Objectives: Organ transplant is widely regarded as the optimal treatment for patients with end-stage organ failure; however, the scarcity of organs has evolved into a substantial medical and social dilemma. To gain insight into recent advancements in global research on brain death organ donor management, we compiled relevant literature for a comprehensive bibliometric analysis of the field.
Materials and Methods: We used the CiteSpace (6.2.R3) tool to perform a visualization analysis of the literature on management of organ donors after brain death, which we conducted with the Web of Science database.
Results: Using a time period from 1992 to 2024, we examined annual publication volume, countries, research institutions, authors, and journals associated with the management of organ donors after brain death. The 269 research articles originated from 37 countries and regions. The United States was the foremost country in publishing articles on the management of brain dead donors. Harvard University emerged as the leading publisher in this field of research. We noted the top 3 authors by publication volume as K. J. Wood, B. Gridelli, and T. Kawai. Visualization of hotspots and frontiers encompassed kidney transplant, intestinal failure, graft dysfunction, and organ donor evaluation, among other areas.
Conclusions: Our comprehensive overview of the organ donation management field can serve as a valuable resource for researchers looking to delve deeper into the specific aspects, thereby contributing to the ongoing advancement of brain death organ donor management.

Key words : Brain dead donor, End-stage organ failure, Transplantation

Introduction
Transplantation stands as the ultimate treatment option for end-stage diseases.¹ However, mortality rates on transplant wait lists remain high.² In the United States, the numbers of deceased organ donors and solid-organ transplants have consistently increased in recent years, with approximately 36 500 transplants from 10 700 deceased donors performed in 2018 alone.³ Despite an increase in annual lung transplants, the number of patients added to wait lists in recent years has simultaneously increased. This paradox has suggested that the surge in supply has not adequately met the escalating demand, resulting in an insufficient supply of suitable donor. Further exacerbating the shortage has been the low utilization rate of potential donor lungs, with only 20% being transplanted.⁴ To underscore the urgency of the situation, it is crucial to explore the repercussions of inadequate donor management on the imbalance between supply and demand. Despite modifications in allocation policies and advancements in donor management and organ procurement, donor hearts and lungs remain scarce resources, with an 8% wait list mortality rate for both organs in 2018.^5,6 This scarcity is particularly pronounced for donor hearts and lungs because of their heightened susceptibility to the complex, inflammatory physiological changes that follow brain death. A critical need exists to address deficiencies in donor management to alleviate the growing demand-supply disparity in transplantation.³

The scientific management of potential organ donors can significantly boost use of organs and restore functionality to organs that have experienced dysfunction.¹ Organs from deceased potential donors are often rejected because of suboptimal quality.⁷ Adequate donor management to maximize the number of organs available for donation is crucial for expanding the pool or organ donations.

Unlike typical systematic reviews, bibliometric analysis offers a unique quantitative approach for assessment of scientific literature. Researchers can explore the developmental trajectory of a specific field of study and identify emerging trends. Such analysis facilitates knowledge on countries/regions, institutions, authors, and keywords within the scientific literature. CiteSpace, through its capabilities in visualizing and mapping citation patterns, collaboration networks, and research trends, offers a comprehensive interpretation of the development process within a specific research field.

In this study, we aimed to gain insights into the developmental trajectory, research focal points, and cutting-edge trends within the field of brain dead donor management. By collecting both qualitative and quantitative data from publications, we aimed to identify key countries, institutions, authors, and journals based on publication frequency and citations. Our results can serve as a valuable reference for understanding the current state of brain dead donor management and can also provide scholars entering or considering entry into this field with essential insights into its existing status, emerging trends, and potential future research directions.

Materials and Methods
The Thomson Reuters Web of Science Core Collection (WoSCC; Clarivate Analytics) was selected as the primary database for literature retrieval in this study. We selected WoSCC based on its reputation as one of the most comprehensive, systematic, and authoritative databases globally. With a collection of over 12 000 influential journals worldwide, the database covers high-quality scientific literature across the biomedical, natural, and social sciences. Recognized for its reliability, WoSCC has been widely used for bibliometric analysis and visualizing scientific literature in numerous extensive studies. Given its extensive coverage and reputation for indexing reputable journals, we deemed WoSCC as a reliable source for obtaining a comprehensive dataset related to organ donation, brain death, and donor maintenance. We searched the database from January 1, 1992, to May 8, 2024, focusing on articles and reviews in the English language. We initially retrieved 3119 records; after screening for eligibility criteria, we ultimately included 269 articles for further analysis.

We employed a bibliometric approach to quantitatively assess published articles, examining characteristics such as year of publication and publication quantity, as well as country/region, institution, author, journal, citations, and key words to explore research hotspots. We utilized CiteSpace (version 6.2.R3) for bibliometric analyses and data visualization. CiteSpace generated a citation map and facilitated co-citation visualization analysis, aiding in identification of fundamental knowledge and hotspots within the field of research on brain death organ donor management. We also used the software to predict potential research frontiers within this domain.

Results
Our analysis on organ donation management over the past 32 years revealed a number of publication trends. The depicted trend underscored the dynamic nature of research output in the field of organ donation management (Figure 1). The 269 articles originated from 37 countries and regions. The United States, Italy, England, Brazil, Spain, Japan, People’s Republic of China, Germany, Australia, and Canada were the most common locations for publishing articles on organ donation management (Figure 2 and Table 1), with the United States being the leading country. The size of the institution body represents the number of papers published by this institution (Figure 3). The top 5 research institutions with the largest number of publications were Harvard University, University of Pittsburgh, University of Oxford, Universidade de São Paulo, and Columbia University (Table 2).

Citation counts
Analysis and interpretation of technical literature network mapping served as a fundamental approach in literature information mining. Connection lines between nodes denoted co-cited relationships, with the color indicating the time of the first co-citation. The length and thickness of these lines conveyed strength of connection between nodes.^8,9 To provide a comprehensive summary, we considered the concept of co-citation. Nodes that were frequently co-cited reflected a thematic connection, indicating shared relevance within the literature network. The total number of citations that a node accumulated represented its effect and influence in the field, thereby highlighting key contributions and emerging trends over time. This integrated analysis of citation frequency, co-citation patterns, and node characteristics enhanced our understanding of the intellectual structure and development of brain death organ donor management research.

Authors and co-cited authors
The top 3 authors in terms of publication volume were K. J. Wood, B. Gridelli, and T. Kawai (Figure 4), with higher connection density between authors who cooperated more often and closer connection between teams that cooperated, forming different research groups around the core authors. Analyses of co-citation data showed that certain authors had important contributions to the field, forming distinct research clusters around core authors. For example, K. J. Wood, with a total citation frequency of 13, was a pivotal figure since 1996 with sustained influence. B. Gridelli and T. Kawai also exhibited substantial influence, with 13 and 10 citations, respectively, highlighting their prominence in research on brain death organ donor management.

Distribution of articles by journals
The top 5 journals published 62 articles on the management of brain death organ donors, accounting for 23.05% of all articles included in this study (Table 3). The journal Transplantation published the highest number of articles (n = 23). T. Kawai authored the most frequently cited article in the New England Journal of Medicine in 2008, which was referenced 424 times.

Keyword analysis of research hot spots
We designed a network map of keywords (Figure 5) and a time-view map of keywords (Figure 6) related to the management of brain death organ donors in the past 32 years based on a comprehensive analysis of 269 articles. From the parameter area at the upper left corner of the obtained network,¹⁰ the network modularity value was 0.9163. The modularity value is an evaluation index that reflects the degree of network modularization. The value of modularity ranges from 0 to 1, with greater values indicating better modularity of the clustering network. We obtained a Silhouette value of 0.9904, which is an index that measures network homogeneity and ranges from -1 to 1. A larger Silhouette value indicates a clearer theme for each cluster.^11-13

The frequency of co-occurrence of keywords was often used to indicate the direction of the publication’s research. We extracted 367 keywords from 269 articles. We used CiteSpace to view the time frequency of keywords obtained via co-citation analysis (Figure 6). The core documents co-cited were subject to cluster analysis, resulting in 9 major categories: kidney transplantation, brain death, transplantation, tolerance, organ donation, liver transplantation, organ transplantation, organ donor, donor management, and neuroprotection, among others.

Discussion
We conducted a bibliometric analysis of 269 pieces of literature related to the management of brain death organ donors in the WoSCC database from 1992 to 2024, revealing interesting and valuable insights. First, this field of investigation proved to be highly active. Throughout the study period, the number of publications on the management of brain death organ donors increased globally. Another intriguing aspect of the bibliometric analysis was the visualization of global trends, encompassing countries, organizations, and authors. Given the early focus on related research in the United States compared with other regions, the United States emerged as the leading country, with US scientists serving as the primary driving force. The United States boasted a high academic reputation in brain death organ donor management, as indicated by characteristics such as total number of publications, total link strength, and centrality (Table 1). Researchers in Italy, England, and Brazil also made substantial progress, with robust collaborations with the United States. Strengthened international cooperation was shown to be necessary to foster development of research on brain death organ donor management.

The top 4 high-producing institutions were located in the United States (Table 2), and K. J. Wood, B. Gridelli, and T. Kawai emerged as the most prolific contributors. They actively collaborated with others, maximizing regional advantages and further enhancing their academic impact. In terms of journal distribution, the top 5 journals publishing articles on the management of brain death organ donors were all specialist publications, none of which were comprehensive, suggesting that research in the management of brain death organ donors is relatively esoteric. Most of these top 5 journals were classified as quartile, with 1 or 2 publications indexed by the Science Citation Index primarily focusing on surgery or transplantation. Although impact factors have been widely utilized to evaluate research quality,¹⁴ its value has often been scrutinized. Therefore, in the present study, we did not analyze or discuss impact factors.

Donor management of organ donation in the intensive care unit
Organ donation can improve the survival rate and quality of life for patients with end-stage organ failure, resulting in a profound impact on society.¹⁵ However, the inadequate availability of donor organs remains a major challenge. The intensive care unit (ICU) frequently treats patients with devastating neurological injuries who require advanced life support, as well as patients with poor prognoses in which life support is withdrawn. Consequently, the ICU plays a crucial role in organ donation and donor management, and its involvement in donor management and the provision of systematic organ support can maximize organ acquisition.¹⁶

Brain death/brain-heart double death donor management
With progressive brain stem ischemia and brain death, systemic pathophysiological responses cause damage to other organs. Up to 20% of donors after brain death die of cardiovascular failure before donation. Predictive and therapeutic measures to protect brain dead donors can improve donation success and the quality of donor organs.¹⁷

Hemodynamic support
Usually, complications of brain death, such as neurogenic pulmonary edema, distributive shock, diabetes insipidus, and endocrine failure can affect hemodynamic parameters and urine volume. Dehydration treatment in patients with severe neurological injury can also affect volume status and cause metabolic disorders that are difficult to correct. The ICU can utilize various bedside monitoring methods to guide fluid therapy, including ultrasonography and pulmonary thermodilution. However, results of the Monitoring Organ Donors to Improve Transplantation Results found that use of mean arterial pressure (MAP), invasive monitoring of cardiac index (CI), and pulse pressure variation for plan-oriented fluid therapy showed no substantial difference in the number of transplanted organs and recipient mortality compared with conventional care. In the future, we should explore simpler and more convenient methods and devices for management.¹⁸ The overall objective of management of donors after brain death is to maintain blood volume, perfusion pressure (MAP ≥60-70 mm Hg, 1 mm Hg = 0.133 kPa), and urine volume ≥1 mL/kg/hour, with a left ventricular ejection fraction >45%. Lactic acid monitoring, arterial blood gas monitoring, and invasive and noninvasive hemodynamic monitoring are helpful for further treatment.¹⁹ For vasopressor therapy, dopamine and vasopressin should be considered first. In cases of severe shock, norepinephrine, phenylephrine, dobutamine, and epinephrine may be selected. Brain death often causes arrhythmias, which further affect hemodynamics; thus, it is necessary to avoid overreaction of sympathetic storm and choose short-acting drugs. Isoproterenol or epinephrine may be used for bradycardia and amiodarone or lidocaine for ventricular tachycardia.²⁰ The use of a low dose of dopamine (4 μg/kg/min) in kidney donors can reduce the dialysis rate after transplant without increasing adverse reactions,²¹ possibly because stimulation of the dopamine D3 receptor reduces ischemia-reperfusion injury.

Respiratory support
The lungs of donors after brain death are often unsuitable for transplant because of trauma, infection, barotrauma, decreased gas-exchange function from false aspiration, neurogenic pulmonary edema, and respiratory distress syndrome.²² In a multicenter randomized controlled study, lung management strategies (including lung protective ventilation, spontaneous respiration stimulation tests using low-level continuous positive airway pressure) optimized volume status, and the use of lung reexpansion techniques have doubled lung donation rates for potential donors who were initially unable to reach the critical ratio of arterial blood oxygen partial pressure to inhaled air oxygen concentration. Importantly, the incidence of primary graft dysfunction was not increased.²³ The management of transplanted lungs involves maintaining a strict fluid balance with a target central venous pressure of <8 mm Hg. Although there have been concerns about the potential side effects of this protocol on transplanted kidneys, recent evidence suggests that it is safe.²⁴

Hormone replacement therapy
Hormone support therapy is widely used in ICU donor management, but its role has not been fully clarified. Several studies have shown that hemodynamics, organ acquisition rates, and postoperative cardiac transplant function improve after the application of thyroid hormone. However, no meta-analysis of randomized prospective studies has provided conclusive evidence to support this.²⁵ Hormone replacement therapy may be considered when hemodynamic targets are not achieved after adequate fluid resuscitation and when vasopressors exceed the intended dose (dopamine/dobutamine > 10 μg/kg/min or epinephrine/norepinephrine >0.5 μg/kg/min) or if the left ventricular ejection fraction is <45%. The use of the drug is not uniform, and the effects of oral and intravenous preparations are similar.²⁶ Cortisol therapy can also improve oxygenation, reduce the dosage of pressor drugs, and increase the rate of organ acquisition, although the ideal dose still needs further study.²⁷ Vasopressin can improve the organ acquisition rate, reduce the use of positive inotropic drugs, treat diabetes insipidus, and reduce blood sodium levels. Arginine vasopressin (0.01-0.04 IU/min) can reduce the dosage of catecholamines. For diabetes insipidus with hypernatremia, desmopressin is given intravenously at an initial dose of 1 to 4 μg, followed by 1 to 2 μg or higher doses every 6 hours, depending on urine volume, osmotic pressure, and blood sodium levels.

Donor infection
For patients with severe craniocerebral injury and brain death, several complications often arise: severe damage to the cellular immune system, displacement of intestinal flora due to hemodynamic instability, placement of intravascular catheters and other monitoring devices after admission, and multiple skin, mucosal, and other tissue and organ injuries associated with craniocerebral injury. These factors make donors highly susceptible to various infections. Therefore, it is crucial to consider the risk of infection before organ acquisition and the potential subsequent infection of the recipient. A study found that, despite no evidence of infection, bacteremia was present in 5% of donors when evaluated before organ retrieval, including blood cultures.²⁸ In studies primarily involving donors with endocarditis and meningitis, the recipient’s risk of infection was significantly reduced when the donor received anti-infective therapy for at least 48 hours. Consequently, all donors must undergo at least 2 blood cultures. Lung transplant donors must have respiratory secretion cultures, and kidney transplant donors must have urine cultures. Recipients must be treated for at least 7 days based on bacteriological evidence or the anti-infective regimen applied to the donor.²⁹ Serological positivity for syphilis is not a contraindication for transplant, but the recipient must receive appropriate treatment after transplant. When the donor has active tuberculosis and has not received effective treatment for at least 2 months, the organ is deemed unsuitable for transplant.

For viral and fungal infections, all donors must be tested for hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, human T-cell leukemia virus, cytomegalovirus, herpes simplex virus, and Epstein-Barr virus.²⁹ For HCV-positive liver and kidney donor transplant to HCV carriers, the use of organs from donors positive for HBV nuclear antibodies may require postoperative immunoglobulin or oral antiviral treatment. The situation with HBV and HCV infections is more complex and requires contact and negotiation with the transplant team and organ procurement organization.²⁹ Systemic invasive fungal infections are a contraindication for transplant.²⁹

Other complications
Hypothalamic injury causes hypothermia after brain death. However, randomized controlled trials have shown that, compared with normal temperature, maintaining a temperature of 34 to 35 ℃ is associated with a decreased dialysis rate within 7 days after kidney transplant.³⁰ Whether these results apply to other organs requires further research. The pathophysiological changes of brain death include acute kidney injury and disseminated intravascular coagulation. Some centers use heparin to minimize microthrombosis, but results from randomized controlled trials have not shown any significant benefits from this practice.³¹

Extracorporeal membrane oxygenation (ECMO) to support heart and lung function can guarantee effective blood perfusion to organs. Several studies have reported that ECMO can be used for donors after brain death with hemodynamic instability, helping to maintain organ perfusion, allowing time for organ function evaluation, and improving the success rate of organ donation.³² However, because of the effects of cost, ethics, and other factors, the application of ECMO requires further research.

Management of potential donors after cardiac death
In general, the withdrawal of life-sustaining treatment (WLST) from donors after cardiac death to death is less than 60 minutes, with the maximum time not exceeding 120 minutes.³³ This time frame is critical for the viability of the donor and the function of the organs. The total warm ischemia time is the period from the withdrawal of life support to in situ organ perfusion. The time of functional warm ischemia is from the onset of hypotension (systolic blood pressure <50 mm Hg) and/or severe hypoxemia (oxygen saturation <70%) to the in situ organ perfusion stage. The graft complication rate is proportional to warm ischemia time, and different organs have varying tolerance to ischemia: liver of 30 minutes, pancreas of 30 minutes, lung of 60 minutes, and kidney of 120 minutes, although the actual time may be prolonged.¹⁷

A meta-analysis indicated that there was great inconsistency in uncontrolled donor after cardiac death practices, including the time from refractory cardiac arrest to confirmation of death (5-30 min), the time from cessation of chest compressions to declaration of death (5-20 min), the timing of initiation of organ protection (before or after death), the signing of organ protection consent forms, and the method of protection. The maximum allowable time for organ protection from after cardiac arrest until when cardiopulmonary resuscitation (CPR) is performed ranges from 15 to 30 minutes. The time from CPR to catheterization is 90 to 120 minutes, and the time from catheterization to organ procurement is 120 to 360 minutes.³⁴ All guidelines recommend the use of ECMO for organ protection, and some centers use in situ cooling with intraperitoneal perfusion of cold preservation fluid for this purpose.³⁵

Intensive care unit management of donors after cardiac death primarily includes intervention and optimization of organ function before death, the process of WLST, and care after death. This encompasses maintaining hemodynamic stability, ensuring internal environment stability, lung protective ventilation, cardiovascular support, and the use of appropriate analgesic and sedative drugs to increase end-of-life comfort. Before WLST, positive inotropic drugs and vasopressors can be used to ensure tissue perfusion. To minimize the time of warm ischemia and expedite the organ acquisition process, WLST is performed in the operating room whenever possible. However, because end-of-life monitoring in the ICU has improved, some centers opt to withdraw life support in the ICU, with immediate transport to the operating room after the declaration of death.³⁵ The use of drugs before WLST to optimize organ perfusion and improve ischemia-reperfusion injury caused by circulatory failure, such as vasodilators, positive inotropic drugs, and heparin-like drugs, remains controversial as it is perceived to benefit only the recipient.

The pathophysiological changes in a transplant donor before the confirmation of death may cause damage to multiple organs, making management before organ acquisition critically important. Support and intervention in hemodynamics, respiratory function, endocrine balance, and infection control can maximize the success of organ acquisition. With full recognition of the role of the ICU in organ donation, early identification, maintenance, and improvement of donor organ function, along with systematic monitoring and management, are crucial in narrowing the substantial gap between organ supply and demand.

Strengths and limitations
To the best of our knowledge, our bibliometric analysis is the first to describe milestones and trends in research on brain death organ donor management over the last 32 years. This analysis has the advantage of being unbiased, illustrating both areas of development in the field and highlighting areas that have not been thoroughly investigated. However, our study had some limitations. First, we exclusively extracted data from the WoSCC database and did not include other databases, such as Medline or Embase. Nevertheless, we are confident that the WoSCC database generally encompassed all mainstream documents in the natural sciences. Second, we selectively analyzed the characteristics of the information, which may result in overlooking some key points and details. Nonetheless, we have endeavored to comprehensively analyze the development and research content of management of brain dead organ donors as thoroughly as possible. We aimed to summarize the subject and provide guidance during this period of rapid development in research on brain dead organ donor management.

Conclusions
In our bibliometric analysis to examine the research developments, hotspots, and frontiers in the management of brain death organ donors, we focused on countries, institutions, core authors, reference co-citation, keywords, and journals, revealing a promising future for the discipline. The field of transplantation is experiencing continuous growth, evident in the increasing number of publications each year. The top 5 institutions, predominantly located in the United States and European countries, underscore their exceptional contributions to advancements in transplantation. Furthermore, our analysis delved into the main research focus and hotspots within the management of brain dead organ donors for each period, as determined through the examination of key words and citations; the reasons for insufficient number and quality of organ donations were also analyzed. Finally, our exploration of emerging trends, visualizing publications over the last 32 years in the management of brain dead organ donors, brings to light several potential research hotspots for the future.

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