Introduction
Since the COVID-19 pandemic was declared on March 11, 2020, there have been 536,590,224 confirmed cases of COVID-19 and 6,316,655 deaths reported to the World Health Organization.1 This figure is widely accepted to be under-reported, as is the case for most infectious diseases,2 particularly in resource-poor settings with limited diagnostic capacity and health care access.2 Throughout the pandemic, different waves have caused different levels of disease severity.3 At the height of the pandemic, up to 20% of patients followed a severe disease trajectory, with up to a quarter of hospitalized patients requiring intensive care unit (ICU) admission4 for acute respiratory distress syndrome and multi-organ failure.5
The optimal approach to treating COVID-19 is continually evolving, with the latest research showing that corticosteroids and interleukin-6 inhibitors probably confer important benefits on patients with severe COVID-19.6 However, with little conclusive evidence in the way of treatment, management remains largely supportive.5 In the critical care environment, 2 fundamental invasive interventions include ventilatory support and intravenous therapy. The latter requires invasive vascular access devices (VADs), such as peripherally inserted vascular access, peripherally inserted central access, femorally inserted central access, and centrally inserted central access midline catheters or mini-midline catheters, to name a few. Rates of centrally inserted central access insertion alone in the ICU are reported to be between 50% and 80%,7–9 even before the high acuity of COVID-19 positive patients is considered.
Despite these interventions existing almost co-dependently,10 ventilation research has dominated the literature since the pandemic began, with little research conducted on VADs. In a recent Cochrane rapid review, Smith et al.11 identified a lack of evaluation research focused on intravenous care bundles in the COVID-19 ICU population. At the same time, guidelines for mechanical ventilation alone have been issued by several organizations and societies, including the Society of Critical Care Medicine, the Chinese Thoracic Society, the Australian and New Zealand Intensive Care Society, the World Health Organization, the United States Centers for Disease Control and Prevention, and the National Institutes of Health.12
The lack of VAD research is concerning, given that clinical management of this cohort is paradoxical to standard treatment, and these patients are nursed up to 18 hours a day in the prone position.13 Prone positioning is the technique of placing a patient on their stomach to redistribute blood and airflow more evenly and improve oxygenation.14 Systematic proning of critically ill patients is one of this cohort’s most widely accepted supportive measures.15–17 This systematic proning increases the risk of dressing soiling and dehiscing, subsequently increasing the risk of infection.18 Additionally, VADs themselves are associated with an increased prevalence of thrombus.19 Along with the coagulopathic, thrombotic manifestations of COVID-19,20 these patients are at heightened risk of developing clots and device-related thrombi. This is particularly pertinent, given that these individuals already require a high level of complex care and fundamentally lack the physiological reserve to withstand or tolerate additional injury.21,22 Therefore, it is essential to identify the techniques and approaches to VAD insertion, care, and maintenance in the critically ill COVID-19 population. Understanding this activity is crucial since this cohort is at a greater risk of VAD complications and vessel health compromise.
This scoping review aims to systematically map the available literature on approaches to vascular access and VAD care and maintenance in patients with COVID-19, and identify key concepts, clinical approaches, sources of evidence, and gaps in the research on this subject.23 Key concepts refer to recurring subject matter within the included literature. The results from the proposed scoping review will guide the next phase of research concerning approaches to vascular access and VAD care and maintenance in patients with COVID-19.
A preliminary search of PROSPERO, MEDLINE (PubMed), the Cochrane Database of Systematic Reviews, and JBI Evidence Synthesis was conducted and no existing scoping reviews or systematic reviews on the topic were identified.
The objective of this scoping review is to identify the types of evidence available; approaches to vascular access in patients with COVID-19; knowledge gaps; key concepts in the literature; and how research is conducted on this topic.23
Review questions
What evidence is available on vascular access in ICU patients with COVID-19?
- What types of research have been conducted on VADs in patients with COVID-19?
- In what geographical areas has this research been conducted?
- What complications, including thrombosis and infection, have been identified?
- What device selection, insertion site and techniques, and care and maintenance of VADs have been identified for this cohort of patients?
- What key concepts have been identified in the literature?
Inclusion criteria
The main benefit of a scoping review is the potential to capture a broad variety of evidence, not only academic literature.24 Empirical and theoretical studies of any design relating to vascular access, including the insertion, care, and maintenance of VADs in critically ill patients with COVID-19 requiring ICU admission, will be included. All relevant patient demographics, including ethnic backgrounds and geographical areas, will be included. Adult-only (age 18 and over) results will be included, but no upper-age restrictions will be applied.
Participants
The population in this scoping review is critically ill patients with a positive diagnosis of COVID-19 confirmed by a laboratory polymerase chain reaction swab. First-time diagnosis and individuals with re-infection are eligible for inclusion. Patients with any and all co-morbidities will be included. Pediatric, neonatal, and obstetric evidence will be excluded. Patients with asymptomatic, mild, or moderate disease not requiring hospitalization or admission to critical care will be excluded.
Concept
The concept to be explored is vascular access in critically ill patients with COVID-19. This may include the decision-making surrounding VAD type, insertion site and techniques, care, maintenance, and complications of the device. “Care” and “maintenance” refer to any interventions used to prevent device-related complications. As the focus of this scoping review is vascular access to provide intravenous therapy, drug administration and monitoring, vascular access for the purpose of extracorporeal membrane oxygenation will not be included. Real-life experiences are the focus of the proposed scoping review; for this reason, simulation scenarios and related literature will also be excluded.
Context
The context is severe disease progression requiring organ support in an ICU. Synonyms for the population, concept, and context have been identified and are listed in Appendix I. These extended search terms will be entered into each database to generate relevant research results.
Types of sources
Randomized controlled trials, both registered and ongoing, case-control studies, qualitative and quantitative research, case studies, literature reviews, protocols, policies, and guidelines will be eligible for inclusion. Due to the continually emerging nature of COVID-19 evidence, and to ensure the proposed scoping review is as thorough as possible, gray literature will also be included,25 and may include opinion pieces, podcasts, or blogs.26 The reference lists of relevant studies will also be scanned for additional studies.
Methods
A scoping review is particularly relevant for this subject as evidence is continually emerging.26 The nature of scoping reviews also ensures that both published and gray literature can be incorporated into the literature search, and findings can be generated that complement the findings of clinical trials.26 The proposed scoping review will be conducted in accordance with the JBI methodology for scoping reviews.27,28 The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist29 will be used as a reporting guideline.
Search strategy
A range of databases relevant to nursing and medicine will be searched, including Embase, MEDLINE (Ovid), Web of Science, and PubMed. In order to capture clinical trial literature, the Australian and New Zealand Clinical Trial Registry (ANZCTR), the European Union Clinical Trials Register (EUCTR), and ClinicalTrials.gov will be searched. Greynet.org and the Canadian Agency for Drugs and Technologies in Health Grey Matters tool25 will be used to search for gray literature.
An academic librarian will guide the search strategy. Boolean operators “AND” and “OR” will be used to combine or exclude keywords in the search. Truncation will be used to search for terms beginning with the same letters simultaneously. As international data is being sought, British/Irish and American spelling and terminology will be included. Colloquialisms were considered but are not relevant in this instance.
Publication dates will be filtered from 2019 to the present to reflect the period when the COVID-19 pandemic emerged. Only English-language results will be included at this time due to funding constraints.
As recommended by JBI, a 3-step approach will be followed to undertake the search.26 These steps will be followed in collaboration with an academic librarian. First, an initial limited search for a range of articles relating to vascular access in ICU patients with COVID-19 was undertaken in Embase and MEDLINE (Ovid). An analysis of the recurring words and terms in the titles and abstracts of the results was conducted, and Emtree and MeSH terms were identified in the respective databases. The search terms are listed in Appendix I, while the search strategy is presented in Appendix II. Second, the critical terms identified will be used to inform the second search. The search strategy will be translated to all of the databases mentioned above with the help of the academic librarian. Third, the reference lists of all included results will be screened for additional relevant data sources. A second librarian will apply the Peer Review Electronic Search Strategy (PRESS) checklist.26
Study selection
Following the comprehensive search, all relevant citations will be uploaded into EndNote v.X9 (Clarivate Analytics, PA, USA) and duplicates removed. A pilot test26 will be conducted using the predefined eligibility criteria. Once a high level (90%) of agreement on the relevant citations has been achieved, 2 researchers will independently screen titles and abstracts against the inclusion and exclusion criteria. Any studies selected by either or both of the reviewers will proceed to the second stage of screening and undergo a full-text review. These will, once again, be reviewed against the predetermined eligibility criteria. Disagreements on study selection will be resolved through discussion or, if required, through mediation by a third independent reviewer. The results of the search will be reported in full in the final scoping review and presented in a PRISMA flow diagram.30
Data extraction
A pilot review will be conducted during the data extraction process by 2 independent members of the review team. The data to be extracted, as suggested by JBI,28 includes: author(s); year of publication; origin/country of origin (where the source was published or conducted); aims/purpose; population and sample size within the source of evidence; methodology/methods; intervention type, comparator, and details of these (eg, dose of the intervention); duration of the intervention; outcomes and details of these (eg, how measured); VAD type; and key findings that relate to the scoping review questions. A data extraction instrument will be developed for the scoping review using a template from JBI.28 The data extraction instrument may be updated during the review process as required, and any modifications will be detailed in the scoping review. Any disagreements that arise between the reviewers will be resolved through discussion or with an additional reviewer.
Data analysis and presentation
The proposed scoping review will provide a map and basic summary of the evidence27 available on vascular access in critically ill patients with COVID-19. The review will not synthesize the findings into a final set of results, or aim to inform practice or decision-making.25,26 An overview of the aggregated findings, including the primary sources and types of research,26 will be reported. Results of the search will be presented in a PRISMA flow diagram.30
The results will be categorized by study design, country of origin, VAD type, clinical concepts, complications, and year of publication. Results will be reported in tabular format,25 with relevant data presented graphically. A narrative summary will accompany the tabulated results and describe how the results relate to the review objective and research questions. Once the mapping of the available evidence is complete, any gaps in the research relating to approaches to vascular access and VAD care and maintenance in patients with COVID-19 will be identified. This will further guide ongoing research on this important and evolving topic.
Funding
This scoping review protocol is a partial requirement for a masters of science in advanced practice nursing at the University of Galway for EM.
EM is the recipient of funding from the Surgery, Anaesthetics and Critical Care Department of St James’s Hospital, Dublin, and the University Hospital, Limerick. The funders had no input into the development of this protocol.
Author contributions
Designing the analysis: EM, PC; collecting the data: EM, OH, RE; contributing toward data and analysis tools: EM, PC, OH; performing the analysis: EM, OH, RE; writing the manuscript: EM.
Acknowledgments
David Mockler, academic librarian, and John Stearne Medical Library, Trinity Centre for the Health Sciences, St James’s Hospital, Dublin, for assistance with searches and search strategy development.
Appendix I: Search terms and synonyms
The following terms will be used for search strategies across the databases.
PCC template for synonym generation for searches |
P (POPULATION) |
C (CONCEPT) |
C (CONTEXT) |
Covid-19 + patients |
Vascular access |
Intensive care |
• Coronavirus • Coronavirus* • Coronavirus disease 2019 • Coronavirus disease* 2019 • Covid-19 associated coagulopathy • 2019 novel coronavirus epidemic • 2019 novel coronavirus infection • 2019-ncov disease • 2019-ncov infection • Coronavirus disease 2019 pneumonia • coronavirus disease-19 • Coronavirus infection 2019 • Covid • Covid 19 • Covid 19 induced pneumonia • Covid 2019 • Covid-19 • Covid-19 induced pneumonia • Covid-19 pneumonia • Covid19 • ncov 2019 disease • ncov 2019 infection • New coronavirus pneumonia • Novel coronavirus 2019 disease • Novel coronavirus 2019 infection • Novel coronavirus disease 2019 • 2019-ncov disease • 2019-ncov infection • Coronavirus disease 2019 pneumonia • Coronavirus disease-19 • Coronavirus infection 2019 • Novel coronavirus infected pneumonia • Novel coronavirus infection 2019 • Novel coronavirus pneumonia • Paucisymptomatic coronavirus disease 2019 • Sars coronavirus 2 infection • Sars coronavirus 2 pneumonia • Sars-cov-2 disease • Sars-cov-2 infection • Sars-cov-2 pneumonia • Sars-cov2 disease • Sars-cov2 infection • Sars-cov2 pneumonia • Sarscov2 disease • Sarscov2 infection • Severe acute respiratory syndrome 2 • Severe acute respiratory syndrome 2 pneumonia • Severe acute respiratory syndrome coronavirus 2 • Severe acute respiratory syndrome coronavirus 2 infection • Severe acute respiratory syndrome coronavirus 2019 infection • Severe acute respiratory syndrome cov-2 infection • Wuhan coronavirus disease • Wuhan coronavirus disease* • Wuhan coronavirus infection • Wuhan coronavirus infection* • Severe acute respiratory syndrome* |
• Vascular access • Vascular access* • Vascular access catheter* • Vascular access device* • Iv therap* • Intravenous drug administration • Intravenous drug therap* • picc* • cicc* • ficc* • pivc* • peripheral* inserted venous catheter* • Peripheral inserted central venous catheter* • femoral*inserted central catheter* • Central venous catheter* • Central line* • Intravenous catheter* • ivc* • Peripheral venous catheter* • Midline catheter* • Mini midline catheter* • Mini-midline catheter* • catheterisation* • catheterization* • Insertion site* • Power injector* • Power injectable* • vad* • intravenous* • cannulation • cannula* |
• Intensive care • Intensive care unit • Intensive care unit* • Intensive therapy unit* • Intensive therapy* • ICU* • Intensive care department* • Intensive treatment • Intensive treatment unit • Intensive treatment unit* • Intensive treatment department • Critical care • Critical care unit* • Critical care department* • High dependency department* • High dependency unit* • High dependency* • itu* • hdu* • critical illness* • critical* ill* |
Appendix II: Search strategy
Embase
Date searched: June 21, 2022
No |
Search |
Results retrieved |
1 |
‘vascular access device’/exp |
4053 |
2 |
(dialock OR vectra OR ‘haemodialysis/central venous catheterization kit*‘ OR ‘hemodialysis/central venous catheterization kit*‘ OR ‘implantable vascular access device*‘ OR ‘vascular access device*‘ OR ‘vascular catheter introduction set’ OR ‘vein pick’):ti,ab,kw |
1855 |
3 |
(‘av graft’ OR flixene OR ‘flixene graft’ OR ‘arteriovenous anastomotic graft’ OR ‘arteriovenous external shunt’ OR ‘arteriovenous graft’ OR ‘arteriovenous shunt’ OR ‘arteriovenous shunt graft’ OR ‘dialysis arteriovenous graft’ OR ‘haemodialysis arteriovenous graft’ OR ‘hemodialysis arteriovenous graft’ OR ‘synthetic arteriovenous graft’):ti,ab,kw |
3302 |
4 |
(‘avf needle’ OR dora OR ‘safetouch ii’ OR ‘arteriovenous fistula needle’ OR ‘dialysis needle’ OR ‘fistula needle’ OR ‘haemodialysis needle’ OR ‘hemodialysis needle’):ti,ab,kw |
627 |
5 |
(‘agilis nxt’ OR ‘arnold aspiration sheath’ OR ‘cps direct’ OR dryseal OR ‘dryseal flex introducer sheath’ OR epsylar OR introsyte OR ‘introsyte-n’ OR ‘micro-introducer’ OR ‘r-100’ OR sentrant OR spinvision OR vascu-sheath OR visisheath OR ‘cardiovascular device introducer’ OR ‘introducer sheath’ OR ‘large-bore introducer’ OR ‘non-steerable cardiovascular device introducer’ OR ‘percutaneous introducer sheath’ OR ‘single-use steerable vascular catheter introduction kit’ OR ‘steerable cardiovascular device introducer’ OR ‘vascular catheter introduction kit’ OR ‘vascular catheter introduction kit, steerable, single-use’ OR ‘vascular catheter introduction needle’ OR ‘vascular introducer’):ti,ab,kw |
1346 |
6 |
‘intravenous catheter’/de |
8514 |
7 |
(‘surflo’ OR ‘angiocatheter’ OR ‘intravenous catheter*‘ OR ‘saf-t-intima’ OR ‘venous line’ OR ‘venous catheter*‘ OR ‘vein catheter*‘):ti,ab,kw |
34,281 |
8 |
‘central venous catheter’/exp |
29,108 |
9 |
(‘vortex port’ OR ‘central vein catheter*‘ OR ‘central venous catheter’ OR ‘cv cath’ OR ‘central intravenous catheter’ OR ‘central line’ OR ‘central venous line’ OR broviac OR ‘cvp line’ OR groshong OR leonard OR ‘leonard catheter*‘ OR ‘orion ii’ OR ‘pediasat’):ti,ab,kw |
23,054 |
10 |
(‘bioflo’ OR ‘groshong nxt’ OR ‘groshong nxt clearvue’ OR ‘lifecath picc expert’ OR ‘neostar’ OR ‘nutriline (peripherally inserted central venous catheter)’ OR ‘per-q-cath plus’ OR ‘poly per-q-cath catheter’ OR ‘power v-cath’ OR ‘powerpicc solo catheter’ OR ‘premicath’ OR ‘spectrum turboject’ OR ‘synergy xs’ OR ‘vascu-line’ OR ‘peripherally inserted central catheter’ OR ‘peripherally inserted central venous catheter’ OR ‘peripherally-inserted central venous catheter’ OR ‘pic line’ OR ‘picc line’ OR ‘Femorally inserted central catheter*‘ OR FICC):ti,ab,kw |
2714 |
11 |
‘peripheral venous catheter’/exp |
1780 |
12 |
(‘abbocath’ OR ‘angiocath’ OR ‘angiocath autoguard’ OR ‘bd angiocath’ OR ‘bd angiocath autoguard’ OR ‘bd angiocath-n autoguard’ OR ‘bd cathena safety iv catheter’ OR ‘bd insyte’ OR ‘bd insyte autoguard’ OR ‘bd insyte-n’ OR ‘bd insyte-n autoguard’ OR ‘bd insyte-w’ OR ‘bd nexiva’ OR ‘bd nexiva bd q-syte’ OR ‘bd nexiva diffusics’ OR ‘clarivein’ OR ‘insyte autoguard’ OR ‘intracath (peripheral venous catheter)’ OR ‘introcan’ OR ‘jelco’ OR ‘midline catheter kit’ OR ‘neoflon’ OR ‘nexiva’ OR ‘powerstick’ OR ‘supercath 5’ OR ‘surflash’ OR ‘volumeview’ OR ‘peripheral intravenous catheter’ OR ‘peripheral intravenous catheterization kit’ OR ‘peripheral vascular catheter*‘ OR ‘peripheral venous access catheter*‘ OR ‘peripheral venous catheter*‘ OR ‘peripheral venous line’):ti,ab,kw |
1765 |
13 |
(‘powerglide’ OR ‘midline catheter*‘ OR ‘midline venous catheter*‘ OR ‘ric line’ OR ‘rapid infusion catheter*‘):ti,ab,kw |
283 |
14 |
‘intravenous drug administration’/exp |
391,698 |
15 |
((Administration OR ‘drug administration’ OR infusion* OR dose OR injection* OR ‘fluid therapy’ OR drip OR transfusion*) NEAR/3 intravenous):ti,ab,kw |
169,434 |
16 |
(‘iv administration’ OR ‘IV drug administration’ OR ‘IV drug delivery’ OR ‘IV drug injection’ OR ‘IV drug therap*’ OR ‘iv fluid administration’ OR ‘iv infusion’ OR ‘iv injection’ OR ‘IV medication*’ OR ‘iv transfusion*’ OR ‘vein infusion*’ OR ‘vein injection*’ OR ‘venous drip’ OR ‘venous infusion*’ OR ‘venous injection*’ OR ‘venous transfusion*’):ti,ab,kw |
25,789 |
17 |
‘vein catheterization’/exp |
15,306 |
18 |
((vein OR venous OR intravenous) NEAR/3 (catheterisation* OR catheterization* OR catheter*)):ti,ab,kw |
36,790 |
19 |
#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 |
580,185 |
20 |
‘intensive care unit’/exp |
252,811 |
21 |
(gicu OR gicus OR ‘icu’ OR ‘icu’s’ OR ‘close attention unit*‘ OR ‘combined medical and surgical icu’ OR ‘combined surgical and medical icu’ OR ‘critical care unit*‘ OR ‘general icu’ OR ‘intensive care department’ OR ‘intensive care unit*‘ OR ‘intensive therapy unit*‘ OR ‘intensive treatment unit*‘ OR ‘medical-surgery icu’ OR ‘medical/surgical icu’ OR ‘medical/surgical icus’ OR ‘medico-surgical icu’ OR ‘mixed medical and surgical icu’ OR ‘mixed surgical and medical icu’ OR ‘respiratory care unit’ OR ‘respiratory care units’ OR ‘special care unit’ OR ‘surgery/medical icu’ OR ‘surgical-medical icus’ OR ‘surgical/medical icu’ OR ‘unit, intensive care’):ti,ab,kw |
288,413 |
22 |
‘intensive care’/exp |
825,011 |
23 |
((Intensive OR critical) NEAR/2 care):ti,ab,kw |
309,683 |
24 |
((burn OR ‘coronary care’ OR ‘intensive care’ OR ‘intensive therapy’ OR ‘close attention’ OR ‘critical care’ OR ‘respiratory care’ OR ‘special care’) NEAR/2 (unit* OR department* OR icu*)):ti,ab,kw |
225,096 |
25 |
((‘combined medical and surgical’ OR ‘combined surgical and medical’ OR general OR ‘medical-surgery’ OR ‘medical/surgical’ OR ‘medico-surgical’ OR ‘surgery/medical’ OR surgical-medical OR ‘surgical/medical’) NEAR/3 ICU*):ti,ab,kw |
5937 |
26 |
‘critically ill patient’/exp |
57,519 |
27 |
‘critical* ill*‘:ti,ab,kw |
94,477 |
28 |
#20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 |
1,117,472 |
29 |
‘coronavirus disease 2019’/exp OR ‘Severe acute respiratory syndrome coronavirus 2’/exp |
240,543 |
30 |
(‘2019 nCoV’ or 2019nCoV or ‘2019‐novel CoV’):ti,ab,kw |
2128 |
31 |
(‘corona vir*’ or coronavir* or ‘neocorona vir*’ or neocoronavir*):ti,ab,kw |
108,653 |
32 |
COVID:ti,ab,kw |
252,892 |
33 |
‘COVID 19’:ti,ab,kw |
248,073 |
34 |
(‘nCov 2019’ or ‘nCov 19’):ti,ab,kw |
860 |
35 |
(‘SARS‐CoV‐2’ or ‘SARS‐CoV2’ or SARSCoV2 or SARSCoV‐2):ti,ab,kw |
97,757 |
36 |
(‘SARS coronavirus 2’ or ‘SARS‐like coronavirus’ or ‘Severe Acute Respiratory Syndrome Coronavirus‐2’):ti,ab,kw,kw |
25,291 |
37 |
(‘2019 new coronavirus’ OR ‘2019 novel coronavirus’ OR ‘2019-ncov’ OR ‘hcov-19’ OR ‘human coronavirus 2019’ OR ‘sars coronavirus 2’ OR ‘sars-cov-2’ OR ‘sars2 (virus)’ OR ‘severe acute respiratory syndrome coronavirus 2’ OR ‘wuhan coronavirus’ OR ‘wuhan seafood market pneumonia virus’ OR ‘ncov-2019’ OR ‘novel 2019 coronavirus’ OR ‘novel coronavirus 2019’ OR ‘novel coronavirus-19’):ti,ab,kw,kw |
98,705 |
38 |
#29 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 |
311,185 |
39 |
‘vascular access’/exp |
30,877 |
40 |
((Vein* OR artery OR arterial OR venous OR intravenous OR vascular OR intravascular) NEAR/3 access*):ti,ab,kw |
39,502 |
41 |
((‘vascular access’ OR ‘venous access’) NEAR/3 (covid OR safety OR efficacy OR manage* OR optimi?ation OR maintenance OR innovative OR novel OR preferred OR method* OR route* OR improve OR procedure* OR complication*)):ti,ab,kw |
4956 |
42 |
((‘vascular access device’ OR ‘venous access device’ OR catheter*) NEAR/4 (select OR selection OR insert* OR maintenance OR management OR function* OR safety OR efficacy OR position* OR optimi?ation OR placement*)):ti,ab,kw |
51,001 |
43 |
#39 OR #40 OR #41 OR #42 |
98,324 |
44 |
#19 AND #28 AND #38 AND #43 |
84 |
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