Web of Science is a large global, comprehensive, multidisciplinary, and high-impact academic information repository. It comprises articles in natural science, biomedicine, and other fields, thus guaranteeing our high-quality research analysis (13, 14). Articles on hypothermia and human diseases were retrieved from the Web of Science Core Collection (WoSCC) from 1 January 2005, to 31 August 2024. The following search terms were used: [TS = (hypothermia) OR TS = (low temperature) OR TS = (cold stress) OR TS = (cold exposure)] AND TS = (disease) AND TS = (injury). A total of 1,553 articles were retrieved. In order to ensure the quality and reliability of the data, we only included the original research papers and review articles that have been published. The conclusions and data of conference papers and other types of articles may not have been fully verified because they have not been peer reviewed and the content may change. Citing these literatures may affect the accuracy and reliability of our research conclusions, so they were not included in this study. During the literature screening process, we also excluded articles that are not related to the topic of this study and duplicate publications. Through this series of rigorous screening steps, we finally included and analyzed 706 high-quality articles. They were saved as plain text files and exported as full records and cited references.

This study used CiteSpace 6.4.R1, VOSviewer 1.6.20, R version 4.4.0 and Microsoft Office Excel 2019 as the software for bibliometric analysis. CiteSpace is a document visualization analysis software widely used for bibliometric analysis and data visualization (15, 16). VOSviewer has strong graphics processing capabilities and processes large-scale data (17). The number of publications were analyzed using the linear growth function in Excel; VOSviewer was used for analyzing and visualizing collaboration among countries, institutes, and authors, as well as keyword co-occurrence and overlay analysis. CiteSpace was used to analyze the double-graph overlay of journals and keyword timelines and to identify the burst keywords (Figure 1).

The number of publications can reflect the pace and trend of research (17). An enumeration analysis of annual publications on hypothermia and human diseases since 2005 (Figure 2) demonstrated a gradual increase from 17 to 52 (2005–2023). The number of publications has declined in some years; nonetheless, the overall trend is steadily increasing. We assessed the publication versus year using a linear growth function; R² = 0.8451 indicated a strong correlation, suggesting that articles on hypothermia and human diseases show significant growth and development. Additionally, the correlation between hypothermia and human diseases has attracted widespread attention from researchers.

We analyzed the number of research articles published by countries to investigate the countries/regions that have contributed substantially to hypothermia and human diseases. The United States published the maximum number of research articles on hypothermia and human diseases (235), followed by China (152), Japan (49), Germany (48), England (40), and Canada (39) (Figure 3A). The cooperation among countries was visualized using VOSviewer (Figure 3B). The United States demonstrated the closest cooperation with China, followed by Canada. Strong cooperation and contacts were visualized among other countries, suggesting close academic ties and frequent academic interactions. Good academic cooperation will promote rapid research development.

A total of 402 institutes research hypothermia and human diseases worldwide. Johns Hopkins University and Harvard University (14) published the maximum number of research articles, followed by the University of California System and Pennsylvania Commonwealth System of Higher Education (12) (Figure 4A). The cooperation among institutes can reflect the research activity (Figure 4B). The strongest cooperation was observed between the University of Pittsburgh and Johns Hopkins University, followed by that between the China Medical University and Osaka City University and Cleveland Clinic Foundation and Shanghai Jiao Tong University.

A total of 632 authors had written research articles on hypothermia and human diseases (Figure 5). Among them, Ishikawa Takaki, Maeda Hitoshi, Michiue Tomomi, Zhao Dong, and Zhu Bao-li constituted the first echelon of high-yield authors, followed by Halpern Melissa D., Dvorak Bohuslav, among others. Additionally, researchers from China developed a novel and powerful research network on hypothermia and human diseases.

The leading 20 journals have been listed by the latest impact factor (IF) (Table 1). Nature Reviews Drug Discovery had the highest impact factor (IF = 122.7), followed by Lancet (IF = 98.4). All leading 20 journals with impact factor rankings were in the first quartile (Q1) of the Journal Citation Reports. Among them, the United States and the United Kingdom published the highest number of journals (eight journals each). Gastroenterology, Lancet Public Health, European Urology, and Science Translational Medicine published the most papers, with two. Therapeutic Hypothermia and Temperature Management published the highest number of articles (13), followed by PLoS One (11). The New England Journal of Medicine was the most cited journal (332 citations), followed by the Lancet (248 citations) (Figure 6A). The quality of articles suggested that research on hypothermia and human diseases has been recognized and commended by academic circles.

Double-graph overlay analysis of the citing and cited journals facilitated measuring and visualizing the data to elucidate the flow process of the knowledge system (Figure 6B). Four key citation paths were identified, and the fields of citing journals focused on “Molecular, Biology, Immunology” and “Medicine, Medical, Clinical.” The fields cited focused on “Molecular, Biology, Genetics” and “Health, Nursing, Medicine.” Thus, research on hypothermia and human diseases, encompassing both basic and practical application research, focuses on pathological mechanisms and clinical treatment.

In this study, we conducted a bibliometric analysis to analyze the studies on hypothermia and human diseases from 2005 to 2024. Since 2005, hypothermia and human diseases research has displayed a rapid growth trend. Particularly in 2022, 59 articles were published annually, indicating that research hotspots associated with hypothermia and human diseases have increasingly attracted attention. The increasing incidence of extreme cold weather has contributed to the widespread research attention on human diseases (18–20). In clinical practice, hypothermia has been recognized as a treatment mode. These factors have contributed to the rapid development of this field.

This study included 706 research articles published across 76 countries. Of these countries, the United States and China published the highest number of articles. Additionally, among the countries with the highest frequency of cooperation, the United States plays a central role in international cooperation. Therefore, the United States holds a leading position in hypothermia and human disease research and has substantially contributed to this field. This finding may be attributed to the high national economic condition and considerable medical investment in the United States. Moreover, hypothermia treatment requires advanced intensive care support, which may be unavailable in low- and middle-income countries (21). Therefore, strengthening exchanges and cooperation among research institutions in developed countries to improve their technical level and reduce their dependence on expensive instruments and equipment, while strengthening assistance to countries with insufficient medical conditions, may be a key way to solve the problem.

Of the 402 institutes, 13 of the leading 30 institutes are located in the United States, consistent with the country-wise distribution of published articles. China ranks second in the number of publications; nonetheless, only six universities were listed in the leading 30 institutes. Japan ranks third in the number of publications, with only one institute in the leading 30. In contrast, the German Berlin Institute of Health ranks sixth, with 10 publications. Thus, the economy and resources limit the research output; however, various institutes are actively seeking international cooperation to improve scientific and technological competitiveness.

Peer-reviewed journals are central to the publication of scholarly work, with core journals publishing important research. Researchers can identify potential journals for submissions based on the number of published articles focusing on hypothermia and human diseases. Therapeutic Hypothermia and Temperature Management has published the highest number of articles. IF is a common indicator that evaluates a journal’s influence. Nature Reviews Drug Discovery has the highest IF (122.7). Q1 journals accounted for all of the leading 20 journals with IF rankings. Additionally, China has substantially contributed to hypothermia and human disease research; nonetheless, Asian publishing houses are underrepresented in the leading 10 journals. This drawback highlights the need to establish and develop internationally recognized journals in Asia.

Keywords in a research article reflect the author’s academic contributions, guiding the research direction, framing academic topics, and influencing core articles. Keyword frequency statistics, co-occurrence analysis, and cluster analysis can predict upcoming research topics and hotspots. They are central to assisting researchers explore disciplinary shifts and emerging trends. Based on the leading 25 burst keywords and references in CiteSpace software, the following three research fields and corresponding research hotspots were obtained:

Mechanism underlying the protective effect of therapeutic hypothermia: Therapeutic cerebral hypothermia has a therapeutic role in hypoxic brain injury caused by cardiac arrest (22, 23) and neonatal hypoxic-ischemic encephalopathy (24, 25). Its key protective mechanisms include reducing oxygen consumption in the brain and glucose consumption in low-flow areas (26, 27), delaying destructive enzymatic reactions, inhibiting free radical reactions, protecting lipoprotein membrane fluidity, reducing intracellular acidosis, inhibiting biosynthesis, releasing and uptaking of excitatory neurotransmitters, inhibiting nitric oxide production and apoptosis, repairing DNA damage, and reducing inflammatory reactions (28–31). Researchers should select a cooling method that can not only achieve rapid cooling but also minimize tissue damage. For example, researchers have explored the therapeutic effects of cooling methods, such as systemic hypothermia (32), selective hypothermia, intravascular hypothermia, drug-induced hypothermia (33), and artificial hibernation technology (34) through animal experiments and clinical trials. However, there is a lack of systematic and comprehensive research on the mechanism of therapeutic hypothermia, and there is a lack of sufficient single-cell multimics data and regulatory mechanisms. In view of the differences between experimental animals and humans, the use of organoids for therapeutic hypothermia research may be a hot direction in future research.

Mechanism underlying the damaging effects of severe hypothermia: Severe hypothermia poses a threat to life and can cause freezing to death. The damage to the body is mainly caused by the combined effect of low temperature stress and severe hypothermia. The damaging effects include vascular endothelial cell injury, neuronal mitochondrial swelling, rupture, autophagy, and oxidative stress injury (29, 35–38). Moreover, severe hypothermia activates an inflammatory response, causing pyroptosis, necroptosis (39), and neuronal death. Ferroptosis, triggered by severe hypothermia-induced metabolic disorders is implicated in neuronal death (40). Furthermore, chronic cold exposure increases the risk of lung injury by activating inflammation, oxidative stress, and pyroptosis (9). Cold stress can cause liver damage by activating pathways, such as apoptosis, oxidative stress, and pyroptosis (10). Additionally, hypothermia-induced diseases (3) primarily include cardiovascular diseases, chronic respiratory diseases, metabolic diseases, Alzheimer’s disease, osteoporosis (41), acute kidney injury (42, 43), and acute respiratory infection, which indicate important research topics (44, 45). Although severe hypothermia is a multi-organ and multi-system injury to the body, future research will focus on comprehensiveness while still focusing on the most sensitive cell types to severe hypothermia, such as nerve cells and endothelial cells, which may be key targets for clinical treatment.

Mechanism of action underlying hypothermia: Substantial research progress has been made on therapeutic hypothermia, particularly in neonatal hypoxic-ischemic encephalopathy and other diseases. However, its efficacy varies (46, 47), with numerous mechanisms yet to be elucidated (37). Therapeutic hypothermia exerts a protective effect by inhibiting oxidative stress and inflammation. By contrast, severe hypothermia can cause damage through similar events (48). Thus, to enhance its therapeutic efficacy, researchers should identify steps to optimize the protective effect while minimizing damage. Different organs and different cells are sensitive to temperature differently, and different states of cells respond differently to temperature. It is necessary to emphasize the differences in the regulatory mechanisms of cells by temperature in order to achieve precision therapy. Non-coding RNA has been involved in various aspects of regulatory molecular networks. The regulatory mechanism by which non-coding RNA mediates hypothermia has become a research hotspot. For example, hypothermia-induced miR-25-3p exerts osteoporotic effects by inhibiting osteogenic differentiation and autophagic activity (41). The RNA-binding protein RBM3 prevents nitric oxide-induced neuronal apoptosis via miR-143 (49). Therefore, the mentioned regulatory mechanism may gain attention in the future.

Low temperature is closely related to human life. Low temperature can not only affect the immune system and cause colds, but also lead to frostbite and even freezing to death. It can also play a protective role by reducing cell metabolism through moderate low temperature. Therefore, comprehensive and in-depth research on low temperature can guide clinical precision treatment of related diseases caused by low temperature, and can also guide humans to strengthen protective measures against low temperature. At the same time, it can also improve low temperature treatment methods to better serve human health.

This study has some limitations. First, WoSCC contains a wide spectrum of scientific publications. To ensure high-quality findings, our analysis was restricted to this database; however, it did not affect the overall trends. Second, CiteSpace and VOSviewer cannot completely replace systematic reviews, despite their use in bibliometric analysis. Third, newly published high-quality studies may not have been included because of various factors and should be considered in the future. Overall, our study provides a strong foundation for understanding the research topics, hotspots, and development trends in hypothermia and human diseases.