors will not be interested in publishing the paper. This example demonstrates selective non-publication of studies (ie, publication bias). Alternatively, suppose that a study report is published but results for pain intensity and function are omitted entirely or presented incompletely; for example, a statement that pain and function scores were “not different between groups,” without summary statistics, effect estimates, or measures of precision. This example demonstrates selective non-reporting of study results (ie, outcome reporting bias).

A meta-analysis result will be biased when the available evidence (from studies or results) differs systematically from the missing evidence. However, existing methods have limited ability to determine which meta-analyses are at risk of bias due to missing evidence. 8 9 For example, several tools have been developed to help users assess whether selective non-reporting of study results has occurred, but not its impact on a meta-analysis. Furthermore, current methods tend to focus on only one type of non-reporting bias (only selective non-publication of studies, or only selective non-reporting of study results). This limitation of existing methods leaves users to decide their own approach for combining the risks of each type of bias into an overall judgment of risk of bias in the meta-analysis result; likely leading to inconsistency in judgments. In this paper, we describe the ROB-ME (risk of bias due to missing evidence) tool, the first structured approach for assessing the risk of bias that arises when entire studies, or particular results within studies, are missing from a meta-analysis because of the P value, magnitude, or direction of the study results.

Summary points

The reporting of primary studies or results might be influenced by the P value, magnitude, or direction of the study results; this influence can lead to bias in a meta-analysis, because the available evidence (from studies or results) differs systematically from the missing evidence

Existing methods mostly help users assess whether selective non-publication of studies or selective non-reporting of study results has occurred, but not its impact on a meta-analysis, which leaves users to decide their own approach for combining the risks of each type of bias into an overall judgment of risk of bias in a meta-analysis result

The ROB-ME (risk of bias due to missing evidence) tool is a structured approach for assessing the risk of bias that arises when entire studies, or particular results within studies, are missing from a meta-analysis because of the P value, magnitude, or direction of the study results

The tool consists of three preliminary steps: select and define which meta-analyses will be assessed, determine which studies meeting the inclusion criteria for the meta-analyses have missing results, and consider the potential for missing studies across the review; these steps inform an assessment of risk of bias due to missing evidence in a particular meta-analysis result

The tool is anticipated to help authors and users of systematic reviews identify meta-analyses at high risk of bias and interpret results appropriately

Development of the ROB-ME tool

We followed the framework for developing risk of bias tools recommended by Whiting et al. 10 A core group (MJP, JACS, and JPTH) coordinated development of the tool, which included assembling the team of collaborators, preparing meeting materials, and leading the drafting and revising of the tool. Preliminary work to inform development of the tool included a cross sectional study of how selective non-reporting of study results was assessed in Cochrane reviews, 11 a systematic review of scales, checklists and domain based tools for assessing risk of non-reporting biases in studies and meta-analyses of studies, 8 and a non-systematic review of the empirical evidence of non-reporting biases. 5

Informed by the preliminary work, the core group developed an initial proposal for a new tool for assessing risk of bias due to missing evidence in a meta-analysis result and presented it at a development meeting in April 2017. Seventeen contributors with expertise in the empirical evidence of non-reporting biases, graphical and statistical approaches to assess non-reporting biases, and methods for identifying and accessing trial protocols, trials register entries, and information submitted to regulators (eg, clinical study reports) attended the meeting. Through a series of presentations and facilitated discussion sessions, meeting participants agreed on the scope, structure, and content to be addressed by the new tool and identified topics for further consideration.

Following the development meeting, the lead author (MJP) prepared initial drafts of the ROB-ME tool and discussed them with meeting participants via video conferences in August and November 2017. The core group developed the tool, the assessment framework underpinning it and accompanying guidance further between 2018 and 2020 while drafting a chapter on the topic for the 2019 edition of the Cochrane Handbook for Systematic Reviews of Interventions . 7 Additional edits were made in response to feedback received on a draft of the tool presented at the 2018 Cochrane Colloquium 12 and a draft was sent to all coauthors of this paper. A preliminary version of the tool (template and detailed guidance) was uploaded to https://www.riskofbias.info/ and presented in a webinar in October 2020, at which systematic reviewers were invited to provide feedback via a template form seeking views on each component of the tool. Twelve systematic reviewers subsequently provided written feedback via the template form or by commenting directly on the tool template; six had piloted the tool on a meta-analysis they were conducting before providing feedback. All systematic reviewers viewed the tool favourably, although some edits to the instructions and wording of questions (but not to the structure of the tool) were suggested. This written feedback, along with verbal feedback received from attendees of seven webinars delivered throughout 2021 and 2022 was considered by the core team, who revised the tool by amending the wording to improve clarity. The final version was sent to all coauthors for approval.

The ROB-ME tool

The full ROB-ME tool is available at https://www.riskofbias.info/ . Four worked examples of applying the tool are provided in appendices 1-4 of the supplement.

Terminology

Throughout this article, we use the phrase “study outcome” to refer to an outcome measurement collected on, or by, participants in a study; a measurement could be continuous or non-continuous (eg, a binary event or rate). We use the phrase “study result” to describe the combination of a point estimate and a measure of its precision (or the summary statistics required to calculate these) for a particular study outcome. 7 13 An example of a study outcome might be the pain at the end of eight weeks of treatment, measured using a 100 point visual analogue scale. A corresponding study result for this outcome might be an estimated difference in mean pain scores between intervention groups with 95% confidence interval.

Scope of the tool

The ROB-ME tool is designed for authors or users of systematic reviews to assess risk of bias due to missing evidence in a pairwise meta-analysis of the effect of interventions. It can be applied regardless of the number and types of studies with results available for inclusion in the meta-analysis, including in cases where only one of the studies identified has results available. The tool is not designed for assessing risk of bias due to missing evidence in a network meta-analysis; a tool for this purpose (ROB-MEN) is available and described elsewhere. 14

The ROB-ME tool is not intended to examine a related source of bias, which we describe as the risk of bias in selection of the reported result. This bias arises when an available study result was selected for reporting by the study authors from among multiple measurements or analyses, on the basis of the P value, magnitude, or direction of these multiple results. 15 For example, study investigators might measure pain using two measurement instruments, yet report results only for the instrument that yielded a significant effect estimate. In this circumstance, a study result is available for inclusion in a meta-analysis of pain scores, although the study result is at high risk of bias because of the way it was selected for reporting. Risk of bias in selection of the reported result is considered in tools designed to assess risk of bias in a study result (such as the RoB 2 tool for assessing risk of bias in randomised trials 15 and the ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions 16 ). By contrast, ROB-ME is used to assess risk of bias in a meta-analysis result and looks at the risk of bias arising from omission of results from one or more studies from the meta-analysis. ROB-ME is therefore not designed to replace the assessment of risk of bias in selection of the reported result in a study, and so users assessing that source of bias should continue to apply RoB 2 or ROBINS-I as appropriate, in addition to ROB-ME. Table 1 specifies which risk-of-bias tool to use when confronted with different reporting scenarios.

Tools needed to assess risk of bias in different reporting scenarios. Note that not all scenarios represent a high risk of bias

• View inline

How to conduct ROB-ME assessments

Application of the ROB-ME tool to a systematic review consists of four steps ( fig 1 ). Firstly, select and define which meta-analyses will be assessed for risk of bias due to missing evidence. Secondly, determine which studies meeting the inclusion criteria for the meta-analyses have missing results and thus cannot contribute to the meta-analyses. Thirdly, consider the potential for missing studies across the systematic review. And finally, assess risk of bias due to missing evidence in each meta-analysis.

Summary of the process of assessing risk of bias due to missing evidence in meta-analyses

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We recommend that the tool is completed by at least two users independently, with any discrepancies resolved via discussion, or adjudication from another user. We recommend that step 1 is conducted at the protocol stage, step 2 during data collection or when assessing risk of bias in the results of included studies, and steps 3 and 4 after generating meta-analysis results, but before assessing certainty in the body of evidence (eg, via GRADE (grading of recommendations assessment, development and evaluation) 17 ).

Planning the risk-of-bias assessment

Assessing risk of bias due to missing evidence in all meta-analyses in a systematic review might not be possible (eg, when resources are limited). In such cases, users should select which meta-analyses to assess for risk of bias based on which outcomes are most important for decision making (step 1). Such outcomes tend to be those selected for inclusion in summary of findings tables. 18 Ideally, users should prespecify the meta-analyses they intend to assess for risk of bias and indicate the population, intervention, comparator, and outcome (PICO) for each meta-analysis (ie, define the question that each meta-analysis aims to answer). 7 19 Users should also seek to define fully the types of studies and results that are eligible for inclusion in each meta-analysis to be assessed for risk of bias: doing so helps clarify which results are missing.

Evidence of selective non-reporting of results should then be gathered for each study that is eligible for inclusion in the meta-analyses selected for ROB-ME assessments (step 2). Users should start by assembling available sources of information about each eligible study. These sources might include the trials register entry (eg, at ClinicalTrials.gov), study protocol, statistical analysis plan, reports of results of the study (eg, journal article, clinical study report), or information obtained directly from the study authors or sponsor (eg, data files supplied). If study plans are available (eg, in a trials register entry, 20 study protocol, or statistical analysis plan), then details of prespecified outcomes should be compared with other sources of information about a study, such as a journal article presenting the main findings, to identify any outcomes without results available. Users might find it helpful to construct a matrix for each eligible study that lists all outcomes described in the study plans and records whether results were available for each. If no study plans are available, users can crosscheck the methods and results sections against one another to identify any outcomes with no results reported, or results reported incompletely (ie, without both a point estimate and measure of precision, or means of deriving these values).

Once users have identified that a study does not have a result available for inclusion in a meta-analysis, they should consider why the result is unavailable. Possible reasons include: the outcome was not measured at all by the study investigators; the outcome was measured but not analysed by study investigators (eg, due to a substantial amount of missing data); the outcome was measured and analysed but the result did not support the investigators’ hypothesis (eg, a non-significant result was observed in a superiority trial); or another reason that might or might not be related to the nature of the result ( box 1 ). Building on the ORBIT (outcome reporting bias in trials) approach, 6 we recommend that users of ROB-ME record in a matrix whether results were available for each study meeting the inclusion criteria for the meta-analyses, which lists each study in rows and each meta-analysis to be assessed for risk of bias in columns (see examples of completed matrices in the supplement). When completing the matrix, assessments of availability of results should be based on all the sources of information about a study obtained by users. Therefore, if harms results were not reported in a journal article but were provided by study authors on request, then ROB-ME users should specify in the matrix that they have a study result available for inclusion in the meta-analysis.

Possible scenarios in which study results are missing (adapted from Kirkham et al 6 )

Example scenarios where it is reasonable to suspect, given a lack of explanation from the study investigators, that a result is missing because of the p value, magnitude, or direction of the result.

Study authors report in the methods section, trials register entry, protocol, or elsewhere that they measured (or intended to measure) the outcome of interest, but results are missing for the outcome

All results for an outcome were non-significant and are reported incompletely (eg, described only as “results were not significant,” means were reported with no measure of precision, or change scores within the experimental group were reported but no data for the comparison group were presented), whereas results for other outcomes that were significant are reported completely

Results are missing for one of two outcomes that tend to be measured together (eg, results are available for cause specific mortality and are favourable to the experimental intervention, yet results for all cause mortality, which must have been assessed given that cause specific mortality was also assessed, are missing)

Study authors prespecified that they would report results separately for different outcomes (eg, myocardial infarction, stroke, hypertension) yet instead report results for a composite outcome (eg, cardiovascular events) that happens to be significant and favourable to the experimental intervention

Summary statistics (number of events, or mean scores) are available only globally across all groups (eg, study authors state that 10 of 100 participants in the study experienced adverse events, but do not report the number of events by intervention group)

A result is expected to have been generated for an outcome but it is not available and there is notable concern about the conflicts of interest of primary study investigators or funders involved in the analysis or reporting, which have likely influenced them to withhold results that are unfavourable to the intervention (an assessment using TACIT (tool for addressing conflicts of interest in trials) 21 for the study should facilitate this judgment).

Example scenarios where it is reasonable to assume that a result is missing for a reason unrelated to the P value, magnitude, or direction of the result

It is clear that the outcome of interest was not measured in the study based on examination of the study protocol or statistical analysis plan or correspondence with the authors and sponsors

It can be assumed that the outcome of interest was not measured in the study because the instrument or equipment needed to measure the outcome was not available at the time or location where the study was conducted

The outcome of interest was measured but data were not analysed at all owing to a reason unrelated to the nature of the results (eg, the measurement instrument had a fault, funding for the research team discontinued, study staff changed jobs)

Study authors state that results for all outcomes measured appear in an appendix, but the appendix has been removed (or was not uploaded) by mistake

Study authors report results in a format unsuitable for inclusion in a meta-analysis for a reason unrelated to the P value, magnitude, or direction of the result (eg, study investigators report median and (interquartile) range for a continuous outcome because the data were skewed)

Users of ROB-ME should then consider whether it is possible that some eligible studies, in addition to those considered in step 2, were not identified because of the P value, magnitude, or direction of their results (step 3). We anticipate this scenario will be the case for most systematic reviews, apart from those for which an inception cohort was defined (eg, only prospectively registered studies or studies identified for a prospective meta-analysis were eligible for inclusion in the review). In such reviews, all such studies are identified before their results became known.

Assessing a specific meta-analysis result

In step 4, users of the ROB-ME tool answer eight signalling questions, which seek to elicit information about what happened or was observed ( box 2 ). Answers to the signalling questions are informed by the material collated in steps 1 to 3. Step 4 should be completed for each meta-analysis assessed for risk of bias.

Summary of information assessed by the ROB-ME tool

Assessment of non-reporting bias within studies (known unknowns).

Of the studies identified, whether:

Any studies had no result available for inclusion in the meta-analysis, likely because of the P value, magnitude, or direction of the result generated

(If applicable) a notable change to the summary effect estimate would have been likely if the omitted results had been included

There were any studies for which it was unclear that an eligible result was generated

(If applicable) a notable change to the summary effect estimate would have been likely if the potentially omitted results had been included

Assessment of non-reporting bias across studies (unknown unknowns)

Circumstances indicate potential for some eligible studies not being identified because of the P value, magnitude or direction of the results generated

(If applicable) it is likely that studies not identified had results that were eligible for inclusion in the meta-analysis

(If applicable) the pattern of observed study results suggest that the meta-analysis is likely to be missing results that were systematically different (in terms of P value, magnitude, or direction) from those observed

(If applicable) sensitivity analyses suggest that the summary effect estimate was biased owing to missing results

ROB-ME=tool for assessing risk of bias due to missing evidence. For the precise wording of signalling questions and guidance for answering each one, see the full risk-of-bias tool at https://www.riskofbias.info/ .

The response options for the signalling questions are: yes; probably yes; probably no; no; no information; and not applicable. To maximise simplicity and clarity, the questions are phrased such that a response of “yes” indicates higher risk of bias and “no” indicates lower risk of bias. Responses of “yes” and “probably yes” have the same implications for risk of bias as do responses of “no” and “probably no.” The definitive versions (“yes” and “no”) would typically be selected when firm evidence is available in relation to the signalling question, whereas the “probably” versions would typically be selected when firm evidence is lacking and some judgment has been made. Guidance on how to answer each signalling question is provided in the tool available at https://www.riskofbias.info/ .

Signalling questions relating to the assessment of non-reporting bias within studies

The first four signalling questions ask users to consider the extent of missing results in the studies identified for the meta-analysis being assessed for risk of bias (ie, known unknowns). If they determine that one or more of the studies is missing from the meta-analysis because of selective non-reporting of study results, users should consider whether the amount of missing evidence matters. This means whether inclusion of the omitted results would likely lead to a notable change in the summary (combined) effect estimate, given the likely weight and direction of effect in studies omitted from the meta-analysis (if known), meta-analysis model used (such as fixed effect or random effects), and extent of heterogeneity observed. To clarify the potential for bias in the meta-analysis result, users could generate a forest plot displaying studies with results, along with information about studies known to be missing from the meta-analysis due to selective non-reporting of their results (see fig 2 for an example).

Example forest plot showing results missing from a meta-analysis of the effect of preoperative exercise training compared with usual care on postoperative complications (data taken from Gravier et al 22 )

Signalling questions relating to the assessment of non-reporting bias across studies

The remaining four signalling questions ask users to consider the risk that the meta-analysis result is biased because additional studies or study results, beyond those already identified, are missing (ie, unknown unknowns). Factors to consider include whether missing studies are likely to have had eligible results because the outcome is typically measured in all studies on the topic; whether the pattern of results included in the meta-analysis reveals a tendency for studies with particular results, such as those with P>0.05, to be missing (as observed through graphical methods such as contour enhanced funnel plots 23 ); and whether the findings of appropriate sensitivity analyses, which might include restricting the meta-analysis to the largest studies or using selection models 24 25 26 or regression based adjustment methods, 27 28 suggest that a meta-analysis result is not robust to plausible assumptions about the extent and nature of missing evidence.

Risk-of-bias judgment

ROB-ME operates in the same way as the RoB 2 15 and ROBINS-I 16 tools, in which responses to signalling questions provide the basis for a judgment about the risk of bias in the specific meta-analysis result being assessed. The tool includes an algorithm that maps responses to signalling questions onto a proposed risk-of-bias judgment (see appendices 5 and 6 in the supplement). Possible risk-of-bias judgments are:

Low risk of bias: the meta-analysis result is unlikely to be biased due to missing evidence

High risk of bias: the meta-analysis result is likely to be biased due to missing evidence

Some concerns: uncertainties about the extent or potential impact of missing evidence exist that preclude a judgment of low or high risk of bias

Although ROB-ME considers only the summary effect estimate, we recognise that suppression of results could affect other statistics, such as the estimate of heterogeneity, and in turn the width of the confidence interval for the summary effect estimate.

Presentations of risk-of-bias assessments

Users of ROB-ME should present risk-of-bias judgments in the main systematic review report (eg, in a table or within the forest plot), along with a brief free text justification for each judgment. In addition, we encourage reporting of the completed results matrix (step 2) and answers to all questions in steps 3 and 4 (with supporting text, where applicable) as supplementary material. Only consensus judgments and answers, rather than judgments and answers from individual users, should be presented.

Inadequate consideration of risk of bias due to missing evidence could lead to ineffective or harmful treatments being recommended but, despite the implementation of various initiatives to resolve the problem, selective non-publication of studies and selective non-reporting of study results persists. 2 3 For this reason, systematic reviewers should routinely assess the possibility that these issues have biased the results of meta-analyses they have conducted. We developed the ROB-ME tool to help reviewers undertake these assessments. The risk-of-bias judgments drawn from ROB-ME should help distinguish stronger from weaker synthesised evidence and influence the certainty of conclusions drawn from a systematic review (potentially as part of a GRADE assessment 17 ).

The ROB-ME tool includes several innovations in the assessment of non-reporting biases. In the original Cochrane tool for assessing risk of bias in randomised trials, 29 users were prompted to judge the risk of selective reporting bias at the study level, based on whether any results in the study were selectively reported. In reviews adopting this approach, many studies have been judged at high risk of selective reporting bias 11 ; however, the corresponding risk of bias in meta-analyses affected by selective non-reporting of study results is infrequently acknowledged, because no guidance on how to reach such a judgment was provided. ROB-ME explicitly deals with this gap, directing assessments at the level of the meta-analysis result and outlining what factors need to be considered to determine whether the amount of evidence known or assumed to be missing matters. Furthermore, to our knowledge, ROB-ME is the first tool to help users reach an overall judgment about risk of bias in a meta-analysis result arising from both missing studies and missing results in studies.

Of the various components of ROB-ME, we anticipate that assessment of non-reporting bias within studies will be the most resource intensive, yet also the most valuable. This value arises because the impact of selective non-reporting of results in a set of studies known to be missing from a meta-analysis can be quantified more easily than the impact of selective non-publication of an unknown number of studies. Furthermore, if systematic reviewers suspect that a meta-analysis result is biased because results were missing selectively from a large proportion of the studies identified, then the assessment of non-reporting bias across studies is unlikely to change their judgment (other than increasing their certainty that the meta-analysis result is at high risk of bias). This role of the assessment of non-reporting bias within studies does not imply that the assessment across studies should be considered an optional component of the tool. Despite their well known limitations, 1 30 methods originally developed for an assessment across studies (such as funnel plots, tests for funnel plot asymmetry, and sensitivity analyses) are useful when the assessment of selective non-reporting within studies is limited (eg, when detailed study plans are unavailable for most studies included in the review).

The ROB-ME tool was designed to complement tools such as RoB 2 15 and ROBINS-I 16 for assessing risk of bias in study results. These tools enable assessment of bias in selection of the reported result, a domain of bias related to, but not dealt with by, ROB-ME. As a rule of thumb, ROB-ME should be used when systematic reviewers do not have a result from a study to include in a particular meta-analysis, whereas RoB 2 or ROBINS-I should be used to assess whether a result that is available for inclusion might have been cherry picked 31 from among multiple measures or analyses. Assessments of risk of bias due to missing evidence and risk of bias in selection of the reported result will likely be informed by the same sources of information about studies (eg, study protocols, register entries), so we advise systematic reviewers to apply step 2 of ROB-ME (completion of the results matrix) in parallel with RoB 2 or ROBINS-I.

The ROB-ME tool is most suitable for assessing meta-analyses of evidence from randomised trials. We believe that it can also be used to assess meta-analyses of non-randomised studies of interventions (eg, cohort studies, interrupted time series studies), but some components of the tool will not apply to such studies. For example, the applicability of tests for funnel plot asymmetry in the context of meta-analyses of non-randomised studies of interventions is unclear, 30 so these should not be used in the assessment of non-reporting bias across studies. Furthermore, analyses of non-randomised studies are less likely than randomised trials to be registered or have a publicly accessible protocol, so comparison of prespecified with reported outcomes will usually not be possible. However, assessment of selective non-reporting of study results can still be undertaken for such studies, for example, by comparing the methods and results sections of a study report.

Plans for future development of the ROB-ME tool include further refining to ensure that it is suitable for assessing types of pairwise synthesis other than meta-analysis that yield a point estimate of an intervention effect (such as calculation of the median effect across studies when meta-analysis is not possible or appropriate). 32 33 We also plan to develop an interactive online version of the tool to facilitate use and prepare a bank of worked examples for educational purposes. We will also explore how ROB-ME judgments should feed into the GRADE framework for assessing certainty in the body of evidence. We welcome feedback from users of ROB-ME and any subsequent updates to the tool will be uploaded to https://www.riskofbias.info/ .

The ROB-ME tool deals with gaps in existing approaches for assessing risk of non-reporting biases. We hope that the tool will be useful to authors and users of systematic reviews, by helping to identify meta-analyses at high risk of bias and facilitating appropriate interpretation of results.

Acknowledgments

We thank Sarah Dawson, Kay Dickersin, Carl Heneghan, Toby Lasserson, Hannah Rothstein, and James Thomas for their participation at the development meeting and comments on early drafts of the ROB-ME tool; Robert Boyle, Mahnuma Estee, Alix Hall, Kylie Hunter, Alison Su-Hsun Liu, David Marshall, Paul McCann, Riaz Qureshi, Jelena Savović, Rik van Eekelen, Rui Wang, and Rebecca Wilson for providing feedback on a preliminary version of the tool; and Phi-Yen Nguyen for providing feedback on a more advanced version of the tool.

Contributors: All authors declare to meet the ICMJE conditions for authorship. MJP, JACS, and JPTH conceived the project and oversaw the project. MJP led the research to inform the tool and prepared all materials for the development meeting. MJP, JACS, IB, AH, TL, LAS, AJS, KD, JJM, EHT, and JPTH attended and contributed to the development meeting. RGE took notes at the development meeting. MJP, JACS, and JPTH wrote the first draft of the ROB-ME tool. All authors contributed to the development of the ROB-ME tool and to writing associated guidance. MJP led the drafting of this manuscript. All authors reviewed and commented on drafts of the manuscript. All authors approved the final version of the manuscript. MJP is the guarantor of this work. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: MJP was supported by a National Health and Medical Research Council (NHMRC) Early Career Fellowship (1088535) and an Australian Research Council Discovery Early Career Researcher Award (DE200101618) during the conduct of this research. JACS is supported by the NIHR Bristol Biomedical Research Centre and Health Data Research UK South-West and is a member of the MRC Integrative Epidemiology Unit at the University of Bristol. TL was supported by grant UG1 EY020522 from the National Eye Institute, National Institutes of Health. JEM is supported by an Australian NHMRC Investigator Grant (GNT2009612). JPTH is a National Institute for Health and Care Research (NIHR) senior investigator (NF-SI-0617-10145), is supported by the NIHR Bristol Biomedical Research Centre and NIHR Applied Research Collaboration West (ARC West) at University Hospitals Bristol NHS Foundation Trust, and is a member of the MRC Integrative Epidemiology Unit at the University of Bristol. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Competing interests: All authors have completed the ICMJE disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; JJK is a statistical editor for The BMJ , for which he receives remuneration; EM-W has received grants/contracts from the Patient Centered Outcomes Research Institute, National Institutes of Health, Arnold Ventures, and Robert Wood Johnson Foundation, has received consulting fees for editorial work from Origin Editorial, payment/honorariums from the American Public Health Association and National Institutes of Health, and has an unpaid leadership role in the American Psychological Association; LB has received grants/contracts from the state of Colorado, Cochrane, and the US Environmental Protection Agency, has received consulting fees for work as a conflict of interest advisor from Health Canada, has received support for travel from the National Academy of Science Engineering and Medicine, Cochrane and the World Congress on Research Integrity, and has an unpaid chair role for the National Academy of Science Engineering and Medicine committees; EHT has received an honorarium for a lecture on publication bias from the University of British Columbia, Canada; all other authors declare having no competing interests.

Patient and public involvement: Patients and members of the public were not involved in this methodological research. Our motivation for developing the ROB-ME tool arose from our concerns as people who interact with the healthcare system that bias due to missing evidence in meta-analyses can lead to ineffective or harmful treatments being delivered to patients. We plan to disseminate the research widely, including to community participants in evidence synthesis organisations, as we believe increased awareness about non-reporting biases and its consequences can help minimise the problem.

Provenance and peer review: Not commissioned; externally peer reviewed.

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• Campbell M ,

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• Volume 13, Issue 11
• Nebulised furosemide for the treatment of patients with obstructive lung disease: a systematic review protocol
• Article Text
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• http://orcid.org/0000-0003-4643-2960 Richard Veldhoen ,
• http://orcid.org/0000-0002-9027-7198 John Muscedere
• Department of Critical Care Medicine , Queen’s University , Kingston , Ontario , Canada
• Correspondence to Dr John Muscedere; john.muscedere{at}kingstonhsc.ca

Introduction Obstructive lung diseases (OLDs) such as asthma and chronic obstructive pulmonary disease are major global sources of morbidity and mortality. Current treatments broadly include bronchodilators such as beta agonists/antimuscarinics and anti-inflammatory agents such as steroids. Despite therapy patients still experience exacerbations of their diseases and overall decline over time. Nebulised furosemide may have a novel use in the treatment of OLD. Multiple small studies have shown improvement in pulmonary function as well as dyspnoea. This systematic review will aim to summarise and analyse the existing literature on nebulised furosemide use in OLD to guide treatment and future studies.

Methods and analysis We will identify all experimental studies using nebulised/inhaled furosemide in patients with asthma or chronic obstructive pulmonary disease that report any outcome. Databases will include EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment and the NHS Economic Evaluation Database (1995–2015). We will also search ClinicalTrials.gov and the WHO-International Clinical Trials Registry Platform. Two reviewers will independently determine trial eligibility. For each included trial, we will perform duplicate independent data extraction, risk of bias assessment and evaluation of the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Ethics and dissemination Ethical approval will not be applicable to this systematic review. The results of the study will be communicated through publication in peer-reviewed journals.

PROSPERO registration number CRD42021284680.

• chronic airways disease

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

http://dx.doi.org/10.1136/bmjopen-2022-070155

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STRENGTHS AND LIMITATIONS OF THIS STUDY

The search strategy is designed to broadly include as many publications as possible, which is a strength when the volume of the literature is anticipated to be low.

Subgroup analyses will help to identify if there are important differences between the major types of obstructive lung diseases.

Biases within the primary studies will be assessed and reported, but may ultimately not be apparent and can contribute to bias within the conclusions of the systematic review.

The major limitation is that conclusions will depend on the size and quality of the existing literature and may be limited by a small number of studies as well as heterogeneity of the patients, treatment settings and measured outcomes.

Introduction

Obstructive lung diseases (OLDs) are broadly characterised by inappropriate bronchoconstriction, worsening gas exchange, inflammation and dyspnoea. The two most prevalent forms of OLD are chronic obstructive pulmonary disease (COPD) and asthma. In 2019, COPD had an estimated global prevalence of 212 million people causing an estimated 3.28 million deaths annually while asthma has an estimated global prevalence of 262 million people and causes 461 000 deaths annually. 1 OLDs are associated with progressive decline in pulmonary function over time as well as increased morbidity and mortality compared with matched controls, particularly with associated exacerbations. OLDs include a spectrum of pathological changes ranging from potentially reversible to permanent. Potentially reversible changes may include airway inflammation, mucus hypersecretion, recruitment of inflammatory mediator cells and hyperplasia or hypertrophy of mucous glands/goblet cells/vascular smooth muscle. Permanent changes include fibrosis, destruction of small airways and emphysema. 2

Current treatments for OLD broadly take the form of bronchodilators (primarily beta agonists and antimuscarinic agents) and anti-inflammatories (primarily inhaled/systemic steroids). These medications are the mainstays of both COPD and asthma and treatment, though asthma therapies also include more specific immunomodulating treatments in specific asthma phenotypes. These immunotherapies are currently specific to severe asthma and are currently limited by expense and specialist prescribing. 3 4 Novel therapies for the spectrum of OLD are desirable to both improve pulmonary function and alleviate symptoms beyond our current treatments.

Furosemide is best known as a diuretic but it is also known to have potent bronchodilator and anti-inflammatory effects. 5 6 Multiple small interventional studies have assessed its ability to improve pulmonary function as well as improve dyspnoea. 7–10 Nebulised furosemide has been shown to stimulate slowly acting stretch receptors and inhibit rapidly acting stretch receptors in an animal model, with both actions posited to reduce dyspnoea. 11 Subsequent human trials have shown decreased dyspnoea in various settings 7 9 10 12 13 though results are inconsistent. 14 15 These effects on stretch receptors are also thought to reduce parasympathetic outflow and cholinergic tone within the smooth muscle of the airways, 16–18 and may explain beneficial changes in respiratory mechanics that are observed in patients with OLD treated with nebulised furosemide. 6 The adverse effects of nebulised furosemide, in contrast to oral or intravenous routes, are not well defined as it has primarily been used in small experimental studies. In a small number of studies of dyspnoea relief with nebulised furosemide increased diuresis has been reported, while the majority reported either no adverse events or no increase in diuresis. 19

Considering the putative mechanisms of action for nebulised furosemide, it may be a beneficial treatment for the reversible pathologies underlying OLD and resultant dyspnoea and has the advantages of low cost, established safety, widespread availability and patient/clinician familiarity/comfort. This study aims to broadly summarise the available evidence regarding treatment of OLD with nebulised furosemide to provide a foundational summary of the literature and guide future studies.

Research question

Does nebulised furosemide improve pulmonary function and/or dyspnoea in patients with acute or chronic OLD when compared with any other treatment or placebo?

This systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. 20 The review protocol will be reported in accordance with the PRISMA protocol and has been registered with the International Prospective register of systematic reviews (PROSPERO). 21–23

Patient and public involvement

No patient involved.

Eligibility criteria

Types of studies.

The systematic review will include any primary interventional study with a controlled study design including quasi randomised and randomised controlled trials (RCTs). All published manuscripts and abstracts in English will be eligible. Case reports, letters to the editor, editorials, meta-analyses, narrative reviews and non-English manuscripts will be excluded but will be reviewed for eligible references.

Types of participants

Studies must include patients diagnosed with and being treated for OLD of any type. We will record the method of diagnosis as reported by the authors. We will exclude studies in which the majority are neonatal patients (>50%). Patients with both fixed and reversible airways’ obstruction will be included.

Types of interventions

Included studies will use nebulised/inhaled furosemide with the effect measured against any comparator including placebo or no treatment. We will include studies reporting chronic disease treatment and acute exacerbations of OLD.

Types of outcomes

Included studies will report any outcome of treatment with nebulised furosemide. Patient-centred outcomes such as symptom improvement, physiological outcomes such as improvement in forced expiratory volume over 1 s (FEV1) and rates of exacerbation/medical contact/hospitalisation are all examples of acceptable outcomes. Validated assessment tools such as the St. George’s Respiratory Questionnaire will be reported when available. 24 Adverse drug reactions will be summarised if reported within the studies.

Search methods for identification of trials

The literature search will be conducted using a two-step approach to maximise the number of studies discovered. First, an initial search of MEDLINE will be performed through the Ovid research platform. Revisions to the search strategy will be made and then the search will be repeated through MEDLINE (1946-present), EMBASE (1947-present), Cochrane Database of Systematic Reviews (2005 to present), ACP Journal Club (1991 to present), Database of Abstracts of Reviews of Effects (1991 to 2015), Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials (1991 to present), Cochrane Methodology Register (1995–2012), Health Technology Assessment (2001–2016) and the NHS Economic Evaluation Database (1995–2015). The searches above will be performed using Ovid. We will also search ClinicalTrials.gov, and the WHO-International Clinical Trials Registry Platform (WHO-ICTRP) using their individual search functions.

Sample search strategy

Please see online supplemental information for other search drafts.

Supplemental material

EMBASE (searched via Ovid research platform)

exp chronic obstructive lung disease/

chronic obstructive pulmonary disease.mp.

chronic obstructive lung disease.mp.

exp asthma/

exp asthma-chronic obstructive pulmonary disease overlap syndrome/

asthma-chronic obstructive pulmonary disease overlap syndrome.mp.

exp obstructive airway disease/

obstructive airway disease.mp.

1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11

exp furosemide/

furosemide.mp.

exp loop diuretic agent/

loop diuretic agent.mp.

13 or 14 or 15 or 16 or 17

exp nebulization/

(nebulization or nebulized or nebulize or nebules or nebulizer or nebulizing).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]

inhaled.mp.

19 or 20 or 21

12 and 18 and 22

Study records

After identifying all potentially relevant studies, the abstracts will be screened independently by reviewers for inclusion based on the criteria above. The screening will be conducted in duplicate by two authors using Covidence software. Disagreement over the inclusion of a manuscript will be resolved by a third party.

Data collection

Data from each study will be extracted independently by two reviewers using a data abstraction form that will be piloted on 10 randomly selected included studies. Initial abstracted data will include title, first author, year of publication, study design, number of centres, diagnosis, relevant baseline patient data, intervention, comparator, study setting, primary outcome (definition, results), secondary outcomes (definitions, results), timeline of intervention, outcome measurement, blinding/concealment and randomisation. The form will then be refined and applied to the entire record set. All data will be collected in duplicate. Disagreements will be settled by consensus or adjudicated by a third author where consensus cannot be reached.

Assessing risk of bias

Included studies will be evaluated using a modified Cochrane Collaboration tool for assessing risk of bias in randomised control trials. 25 We will use the Newcastle-Ottawa Scale for assessing the quality of non-randomised studies. 26 Primary outcomes for each study will be described and assessed as ‘high’, ‘low’ or ‘unclear’ risk of bias. Two reviewers will independently assess the risk of bias in each study and disagreement will be resolved by discussion. We will consider the risk of bias ‘high’ if bias is present and likely to affect the outcome or ‘low’ if bias is not present or is present but is unlikely to affect the outcomes.

Summarising data and treatment effects

The outcome data will be presented in tables and narratively as appropriate. Meta-analysis of primary and secondary outcomes will be conducted when possible. Meta-analyses will be modelled with random effects if there are at least five studies included in the analysis, to allow for reliable estimation of between study variance, and will otherwise be described narratively. Dichotomous outcome effect estimates will be reported as risk or ORs depending on the underlying studies included in the estimates. Continuous outcomes will be pooled using the inverse variance method and reported as the mean differences. All effect estimates will be provided alongside a 95% CI. Meta-analyses will be presented as forest plots, where applicable. In situations where there are few studies (precluding accurate random effects modelling as above), and the studies have clear evidence of heterogeneity, we will narratively describe the individual results rather than analyse by meta-analysis as recommended previously. 27 Primary authors will not be contacted regarding missing data or for clarification of data. Analyses will be conducted in RevMan V.6.

Due to the variety of indications for the inhaled furosemide that we expect in the included studies, it is unlikely that we will be able to conduct a meta-analysis for the primary analysis but will report aggregated data on the following prespecified subgroups where possible: diagnosis (COPD and asthma), treatment acuity (exacerbation, chronic management, challenge testing) and age (adults, children). Within these subgroups, we will report the effect based on study quality (high/low).

Assessment of heterogeneity

Heterogeneity will be determined for data that are appropriate for quantitative analysis. Each outcome will be assessed using the χ 2 test and intraclass correlation (I 2 ) alongside narrative discussion of the validity of these estimates based on the number of included studies.

Assessment of reporting bias

We will investigate the possibility of publication bias using a funnel plot, provided there are at least 10 included studies. 28 29 Risk of bias will be assessed by visual inspection of a funnel plot constructed by plotting effect size versus SE.

Assessment of confidence in estimates of effect

We will assess the quality of evidence for the interventions and outcomes using the Grading of Recommendations, Assessment, Development and Evaluations approach and rating system. 30 RCTs will start as high-quality evidence but may be rated down by one of the following: risk of bias, imprecision, inconsistency, indirectness and publication bias. Quality of evidence will be assessed by two independent reviewers. Disagreements will be resolved by consensus, involving a third author as needed.

The major and most commonly used therapeutic options for OLDs have not changed considerably in the past years. Beyond bronchodilators and steroids, biologics have shown promise in specific and relatively uncommon phenotypes of asthma but are not commercially available for use in COPD. Repurposing of furosemide, a well-known, inexpensive, safe and potentially beneficial drug would be an important additional therapy. The current literature on this topic is relatively limited, has small samples and diverse methodology. A systematic review of the use of furosemide in OLD will allow summary and synthesis of the current information and either provide insight into its utility or justification for further research and experimentation. Ultimately, this may provide improved patient care without needing lengthy drug development or safety studies.

Our systematic review will use rigorous methodological approaches to evaluate and combine the current evidence. Our main objective is to summarise evidence for physiological or clinical effects of nebulised furosemide on patients with OLD, and due to the small body of literature we will include all reported outcomes. The size of existing literature is the greatest limitation of this study, as the treatment effect estimates may have low certainty.

In summary, this review will serve to summarise the known effects of nebulised furosemide for patients with OLD and may justify further experimental studies.

Ethics and dissemination

This study is a secondary analysis of publicly available previously published studies, and no specific ethics approval was necessary. The resulting systematic review will be published in a peer-reviewed journal.

Ethics statements

Patient consent for publication.

Not applicable.

Acknowledgments

We thank the team at Bracken Health Sciences Library Reference & Research Services, Queen’s University, Kingston, ON, Canada for their aid in reviewing our search strategies and specifically Sandra Halliday and Angélique Roy for their expertise.

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Supplementary materials

Supplementary data.

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• Data supplement 1

Contributors JM proposed the original question and performed an initial survey and summary of the literature. He aided in all other aspects of writing and preparing the protocol. RV formulated and revised the search strategy and prepared the manuscript.

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• Published: 23 November 2023

Impact of frailty on the outcomes of patients undergoing degenerative spine surgery: a systematic review and meta-analysis

• Wonhee Baek 1 ,
• Sun-Young Park 2 &
• Yoonjoo Kim 3  

BMC Geriatrics volume  23 , Article number:  771 ( 2023 ) Cite this article

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Metrics details

Degenerative spinal diseases are common in older adults with concurrent frailty. Preoperative frailty is a strong predictor of adverse clinical outcomes after surgery. This study aimed to investigate the association between health-related outcomes and frailty in patients undergoing spine surgery for degenerative spine diseases.

A systematic review and meta-analysis were performed by electronically searching Ovid-MEDLINE, Ovid-Embase, Cochrane Library, and CINAHL for eligible studies until July 16, 2022. We reviewed all studies, excluding spinal tumours, non-surgical procedures, and experimental studies that examined the association between preoperative frailty and related outcomes after spine surgery. A total of 1,075 articles were identified in the initial search and were reviewed by two reviewers, independently. Data were subjected to qualitative and quantitative syntheses by meta-analytic methods.

Thirty-eight articles on 474,651 patients who underwent degenerative spine surgeries were included and 17 papers were quantitatively synthesized. The health-related outcomes were divided into clinical outcomes and patient-reported outcomes; clinical outcomes were further divided into postoperative complications and supportive management procedures. Compared to the non-frail group, the frail group was significantly associated with a greater risk of high mortality, major complications, acute renal failure, myocardial infarction, non-home discharge, reintubation, and longer length of hospital stay. Regarding patient-reported outcomes, changes in scores between the preoperative and postoperative Oswestry Disability Index scores were not associated with preoperative frailty.

Conclusions

In degenerative spinal diseases, frailty is a strong predictor of adverse clinical outcomes after spine surgery. The relationship between preoperative frailty and patient-reported outcomes is still inconclusive. Further research is needed to consolidate the evidence from patient-reported outcomes.

Peer Review reports

As the incidence of degenerative spinal diseases has increased and with advancements in medical technology [ 1 , 2 ], the number of older adults undergoing spine surgeries has increased [ 3 , 4 ]. Accordingly, difficulties encountered during spine surgeries have also increased [ 4 , 5 ]. Because the outcomes of patients undergoing spine surgery are affected by their preoperative characteristics [ 6 , 7 , 8 ], it becomes imperative to gain insights into factors that may impact postoperative outcomes in this population, including frailty. Frailty is defined as a multidimensional state of loss of physical, cognitive, social, and psychological functioning [ 9 ]. The older the age, the higher the frailty; however, compared to chronological age, frailty status can better predict complications and mortality following spine surgery [ 10 ]. Most patients undergoing spine surgeries are prefrail or frail [ 7 , 11 ], conditions which are often associated with preoperative pain, spinal deformity, and reduced ability to perform activities of daily living. For spine surgery, the incidence of postoperative complications and non-home discharge, length of hospital stay, and mortality rates are higher among patients with preoperative frailty than among those without [ 7 , 12 ]. Therefore, preoperative risk stratification of frailty is helpful for predicting postoperative deterioration; this in turn can help prevent the worsening of outcomes after a spine surgery [ 9 ].

Patients with frailty who have undergone spine surgery do not experience the same level of benefit in terms of clinical outcomes (COs) as those who are not frail [ 13 , 14 ]. Even then, such patients often opt for spine surgery to alleviate pain and improve function rather than for survival (unlike patients who opt for cancer surgery) [ 15 ]. Therefore, providing patients with information on the benefits of patient-reported outcomes (PROs) after spine surgery can help them make informed decisions and receive more patient-centred care. With the increased emphasis on the importance of PROs, research has increasingly focused on how PROs in frail patients have changed following spine surgery [ 13 , 16 ]. However, there is a lack of understanding of the benefits and expected types of PROs in spine surgery. Therefore, a systematic literature review and meta-analysis of the relationship between preoperative frailty and the postoperative outcomes of surgery for patients with degenerative spinal disease is necessary.

A 2021 systematic review and meta-analysis of 32 studies on preoperative frailty and outcomes of spine surgery revealed that frailty was associated with increased adverse events, mortality, length of hospital stay, readmission, reoperation, non-home discharge, intensive care unit stay, and PROs following a spine surgery [ 17 ]. However, this review had the following limitations: studies on simple procedures such as kyphoplasty were included in the review; therefore, the risk of bias regarding non-surgical procedures could not be ruled out. Furthermore, because disease pathogenesis and progression differ between patients with spinal neoplasms and metastases and those with degenerative spine disease, both cohorts must be analysed separately. However, the study mentioned above included both patients with spinal neoplasms and those with degenerative spinal diseases. Moreover, interpretation of the findings of the meta-analysis was limited because the postoperative adverse events were not differentiated in detail, a synthesis of evidence on the patient-reported outcomes was not performed, and the method for the meta-analysis was not described clearly [ 17 , 18 , 19 ].

Two parameters help to identify frailty status. These include the frailty phenotype [ 20 ] and the frailty index (FI) [ 21 ]. Regarding the frailty phenotype, frailty is determined by the following symptoms: unintentional weight loss, self-reported exhaustion, weakness, slow walking speed, and low physical activity [ 20 ]. The FI is obtained by dividing the sum of a patient’s deficits by the total sum of frailty-related deficits. It has two types, namely adult spinal deformity (ASD)-FI [ 13 ] and cervical deformity (CD)-FI [ 22 ]. Recently, modified FI (mFI) has also been used for determining frailty [ 23 ]; each clinical institution has developed and used a different frailty tool [ 24 ]. Determining the risk stratification of frailty before spine surgery helps determine the prognosis and treatment of patients. Thus, we aimed to explore the following: (1) tools used to measure the frailty of patients prior to surgery for degenerative spine disease, (2) types of frailty-related health-related outcomes following spine surgery, and (3) association between preoperative frailty and health-related outcomes.

We followed the recommendations of the Cochrane Handbook to confirm the outcome of frailty [ 25 ]. The final protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42021286341).

Search strategy

Electronic bibliographic databases, including Ovid-MEDLINE, Ovid-EMBASE, Cochrane Library (Cochrane Database of Systematic Reviews), and CINAHL (Cumulative Index of Nursing and Allied Health), were screened for relevant articles. The search terms were “spine,” “frailty,” “postoperative,” and “outcome” and the Boolean operators OR and were used to combine them. The search was completed on July 16, 2022. The search strategies for each database are presented in Supplementary Material Table 1.

Eligibility criteria

The inclusion criteria were as follows: (1) articles on patients who underwent spine surgery; (2) articles on studies that compared health-related outcomes (COs and PROs) after spine surgery with respect to preoperative frailty status, (3) articles in English published in peer-reviewed journals; and (4) articles on prospective or retrospective cohort, case-control, and cross-sectional studies. The exclusion criteria were as follows: (1) reviews, case reports, and unpublished manuscripts; (2) articles on studies that included spinal tumours; (3) articles on experimental studies (interventions could confound the relationship between frailty and postoperative health-related outcomes); (4) articles on studies that included non-surgical procedures. No restrictions were placed on the timing of publication.

Article selection and data extraction

Articles were first downloaded using reference management software (EndNote version 20, Clarivate Analytics, USA). Then, Rayyan was used to screen the downloaded articles and remove any duplicates [ 26 ]. Two authors (WB and YK) independently read the titles and abstracts of the remaining articles and selected those that met the eligibility criteria. Thereafter, the full texts of the selected articles were reviewed; any discrepancies in the selection process were resolved after discussion with another author (SP). Using a standardized record extraction form, the two aforementioned reviewers independently extracted the following data from the selected articles: first author’s name, year and country of publication, demographic and clinical characteristics of the study population, population demographics, type of surgery, measurement tool and outcomes, and follow-up duration.

Risk of bias in individual studies

The Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) was used to assess the quality of the included studies [ 27 ]. The RoBANS evaluated the risk of bias for the following six domains: participant selection, confounding variables, measurement of exposure, blinding of outcome assessments, incomplete outcome data, and selective outcome reporting. Each domain was assessed as having a “low risk of bias”, “unclear risk of bias,” or “high risk of bias.” The two aforementioned authors independently evaluated the methodological quality of the studies and later combined their findings.

Synthesis and statistical analysis

All data analyses were performed using R (version 4.0.3, R Foundation for Statistical Computing, Austria). We performed a qualitative synthesis to determine what tools were used to measure frailty in patients undergoing spine surgery and what indicators were used for frailty and health-related outcomes. Thereafter, quantitative synthesis was performed to confirm the direction and magnitude of the association between frailty and health-related outcomes.

We divided the postoperative health-related outcomes into COs and PROs. The meta-analysis was performed if the following conditions were met: (1) there were three or more papers that could be synthesized, (2) the participants could be divided into frail and non-frail groups, (3) COs were synthesized only if the terms used in each paper were identical, and (4) the same participants were extracted from the same database in the same year (the paper that was published first was selected).

The Mantel–Haenszel method was used to estimate the pooled odds ratio (OR) with the 95% confidence interval (CI) for dichotomous variables. The inverse variance method was used to estimate the pooled mean difference (MD) with the 95% CI for continuous variables. A fixed-effect model was used for homogeneous studies, while a random-effects model was used for heterogeneous studies [ 25 ]. The I 2 value was used to investigate the heterogeneity among the included studies; an I 2 value > 50% was considered indicative of substantial heterogeneity [ 28 ].

Because tests for publication bias need to be evaluated when there are more than 10 studies in a meta-analysis, statistical tests were not attempted to identify publication bias in our study. Sensitivity analysis was performed while excluding papers that were judged to increase the heterogeneity and cause a bias in the effect size in the meta-analysis [ 25 ]. Statistical significance was defined by p-value < 0.05.

Study selection

The study selection process is shown in Fig.  1 . The initial search of the databases yielded 1,075 potentially relevant articles; one additional article was identified from other sources [ 29 ]. Among these, 732 articles remained after the removal of duplicates. After screening their titles and abstracts, 632 of these articles were excluded. The full texts of the remaining 100 articles were reviewed, and 62 articles were further excluded. The remaining 38 articles were finally included for quality evaluation and qualitative synthesis [ 7 , 10 , 11 , 12 , 13 , 14 , 16 , 22 , 23 , 24 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. Among these, 17 were subjected to a quantitative synthesis for the meta-analysis [ 10 , 13 , 16 , 22 , 29 , 30 , 33 , 35 , 39 , 40 , 41 , 42 , 47 , 49 , 52 , 55 , 56 ].

Preferred reporting items for systematic reviews and meta-analyses-based flowchart of the article screening and selection process

Study characteristics

The characteristics of the included studies are presented in Table  1 . The countries of the patients who participated in the study were North America (n = 25) [ 7 , 10 , 11 , 12 , 13 , 14 , 22 , 23 , 24 , 29 , 31 , 32 , 37 , 40 , 41 , 42 , 43 , 44 , 45 , 47 , 48 , 49 , 51 , 52 , 53 , 56 ], Korea (n = 5) [ 30 , 33 , 34 , 35 , 36 ], China (n = 2) [ 16 , 50 ], Europe (n = 2) [ 38 , 46 ], Japan (n = 2) [ 54 , 55 ]. One study included patients from Europe, Asia, and North America [ 39 ]. Overall, 34 retrospective cohort studies [ 7 , 10 , 13 , 14 , 16 , 22 , 23 , 24 , 29 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ], 3 prospective cohort studies [ 11 , 30 , 39 , 48 ], and 1 mixed retrospective and prospective cohort study [ 12 ] were included. The articles were published between 2016 and 2022. Overall, the studies comprised 474,651 patients who underwent spine surgery (mean age: 56.6–78.3 years).

Risk of bias

Supplementary Material Fig. 1 summarizes the results of the assessments of the risk of bias in the included studies. The overall quality of the included studies was good. However, there were concerns regarding selection bias for six out of 38 studies [ 23 , 29 , 36 , 45 , 46 , 47 ]. These studies analysed multi-centre data and had a retrospective design, but did not report the confounding variables. Eleven studies [ 10 , 14 , 16 , 22 , 23 , 29 , 34 , 35 , 40 , 52 , 53 ] did not report the presence of incomplete outcome data, such as missing data or non-response rates. In more than 80% of the studies, five of the six evaluated domains were assessed as having a low risk of bias (attrition bias was excluded). No studies were excluded based on quality assessment.

Frailty measurements

The measurement tools for preoperative frailty included the mFI-11 (n = 15) [ 10 , 12 , 16 , 23 , 30 , 32 , 33 , 35 , 41 , 44 , 49 , 50 , 53 , 54 , 55 ], mFI-5 (n = 10) [ 7 , 30 , 31 , 34 , 44 , 45 , 52 , 53 , 55 , 56 ], ASD-FI (n = 6) [ 13 , 37 , 38 , 39 , 42 , 47 ], Hospital Frailty Risk Score (n = 2) [ 14 , 46 ], Johns Hopkins Adjusted Clinical Groups indicator (n = 2) [ 24 , 51 ], mCD-FI (n = 2) [ 29 , 43 ], frailty phenotype (n = 3) [ 11 , 36 , 48 ], CD-FI (n = 1) [ 22 ], comprehensive geriatric assessment (n = 1) [ 30 ], and mASD-FI (n = 1) [ 40 ]. In these studies, the patients were divided into non-frail, prefrail, frail, or severely frail groups or into the low frailty, medium frailty, and high frailty groups, according to their criteria.

Health-related outcomes after spine surgery

In the included studies, postoperative health-related outcomes were classified into COs and PROs (Table  1 ; Fig.  2 , and Supplementary Material Table 2).

Health-related outcomes in terms of preoperative frailty status. IADL, instrumental activities of daily living; EQ-5D, EuroQol-5D; JOA, Japanese orthopedic association scale; mJOA, modified Japanese orthopedic association scale; NDI, neck disability index; ODI, Owestry disability index; NRS, numerical rating scale; PQRS, postoperative quality of recovery scale; ADL, activity of daily living; SF-36, 36-item short-form survey; SRS-22, Scoliosis Research Society 22-question; VAS, visual analog scale; QALY, quality-adjusted life years; ICU, intensive care unit

Clinical outcomes

All studies, except one [ 47 ], considered COs as postoperative health-related outcomes. The COs included postoperative complications and supportive management procedures.

In 35 studies, the postoperative complications were addressed as COs [ 7 , 10 , 11 , 12 , 14 , 16 , 22 , 23 , 24 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. The postoperative complications were further divided into general and surgical complications. The general complications comprised anaemia; electrolyte abnormalities; cardiovascular, gastrointestinal, pulmonary, renal, and urinary complications; delirium; deep vein thrombosis; falls; and sepsis/septic shock. The surgical complications comprised dural tears, excessive bleeding, hematomas, instrumentation failure, neurological symptoms, positional and wound-related complications, pseudoarthrosis, pneumoperitoneum, and kyphosis. These complications were classified as minor or major or I–IV (Clavien–Dindo classification) [ 57 ]. In five studies [ 16 , 22 , 37 , 38 , 39 ], the definition provided by Glassman et al. was used to determine the major complications [ 58 , 59 ]. In 13 studies [ 10 , 12 , 23 , 24 , 29 , 32 , 35 , 41 , 44 , 49 , 50 , 52 , 53 ], mortality was considered a postoperative complication.

Supportive management procedures included transfusion for bleeding [ 10 , 41 , 46 , 52 ], admissions to intensive care units [ 14 , 22 ], length of hospital stay [ 11 , 12 , 14 , 22 , 24 , 29 , 31 , 32 , 33 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 45 , 50 , 53 , 56 ], length of bed rest [ 33 ], nonhome discharge [ 7 , 11 , 12 , 14 , 22 , 24 , 29 , 32 , 50 , 51 , 52 , 53 , 56 ], postoperative ventilator use [ 52 ], reintubation [ 35 , 52 , 56 ], readmission [ 7 , 14 , 24 , 31 , 44 , 50 , 52 , 53 , 56 ], reoperation [ 7 , 10 , 29 , 31 , 33 , 37 , 38 , 40 , 41 , 43 , 46 , 50 , 53 ], and emergency room visit [ 14 ].

Other COs included costs [ 13 , 14 , 24 , 51 ], frailty status [ 48 ], and radiographic imaging findings [ 13 , 16 , 43 , 54 ].

Patient reported outcomes

Eleven studies assessed PROs [ 13 , 16 , 29 , 33 , 40 , 42 , 43 , 47 , 48 , 50 , 54 ]. The PROs were assessed using the instrumental activities of daily living [ 48 ], EuroQol-5D (EQ-5D) [ 13 , 29 , 40 ], Japanese Orthopaedic Association (JOA) score [ 16 ], modified mJOA score [ 43 ], Neck Disability Index [ 29 , 43 ], Oswestry Disability Questionnaire (ODI) [ 13 , 16 , 33 , 40 , 42 , 47 , 50 , 54 ], numerical rating scale for pain [ 29 , 42 , 43 , 47 ], Postoperative Quality of Recovery Scale for cognitive recovery and activities of daily living [ 48 ], Pain Catastrophizing Scale [ 40 ], 36-Item Short Form Survey (SF-36) [ 47 , 50 , 54 ], Scoliosis Research Society 22-question [ 16 , 40 , 42 , 54 ], and visual analogue scale for pain [ 16 , 33 , 54 ].

Substantial clinical benefit was determined based on changes in the ODI, SF-36 score, and back and leg pain score after the surgery [ 33 , 47 ]. The quality-adjusted life years were determined using the EQ-5D [ 13 ].

Meta-analysis of the selected outcomes

Synthesis of meta-analysis results regarding the clinical outcomes.

Results of the meta-analysis of the COs are presented in Table  2 . A forest plot depicting significant associations between COs and frailty is shown in Fig.  3 . Compared to the non-frail group, the frail group was more likely to experience the following COs: mortality (OR = 2.5; 95% CI = 1.4–4.4) [ 10 , 35 , 52 ], major complication (OR = 2.8; 95% CI = 2.3–3.5) [ 39 , 42 , 49 , 56 ], any complication (OR = 2.1; 95% CI = 2.0–2.3) [ 10 , 29 , 35 , 39 , 40 , 42 , 52 , 55 , 56 ], general complication (OR = 1.6; 95% CI = 1.4–1.7) [ 22 , 30 , 52 ], acute renal failure (OR = 3.3; 95% CI = 1.8–6.1) [ 16 , 35 , 52 , 56 ], cardiac arrest (OR = 2.9; 95% CI = 1.7–5.0) [ 29 , 35 , 52 , 56 ], deep vein thrombosis (OR = 1.4; 95% CI = 1.0–2.0) [ 16 , 35 , 52 , 56 ], gastrointestinal complication (OR = 0.9; 95% CI = 0.4–1.9) [ 16 , 29 , 33 , 42 ], myocardial infarction (OR = 4.8; 95% CI = 3.3–7.0) [ 35 , 52 , 56 ], pneumonia (OR = 2.4; 95% CI = 1.4–4.1) [ 16 , 29 , 35 , 52 , 56 ], pulmonary embolism (OR = 1.5; 95% CI = 1.0–2.1) [ 35 , 52 , 56 ], sepsis (OR = 2.4; 95% CI = 1.7–3.2) [ 10 , 35 , 52 , 56 ], stroke/cerebrovascular accident (OR = 2.1; 95% CI = 0.5–8.5) [ 16 , 35 , 41 ], urinary tract infection (OR = 2.2; 95% CI = 1.1–4.6) [ 10 , 29 , 33 , 35 ], surgical complication (OR = 1.6; 95% CI = 1.4–1.9) [ 22 , 30 , 52 ], deep wound infection (OR = 1.8; 95% CI = 1.3–2.5) [ 16 , 29 , 52 , 56 ], implant-related complication (OR = 2.1; 95% CI = 1.4–3.2) [ 29 , 33 , 41 , 42 , 55 ], neurological complication (OR = 1.1; 95% CI = 0.6–1.7) [ 16 , 29 , 33 , 41 , 42 ], superficial surgical site infection (OR = 1.7; 95% CI = 1.3–2.2) [ 29 , 35 , 52 , 56 ], length of stay (MD = 3.1; 95% CI = 1.2–5.0) [ 13 , 16 , 24 , 33 , 37 , 38 , 51 ], non-home discharge (OR = 2.6; 95% CI = 2.1–3.2) [ 22 , 52 , 56 ], reintubation (OR = 3.4; 95% CI = 2.4–4.7) [ 35 , 52 , 56 ], and reoperation (OR = 1.0; 95% CI = 0.4–2.5) [ 10 , 29 , 33 , 52 ]. The forest plot for each CO is presented in Supplementary Material Fig. 2.

Forest plots of the clinical outcomes that showed significant results in the meta-analysis. SSI, surgical site infection; OR, odds ratio; MD, mean difference; CI, confidence interval

The incidence rates of complications in the frail group and the robust group are presented in Supplementary Table 3. In the robust group, the five most prevalent complications, in descending order, were as follows: gastrointestinal complications (5.6%), urinary tract infection (4.6%), implant-related complications (1.5%), neurological complications (1.4%), and superficial surgical site infections (0.6%). In contrast, in the frail group, the five most prevalent complications, in descending order, were as follows: implant-related complications (21.5%), neurological complications (13.6%), urinary tract infections (9.3%), gastrointestinal complications (5.6%), and stroke/cerebrovascular accidents (2.1%).

Synthesis of meta-analysis results regarding the patient-reported outcomes

Results of the meta-analysis of the PROs are presented in Table  2 . A forest plot for the PROs is shown in Supplementary Material Fig. 3. Changes in the ODI scores between pre- and post-surgery, categorized by frailty, were synthesized based on three papers [ 13 , 16 , 47 ]. The changes between pre- and post-operative ODI scores were not associated with preoperative frailty (MD= -9.6, 95% CI= -23–3.8).

Sensitivity analysis

A sensitivity analysis was performed to identify the relationship between any complication and frailty, which had the highest number of synthesized papers. As shown in the forest plot for any complication (Supplementary Material Figs. 2 and 3), it was judged that heterogeneity occurred due to the articles by Passias et al. [ 29 ] and Kim et al. [ 35 ]. When a meta-analysis was performed by removing those two articles, the I 2 value was reduced to 53% and 47%, respectively (Supplementary Material Fig. 4). Therefore, after removing these two papers, the meta-analysis was performed again (Supplementary Material Fig. 5). A fixed-effect model was selected because the heterogeneity was reduced to 10% for I 2 . The OR for any complication was 2.1 (95% CI = 2.0–2.3), which did not differ significantly from the original OR of 2.1. The findings of the sensitivity analysis indicate that the results of this study are reliable.

This systematic review and meta-analysis examined the association between preoperative frailty and postoperative health-related outcomes in patients who underwent spine surgery for degenerative spinal disease. In the 38 included studies, 10 frailty instruments were used to measure preoperative frailty and two typologies of health-related outcomes for the preoperative frailty status were identified. Preoperative frailty was observed to be associated with postoperative adverse health-related outcomes. It increased the incidence of adverse COs, including mortality and complications, but there was no significant difference with respect to the improvement of the postoperative PROs.

Research on frailty has increased appreciably recently; this includes studies on preoperative frailty and its association with COs [ 15 , 60 ] or PROs [ 61 ] and studies on the construct validity of frailty instruments [ 62 ]. Previous studies conducted in surgical settings highlight the important role of frailty as a prognostic factor for considering surgery [ 15 , 60 , 61 , 63 ]. A systematic review and meta-analysis of 19 studies on patients undergoing cardiac surgery revealed that frailty was associated with a two-fold greater risk of mortality, greater complications, and five-fold greater risk of non-home discharge [ 60 ]. In another systematic review and meta-analysis of 71 studies on adult patients undergoing cancer surgery, frailty was found to be related to a three-fold, two-fold, and four-fold greater risk of 30-day mortality, postoperative complications, and long-term mortality, respectively [ 15 ]. Our findings corroborate and extend the existing evidence on the association of preoperative frailty with postoperative adverse COs.

Factors other than age should be considered when predicting postoperative recovery in patients with degenerative spinal diseases [ 17 , 20 ]. The prevalence of frailty is increasing among individuals undergoing spine surgeries. Analysis of a patient population that underwent spine surgery, using data from the American College of Surgeons National Surgical Quality Improvement Program database, revealed that the number of frail patients doubled from 2005 to 2016 [ 44 ]. This suggests that frailty is an important variable to consider for risk stratification when predicting postoperative recovery in patients with degenerative spinal disease [ 17 , 20 ]. The frailty score may serve as a preoperative screening tool to aid in decision-making and perioperative management. It can help monitor patients’ health, thereby allowing healthcare professionals to identify high-risk patients and develop better treatment strategies. It can also help guide discussions among healthcare professionals, patients, and family members to reduce surgical vulnerability, enable pre-habilitation to increase patient resilience, and customize perioperative care [ 64 , 65 ].

In our qualitative synthesis, clinical outcomes were identified as health-related outcomes in all but one study [ 47 ]. Postoperative complications can be divided into general and surgery-related complications. Supportive management strategies include blood transfusions and unplanned intubations; these represent additional supportive care provided to patients with problems that are not part of the normal recovery process.

Among the COs in this study, 19 items were synthesized for quantitative analysis, and 3–9 studies participated in the synthesis. If there are fewer than 10 studies, statistical confirmatory tests for publication bias (e.g. the funnel test) are not recommended [ 25 ]; thus, publication bias could not be confirmed in this study. Therefore, items that showed heterogeneity, such as any complications, pneumonia, length of hospital stay, non-home discharge, and reoperation, should be interpreted carefully. In case of any complications, a sensitivity analysis was performed because the number of studies was considerably large and heterogeneity was noted across the studies. This analysis identified two studies as outliers [ 29 , 35 ], and the synthesis was attempted again by excluding them. The re-analysis revealed that the heterogeneity improved and the effect size did not affect the existing results.

The meta-analysis of the clinical outcomes in this study revealed that the risk of mortality in the frail group was 2.5 times higher than that in the non-frail group. Furthermore, the probability of major complication, any complication, general complication, acute renal failure, cardiac arrest, deep vein thrombosis, myocardial infarction, pneumonia, pulmonary embolism, sepsis, stroke/cerebrovascular accident, surgical complication, deep-wound infection, implant-related complication, superficial surgical site infection, length of hospital stay, nonhome discharge, and reintubation was higher in the frail group than in the non-frail group. Notably, the order of complication prevalence was different between the robust and frail groups. In the robust group, the most common complication was relatively simple gastrointestinal complications, while in the frail group, relatively severe implant-related complications, which might necessitate reoperation, were the most common. The increased incidence of complications or the severity of complications in frail patients can be attributed to several factors. Frailty is linked to reduced immune function, which can result in compromised ability to cope with complications such as infections during the stress of post-surgery recovery [ 66 ]. Frailty is associated with decreased metabolic activity, such as high levels of glucose and LDL cholesterol, which can impair tissue nutrient supply and metabolic functions [ 67 ], ultimately hindering post-surgery recovery capacity. Furthermore, frailty is associated with low physical activity levels and reduced muscle mass [ 66 , 68 ], which might persist post-surgery, leading to compromised recovery due to limited physical activity. Healthcare professionals who deliver postoperative care to frail patients should be aware of these complications. This can lead to increases in the time of direct nursing care and the cost of physical resources such as ICU and rehabilitation, as well as convalescent care beds [ 69 ].

Another key knowledge gap that thwarts a more meaningful prognosis is the lack of data on PROs. Studies have paid considerable attention to frailty as an important preoperative risk indicator for COs [ 15 , 61 ]; similar studies for PROs are few. Data on cognitive outcomes, functional outcomes, and quality of life are lacking. In our systematic review, only 11 of 38 studies reported the effects of frailty on the PROs (e.g., quality of life, ODI, and pain); the multidimensional health status of patients was reported in just six studies [ 13 , 29 , 40 , 47 , 50 , 54 ]. The wide variety of outcome measures limited the comparison of results among the included studies. The meta-analysis revealed that frailty was not significantly associated with the postoperative ODI and changes in the perioperative ODI; however, it had a conflicting relationship with the COs. Specifically, compared to non-frail patients, frail patients experienced greater improvements in ODI, quality of life, and pain [ 47 ]. Such improvements are partly explained by corrections in postural deformity, as frail patients have worse preoperative sagittal imbalances than those who do not [ 70 , 71 ]. When choosing the best treatment options for patients with degenerative spinal diseases, it is necessary to consider their preferences and values [ 72 , 73 ]. Frailty assessment can help patients and their families make informed decisions before surgery. It highlights the need for future studies to determine the association between frailty and PROs in patients with degenerative spinal disease.

We identified the typologies of postoperative health-related outcomes associated with preoperative frailty in patients who underwent spine surgery for degenerative spinal disease. These typologies can inform the content and structure of pre-rehabilitation and customized educational programs for patients undergoing spine surgery. They can also be used as basic data for implementing programs or pathways to reverse frailty in patients with spinal diseases and improve their health-related outcomes. Furthermore, the identified typologies can help develop evaluation tools to evaluate frailty-associated health-related outcomes in patients undergoing spine and other surgeries.

Finally, frailty is an important prognostic marker for postoperative health-related outcomes in patients with degenerative spinal disease, but there is a lack of consensus on the best means to accurately and efficiently determine frailty in patients undergoing spine surgery. In this review and meta-analysis, 10 different frailty instruments (including the mFI-5, mFI-11, and ASD-FI) were used to define frailty, and the variability in the evaluations by the same tool was demonstrated. A review of 14 different tools used for the assessment of frailty in a population undergoing spine surgery (age: >18 years) revealed wide variabilities in the tool components, time required to complete the assessment, and efficacy of outcome prediction among the tools [ 74 ]. Furthermore, significant heterogeneity was observed among the tools with respect to the cut-off values for risk establishment and stratification. In acute care hospitals, it is difficult to determine the most suitable tool for clinical practice. Future studies must prospectively validate frailty tools to confirm their effectiveness and applicability as reliable risk-stratification tools for the diagnosis of frailty among patients with degenerative spinal disease.

This study has some limitations. First, a meta-analysis of some items could not be performed due to data heterogeneity. Specifically, although all patients underwent spine surgery, the severity of the surgery differed among the studies because of a mixture of fusion and decompression. Furthermore, the detection of COs differed due to a mixture of prospective and retrospective studies. There were inconsistencies among the studies in the definition of frailty and the scales used for frailty analysis. Furthermore, there was heterogeneity among the frailty tools used. Second, only less than half of the included studies were included in the meta-analyses due to insufficient data (e.g., some studies reported only comparing ratios; for the same patient in the same database, only the first studies published first were considered). Third, because there were few than 10 studies in our meta-analysis, we could not identify or evaluate publication bias.

The number of patients undergoing spine surgery for degenerative spinal diseases is increasing. Thus, despite the aforementioned limitations, our study is of high clinical value because it evaluated the effects of frailty on the health-related outcomes of these patients. Our findings can guide future studies and aid healthcare professionals who treat patients with degenerative spinal diseases.

This systematic review and meta-analysis identified frailty as a strong predictor of COs in patients after spine surgery; however, preoperative frailty and PROs are still inconclusive. Further studies are needed to investigate the association between frailty and PROs. With the increasing number of frail patients undergoing spine surgery for degenerative spinal diseases, healthcare professionals should be aware of the effects of frailty and develop improved and focused perioperative management strategies for stratified frail patients. In particular, the development of interventions comprising treatment goals and plans that consider preoperative frailty as a risk factor for mortality and poor functional recovery can be an important cornerstone of preoperative management. Future research should focus on the development and implementation of interventions that could potentially improve postoperative cognitive, functional, and adverse outcomes in frail patients undergoing spine surgery.

Data Availability

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Abbreviations

Patient-reported outcome

Frailty index

Modified frailty index

Adult spinal deformity

Cervical deformity

The Risk of Bias Assessment Tool for Nonrandomized Studies

Confidence interval

Mean difference

Japanese Orthopaedic Association

Oswestry Disability Questionnaire

36-Item Short Form Survey

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We are grateful to Euna Ju of the research staff for supporting this study.

This work was supported by the National Research Foundation of Korea grant to WB, which is funded by the Korea government [Ministry of Science and ICT; grant number NRF-2021R1G1A1093450].

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Baek, W., Park, SY. & Kim, Y. Impact of frailty on the outcomes of patients undergoing degenerative spine surgery: a systematic review and meta-analysis. BMC Geriatr 23 , 771 (2023). https://doi.org/10.1186/s12877-023-04448-2

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DOI : https://doi.org/10.1186/s12877-023-04448-2

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BMC Geriatrics

ISSN: 1471-2318

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