targeted literature review methodology

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National Guideline Centre (UK). Evidence review for targets: Hypertension in adults: diagnosis and management: Evidence review D. London: National Institute for Health and Care Excellence (NICE); 2019 Aug. (NICE Guideline, No. 136.)

Evidence review for targets: Hypertension in adults: diagnosis and management: Evidence review D.

Appendix b literature search strategies.

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2017 .

For more detailed information, please see the Methodology Review.

B.1. Clinical search literature search strategy

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies for interventions as these concepts may not be well described in title, abstract or indexes and therefore difficult to retrieve. Search filters were applied to the search where appropriate.

Table 10 Database date parameters and filters used

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Table 11: Medline (Ovid) search terms

Table 12 embase (ovid) search terms, table 13 cochrane library (wiley) search terms, b.2. health economics literature search strategy.

Health economic evidence was identified by conducting a broad search relating hypertension in adults population in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional searches were run on Medline and Embase for health economics, economic modelling and quality of life studies.

Table 14 Database date parameters and filters used

Table 15 medline (ovid) search terms, table 16 embase (ovid) search terms, table 17 nhs eed and hta (crd) search terms.

• Cite this Page National Guideline Centre (UK). Evidence review for targets: Hypertension in adults: diagnosis and management: Evidence review D. London: National Institute for Health and Care Excellence (NICE); 2019 Aug. (NICE Guideline, No. 136.) Appendix B, Literature search strategies.
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• NICE Guideline 136: Hypertension in adults: diagnosis and management

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• Cost-effectiveness analysis: Treatment initiation threshold for people with stage 1 hypertension (PDF)

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Introduction, acknowledgements, supplementary data.

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Targeted literature review of current treatments and unmet need in moderate rheumatoid arthritis in the United Kingdom

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Peter C Taylor, Matthew Woods, Catherine Rycroft, Priya Patel, Sophee Blanthorn-Hazell, Toby Kent, Marwan Bukhari, Targeted literature review of current treatments and unmet need in moderate rheumatoid arthritis in the United Kingdom, Rheumatology , Volume 60, Issue 11, November 2021, Pages 4972–4981, https://doi.org/10.1093/rheumatology/keab464

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The burden and treatment landscape of RA is poorly understood. This research aimed to identify evidence on quality of life, caregiver burden, economic burden, treatment patterns and clinical outcomes for patients with moderate RA in the United Kingdom.

A systematic literature review was performed across multiple databases and screened against pre-defined inclusion criteria.

A total of 2610 records were screened; seven studies presenting evidence for moderate RA were included. These patients were found to incur substantial burden, with moderate to severe levels of disability. Compared with patients in remission, moderate RA patients reported higher levels of disability and decreased EQ-5D utility scores. The majority of patients did not feel that their current therapy adequately controlled their disease or provided sufficient symptom relief. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) have not approved advanced therapies (such as biological disease-modifying anti-rheumatic drugs) for patients with moderate disease, which restricts access for these patients.

The evidence available on the burden of moderate RA is limited. Despite current treatments, moderate RA still has a substantial negative impact, given that a DAS28 disease activity score defined as being in the moderate range does not qualify them for access to advanced therapies in the United Kingdom. For these patients, there is a particular need for further studies that investigate their burden and the impact of treating them earlier. Such information would help guide future treatment decisions and ensure the most effective use of resources to gain the best outcomes for patients with moderate RA.

The impact of persistent moderately active rheumatoid arthritis is poorly understood, with limited evidence available.

Available evidence indicates that moderately active rheumatoid arthritis incurs a substantial disease burden.

Access to advanced therapies in the United Kingdom is restricted for moderate rheumatoid arthritis patients.

RA, an autoimmune disease and the most common form of inflammatory polyarthritis [ 1 , 2 ], affects ∼400 000 people in the United Kingdom. Symptoms include fatigue, depression and swollen, stiff and painful joints. Left untreated or undermanaged, RA is characterized by chronic pain, disability, and a 32% excess risk of mortality compared with people of the same age who do not have RA [ 3 ]. RA causes joint damage in 80–85% of patients, with particularly rapid damage occurring during the first 2 years of the disease [ 4 ], highlighting a need for early treatment.

Although RA currently has no cure, the treatment landscape includes disease-modifying anti-rheumatic drugs (DMARDs) to reduce systemic and local inflammation. With reduced inflammation, symptoms improve, structural damage to joints is delayed, and function is preserved. Other treatments include plain analgesics and non-steroidal anti-inflammatory drugs, which target pain but do not prevent the patient’s joints from being eroded by RA.

In the United Kingdom, patients are eligible for different treatments based on their disease activity, defined by the 28-joint disease activity score (DAS28). Patients with moderate RA receive conventional synthetic DMARDs (csDMARDs). Those with severe RA, who have poor response to a combination of csDMARDs, are eligible for advanced therapies [ 5 ]; biological DMARDs (bDMARDs), such as anti-TNF monoclonal antibodies, and small-molecule targeted synthetic DMARDs (tsDMARDs), such as Janus kinase (JAK) inhibitors.

The burden and treatment landscape of RA in the United Kingdom is poorly understood, particularly for patients with moderate RA whose therapeutic options are limited. This literature review identifies evidence for the management of moderate and severe RA in the United Kingdom, the impact on healthcare resource use and costs, symptoms, patient and caregiver quality of life (QoL), disease progression and treatment outcomes.

Comprehensive, targeted literature searches were performed on 17 October 2018 across multiple literature databases using a combination of MeSH ® and free-text terms for RA, disease severity, treatment patterns, QoL, caregiver burden, economic burden and clinical outcomes ( Supplementary Tables S1–S3 , available at Rheumatology online). Websites were searched for conference proceedings and clinical guidelines. Manual bibliography searches of included studies and review of sources identified by the authors and clinical experts were also performed. To identify the latest relevant evidence for the United Kingdom, database searches were restricted to English-language publications, published within the previous 5 years (from August 2013), conducted in humans; conference searches were limited to abstracts published from 2016.

Title and abstracts and full text screening were performed by one researcher, as per the predefined inclusion criteria ( Table 1 ). Any uncertainty was judged by a second researcher. Relevant data were extracted, stratified by moderate, moderate to severe, and severe disease (see the Supplementary Material , available at Rheumatology online, for additional detail).

Eligibility criteria for inclusion in the targeted literature review

DMARDs: disease-modifying anti-rheumatic drugs; JAK: Janus kinase.

The searches for real-world evidence studies were not restricted by outcomes, and all relevant studies were included.

Interventions included evidence for biosimilars, where available.

The database searches were not restricted by country of interest to avoid missing any potentially relevant studies due to issues with referencing in the databases. Instead, the restriction to focus the review on UK studies was applied during screening.

Overview of findings

Fig. 1 presents the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart [ 6 ]. A total of 2610 records were retrieved from the literature databases and screened; 51 met the predefined inclusion criteria. Of these 51 references, four were included from the manual review. Table 2 presents a breakdown of the included topic areas alongside the number of identified references for moderate, severe, and a mixed population of moderate and severe RA. Several publications provided evidence for more than one topic of interest. Most studies ( n  = 38) focussed on patients with moderate or severe disease, with data not split by disease severity. Nine articles focussed on severe RA and four on moderate RA. In addition, of the articles that reported a mixed population, three reported results separately by disease severity.

PRISMA flow diagram

*includes three studies that presented evidence separately for moderate RA patients within a study of moderate to severe RA. Exclusion reason of ‘Population’ includes studies in patients other than those with RA; exclusion reason ‘Study design’ includes studies that did not report information for the topics of interest based on their design (e.g. in vitro studies or commentaries); exclusion reason ‘Intervention’ includes studies investigating non-pharmaceutical interventions; exclusion reason ‘Outcomes’ includes studies that did not present evidence for any of the topics of interest; exclusion reason ‘Other’ includes studies with no UK data or abstracts published before 2016. Adapted from Moher et al. , 2009 [ 6 ]. PRISMA, Preferred Reporting Items for Systemic Reviews and Meta-Analyses.

Summary of papers identified by topic and disease severity

Including one where data were analysed by severity. b Including two where data were analysed by severity. c Some articles provided evidence for more than one topic area. d Including three where data were analysed by severity.

Summary of identified literature

A key finding of the review was that evidence regarding the unmet need for patients with moderate RA is limited while that for moderate to severe and severe RA is better understood. Therefore, this article focusses on the evidence identified for moderate RA; Table 3 presents the included moderate RA studies, along with the topics reported within each. The findings for moderate to severe and severe RA are summarized in the Supplementary Material , available at Rheumatology online.

Studies presenting evidence for moderate RA

Study presented evidence for moderate RA patients within a study of moderate to severe RA.

Summary of treatment guidelines

Key treatment guidelines commonly used by UK clinicians are provided by the National Institute for Health and Care Excellence (NICE) [ 5 ], the Scottish Intercollegiate Guidelines Network (SIGN) [ 7 ], the British Society for Rheumatology/British Health Professionals in Rheumatology (BSR/BHPR) [ 8 ] and the EULAR [ 9 ]. The guidelines from NICE and SIGN are generally consistent, both providing the following key recommendations [ 5 , 7 ]:

csDMARDs as first-line therapy (i.e. methotrexate and sulfasalazine; NICE also recommends another option, leflunomide); and

bDMARDs (adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, abatacept and tocilizumab) when disease activity score DAS28 is >5.1 (i.e. severe disease) and patients display a lack of response to intensive csDMARDs.

The SIGN guidelines differ from NICE recommendations by suggesting a combination DMARD strategy, rather than sequential monotherapy, in patients with an inadequate response to initial DMARD therapy [ 7 ]. The BSR/BHPR guidelines have not been updated since 2010 [ 8 ].

The EULAR guidelines were last updated in December 2019 [ 9 ]. This update specifies methotrexate as first-line therapy, or leflunomide or sulfasalazine where methotrexate is contraindicated. Like SIGN, EULAR recommends combination therapy with csDMARDs and advanced therapies to achieve treatment targets [ 9 ]. If the target is not achieved, other csDMARDs should be used, or advanced therapies added if poor prognostic factors are present. The two key changes to the recommendations since 2016 are [ 10 ]:

the preference of bDMARDs over tsDMARDs, including JAK inhibitors, was revised, placing tsDMARDs alongside bDMARDs in the treatment pathway; and

for patients not fully responsive to a csDMARD and with poor prognostic factors, the previous recommendation—to ‘consider adding’ a bDMARD or tsDMARD—is replaced by the stronger recommendation ‘to add’ a bDMARD or tsDMARD (current practice would be to start with a bDMARD).

Cost and healthcare resource use

Six studies were identified reporting evidence for costs and healthcare resource use: one considered a mixed RA population and presented data separately for patients with moderate RA; three considered use in patients with moderate to severe RA; two considered use in patients with severe RA. The data for patients with moderate RA are presented here; moderate to severe and severe data are summarized in the Supplementary Material , available at Rheumatology online.

Bergstra et al. (2018) [ 11 ] reported the relative lack of access to advanced therapies in the moderate RA population in the United Kingdom, which achieved the lowest clinical criteria score for access to bDMARDs (a composite score taking into account prescription and reimbursement rules) across the 12 included comparator countries [the United States (state of Massachusetts), Mexico, South Africa, Japan, Brazil, the United Kingdom, Spain, Ireland, Portugal, France, India (state of Maharashtra) and the Netherlands]. The United Kingdom was also reported to only have 14.7% of patients using bDMARDs (across the overall RA population); the lowest across all included countries (Spain 16.3%, the Netherlands 28.2%, Portugal 44.5%, the United States 48.6%, Japan 50.5%, France 60.2% and Ireland 75.0%). Their analysis suggested that this lower UK bDMARD usage rate may be due to relatively strict prescription and reimbursement rules in the United Kingdom.

The study also reported a correlation between Gross Domestic Product (GDP) per capita and DAS28 remission. However, while the United Kingdom has a relatively high GDP per capita, it had one of the lowest percentages of patients in DAS28 remission (26.0%), most likely related to the low use of bDMARDs. Indeed, a statistically significant relationship between bDMARD use and patients in DAS28 remission was identified.

Humanistic burden of disease

Twenty-four studies were identified presenting evidence on the humanistic burden of RA: four moderate, 18 moderate to severe and two severe RA. Two of the mixed population studies presented data separately by disease severity; the evidence for patients with moderate RA is presented here; the moderate to severe and severe evidence is summarized in the Supplementary Material , available at Rheumatology online.

In a retrospective study using the BSR Biologics Register for RA (BSRBR-RA), comparing patients with moderate RA treated either with etanercept or csDMARDs, those treated with etanercept had significantly higher disease activity at the time treatment was initiated [ 12 ]. At baseline, the patients treated with etanercept were significantly more likely to be unemployed because of disability (33% vs 16%), had a longer disease duration (14.1 vs 10.2 years), numerically higher DAS28 score (4.6 vs 4.4), a higher level of disability [HAQ Disability Index (HAQ-DI) 1.9 vs 1.5], and a poorer health-related QoL (HRQL), as measured by the 36-item Short Form Health Survey physical component score (27.3 vs 29.8), than patients treated with csDMARDs ( P <0.001 for all). However, these patients had significantly reduced disease activity and better HRQL after 6, 12 and 24 months of treatment compared with patients receiving csDMARD therapy.

One study used a series of patient interviews to investigate the importance of self-care in patients with moderate RA [ 13 ], reporting that patients experienced frustration and even depression as a result of their condition. The majority of patients (six out of nine) did not feel their treatment regimen adequately controlled their disease or provided sufficient symptom relief. However, as a result, they were more open to trying intensive management (by addition of advanced therapies to concomitant csDMARDs). Patients hoped that intensive management would improve their physical symptoms through reduced pain, improved mobility and increased independence.

The other studies in patients with moderate RA were broadly consistent, with HAQ-DI scores ranging from 1.0 to 1.4, indicating moderate to severe levels of disability [ 11 , 14–17 ]. One study reported that compared with patients in remission, HAQ-DI scores in patients with moderate RA were increased by 1.06, and EQ-5D scores were reduced by 0.27 [ 15 ]. HAQ-DI scores were found to progress at a significantly faster rate in all DAS28 categories (including for patients with moderate RA) compared with patients in remission [ 17 ]; as DAS28 scores increased (even within disease severity categories), HAQ-DI scores also increased, as did the rate of HAQ-DI progression [ 17 ].

Caregiver burden of disease

Limited evidence was found reporting the burden for caregivers of patients with RA: one study in moderate RA and no studies in the moderate to severe or severe populations. Caregivers were concerned by the lack of continuity of care for patients, and their main hope was that access to intensive management strategies would increase independence and improve mobility [ 13 ]. However, caregivers’ views were affected by how stable patients were with their current treatment. Basically, caregivers felt stability would be lost when treatments changed.

Treatment patterns

A total of 29 studies presented evidence on treatment patterns: two for moderate, 19 for moderate to severe, and eight for severe RA. The evidence on treatment patterns presented within the moderate studies was extremely limited; therefore, the evidence for the overall RA population is summarized here, focussing on patients with moderate to severe RA.

The studies show that the use of csDMARDs has increased dramatically over time. Researchers report up to 87% of patients have received csDMARDs [ 16 ] (70–87%) [ 16 , 18 , 19 ], with methotrexate the most commonly used treatment (60–88%) [ 18–20 ]. The use of combination csDMARDs has also increased, although the wide range of reported results across the included studies makes it difficult to identify the leading treatment (24–76.3%) [ 16 , 19 , 21 ].

The use of bDMARDs has also increased, although not to the same extent as csDMARDs. In a study of patients who had been initiated on advanced therapies between 2009 and 2010, 23% of patients received only monotherapy with no concomitant csDMARD [ 20 ]. A UK-wide audit of patients with RA between May 2012 and December 2015 showed only 4% received advanced therapies, most commonly etanercept [ 22 ]. However, only 36% of patents eligible for advanced therapies actually received them [ 22 ].

Steroid use was found to vary widely across the United Kingdom ( Table 3 for moderate RA; Supplementary Material , available at Rheumatology online, for moderate to severe and severe RA). A single study was identified in patients with moderate RA, reporting that 23% of patients received steroids [ 15 ]. In patients with moderate to severe RA, steroid use was largely unchanged between 1996 and 2014, staying at ∼12% despite increased use of csDMARDs [ 16 ]. Another study of csDMARDs in patients with moderate to severe RA, undertaken in a single centre, found an extremely high number of patients receiving steroids: 51–65% at baseline rising to 67–78% by the end of 12 months of treatment [ 21 ].

Real-world clinical outcomes

A total of 28 publications were identified that presented evidence on real-world clinical outcomes: three for moderate, 17 for moderate to severe, and eight for severe RA. A summary of key outcomes for the identified studies is presented in Table 4 for moderate RA and in Supplementary Table S4 , available at Rheumatology online, for moderate to severe and severe RA.

Summary of real-world clinical outcomes in moderate RA

bDMARD: biologic DMARD; cs DMARD: conventional synthetic DMARD; DAS28: 28-joint disease activity score; DMARD: disease-modifying anti-rheumatic drug; EQ-5D: EuroQol 5-dimensions; HAQ-DI: HAQ Disability Index.

A significantly greater percentage of patients receiving etanercept (bDMARD) compared with those receiving csDMARDs achieved remission by 6 months (22.4% vs 13.4%, respectively; P < 0.05), 12 months (26.5% vs 16.9%, respectively; P < 0.05), and 24 months (27.5% vs 20.3%, respectively; P < 0.05), despite a significantly higher disease activity at the time of etanercept initiation [ 12 ]. A significantly greater percentage of patients receiving etanercept also achieved a low disease activity status (DAS28 2.6–3.2) compared with patients receiving csDMARDs at 6 months (15.2% vs 12.6%, respectively; P < 0.05) and 24 months (19.4% vs 15.2%, respectively; P < 0.05). A significantly smaller proportion of patients had no change in disease activity, no EULAR response, or experienced disease progression when treated with etanercept compared with csDMARDs (all P < 0.05).

A prospective cohort study evaluated disease activity and outcomes at a single centre aiming to treat to a target DAS28 < 2.6(16), reporting that remission increased from 18% to 27% after a 10-year follow-up. Mean DAS28 and HAQ-DI scores and the proportion of patients with high disease scores (i.e. severe disease) decreased. However, 22% of patients had persistently high disease activity despite treatment with csDMARDs, often in combination with each other, and a range of advanced therapies. Only 9% of patients with persistent high disease activity were receiving advanced therapies, compared with 18–20% of other groups ( P = 0.034). Patients with RA, persistent moderate disease activity and a moderate disability also failed to reach the treat-to-target goal of remission/low disease activity [ 14 ]. These patients continued to have moderate disease and persistent moderate disability even after 12 months of treatment.

Current treatment guidelines are generally aligned, at least when it comes to the use of csDMARDs. According to NICE, csDMARDs (methotrexate, sulfasalazine or leflunomide hydroxychloroquine) are recommended for patients with newly diagnosed RA (as first-line therapy). As RA progresses, treatment options are generally dependent on treatment response and disease severity. Initially, increased csDMARD therapy is recommended, but bDMARDs (typically an anti-TNF initially) may be used where strict criteria are met, including severe disease activity (DAS28 > 5.1) and lack of response to csDMARD combinations. The 2019 update to the EULAR guidelines has also now moved tsDMARDs, which include JAK inhibitors, alongside bDMARDs in the treatment pathway. Here, the notable difference from NICE is that the recommended threshold of disease activity to access advanced therapies is set at DAS28 > 3.2. These strict criteria recommended by NICE may explain why the use of advanced therapies in patients with moderate RA is so low in the United Kingdom, despite the continued and substantial burden of disease these patients experience and that their disease may not be properly controlled using conventional therapy. The evidence indicates a lack of consistency in treatment for patients in the United Kingdom and a significant proportion of patients not receiving appropriate treatment. Widening access to advanced therapies, including JAK inhibitors and biologic therapies, for patients with moderate disease in the United Kingdom would meet a key unmet need in RA. This assumption is supported by a recent UK study [ 23 ] that concluded that patients with moderate RA may benefit from more aggressive, advanced therapy. However, the costs of bDMARDs would need to be reduced by nearly 50% to be considered a cost-effective use of National Health Service (NHS) resources, according to a recent NICE multiple technology appraisal assessing the cost-effectiveness of bDMARDs in patients with moderate RA [ 24 ]. The introduction of cheaper biosimilar products, which are anticipated to be cost-effective in moderate RA, and therefore more likely to be available on the NHS for these patients, may lead to a change in the UK reimbursement landscape for moderate RA.

For patients with moderate disease, RA has been shown to incur a substantial burden in terms of healthcare resource use and costs, increased absenteeism and presenteeism, as well as the humanistic burden for both patients and their caregivers, although evidence on caregiver burden is extremely limited. Even with existing treatment options, a substantial proportion of patients remain outside of disease remission. Although use of advanced therapies does improve outcomes, there is still a large unmet need for patients with moderate disease, who have limited access to these therapies. Increasing access to these more effective therapies and encouraging access earlier in the disease course may help to reduce the burden and improve outcomes for patients with moderate RA.

Despite having what are considered more acceptable DAS28 disease scores, patients with moderate disease still face substantial burdens, with patients stating a desire for reduced pain, better mobility and increased independence. These patients were shown to have significant levels of disability and poor HRQL, a significant level of unemployment due to disability (16–33%), and a prolonged period of time with disease symptoms (10.2–14.1 years). After 6, 12 and 24 months of treatment with advanced therapies, however, these patients had significantly reduced disease activity and better HRQL compared with patients receiving csDMARD therapy, which highlights the substantial humanistic burden for patients with moderate RA and the importance of advanced therapies in helping to reduce this burden. The evidence identified also highlights the importance of providing detailed information on medications to both patients and their caregivers to put their minds at ease. However, there is a clear paucity of evidence available specific to the moderate RA population, particularly for fatigue, pain and limitations of activities, which are shown to be key drivers of the patient burden for the more widely reported ‘moderate to severe’ population. Thus, there is a need for more evidence to better understand the substantial burden in the moderate RA population and help drive treatment decisions in the future.

The use of steroids remains controversial due to the well-documented risks of treatment, including cardiovascular morbidity, infection and osteoporosis. The evidence on steroid use for the overall RA patient population (only one study reported data for moderate patients) varies between studies, between treatment centres and across regions, which makes it difficult to understand the full extent of the associated burden in UK clinical practice. Additionally, this variability is also likely due to the difficulties in accurately capturing steroid use for these patients. However, from the available evidence, there is still a substantial proportion of patients with RA receiving steroid treatment alongside their csDMARD therapy and, despite advances in available and effective targeted therapies, there is the potential that this burden is still extremely high. It is probable that the high disease activity threshold set by NICE for access to targeted therapies is the driver for the ongoing use of steroids in an effort to better control symptoms despite the associated longer-term risks. These points highlight the pressing need for the use of safe and effective treatments to reduce steroid use in these patients.

As with all literature reviews, both the current review and the identified data have certain limitations. First, the database searches were limited to evidence published within the past 5 years. While this ensured that only the most recent—and therefore most relevant—data were found, it does leave the potential for omitting older evidence that may still have provided useful information. Second, given the nature of the studies themselves, the literature identified in this type of review is often heterogeneous, making comparisons between the studies or synthesis of the data challenging. Finally, in areas where evidence is limited, such as in this review and particularly for patients with moderate RA, the evidence base is often restricted to small numbers of studies that report different outcomes or present evidence in different ways, which makes it difficult to check for consistency across results and ensure that an accurate view of the evidence base is being presented.

Although the evidence available on the burden of RA is limited, particularly for moderate disease, there appears to be a significant impact on patients, even with advances in treatment options. This impact is most apparent in patients with RA whose DAS28 disease activity does not qualify them for access to advanced therapies but who still face a substantial disease burden. For the relatively poorly understood moderate RA population in particular, who are not currently eligible for advanced therapies in the United Kingdom, there is a need for further studies that investigate the burden for these patients and the impact of treating them earlier. Such information would help guide treatment decisions in the future and ensure the most effective use of resources to gain the best outcomes for patients.

P.C.T. would like to thank the Oxford NIHR Biomedical Research centre for their support.

Funding : This literature review was conducted by Bresmed Health Solutions Ltd and funded by AbbVie Ltd. Bresmed spent time conducting the burden of illness review and preparing, writing and reviewing the manuscript. As well as funding the study, AbbVie Ltd contributed to the design, reviewed the analysis and interpretation of the data and participated in writing, reviewing and approval of the manuscript.

Disclosure statement : P.C.T. is Norman Collisson Professor of Muscoloskeletal Sciences, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. P.C.T. has received research grants from Celgene, Galapagos, Gilead and Lilly, and has received consultation fees from AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Nordic Pharma, Fresenius and UCB. M.B. is a Consultant Rheumatologist at the University Hospitals of Morecambe Bay and an Honorary Senior Lecturer at the University of Manchester. M.B. has been sponsored to attend regional, national and international meetings by UCB celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Janssen, Bristol-Myers Squib, Novartis and Eli-lilly. He has received honoraria for speaking and attended advisory boards with Bristol-Myers Squib, UCB celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Sanofi-Aventis, Eli-Lilly, Janssen, Amgen, Novartis and Gilead. He has received honoraria from educational groups Revalidaid and TREG consultants. S.B.-H. is an employee of AbbVie Ltd. P.P. is a former employee of AbbVie Ltd. T.K. is an employee of and owns stocks in AbbVie Ltd. M.W. and C.R. are employees of Bresmed Health Solutions Ltd.

Data availability statement

No new data were generated or analysed in support of this research. The evidence underlying this article are available in the article and in its online supplementary material .

Supplementary data are available at Rheumatology online.

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Overview of the Integrative Review

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A reviewer selects literature on a topic and synthesizes and disseminates review findings to a targeted discipline. There are many review methods available for a reviewer to consider. The review question(s) will determine which review method is most appropriate to use. If the reviewer seeks to examine a topic broadly and wants to identify the current state of science on a particular phenomenon, an integrative review would be the method chosen. There are limited resources available to a reviewer to access when seeking guidance on how to conduct an integrative review. This chapter provides an overview of the integrative review method and provides a framework for the different steps that are recommended when conducting such a review.

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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

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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/ .

https://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.

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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.

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• 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: 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; 29 50-54 Published Online First: 19 Apr 2023. doi: 10.1136/bmjebm-2022-112111
• 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; 29 55-61 Published Online First: 19 Apr 2023. doi: 10.1136/bmjebm-2022-112070

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Rapid evidence assessment: increasing the transparency of an emerging methodology

Affiliations.

• 1 Phoenix Australia and Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia.
• 2 Optum, Sydney, New South Wales, Australia.
• 3 Adelaide Health Technology Assessment (AHTA), School of Population Health, University of Adelaide, Adelaide, South Australia, Australia.
• 4 Department of Veterans' Affairs, Canberra, Australian Capital Territory, Australia.
• PMID: 26123092
• DOI: 10.1111/jep.12405

Rationale, aims and objectives: Within the field of evidence-based practice, policy makers, health care professionals and consumers require timely reviews to inform decisions on efficacious health care and treatments. Rapid evidence assessment (REA), also known as rapid review, has emerged in recent years as a literature review methodology that fulfils this need. It highlights what is known in a clinical area to the target audience in a relatively short time frame.

Methods: This article discusses the lack of transparency and limited critical appraisal that can occur in REA, and goes on to propose general principles for conducting a REA. The approach that we describe is consistent with the principles underlying systematic review methodology, but also makes allowances for the rapid delivery of information as required while utilizing explicit and reproducible methods at each stage.

Results: Our method for conducting REA includes: developing an explicit research question in consultation with the end-users; clear definition of the components of the research question; development of a thorough and reproducible search strategy; development of explicit evidence selection criteria; and quality assessments and transparent decisions about the level of information to be obtained from each study. In addition, the REA may also include an assessment of the quality of the total body of evidence.

Conclusions: Transparent reporting of REA methodologies will provide greater clarity to end-users about how the information is obtained and about the trade-offs that are made between speed and rigour.

Keywords: methods development; rapid evidence assessment; rapid review; review methodology.

© 2015 John Wiley & Sons, Ltd.

Publication types

• Research Support, U.S. Gov't, Non-P.H.S.
• Biomedical Research / standards*
• Data Accuracy
• Evidence-Based Medicine / standards*
• Observer Variation
• Prohibitins
• Review Literature as Topic*
• Time Factors

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Original research article, application of mixed reality navigation technology in primary brainstem hemorrhage puncture and drainage surgery: a case series and literature review.

• 1 Department of Neurosurgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing, China
• 2 Pre-hospital Emergency Department, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing, China
• 3 Qinying Technology Co., Ltd., Chongqing, China

Objective: The mortality rate of primary brainstem hemorrhage (PBH) is high, and the optimal treatment of PBH is controversial. We used mixed reality navigation technology (MRNT) to perform brainstem hematoma puncture and drainage surgery in seven patients with PBH. We shared practical experience to verify the feasibility and safety of the technology.

Method: We introduced the surgical procedure of brainstem hematoma puncture and drainage surgery with MRNT. From January 2021 to October 2022, we applied the technology to seven patients. We collected their clinical and radiographic indicators, including demographic indicators, preoperative and postoperative hematoma volume, hematoma evacuation rate, operation time, blood loss, deviation of the drainage tube target, depth of implantable drainage tube, postoperative complications, preoperative and 1-month postoperative GCS, etc.

Result: Among seven patients, with an average age of 56.71 ± 12.63 years, all had underlying diseases of hypertension and exhibited disturbances of consciousness. The average evacuation rate of hematoma was 50.39% ± 7.71%. The average operation time was 82.14 ± 15.74 min, the average deviation of the drainage tube target was 4.58 ± 0.72 mm, and the average depth of the implantable drainage tube was 62.73 ± 0.94 mm. Among all seven patients, four patients underwent external ventricular drainage first. There were no intraoperative deaths, and there was no complication after surgery in seven patients. The 1-month postoperative GCS was improved compared to the preoperative GCS.

Conclusion: It was feasible and safe to perform brainstem hematoma puncture and drainage surgery by MRNT. The technology could evacuate about half of the hematoma and prevent hematoma injury. The advantages included high precision in dual-plane navigation technology, low cost, an immersive operation experience, etc. Furthermore, improving the matching registration method and performing high-quality prospective clinical research was necessary.

Introduction

Primary brainstem hemorrhage (PBH) is spontaneous brainstem bleeding associated with hypertension unrelated to cavernous hemangioma, arteriovenous malformation, and other diseases. Hypertension is the leading risk factor for PBH, and other elements include anticoagulant therapy, cerebral amyloid angiopathy, et al. PBH is the deadliest subtype of intracerebral hemorrhage (ICH), accounting for 6%–10% of all ICH with an annual incidence of approximately 2–4/100,000 people [ 1 – 3 ]. The clinical characteristics of PBH are acute onset, rapid deterioration, poor prognosis, and high mortality (30%–90%) [ 1 , 4 , 5 ].

The inclusion criteria of previous ICH research all excluded PBH, such as STICH and MISTIE trials. There is no clear evidence for the optimal treatment of PBH, and the view of surgical treatment has noticeable regional differences. European and North American countries generally believe that severe disability or survival in a vegetative state is a high mental and economic burden for PBH patients and their families. These countries do not favor surgical treatment. However, many PBH surgical treatments have been carried out in China, Japan, and South Korea. Surgical treatment methods, surgical effects, monitoring methods, and complications have been investigated, and much experience has been accumulated.

In 1998, Korean scholars performed the first craniotomy to evacuate the brainstem hematoma [ 6 ]. However, in 1989, the Japanese scholar Takahama performed stereotactic brainstem hematoma aspiration surgery [ 7 ]. In our opinion, microsurgery craniotomy requires high electrophysiological monitoring and surgical skills, and these limitations are not conductive to popularization. Minimally invasive surgery has the characteristics of a simple operation, minimally invasive, and short operation time, and it is believed to reduce the damage to critical brainstem structures and protect brainstem function as much as possible. More and more minimally invasive treatments have been adopted to improve the precision of PBH puncture, including stereotactic frameworks, robotic-assisted navigation systems, 3D printing techniques, and even laser combined with CT navigation techniques.

Mixed reality navigation technology (MRNT) is based on virtual and augmented reality development. The technology uses CT images to construct a 3D head model and design an individual hematoma puncture trajectory. The actual environmental position is captured by a camera during surgery and was fused with 3D head model synchronously. MRNT not only display the model image combined with actual environment but also navigate the puncture trajectory in real time, allowing the surgeon to precisely control puncture angle and depth to achieve a perfect procedure. This technology makes the head utterly transparent during the surgery and brings an immersive experience to the surgeon.

MRNT has broad application prospects. However, it is still in its infancy, and its application in neurosurgery has rarely been reported. Furthermore, there is no report on application of MRNT in the surgical treatment of PBH. In this study, we used MRNT to perform brainstem hematoma puncture and drainage surgery in seven patients with PBH to share practical experience to verify the feasibility and safety of the technology.

Materials and methods

General information.

With the approval of the Ethics Committee of the Chongqing Emergency Medical Center, we included seven patients diagnosed with PBH from January 2021 to October 2022. All underwent brainstem hematoma puncture and drainage surgery with MRNT under general anesthesia. Indications for surgery were patients who 1) were 18–80 years of age; 2) had hematoma volume greater than 5 mL and less than 15 mL; 3) had a diameter of the hematoma greater than 2 cm; 4) had hematoma deviating toward one side or the dorsal side; 5) had GCS less than 8; and 6) had surgery within 6–24 h after onset. Family members were informed and signed the consent form [ 8 ]. Exclusion criteria were patients who had 1) brainstem hemorrhage caused by cavernous hemangioma, arteriovenous malformation, and other diseases; 2) GCS >12; 3) bilateral pupil dilation; 4) unstable vital signs; 5) severe underlying disease; or 6) coagulation dysfunction.

Mixed reality navigation technology (MRNT)

All patients preparing for surgery were required to wear sticky analysis markers in the parieto-occipital region and undergo a CT scan before surgery. CT image scanning was performed with a 64-slice CT scanner (Lightspeed VCT 6, General Electric Company, United States of America). The image parameters included in the exposure were 3 mAS, the thickness was 5mm, and the image size was 512 × 512. The DICOM data were analyzed to construct the 3D model of the hematoma and head, and the volume of brainstem preoperative hematoma was calculated using software (Medical Modeling and Design System). In addition, the hematoma puncture trajectory was designed according to the constructed head model.

After general anesthesia, the sticky analysis markers were replaced with bone nail markers, keeping the same position [ 9 ]. Based on the principle of near-infrared optical navigation, the camera captured the actual space position in real-time, fused it with the markers of the 3D head model (HSCM3D DICOM), and transmitted the information to the wearable device (HoloLens). During surgery, the camera continuously tracked the position of the puncture needle to achieve navigation function. In short, the image processing software matched and fused information from camera systems and wearable device through multiple markers. When controlling the movement of surgical tools, the software also processed the dynamic tool position data and fused it with the virtual model through wireless transmission.

Surgical procedures

Hydrocephalus patients were first treated with external ventricular drainage (EVD), and the frontal Kocher point was selected as the cranial entry point. The procedures were cutting the skin, drilling the skull, cutting the dura mater, puncturing in the direction of the plane of binaural connection, fixing the drainage tube, and suturing it layer by layer.

The patient was placed in a prone position with the head frame fixed. The puncture point was 2 cm below the transverse sinus and 3 cm lateral to the midline of the hematoma side. After cutting the skin, the muscle was separated. The dura mater was cut through a drilled hole. Wearing HoloLens, the surgeon synchronously observed actual head structure and fused puncture trajectory from multiple angles and used dual-plane navigation technology [ 9 ] for hematoma puncture. After watching that the drainage tube was in place, the puncture needle was removed, and a 5 mL empty syringe was connected for suction. The drainage tube was fixed and sutured layer by layer. The head CT was reviewed immediately after the surgery, and the decision whether to inject urokinase according to the drainage tube’s position and the residual hematoma volume. Urokinase was injected from a drainage tube for 2-3 w units every 12 h, usually 4–6 times, and kept for 1.5 h before opening the tube. The retention time of the drainage tube was no more than 72 h after the surgery. The surgical procedure to apply MRNT is shown in Figure 1 .

Figure 1 . Surgical procedure for brainstem hematoma puncture and drainage surgery with MRNT (A) Patients were required to wear sticky analysis markers in the parieto-occipital region. (B) The camera captured the real space position of the calibration plate, puncture needle, and head. (C) Wearing HoloLens, the surgeon viewed the two planes of the image. (D) MRNT displays the model image and the actual environment synchronously, allowing the surgeon to perform precise surgery. (E) The real-time navigation of MRNT showed that the puncture needle was close to the hematoma target. (F) The surgeon was aspirating the hematoma.

Clinical and radiographic indicators

The indicators for analysis included: demographic indicators, preoperative and postoperative hematoma volume, hematoma evacuation rate, operation time, blood loss, deviation of the drainage tube target, depth of implantable drainage tube, postoperative complications, and preoperative and 1-month postoperative GCS, etc.

The deviation of the drainage tube target was defined as the distance between the tip of the drainage tube and the planned puncture hematoma target. The deviation calculation was done with the BLENDER 2.93.3 software, which used the 3D global coordinate system to visualize the distance.

The head CT examination was reviewed within 24 h after surgery, and the postoperative hematoma volume was measured by non-operators using previous software (Medical Modeling and Design System). Hematoma evacuation rate = (preoperative hematoma volume - postoperative hematoma volume)/preoperative hematoma volume.

Statistical analysis

All statistical analyses were performed with SPSS (version 21, IBM, Chicago, IL, United States). Quantitative variables are presented as means ± standard deviations. The normality of quantitative variables was assessed through the Kolmogorov-Smirnov test. If the distribution was found to be normal, paired t -test were performed. The categorical variables are presented as percentages and tested by χ2 or Fisher’s test. A p -value less than 0.05 was considered statistically significant.

From January 2021 to October 2022, seven patients were diagnosed with PBH and underwent brainstem hematoma puncture and drainage surgery with MRNT. A summary of the demographic and clinical characteristics of the patients was provided in Table 1 . Among the seven patients, five were men, with an average age of 56.71 ± 12.63 years (37–74 years). The seven cases had underlying hypertension, and four cases had diabetes. The average time from onset to admission was 4.2 ± 1.47 h. Seven patients had prominent disturbances of consciousness, four required ventilator assistance, and three had a high fever.

Table 1 . Demographic and clinical characteristics of seven patients.

According to the brainstem hematoma classification advocated by Chung [ 10 ], 2 cases belonged to small unilateral tegmental type, 4 cases belonged to basal-tegmental type, and other 1 case belonged to bilateral tegmental type. The average volume of preoperative brainstem hematoma was 8.47 ± 2.22 mL (range, 5.45–12.2 mL), the average volume of postoperative brainstem hematoma was 4.16 ± 1.17 mL (range, 3.14–5.95 mL), and the differences were significant. The average hematoma evacuation rate was 50.39% ± 7.71% (range, 41.65%–63.23%). Four of the seven patients underwent EVD first (57.1%), and one underwent EVD 2 days after hematoma puncture and drainage surgery. The average operation time was 82.14 ± 15.74 min, the average blood loss was 32.2 ± 8.14 mL, the average deviation of the drainage tube target was 4.58 ± 0.72 mm (range, 3.36–5.32 mm), and the average depth of the implantable drainage tube was 62.73 ± 0.94 mm (range, 61.42–64.23 mm). Three patients were injected with urokinase after surgery, and the average retention time of the drainage tube was 53.56 ± 7.83 h.

There were no intraoperative deaths in seven patients. Two patients had slight intraoperative fluctuations in vital signs. The most common postoperative comorbidity was pneumonia (7/7, 100%), followed by gastrointestinal bleeding (5/7, 71.43%). There were no rebleeding incidents, ischemic stroke, intracranial infection, or epilepsy within 2 weeks after surgery. The preoperative high fever symptoms were relieved after surgery. Only one patient died due to pneumonia 12 days after surgery, one patient gave up 20 days after surgery. Two patients were conscious and three patients were still in a coma 1 month after surgery.

The average preoperative GCS was 6.57 ± 1.51, and the average postoperative GCS was 10.00 ± 2.83 1 month after surgery. The improvement was statistically significant. The representative cases are shown in Figure 2 and Figure 3 .

Figure 2 . The representative case 2 (A) Preoperative CT showed PBH in the axial, sagittal, and coronal planes. (B) The 3D model constructed from CT images showed hematoma and designed the puncture trajectory from the axial, sagittal, and coronary positions. (C) Postoperative CT of the axial plane showed that the drainage tube location was precise. The yellow circle indicated the tip of the drainage tube. (D) Fusion of preoperative and postoperative 3D model showed that the preoperative hematoma volume was 5.45 mL, the postoperative hematoma volume was 3.18 mL, the hematoma evacuation rate was 41.65%, the deviation of the target drainage tube was 4.22 mm, and the depth of the implantable drainage tube was 63.42 mm.

Figure 3 . The representative case 5. (A) Preoperative CT showed PBH in the axial, sagittal, and coronal planes. (B) The 3D model constructed from CT images showed hematoma, lateral ventricular, and a designed puncture trajectory from axial, sagittal, and coronary positions. (C) Postoperative CT of the axial plane showed that the drainage tube location was precise. The yellow circle indicated the tip of the drainage tube. (D) Fusion of the preoperative and postoperative 3D model showed that the preoperative hematoma volume was 10.21 mL, the postoperative hematoma volume was 5.95 mL, the hematoma evacuation rate was 41.72%, the deviation of the drainage tube target was 3.36 mm. The depth of the implantable drainage tube was 61.84 mm.

The brainstem is small, deep in the skull, and includes the midbrain, pons, and medulla oblongata. The brainstem is the center of life, controlling respiration, heart rate, blood pressure, and body temperature. About 60%–80% of PBH occurs in the pons due to the rupture of the perforating vessels of the basilar artery [ 1 , 2 ]. Hypertension is one of the most common causes of severe cerebrovascular disease. By causing mechanical and chemical damage to essential structures in the brainstem, such as the nucleus clusters and the reticular system, the hematoma quickly induces clinical symptoms such as coma, central hyperthermia, tachycardia, abnormal pupils, and hypotension. The prognosis is extremely poor, which presents a challenge to existing treatment methods.

The conservative treatment strategy for PBH is mainly related to the hypertensive treatment strategy for ICH [ 11 ]. Since the primary damage of PBH is irreversible, surgical treatment is believed to relieve mechanical compression of the hematoma and prevent secondary injury, improving prognosis [ 1 , 12 , 13 ]. However, there have been some controversies about surgical treatment. Due to the high mortality and disability rate of PBH, it is necessary to strictly evaluate the indications for surgery. Indications for surgery proposed by Shresha included a hematoma volume greater than 5 mL, a relatively concentrated hematoma, GCS less than 8, progressive neurological dysfunction, and uneventful vital signs, particularly requiring ventilatory assistance [ 14 ]. Huang established a brainstem hemorrhage scoring system and suggested patients with a score of 2–3 might benefit from surgical treatment. A score of 4 was a contraindication to surgical treatment [ 15 ]. A review of 10 cohort studies showed that the patients in the surgical group were 45–65 years old, unconscious, with a GCS of 3–8, and the hematoma volume was approximately 8 mL. The surgical group had a better prognosis and lower mortality than the conservative treatment group. The research also suggested that older age and coma were not contraindications for brainstem hemorrhage surgery [ 16 ]. According to the Chinese guidelines for brainstem hemorrhage, we specified the following surgical indications: age 18–80 years old, hematoma volume greater than 5 mL and less than 15 mL, hematoma diameter greater than 2 cm, hematoma deviated to one side or the dorsal side, GCS less than 8, surgery performed within 6–24 h after onset, and family consent [ 8 ].

The surgical treatments for PBH included microscopic craniotomy to evacuate the hematoma, which removed the hematoma as much as possible, performed hemostasis, and removed the fourth ventricular hematoma to smooth the circulation of cerebrospinal fluid. However, this technology required various intraoperative monitoring methods and proficient surgical skills. The most widely chosen method was stereotactic hematoma puncture and drainage surgery. To achieve precise puncture of the brainstem hematoma, surgeons had used invasive stereotaxic frames [ 17 ], robot-assisted navigation systems [ 18 ], the 3D printing technology navigation method [ 19 ], and laser combined with CT navigation technology [ 13 ]. The above techniques had shortcomings, including invasive placement positioning framework, the risk of skull bleeding and infection, expensive costs of robot-assisted and neuronavigation systems, the lengthy procedure of 3D printing technology, etc.

We innovatively used MRNT to perform brainstem hematoma puncture and drainage surgery. Our team used this technology to successfully perform intracranial foreign body removal [ 20 ] and minimally invasive puncture surgery for deep ICH, with a deviation of the drainage tube target of 5.76 ± 0.80 mm [ 9 ]. Based on previous experience and technical improvement, we applied technology to perform brainstem hematoma puncture and drainage surgery. The average volume of preoperative brainstem hematoma was 8.47 ± 2.22 mL, postoperative brainstem hematoma was 4.16 ± 1.17 mL, and the average hematoma evacuation rate was 50.39% ± 7.71%, which prevented hematoma primary compression and secondary injury. The surgical procedure under general anesthesia took an average of 82.14 ± 15.74 min, the average target deviation was 4.58 ± 0.72 mm, and the average depth of the implantable drainage tube was 62.73 ± 0.94 mm. The depth of the drainage tube was longer than that in the application of deep ICH, which required higher precision. Moreover, we found MRNT was safe in seven patients.

A comparison of the precision of augmented reality technology, mixed reality technology, and traditional stereotactic methods have been discussed in previous literature. Van Doormaal et al. conducted a holographic navigation study using augmented reality technology. They found that the fiducial registration error was 7.2 mm in a plastic head model, and the fiducial registration error was 4.4 mm in three patients [ 21 ]. A meta-analysis was conducted to systematically review the accuracy of augmented reality neuronavigation and compare it with conventional infrared neuronavigation. In 35 studies, the average target registration error of 2.5 mm in augmented reality technology was no different from that of 2.6 mm in traditional infrared navigation [ 22 ]. Moreover, In the study of neuronavigation using mixed reality technology, the researchers received a target deviation range of 4–6 mm [ 23 – 25 ].

The augmented reality technology application scenarios mainly involve intracranial tumors and rarely involve ICH. Qi et al. used mixed reality navigation technology to perform ICH surgery. They also used markers for point registration and image fusion. The results showed that the occipital hematoma puncture deviation was 5.3 mm due to the prone and supine position, and the deviation in the basal ganglia was 4.0 mm [ 26 ]. Zhou et al. also presented a novel multi-model mixed reality navigation system for hypertensive ICH surgery. The results of the phantom experiments revealed a mean registration error of 1.03 mm. The registration error was 1.94 mm in clinical use, which showed that the system was sufficiently accurate and effective for clinical application [ 27 ]. A summary of the deviations in the application of MR or AR was provided in Table 2 .

Table 2 . Reported cases of deviations in the application of MR or AR in neurosurgery.

In addition to precision puncture and hematoma drainage, surgical treatment of PBH also required further discussion on the timing of surgery, external ventricular drainage, and fibrinolytic drugs. Shrestha et al. found that surgical treatment within 6 h after onset was associated with a good prognosis [ 14 ]. The ultra-early operation alleviated the hematoma mass effect and reduced secondary injury. In particular, for patients with a severe condition, early hematoma aspiration could immediately eliminate harmful effects and prevent worse clinical outcomes [ 17 ] However, many primary hospitals are not equipped with PBH surgical treatment abilities. Patients have to waste a lot of time in the transfer process, which is a big challenge in clinical treatment. PBH can also cause cerebrospinal fluid circulation disorder that induces patients to become unconscious. External ventricular drainage is beneficial in improving cerebrospinal fluid circulation, managing intracranial pressure, and facilitating patient recovery [ 17 ]. In our study, external ventricular drainage was performed in five cases of seven patients. Previous research investigating the effects of rtPA on ICH and ventricular hemorrhage by MISTIE and CLAEA demonstrated that fibrinolytic drug administration did not increase the risk of hemorrhage [ 30 – 33 ]. Currently, there is no evidence and consensus to verify the effects of the thrombolytic drug used in PBH. We also found that urokinase did not increase the risk of bleeding and improve drainage efficiency, as reported in previous literature [ 13 , 18 ].

Compared with the expensive neuronavigation system, mixed reality navigation technology was an independent research and development project, the equipment of the technology was simple, and the cost was low. The effect of the technology met the clinical application of intracerebral hemorrhage surgery, and was beneficial to popularization for primary hospital.

There were also some limitations in our technology. Firstly, in order to introduce our innovative mixed reality navigation technology earlier and faster, we reported few cases, so there are not enough data to verify the advancement of the technology. At present, it was difficult to perform a cohort study because of the small number of patients enrolled. We plan to carry out clinical study with other centers in the future. Secondly, navigation technology was mainly based on point-matching technology, which enabled the fusion of the image model with the actual space through markers. Implementing invasive markers in the skull might carry potential risks of bleeding or infection. Moreover, the procedure required CT examinations before surgery, which delayed surgery time, and increased costs. Some researchers proposed the face registration plan, but the target deviation of the face registration was higher than that of the point registration, and the clinical practicability was poor [ 34 ]. Clinical practice must explore a precise, simple, fast, and noninvasive matching and fusion innovative solution.

It was feasible and safe to perform brainstem hematoma puncture and drainage by MRNT. Early minimally invasive precise surgery could prevent hematoma primary and secondary injury, and improve the prognosis of patients with PBH. The advantages included high precision in dual-plane navigation technology, low cost, an immersive operation experience, etc. Furthermore, improving the matching registration method and performing high-quality prospective clinical research was necessary.

Data availability statement

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

Ethics statement

The studies involving humans were approved by Ethics Committee of the Chongqing Emergency Medical Center. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

XT: Writing–original draft, Data curation, Software. YaW: Writing–original draft. GT: Conceptualization, Project administration, Writing–original draft. YiW: Investigation, Resources, Software, Writing–original draft. WX: Resources, Formal Analysis, Writing–original draft, Writing–review and editing. YL: Methodology, Writing–original draft. YD: Writing–review and editing. PC: Writing–review and editing, Conceptualization, Writing–original draft.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was financially supported by the Fundamental Research Funds for the Central Universities (2022CDJYGRH-015) and Medical Research Project of Science and Technology Bureau and Health Commission, Chongqing, China (2023MSXM076).

Conflict of interest

Author YiW was employed by Qinying Technology Co., Ltd.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: primary brainstem hemorrhage, mixed reality navigation technology, brainstem hematoma puncture and drainage surgery, neuronavigation, deviation

Citation: Tang X, Wang Y, Tang G, Wang Y, Xiong W, Liu Y, Deng Y and Chen P (2024) Application of mixed reality navigation technology in primary brainstem hemorrhage puncture and drainage surgery: a case series and literature review. Front. Phys. 12:1390236. doi: 10.3389/fphy.2024.1390236

Received: 23 February 2024; Accepted: 26 March 2024; Published: 17 April 2024.

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Copyright © 2024 Tang, Wang, Tang, Wang, Xiong, Liu, Deng and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yongbing Deng, [email protected] ; Peng Chen, [email protected]

† These authors share first authorship

This article is part of the Research Topic

Multi-Sensor Imaging and Fusion: Methods, Evaluations, and Applications – Volume II