EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Machine perfusion of liver grafts has gained popularity for its abilities to preserve liver grafts, reduce cold storage damage, and evaluate graft viability before transplant. However, debate persists regarding the optimal solutions, logistics, and biomarkers for assessing graft quality. To shed light on the lengthy debates surrounding the use of machine perfusion in liver graft preservation, this study utilized bibliometric analysis to evaluate the status and development trends of main research areas.
Materials and Methods: On December 10th, 2022, we conducted a literature search using the Web of Science database to identify articles related to liver machine perfusion. The search included only original studies and reviews and excluded meeting abstracts, letters, notes, editorials, short surveys, book chapters, and errata. We identified the number of citations and encompassed various aspects, such as annual trends, countries, institutions, authors, journals, and key words. We used VOSviewer version 1.6.18 to generate tables and figures.
Results: After manually removing irrelevant papers, we included 264 articles (89 reviews; remaining were original studies). The articles were cited 5743 times, averaging 21.92 per article. We found that the United Kingdom (n = 76) was the country that produced the most articles, followed by the United States (66 articles). Most papers in our search were published in Liver Transplantation (n = 31) and Transplantation (n = 16).
Conclusions: Bibliometric analysis provided insights into debates and advancements in liver graft preservation using machine perfusion. The analysis showed leading countries and key research areas in the field. This overview serves as a valuable resource for researchers, offering a foundation for further exploration and guiding future investigations in the field of machine perfusion for liver graft preservation.

Key words : Bibliometric analysis, Hypothermic machine perfusion, Machine perfusion, Normothermic machine perfusion

Machine perfusion (MP) of liver grafts has become more widely used in recent years, owing to its capabilities to maintain grafts in settings that are nearly physiologic before implantation, to mitigate damage from cold storage, and to evaluate graft viability before transplant.^1-3 Machine perfusion may lower the risk of primary nonfunction, early allograft dysfunction, and biliary complications by minimi-zing ischemia-reperfusion injury and damage to cholangiocytes during preservation.⁴ In addition, MP is linked to organ restoration and reconditioning, which could potentially increase the number of qualified organ donors beyond the current standards.¹

Since the introduction of the first hypothermic machine perfusion (HMP) for liver grafts in 2010⁵ and the introduction of the first normothermic machine perfusion (NMP) in 2015,⁶ great advan-cements have been made in the field; initially, advancements were challenged with debates over its applicability and safety.^7,8 After confirmation of the technology’s safety, a new debate arose regarding the outcome, logistics, optimal solutions to be used, and, most recently, the best biomarkers to assess graft quality during MP.^9-11 The increased number of articles and publications, which we aimed to evaluate based on the authors, institutions, and countries through bibliometric analysis, mirrors this change and the discussion over the previous 10 years.

Bibliometrics is a type of research that can be used to learn more about the history and advancement of a topic.^12,13 Research patterns and connections between academic institutions, scholarly publications, and countries can be revealed by combining this method with data visualization.

To shed light on the lengthy controversies surrounding the use of MP in liver graft preservation and to address its evolution, we used bibliometric analysis to evaluate the status and development trends of major research areas, productive authors, institutes, journals, and country perspectives. This study analyzed the patterns of collaboration between countries and organizations and explored the priorities and hotspots by analyzing key words and topics. To our knowledge, no study has utilized bibliometric analysis to conduct a comprehensive evaluation of clinical research on the use of MP in liver transplant.

Materials and Methods

Data collection and retrieval methods

We conducted the literature search on December 10, 2022. We queried the Web of Science database using the terms “machine perfusion” OR “subnormothermic perfusion” OR “perfusion machine” OR “machine preservation” OR “automated perfusion” OR “hypot-hermic perfusion” OR “normothermic perfusion,” and we limited our search to “liver” OR “hepatic” OR “liver transplant” whether they have appeared in all fields. We excluded the following terms: kidney OR renal OR heart OR lung OR hepatectomy OR porcine OR pig OR rat OR swine OR mice.

For our analysis, we only included original studies or reviews. Other types of documents, like meeting abstracts, letters, notes, editorials, short surveys, book chapters, and errata, were not included. We included articles from the source type “journal,” and any articles labeled with the key word “animals” were excluded. Articles with missing information were manually removed from the spreadsheet. We did not restrict our search to a particular language. The vast majority of the articles were written in English, but we also found 3 in German, 2 in Hungarian, and 1 in Spanish.

All analyses were based on the number of citations. We analyzed annual trends, countries, institutions, authors, journals, key words, and articles. We generated tables and figures using VOSviewer version 1.6.18 and MS Excel from Office 365. We used a flow chart to elaborate on our included and excluded results. We chose the most occurring key words by limiting the minimum number of occurrences to 10 and the top documents with at least 50 citations. We analyzed the annual trends by examining the number of publications in each year and the mean number of citations for all the documents in each year.

For the key word analysis, we manually removed words that implied the study design, such as “clinical trial” or “retrospective study,” and redundant words, such as “human,” “male,” “female,” “adult,” etc.

One of the authors, who is a transplant surgeon, performed a screening of the results and included only relevant articles. During the preliminary search, we encountered a number of publications that investigated the performance of MP on cases that were unrelated to transplant or procurement, such as hepatectomy; these were all excluded. Normothermic regional perfusion-related articles were also excluded. Because this research did not require the extraction of patient data, approval from the institutional review board was not necessary.

We analyzed included articles with regard to authorship, where each article’s author was included in the analysis; we then used a threshold of 10 or more articles to extract authors with the highest number of published articles. For affiliations, we set a threshold of 5 articles affiliated with an institution to be included in the analysis. For countries, we set a threshold of 10 articles affiliated with a country to be included in the analysis. The top 10 articles with the highest cited articles were included for further analysis. VOSviewer calculates an indication of how strong a document, an author, an affiliation, or a country is connected (via citation-reference) to others, which is an indicator called “total link strength.”

“Highly cited articles” were defined by Web of Science as articles that perform in the top 1% based on the number of citations received compared with other articles published in the same field in the same year.

VOSviewer network visualization interpretation

In the network visualization graphs, the terms are represented as circles. The weight of the term determines the size of the circle. The size of the circle increases with its weight. The color of an item depends on the cluster to which it belongs. Links are shown by lines between items. According to cocitation relationships, the distance between 2 circles in the visualization generally indicates how closely linked the terms represented by the circle are. The likelihood of a relationship between 2 circles increases with their closeness. Lines illustrate the strongest co-citation connections between circles.

Included studies

Of 707 search results, 344 articles were retrieved. After the manual elimination of irrelevant papers, we ultimately included 264 articles, of which 89 were reviews and the remainder were original studies (Figure 1). All studies were cited 5743 times in total and 4032 times without self-citations, with a mean of 21.92 citations per article.

Figure 2 depicts the annual number of citations and publications since 2010. A notable incremental trend over the years was shown. The year 2022 had the highest number of publications (n = 55) and citations (n = 1552). In 2011, articles were cited 3 times; in 2015, the total number of citations was 104, with this number quadrupled in 2018 with 475 citations and tripled in 2022 with 1552 citations, indicating the largest number of citations in a single year. The average number of citations per document each year was 441.7, and the average number of citations per article was 21.92. Seven of the publications on our list qualified as “highly cited articles” according to the Web of Science classification.

Countries and institutions

The United Kingdom was the source of most publications on this topic (n = 76, 29%), followed by the United States with 66 articles and the Netherlands with 51 articles. In terms of citations, the United Kingdom also had the highest number with 2636, followed by the Netherlands with 2078 and the United States with 890 citations (Table 1). Figure 3 shows the visualization of each country’s contri-bution and their interconnections.

In terms of citations, the University of Groningen topped the list with 1562, followed by the University of Oxford with 1069 and the University of Birmingham with 982. Leuven University Hospital had less than 10 publications in the discipline, yet it scored 770 citations, placing it in fourth place. In terms of the total number of publications, the top 2 contributing institutions were the University of Birmingham (n = 44) followed by the University of Groningen (n = 38) (Figure 4).

Authors and journals

Among all authors returned by the search, 64 authors had at least 5 publications. Fifty-one authors had articles with at least 200 citations. The top 5 authors with MP citations were A. Schlegel with 991, R. Porte with 872, P. Muiesan with 785, P. Dutkowski with 711, and H. Mergental with 682 citations. It is remarkable that 3 of these authors (Schlegal, Muiesan, and Dutkowski) were located in the same cluster in the citation map. Figure 5 shows the most cited authors.

Most publications were published in Liver Transplantation (n = 31), Transplantation (N = 16), the American Journal of Transplantation (n = 12), and Current Opinion in Organ Transplantation (n = 12). In terms of number of citations, Liver Transplantation again had the highest number (n = 832), followed by the American Journal of Transplantation (n = 776) and the Annals of Surgery (n = 475). Figure 6 depicts a density map of the most cited journals.

Top-cited articles

The 10 most cited MP articles are listed in Table 2. The study, “A randomized trial of normothermic preservation in liver transplantation,” conducted by Nasralla and colleagues in 2018 and published in Nature, received the highest count of citations (n = 522). The next highest was “First comparison of hypothermic oxygenated perfusion versus static cold storage of human donation after cardiac death liver transplants an international-matched case analysis” from Dutkowski and colleagues and published in Annals of Surgery (n = 215 citations) and then “Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers” from op den Dries and colleagues and published in the American Journal of Transplantation (n =192 citations).

There were 5 key words that have occurred more than 50 times, including “preservation,” “donation,” “ischemia-reperfusion injury,” “injury,” and “cardiac death.” Figure 7 shows the most occurring keywords and their interconnections across the years.

The use of MP technology for the preservation of liver grafts has been demonstrated to be both technically feasible and safe, with superior graft outcomes compared with the static cold preservation technique.^4,14 In addition, the ability to test graft viability before implantation in the case of questionable grafts has been made possible by the application of this technology.¹⁵ Furthermore, it allows the liver surgeon team to accept multiple offers, even if there is only one team available for the procedure, and it enhances the likelihood that an “elective” liver transplant can be performed during the day instead of the customary “urgent” timetable.¹⁰

The discussion around HMP began with the question of “ideal cannulation,” or whether it is necessary to cannulate both the artery and the portal vein or whether it is enough to cannulate only the portal vein without putting the artery at risk.¹⁶ With the advancement of research, another heated topic in this field emerged, namely, whether to oxygenate the perfusion fluid.^17,18 The necessary timing for placement of the organ on MP was also a point of contention.¹¹ However, discussions around NMP started with the optimal solution for the NMP.^19,20 Another major logistical barrier discussed was whether the NMP should be established at the hospital of the deceased donor and maintained until implantation at the recipient facilities or adopted with a more practical back-to-base approach.¹⁰

In our in-depth review of articles published in the field of MP used in liver preservation, we were able to show the most cited articles on MP and to highlight significant research trends and developments in the field of MP and liver preservation. We believe that providing a global perspective on the use of MP and liver preservation and evaluating the relevance of articles could be an intriguing way to track its development. This list of top-cited articles is of great assistance to transplant surgeons and researchers since it identifies the landmark studies. The list can also facilitate collaborations among researchers from many disciplines, allowing them to get together to investigate MP research in greater depth.

In recent decades, digitization of literature and the creation of online literature databases have enabled researchers to easily and efficiently investigate the body of literature and research performance.²¹ To conduct bibliometric analysis, various databases are used, each with unique characteristics and the ability to provide a variety of services. For practically all fields, the most frequently utilized literature databases are Web of Science and Scopus, both of which require a subscription, and PubMed for biomedical and life sciences, which is a free database.²¹

Web of Science has dominated the academic reference field, primarily through the annual publication of the journal impact factor, a metric for estimating the significance and influence of specific publications. In this analysis, we used the Web of Science database, which includes all articles published in journals indexed in the Science Citation Index Expanded (SCIE), the Social Science Citation Index (SSCI), the Arts and Humanities Citation Index (AHCI), and the newly added Emerging Source Citation Index (ESCI).²¹ Furthermore, when compared with PubMed and Scopus, citation analysis with Web of Science is more detailed and has better graphics, most likely because Web of Science was designed with the intention of satisfying users in citation analysis, a field that scientists have discussed and debated for decades.²²

A bibliometric analysis is a research method that uses quantitative data from published literature to analyze and understand patterns and trends in a particular field of study. It often involves analyzing large sets of data, such as the number of citations received by a particular paper or journal.^12,23 Bibliometric studies can be used to identify the most influential researchers and institutions in a particular field, as well as to identify trends and patterns in research over time. Such studies can also be used to identify gaps in the existing research and to inform future research directions.^21,23

Over the years, the number of articles that were published on MP and liver preservation expanded considerably. Publishing numbers were doubling almost every 2 years, peaking in 2014 with 7 articles and continuing an upward trend to double in 2017 with 16 articles, tripling again in 2019 with 34 articles, and hitting an all-time high in 2022 with 55 articles. This increase in the number of articles was paralleled by an increase in the number of citations, which also showed an exponential increase toward 2022, the year with the highest number of citations (1552), which is an additional indication of the rapidly expanding interest in this topic among transplant surgeons and researchers. Injury, ischemia-reperfusion injury, early graft dysfunction, and biliary compli-cations were among the top most frequently occurring key terms, demonstrating the significance of the centrality of the rule of MP in these topics. This explains the researchers’ emphasis on these outcome metrics.

Most of the articles on our list originated in European countries. The United States was rated second among the world’s leading publishing nations. The substantial government funding for transplant research and the push for the acceptance of high-risk liver transplants, particularly use of donations after circulatory death (DCD) and marginal grafts, are partially responsible for the much greater contribution of European nations to MP research. Given the lengthy no-touch period after cardiac arrest in cases of DCD, this can also be ascribed to the legislation on DCD, which has demanded a reliable technique to test liver grafts. China scored eighth on the list, and Japan ranked sixteenth with only 6 items, demons-trating the contribution of Asian countries.

Most of the top 10 institutions in terms of publications were in Europe. Only 2 American institutions made it into the top 10 list. In terms of citations, however, only 1 American university made the top 10 list, the University of Massachusetts, which once again demonstrated the dominance of eurozone countries and institutions. Because there are no validated recommendations for assessing liver function and viability during HMP and NMP, more research is needed, and we expect this to be a hot topic for future research in the field.

This review was written with the intention of supplementing the existing research on MP from a scientometrics perspective, as well as providing researchers with an overview of current research hotspots and the frontier’s prediction of MP based on a visual analysis of the literature. As a purely quan-titative indicator, bibliometrics is more indicative of an article’s status within the scientific community than of its quality or impact on future research. Therefore, more robust qualitative evaluation techniques, such as peer review and methodological analysis, can be integrated with bibliometric data to provide a more comprehensive view of the dynamics of research. Despite employing a stringent search strategy to compile a comprehensive list of the most cited papers, we may have missed some articles because we only searched the Web of Science database (Scopus, PubMed, and Google Scholar were not searched).

The increase in the number of papers published in recent years demonstrates the increased interest that institutions and researchers have in MP applications in liver transplantation. This review was written to complement existing research on MP technique in liver transplant from a scientometrics perspective, as well as to provide researchers with an overview of current research hotspots and a prediction of future research frontiers based on a visual analysis of existing literature.

Volume: 22 Issue: 1 January 2024

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