Metrological and visual analysis of the status of hypotension in septic shock


 Background:At present, there is a lot of research in the field of septic shock and hypotension, but there is no comprehensive analysis of the current situation, hot spots and frontiers in this field，and many researchers don't know where to start..Therefore，in this study, the research status, research hotspots and frontier trends of septic shock hypotension in the past 30 years were analyzed by knowledge graph, so as to provide a reference basis for further research.Methods: We collected the literature related to hypotension in septic shock in Web Of Science (WOS) from 1991 to 2020, and made a bibliometric analysis of the literature. At the same time, we Use Excel2019 and Adobe Illustrator CC2018 software to analyze the annual volume of articles and draw bar charts and VOSviewer software to draw the relevant maps of countries, authors and institutions to explore the cooperative relationship in this field and CiteSpace software to draw keyword co-occurrence map, cluster timeline map and emergence map of keywords, and analyze the frontiers and hotspots in this field.Results: A total of 1419 articles were obtained, of which the country with the largest number of articles was the United States, and the centrality was the highest. Professor Bellomo Rinaldo in Australia has published the largest number of articles, up to 29 articles, which plays an important role in this field. In the organization cooperation graph, Univ sao Paulo cooperates closely with other agencies and publishes a large number of articles. There are high-frequency keywords such as sepsis, septic shock and hypotensio, 11 clusters such as relative adrenal insufficiency, nitric oxide and thromboxane, and high-prominence keywords of endotoxin and tumor necrosis factor.Conclusion: In the past 30 years, the volume of articles in the field of hypotension in septic shock showed a steady upward trend. Institutions in North America, Australia and Europe have made outstanding contributions to this field, but the degree of inter-country and inter-agency cooperation is worrying. Three major author cooperation groups have been formed, with close ties within the group. In the future, international exchanges and cooperation can be strengthened and the degree of cooperation in this field can be improved. Drugs for the treatment of hypotension, molecular mechanisms including endotoxin and tumor necrosis factor, and physiological and pathological mechanisms of hypotension are the research hotspots and frontiers in recent years.

variety of causes of hypotension in patients with this disease, and it is particularly important to use vasopressor for the cause. At present, norepinephrine and vasopressin are recommended as the first-line symptomatic pressor drugs in the field of critical medicine [3] , but the fundamental treatment of sepsis is also very important in the process of pressor pressure. including the improvement of adrenocortical function, the improvement of disordered blood coagulation system, the improvement of cardiac function, to achieve the combination of cause and symptom.
In the past 30 years, there have been different guidelines for theoretical understanding and clinical treatment of septic shock in the field of hypotension, but some treatments outside the guidelines also depend on people and the times. For example, although norepinephrine is currently a first-line drug for hypotension, the application of m-hydroxylamine is hot in some areas [4] [5] . Therefore, it is very important to analyze the development trend and research status in this field.
CiteSpace is an information visualization software developed by Professor Chen Chaomei of Dreisel University in the United States. Based on co-citation analysis theory and routing network algorithm, it calculates the literature and explores the key path and knowledge turning point of the research. A multivariate, time-sharing and dynamic citation analysis visualization language is used to show the research process through the graph [6] [7] .VOSviewer is a visualization software developed by professors Van Eck and Wa It-man of Leiden University in the Netherlands, which can draw co-occurrence maps of countries, institutions and authors. the software has unique advantages in drawing maps.At present, although there are a large number of studies in the field of septic shock hypotension, there is a lack of systematic research on the development of this field. This paper analyzes the knowledge graph of the data collected from WOS by using CiteSpace software and VOSviewer, and draws the relevant charts of countries, authors, institutions and key words, so as to provide a basis for the future research of hypotension in septic shock.
1 Information and methodology

Data acquisition
The core collection of WOS is searched, and the key word is "Septic AND Hypotension". The search time is from January 1, 1991 to September 15, 2020. The literature type is "Artical" and "Review", and the language is "English". In order to avoid duplication and omission of data, the search and download of data was completed on September 15, 2020.After manual screening and elimination of duplicates, 1419 articles were retrieved including 1282 Artical and 137Review. The study used two independent researchers to review and evaluate the retrieved articles, and different opinions were discussed until a consensus was reached.

Data conversion
The included literature will be exported in Refworks format and other formats, and the literature information includes title, author, abstract, keyword, year of publication, research institution, journal, volume, starting and ending page number. The data format is converted by CiteSpace and VOSviewer to form the document format corresponding to Citespace and VOSviewer.

Data processing
Node types are drawn with countries, authors, research institutions, keywords and so on, and visual analysis is carried out. Brazil, Japan, Australia, and so on, have published more than 60 articles, but the centrality is low, so they can improve their influence in this area in the future, and there is room for improvement both in quantity and quality. The picture shows the label view, the darker the color is, the more cutting-edge the research is. Thailand, New Zealand, Turkey and other countries are currently at the forefront of research, but their publication volume is less and the degree of support in the field is low. The above countries can actively cooperate with countries with more papers to jointly enhance cooperation between countries.   Table 2 is the top 10 authors. According to Price's law [8] , the core author, according to the formula:

Number of posts
According to the integer number of articles, that is, more than 5 articles (including) published by the core authors, a total of 98 authors, accounting for about 10.79% of the total number of articles, these 98 authors occupy a pivotal position in this field, the discipline influence is very high.
There are three more prominent cooperative teams, which are also formed by the top three scholars.1 the team with Professor Bellomo Rinaldo as the core is in close contact and publishes the most articles. The color of the map is the lightest, indicating that the research content is very cutting-edge and hot. The main contents of the study are as follows: animal sepsis hypotension drug trial [9][10] , clinical hypotension drug treatment of septic shock patients [11][12] [13] , clinical treatment of bodily organ damage caused by pressor drugs [14] , etc., the quality of the article is very high, and the average influencing factor is more than 20. 2 the team with Professor Martin Westphal as the core, the color of the map is darker, and the frontier and heat of the research are relatively low. The main contents of the study are related to the clinical drug trials of septic shock and hypotension [15] , the combination of the molecular mechanism of pressor drugs with clinical treatment [16] , and the treatment of cardiac function in patients with septic shock [17] [18] , and formed the research ideas and systems in this field. Its publication quality is very high, the influence is high.3 the team with Professor Vincent jean-Louis as the core, the team mainly studies septic shock and blood coagulation [19] [20] , clinical drug trials [21] , and other related studies.
The research direction of the three teams in the field can represent the development direction of the field, all have their relative attention, and the research level is at the forefront of the field.
Tab. 2 Information of the top 10 authors in the field of septic shock and hypotension in WOS from 1991 to 2020  clusters appear, and the specific analysis is as follows:

Institution
Cluster 0, relative adrenocortical insufficiency (RAI), is one of the main reasons for the occurrence and progression of septic shock. The current incidence of RAI in patients with severe septic shock is 50% Mel 75% [22] [23] . Early application of glucocorticoid (GC) is very important.
When sepsis progresses to septic shock, there are many phenomena, such as increased exudation of adrenocortical neutrophils, hemorrhage and necrosis of cortical cells, injury of vascular endothelial cells, and so on. High levels of endogenous GC and decreased binding capacity of the endogenous glucocorticoid receptor (GR) to ligand GC can lead to decreased response to exogenous and endogenous GC. However, small doses must be used [24][25] [26] , and a prospective, randomized, double-blind, placebo clinical trial [27] has shown that high-dose methylprednisolone sodium succinate is not beneficial in the treatment of septic shock. Although the function of the hypothalamus-pituitary-adrenal axis is not affected in the early stage of sepsis, when it reaches the shock stage of sepsis, it is often associated with adrenocortical insufficiency, resulting in reduced secretion of glucocorticoids and a large number of inflammatory factors such as IL-6, TNF-α, IL-1 and so on [28] . At present, GC can be used to treat an adrenocortical injury in patients with infection, but its specific dosage and timing, early prevention of RAI is still a difficult problem, and a breakthrough can be made in this direction in the future.
Cluster 1, nitric oxide (NO), plays an important role in relaxing blood vessels, regulating blood pressure, and regulating blood supply. During septic shock, the adrenal medulla increases NO synthase activity, produces a large amount of NO, lowers blood pressure excessively, and maintains hypotension. Among the top ten citations, two are related to the field of nitric oxide. According to statistics, sepsis with a coagulation incidence of 50-70% can progress to septic disseminated intravascular coagulation (DIC) [30] , has become a key factor in microcirculation disturbance in septic shock and a key indicator of patient prognosis. During sepsis, inflammatory mediators IL-6, TNF, IL-1, and leukocytes stimulate vascular endothelial cells to express tissue factors, thus initiating exogenous coagulation pathways, leading to microvascular micro thrombosis and microcirculatory disorders. In sepsis, especially in severe sepsis, thrombocytopenia is caused by increased loss or destruction, myelosuppression, and other reasons, accompanied by the weakening of platelet function. therefore, the function of platelets to control the release of vasodilation or contractile substances is significantly weakened, and abnormal coagulation is caused by the decrease of plasma antithrombin level and the inhibition of the fibrinolytic system. Therefore, it is particularly important to control abnormal blood coagulation system in a variety of ways to avoid the occurrence of DIC and reduce the mortality caused by an abnormal blood coagulation.
Cluster 4, pentoxifylline (PTX), is a derivative of methylxanthine and has selective anti-inflammatory effects. Some scholars have found that PTX can inhibit the transcription and production of tumor necrosis factor (TNF), and low-dose PTX can inhibit the expression of bioactive TNF and its mRNA by more than 50% [31] [32] . At present, there are two kinds of anti-inflammatory mechanisms: 1 [33] . PTX may inhibit the activity of phosphodiesterase, reduce the degradation of cyclic adenosine monophosphate (cAMP), increase the concentration of intracellular cAMP, reduce the outflow of calcium-dependent potassium ions, change the phosphorylation type of cell membrane proteins and increase the activity of protein kinase, so as to increase the deformability of cell membrane and improve the hemodynamics of microcirculation so as to achieve its anti-inflammatory effect. 2 [34] . PTX can inhibit the expression of β integrin on T lymphocytes, inhibit the expression of CD25, CD69, and CD98, which can promote cell division, inhibit the specific activation of T lymphocyte antigens, and superantigens, and promote the negative regulation of immune response. 3 inhibit nf-kb pathway. The above mechanisms of pentoxifylline can inhibit the progression of inflammation. However, a piglet trial [35] showed that pentoxifylline, a TNF inhibitor, attenuated both GBS-induced TNF production and the late GBS effect, but caused a progressive decrease in systemic hypotension. The use of pentoxifylline is controversial at present, and how to avoid hypotension in the future can become a research direction.
Cluster 5, interferon-γ (IFN--γ), has an immunomodulatory effect. Some studies [36] have shown that interferon can reverse the immune paralysis caused by sepsis. A mouse experiment [37] showed that IFN--γ at the concentration of 20ng/ml could up-regulate the PRRs related to the activation of inflammatory cells and up-regulate the SR related to the defense of inflammatory cells. And other studies have shown that inflammatory infection understands the abnormal function of cells, especially neutrophils, and interferon can reduce neutrophil count and change granulocyte components to the anti-inflammatory wind. Although there are clinical trials to prove its efficacy, but at present, there are few studies on its molecular mechanism, which can be used as a research direction for in-depth exploration.
Cluster 6, vasopressin or antidiuretic hormone (ADH), is a cyclic peptide hormone secreted by the supraoptic nucleus of the hypothalamus, which can enhance the reabsorption of water by distal tubules and collecting ducts of the kidney, thereby maintaining normal colloidal osmotic pressure in plasma. Persistent hypotension in septic shock seriously affects the secretion of ADH, so ADH is mostly the treatment of the results, how to prevent as soon as possible has become a new direction of exploration. Noradrenaline is generally used for hypotension in patients with septic shock, but it has a great effect on heart rate. M-hydroxylamine has little excitatory effect on the heart, long-lasting pressor effect and weak use of vasoconstriction. At present, there has been active use of m-hydroxylamine in clinic. A multicenter prospective cohort study [38] shows that m-hydroxylamine compared with norepinephrine can reduce hospital stay and protect renal function in patients with sepsis.
Cluster 7, tumor necrosis factor or cachexin, is considered to be the primary mediator of septic shock. Various evidences show that the level of TNF-α increases in septic shock, which is positively correlated with the severity and prognosis of septic shock. At present, there are many drugs to show a tendency towards TNF-α, Zhang HF [39] and so on. In mouse bone marrow macrophages induced by lipopolysaccharide, Fiserol attenuates sepsis-induced multiple organ dysfunction by inhibiting p38MAPK/MK2 signal pathway. Liao FH [40] et al were treated with anti-endotoxin subnanogold cluster, the key pro-inflammatory factor NF-κ B dependent cytokines, which significantly decreased the concentration of plasma TNF-α after LPS challenge, and significantly prolonged the survival time of LPS-induced sepsis mice. Ultra-small gold nanoclusters can activate endotoxin by compressing the bulk density of LPS and targeting lipid An of LPS, which provides a potential treatment for treatment. Huang w [41] et al studied that ITK (-/ -) BTK (-/ -) mast cells showed hyperactive preformation and lipopolysaccharide-induced tumor necrosis factor-α production, when recombined into mast cell deficient SASH mice, it will lead to more severe endotoxin-induced septic hypothermia. The increased activation of kappaB, Akt and p38 in ITK (-/ -) Btk (-/ -) induced by LPS can significantly inhibit the excessive production of TNF-α and reduce the hypothermia of sepsis.
Cluster 8, cardiac insufficiency, is an important manifestation of multiple organ failure in septic shock. As the most important organ of the circulatory system, the heart is extremely sensitive to peripheral hemodynamic changes, and cardiac insufficiency occurs in septic shock.
Timely treatment of cardiac insufficiency is particularly important, which has further guiding significance for the treatment of hypotension.
Cluster 3 and cluster 10, type 2 and grade, guiding evidence levels are divided into high, medium, low and very low levels according to the GRADE system, RCT as high-quality evidence, clinical future studies can be carried out to control hypotension drugs RCT, but in the process of RCT research. Efforts should be made to minimize the influence of five interference factors, such as the degree of bias, subgroup analysis, indirectness of evidence, inaccuracy of results, and bias of reporting conclusions, so as to ensure high-quality RCT research.

Conclusion
Hypotension, as the most important manifestation of septic shock, has been paid more and more attention all over the world, and the level of research in Europe and the United States is relatively high. no matter from countries, institutions and individuals, we should strengthen cooperation with Asia, Africa and South America to promote global treatment and research level of septic shock hypotension. In view of some hot spots and frontiers in the research, we should continue to carry out more in-depth research, but we should also explore some non-hot research to promote the development of the whole discipline.