The bibliometric analysis of most cited 100 papers in anesthesia-induced neurotoxicity

Abstract

Anesthesia-induced neurotoxicity is a major concern for anesthetists for more than 20 years. Many experimental and clinical studies have been conducted on this topic since late 1990s. However, bibliometric analysis of these papers has not been reported. In this study, we aimed to analyze the 100 most cited articles on anesthesia-induced neurotoxicity. It was planned as cross-sectional study. On January 30, 2023, we searched the “Web of Science (WOS)” database for anesthesia-induced neurotoxicity and most cited 100 papers about this topic were obtained. Data such as authors’ names, year of publication, name of the journal, type of paper, and citation numbers were analyzed. The most cited 100 papers were read by the investigators, and the anesthetic, animal type in experimental studies, any protective agent and the method for detecting neurotoxicity used in the studies were also noted. There were 75 articles and 22 reviews in the 100 most cited articles. We found that most of the papers in most cited 100 list were published between 2010 to 1024. Most of the papers (11%) were from Harvard University and almost half of the papers (49%) were published in Anesthesiology. A great number of studies were performed in newborns or early childhood (85.5%) and inhalational anesthetics (54.7%) were the most studied anesthetic type. Most of the most cited 100 papers were published in Q1 journals (P = .012) and the continent of the most journals in this list was America (P = .014). The median total and annual citation numbers of funded papers were statistically significantly higher (P < .001 and P < .001 respectively). Anesthesia-induced neurotoxicity is very important, especially for pediatric anesthetists. This study is the first to conduct a bibliometric analysis of the most cited 100 publications on this field. Although there was a gap in the publications about this topic during COVID-19 pandemic, we believe that there will be many more publications on anesthesia-induced neurotoxicity since the mechanism, outcome and possible protection are still unknown.

1. Introduction

Every day millions of people are exposed to anesthetic drugs during surgery or imaging and interventional processes. A quarter of century before, studies showing anesthesia-induced neurotoxicity, especially anesthesia exposure during early childhood started. Many experimental studies reported that after anesthesia exposure during brain growth spurt results with apoptosis, neuroinflammation, cognitive and learning/memory dysfunction.^[1,2] In clinical design, it is impossible and not ethical to perform prospective randomized trials and to investigate the sole effect of anesthesia on neurotoxicity in children. Retrospective clinical trials have conflicting results; while some trials found anesthesia related awareness or behavioral abnormalities, the others didn’t show such effect.^[3,4]

Even though there are conflicting results in clinical research about anesthesia-induced neurotoxicity is a big concern for pediatric anesthetists. Besides children, experimental studies also showed that anesthesia could be related with postoperative delirium and neurocognitive dysfunction.^[5,6] It was also reported that anesthesia might cause Tau phosphorylation, which links to Alzheimer disease.^[7] These findings arise the concern about the safety of anesthetics so many studies were performed about the effects of anesthesia on the young and the old brain since the pioneering article published in 1999.^[8]

Bibliometric analysis is to analyze the literature by using statistical methods and to quantify the knowledge about a certain topic. Holistic studies about anesthesia-induced neurotoxicity is lacking. Holistic analysis of most cited papers could show the most investigated and most read topics about anesthesia-induced neurotoxicity. This can help anesthetists to understand the most likely effects and mechanisms of anesthesia-induced neurotoxicity and whether the findings of experimental studies reflected in clinical design. The aim of our study was to determine the most cited 100 publications about anesthesia-induced neurotoxicity in the Web of Science (WOS) database; and evaluate the total and annual citation counts, authors, journals, institutions and countries of these articles.

2. Materials and methods

This study was planned as a cross-sectional study.

The data of the study was obtained from “Web of Science (WOS)” database and “advanced mode” feature was used. SU = Anesthesiology AND TS = Neurotoxi* OR SU = Anesthesiology AND TS = Neurodegen* OR SU = Anesthesiology AND TS = Neuroapopt* OR SU = Anesthesiology AND TI = Neurotoxi* OR SU = Anesthesiology AND TI = Neurodegen* OR SU = Anesthesiology AND TI = Neuroapopt* OR SU = Anesthesiology AND AB = Neurotoxi* OR SU = Anesthesiology AND AB = Neurodegen* OR SU = Anesthesiology AND AB = Neuroapopt* OR WC = Anesthesiology AND TS = Neurotoxi* OR WC = Anesthesiology AND TS = Neurodegen* OR WC = Anesthesiology AND TS = Neuroapopt* OR WC = Anesthesiology AND TI = Neurotoxi* OR WC = Anesthesiology AND TI = Neurodegen* OR WC = Anesthesiology AND TI = Neuroapopt* OR WC = Anesthesiology AND AB = Neurotoxi* OR WC = Anesthesiology AND AB = Neurodegen* OR WC = Anesthesiology AND AB = Neuroapopt* were used as the search keys.

The search for the study was performed on January 30, 2023. All articles published from 1975 to January 30, 2023, which was the screening date, were included in our study.

From the published studies on anesthesia-induced neurotoxicity, the 100 most cited articles were determined. The studies, which were not about general anesthesia-induced neurotoxicity, were excluded from the analysis. All publications, including the editorial and case reports, about anesthesia-induced neurotoxicity were included in the study.

The total and the annual citation numbers of the publications, the information of the studies, authors, and journals were determined using WOS database and a statistical package program was used for analysis.

The information about the articles including, group authorship, funding features, open access, and other features were determined from the WOS database were determined and recorded separately for each publication. The definition of “authorship rights of more than 1 person, an organization or an institute in an article, book, paper or other type of work” has been using for the term “group authorship.” WOS reports if there is a group authorship in the studies, as well as the name of the authors of the group, the organization and the institute.^[9,10]

Our study is a bibliometric study and any patient, or related material were not involved in the study so ethics committee approval is not required.

2.1. Statistical analysis

Statistical analysis of the study data was performed using Statistical Package for Social Sciences (version 24.0; Social, Inc., Chicago, IL).

The Kolmogorov–Smirnov and Shapiro–Wilk tests were used to determine the distribution properties of the groups.

According to the results of the normality tests and the number of groups, data with continuous values were analyzed using the Kruskal–Wallis and the Mann–Whitney U tests.

The Spearman’s correlation coefficient was used for the correlation analysis.

Analysis of frequency-indicating data was done with the chi-square test.

Data with continuous values were expressed as median (minimum – maximum) and, the data indicating frequency were expressed as numbers (n) and percentage (%).

A P value below .05 was considered statistically significant. The P value, which was significant in multigroup analyzes, was determined by Bonferroni adjustment, considering the group numbers.

3. Results

We found 997 articles with the given key words in the methods section between 1975 and 2023. 238 publications were evaluated to find out the most cited 100 publications about general anesthesia-induced neurotoxicity. The publication year of most cited 100 papers on anesthesia-induced neurotoxicity was between 2002 and 2018. Most of the papers on this topic were published between 2010 and 2014 (53%), and 2011 has the highest paper count (14%) in the top 100 most-cited papers (Fig. 1).

Figure 1.

The distribution of most cited 100 papers on anesthesia induced neurotoxicity in years.

The median citation count of most cited 100 papers in anesthesia-induced neurotoxicity was [109.5 (57–970)]. The annual citation rate changed between 64.667 and 3.158 citations per year, and median annual citation rate was 9.23 (Table 1).

Table 1.

The characteristics of the most cited 100 articles about “Anesthesia Related Neurotoxicity” in the literature.

Parameters	Subgroups	n	Total number of citations, Median (min–max)	Citations per year, Median (min–max)	P (total number of citations)	P (citations per year)
Years	2000–2004	6	142 (101–299)	6670 (5050–14,950)	.002*	.250*
	2005–2009	26	145,50 (60–970)	9385 (3158–64,667)
	2010–2014	53	101 (58–401)	8250 (4538–36,364)
	2015–2019	15	75 (57–146)	11,250 (7889–20,857)
First Author’s Continent	America	73	113 (58–970)	9.33 (3.15–64.66)	.366*	.511*
	Europe	17	145 (57–318)	11.40 (4.63–21.20)
	Other	10	71.5 (59–400)	6.30 (5.36–36.36)
First Author’s Country	USA	70	114.5 (58–970)	9.23 (3.15–64.66)	.704*	.924*
	England	6	172.5 (75–318)	12.70 (5.35–21.2)
	China	5	63 (59–400)	6.30 (5.36–36.36)
	Japan	3	148 (63–398)	11.38 (5.72–26.53)
	Canada	3	90 (60–103)	11.25 (4.61–12.87)
	Denmark	3	75 (71–229)	7.88 (6.81–17.61)
	Switzerland	3	88 (75–165)	8.33 (4.63–11.78)
	Sweden	2	185 (57–313)	14.90 (11.40–18.41)
	Holland	2	171.50 (81–262)	11.62 (5.78–17.46)
	Germany	1	105 (105–105)	10.50 (10.50–10.50)
	Australia	1	101 (101–101)	7.76 (7.76–7.76)
	Singapore	1	67 (67–67)	6.09 (6.09–6.09)
Journal Q Index	Q1	82	116 (58–970)	10.06 (3.15–64.66)	.063*	.299*
	Q2	6	116.5 (63–400)	8.31 (5.18–36.36)
	Q3	4	68.5 (57–109)	7.8 (5.16–11.4)
	Q4	8	73 (59–200)	6.56 (4.61–14.28)
Journal’s Country	USA	75	118 (57–970)	10.41 (3.15–64.66)	.041*	.088*
	England	20	87.5 (58–251)	8.37 (4.61–22.81)
	Canada	2	64 (59–69)	4.42 (4.31–4.53)
	Denmark	3	63 (59–200)	6.3 (5.36–14.28)
Journal’s Continent	America	77	115 (57–970)	9.66 (3.15–64.66)	.039 †	.361†
	Europe	23	81 (58–251)	7.88 (4.61–22.81)
Name of the Journal	Anesthesiology	49	135 (58–970)	11 (3.15–64.66)	.126*	.226*
	Anesth Analg	17	89 (64–368)	9.07 (3.84–28.30)
	Br J Anaesth	13	94 (58–251)	9.42 (4.76–22.81)
	J Neurosurg Anesthesiol	6	116.5 (63–400)	8.31 (5.18–36.36)
	Paediatr Anaesth	5	75 (60–139)	6.81 (4.61–7.88)
	Acta Anesthesiol Scand	3	63 (59–200)	6.3 (5.36–14.28)
	Curr Opin Anesthesiol	3	75 (57–109)	8.33 (7.26–11.4)
	Can J Anesth	2	64 (59–69)	4.42 (4.31–4.53)
	Anaesthesia	1	105 (105–105)	10.5 (10.5–10.5)
	Int J Obstet Anesth	1	62 (62–62)	5.16 (5.16–5.16)
Publisher Country	USA	84	111.5 (57–970)	9.38 (3.15–64.66)	.373*	.256*
	England	15	94 (58–251)	9 (4.76–22.81)
	Canada	1	69 (69–69)	4.31 (4.31–4.31)
Publisher’s Continent	America	85	110 (57–970)	9.33 (3.15–64.66)	.322†	.954†
	Europe	15	94 (58–251)	9 (4.76–22.81)
Study Type	Review	22	100 (57–308)	8.29 (4.53–19.25)	.190*	.160*
	Article	75	130 (58–970)	9.66 (3.84–64.66)
	Other	3	101 (60–118)	5.05 (3.15–9.07)
Study Topic	Clinical	18	135 (60–970)	11.12 (4.61–64.66)	.219*	.01 *
	Experimental	44	135 (58–401)	10.8 (4.31–28.64)
	In vitro	13	83 (64–299)	6.36 (3.84–14.95)
Studied Animal	Rat	18	122.5 (58–318)	7.69 (4.64–21.2)	.683*	.047*
	Mouse	18	152 (63–398)	11.37 (4.31–26.53)
	Monkey	8	137 (58–401)	14.44 (8.85–28.64)
Anesthetic type	Inhalational	41	130 (58–401)	9.43 (3.84–28.64)	.475*	.086*
	Intravenous	17	107 (58–400)	6.4 (4.61–36.36)
	Both	17	136 (64–970)	11 (6.09–64.66)
Endpoint of the experiment	Pathology	38	114 (58–401)	8.61 (3.84–28.64)	.967*	.466*
	Behaviour tests	4	100 (58–234)	10.68 (9.42–14.88)
	Both	13	144 (59–398)	11.35 (4.64–26.53)
Protective Agent	Yes	12	107 (63–318)	7.37 (4.31–21.2)	.851†	.511†
	No	63	130 (58–970)	10.46 (3.84–64.66)
Age	Young	53	134 (58–970)	11.25 (4.31–64.66)	.575*	.682*
	Adult	6	144 (65–400)	8.79 (4.64–36.36)
	Pregnant	2	142 (140–144)	11.21 (9.33–13.09)
	Young and adult	1	64 (64–64)	6.4 (6.4–6.4)
Fund	Yes	47	145 (90–970)	11.87 (5.05–64.66)	<.0001 †	<.0001 †
	No	53	73 (57–318)	6.31 (3.15–21.20)
Open Access	Yes	73	117 (58–970)	9.43 (3.15–64.66)	.160†	.098†
	No	27	90 (57–257)	7.26 (3.84–16.07)

Bold values are statistically significant.

n = number of articles.

^*Kruskal–Wallis test.

^†Mann–Whitney U test.

The article with highest citation was Wilder RT et al’ s “Early Exposure to Anesthesia and Learning Disabilities in a Population-based Birth Cohort” published in Anesthesiology, and it had 970 citations. The lowest citation count of the first 100 papers was 57.

Creeley CE, DiMaggio C, Hansen TG, Istaphanous GK, Loepke AW, Sanders RD and Stratmann G had the greatest number of papers as first authors in the top 100 most-cited studies in anesthesia-induced neurotoxicity with 3 papers each. The institution where the highest number of publications in the field was Harvard University (11%) followed by Cincinnati Children’s Hospital Medical Center, Columbia University and Washington University in the second place with 7 publications; Imperial College London and University of Pennsylvania in the third place with 5 publications. The names and the institutions of the first authors of the most cited 100 papers on anesthesia-induced neurotoxicity are listed respectively in Tables 2 and 3.

Table 2.

The first authors of the 100 most cited papers about “Anesthesia Induced Neurotoxicity” in the literature.

First authors names	Number of cited articles
Creeley CE; DiMaggio C; Hansen TG; Istaphanous GK; Loepke AW; Sanders RD; Stratmann G	3
Brambrink AM; Cattano D; Ing C; Jevtovic-Todorovic V; Ma DQ; Raper J; Soriano SG; Vutskits L	2
Alvarado MC; Amrock LG; Anand KJS; Bai XW; Berger M; Bittner EA; Block RI; Bong CL; Boscolo A; Braun S; Briner A; Cata JP; Chan MTV; Culley DJ; Davidson AJ; Deng M; Duan X; Eckenhoff RG; Edwards DA; Fredriksson A; Graham MR; Guerra GG; Hayashi H; Head BP; Hu DQ; Hudson AE; Johnson SA; Kahraman S; Kalkman CJ; Kodama M; Lemkuil BP; Liang G; Liu JR; Lu Y; Mellon RD; Noguchi KK; O’Leary JD; Olney JW; Palanisamy A; Pearn ML; Perez-Zoghbi JF; Sanchez V; Satomoto M; Shu Y; Sinner B; Sprung J; Straiko MMW; Sun L; Tang JXX; Twaroski DM; Wang C; Wei HF; Weiss M; Wilder RT; Wise-Faberowski L; Yan J; Yonamine R; Zhang B; Zhao XL; Zhao YL; Zhen Y; Zheng H; Zheng SQ	1

Table 3.

The institutions of the 100 most cited papers about “Anesthesia Induced Neurotoxicity” in the literature.

Institutions of the first authors	Number of cited articles
Harvard University	11
Cincinnati Children’s Hospital Medical Center; Columbia University; Washington University	7
Imperial College London; University of Pennsylvania	5
Mayo Clinic; National Defense Medical College-Japan; Odense Univ Hosp; Oregon Health and Science University; University of California San Diego; University of California San Francisco; University of Geneva; University of Virginia;	3
Duke University; Medical College of Wisconsin; US Food and Drug Administration (FDA); Yerkes Natl Primate Res Ctr	2
Arkansas Children’s Hospital; Capital Medical University; Chinese University of Hong Kong; Cornell University; Emory University; Hebei Medical University; Huazhong University of Science and Technology; Icahn School of Medicine at Mount Sinai; KK Women’s and Children’s Hospital; Oregon Natl Primate Res Ctr; Royal Children’s Hospital Melbourne; Shanghai Jiao Tong University; University Children’s Hospital Zurich; University College London; University of Alberta; University of Amsterdam; University of Colorado System; University of Florida; University of Iowa; University of Manitoba; University of Regensburg; University of Texas System; University of Toronto; University System of Maryland; Uppsala University; Utrecht University	1

When the publication years were grouped and the total and annual citation numbers were evaluated according to the year intervals, there was no significant difference in the annual citation numbers in the analysis made according to the years (P = .250; Kruskal–Wallis test). When the correlation relationship between the year of the study and total and annual citation numbers was examined, there was no correlation between the number of citations per year and the year of study (r = 0.140; P = .165; Spearman correlation test) but there was a weak negative correlation between the total number of citations and the year of the study (r = −0.401; P < .001; Spearman correlation test) (Table 4).

Table 4.

Correlation relationships and correlation coefficients between the number of citations, publication year and journal impact of the 100 most cited studies on “Anesthesia Related Neurotoxicity” (r).

	Reference count	Number of page	Journal last year impact factor	Journal 5 year impact factor	Year of publication
Number of citation	0.927	0.095	0.149	0.110	0.000*
Citations per year	0.233	0.019*	0.050	0.031*	0.165

^*P < .01 Spearman’s correlation analysis.

There were 75 articles and 22 reviews in the most cited 100 articles. There was no statistically significant difference between publication type and year periods (P = .395; Chi-Square test).

There was no statistically significant difference between publication type and total or annual citation numbers (P > .05; Kruskal–Wallis test). Majority of the articles were experimental studies (76%). Mostly used animals in anesthesia-induced neurotoxicity studies designed with animals were rats (29%) and mice (29%) (Table 1). The experimental animal choice according to the first author’s country is shown in Figure 2. 12.9% of the animal studies were on monkeys and 17.3% of the articles were in vitro studies. The number of clinical studies was 24%. Most of the animal and clinical studies’ publisher’s continent was America (87.1%, P = .006; Chi-Square test) and more than half of them were published in Anesthesiology (59.7%, P = .01; Chi-Square test). Annual and the total citation count was similar between all animal and clinical studies. In vitro studies’ annual citation count was significantly lower than animal and clinical studies ([6.363 (3.842–14.95)]; P = .010; Kruskal–Wallis test).

Figure 2.

The study designs of anesthesia-induced neurotoxicity according to countries. P = .045; Chi-Square test.

Most frequently studied anesthetics were inhalational anesthetics (54.7%), and in 22.7% of the studies both inhalational and intravenous (IV) anesthetics were used (generally observational clinical studies). 22.7% of the studies were investigating the neurotoxic effects of IV anesthetics (Table 1). There was no significant correlation between the type of the anesthetic and total or annual citation numbers (P > .05; Kruskal–Wallis test). The anesthetic used in the studies according to first author’s country is shown in Figure 3.

Figure 3.

Distribution of anesthetics used in anesthesia-induced neurotoxicity studies by first author’s countries. P = .032; Chi-Square test.

In experimental studies, outcomes were commonly tested with pathology (50.7%) and behavior tests (5.3%) alone or combined with pathology (17.3%). In clinical trials, evaluation of education (9.3%) and neuropsychiatric tests (13.3%) were commonly used (Table 1).

In 16% of 75 studies, a protective agent was used to reduce the neurotoxic effects of the anesthetic (Table 1). Dexmedetomidine and Xenon were the mostly used protective agents.

Most of the studies were performed in newborns or early childhood (85.5%). The 3.2% of the studies used pregnant animals and their babies were evaluated for anesthesia-induced neurotoxicity. Only 9.7% of the studies investigated the neurotoxic effects of anesthetics in adults (Table 1). A statistically significant difference between the age of anesthesia exposure and total or annual citation numbers was not found (P > .05; Kruskal–Wallis test).

Nearly half of the most cited 100 papers about anesthesia-induced neurotoxicity were published in Anesthesiology (49%) (P = .013; Chi-Square). 85.7% of the papers published in Anesthesiology, was open access (P < .001; Chi-Square). 17% of the papers were published in Anesthesia and Analgesia and 13% were published in British Journal of Anesthesia, 58.8% and 100% of the papers were open access respectively. Comparable with this finding 75% of the journals were published in United States of America (USA). The second most frequent country of the journals was England (20%). The distribution of total citation count was significantly higher in America according to continent of the journal [115 (57–970), P = .039; Mann–Whitney U test] but there wasn’t a significant difference in the annual number of citations according to the journal’ s continent and country. Similarly, the first authors’ country was USA in 70% of the papers. England (6%); China (5%); Japan, Canada, Denmark and Switzerland (3%); Holland and Sweden (2%); Germany, Australia and Singapore (1%) were the other countries of the first authors.

The continent of the journals was America in 66.7% of the papers between 2000 to 2004, 100% of 2005 to 2009, 69.8% of 2010 to 2014, and 66.7% of 2015 to 2019 (P = .014; Chi-Square test).

When the quarter (Q) of the journals in the most cited 100 papers list was evaluated, we found that the percentage of Q1, Q2, Q3, and Q4 was 82%, 6%, 4%, and 8% respectively (Table 3). Most of the articles (86.7%) and reviews (63.6%) and all of the editorials were published in Q1 journals (P = .012; Chi-Square test). There was no statistical relationship between total or annual citation numbers and Q class of the journals (P > .05; Kruskal–Wallis test).

In the most cited 100 papers list in anesthesia-induced neurotoxicity 47% of them were funded and 73% of them were published open access. The median total citation count of open access papers was [117 (58–970)] and median annual citation was [9.437 (3.158–64.667)]. The median total citation count of funded papers was [145 (90–970)], median annual citation was [11.875 (5.05–64.667)] and both total and annual citation count were statistically significant (P < .001 and P < .001 respectively; Mann–Whitney U test). 91.8% of the open access papers were published in Q1 journals and 81.7% of the papers published in Q1 journals were open access (P < .0001; Chi-Square test).

Three studies included group authors. There was no statistically significant difference between total or annual citation numbers and having group authors (P > .05; Mann–Whitney U test).

We could not find a correlation between number of citations and either reference count, number of pages or the impact factor of the journal. When we investigated the relationship between these factors and annual citation number, there was a weak correlation with the number of pages and journal’s 5-year impact factor (r = 0.235; P = .019 and r = 0.216; P = .031 respectively; Spearman correlation test) (Table 4).

Most cited 100 publications about anesthesia-induced neurotoxicity is listed in Table 5.

Table 5.

Information on the first 100 most cited studies included in our study.

Order	First Author	Title	Journal	PubMed ID	Total citation (WOS)	Annular citation (WOS)
1	Wilder RT	Early Exposure to Anesthesia and Learning Disabilities in a Population-based Birth Cohort	ANESTHESIOLOGY	19293700	970,00	64,667
2	Brambrink AM	Isoflurane-induced Neuroapoptosis in the Neonatal Rhesus Macaque Brain	ANESTHESIOLOGY	20234312	401,00	28,643
3	Chan MTV	BIS-guided Anesthesia Decreases Postoperative Delirium and Cognitive Decline	JOURNAL OF NEUROSURGICAL ANESTHESIOLOGY	23027226	400,00	36,364
4	Satomoto, M	Neonatal Exposure to Sevoflurane Induces Abnormal Social Behaviors and Deficits in Fear Conditioning in Mice	ANESTHESIOLOGY	19212262	398,00	26,533
5	DiMaggio, C	Early Childhood Exposure to Anesthesia and Risk of Developmental and Behavioral Disorders in a Sibling Birth Cohort	ANESTHESIA AND ANALGESIA	21415431	368,00	28,308
6	DiMaggio, C	A Retrospective Cohort Study of the Association of Anesthesia and Hernia Repair Surgery With Behavioral and Developmental Disorders in Young Children	JOURNAL OF NEUROSURGICAL ANESTHESIOLOGY	19955889	362,00	24,133
7	Sanders, RD	Dexmedetomidine Attenuates Isoflurane-induced Neurocognitive Impairment in Neonatal Rats	ANESTHESIOLOGY	19352168	318,00	21,200
8	Fredriksson, A	Neonatal exposure to a combination of N-methyl-D-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent Behavioral deficits	ANESTHESIOLOGY	17721245	313,00	18,412
9	Loepke, AW	An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function	ANESTHESIA AND ANALGESIA	18499597	308,00	19,250
10	Eckenhoff, RG	Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity	ANESTHESIOLOGY	15329595	299,00	14,950
11	Kalkman, CJ	Behavior and Development in Children and Age at the Time of First Anesthetic Exposure	ANESTHESIOLOGY	19293699	262,00	17,467
12	Mellon, RD	Use of anesthetic agents in neonates and young children	ANESTHESIA AND ANALGESIA	17312200	257,00	15,118
13	Creeley, CE	Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain	BRITISH JOURNAL OF ANAESTHESIA	23722059	251,00	22,818
14	Sun, L	Early childhood general anesthesia exposure and neurocognitive development	BRITISH JOURNAL OF ANAESTHESIA	21148656	240,00	17,143
15	Culley, DJ	Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats	ANESTHESIOLOGY	14739805	234,00	11,700
16	Hansen, TG	Academic Performance in Adolescence after Inguinal Hernia Repair in Infancy A Nationwide Cohort Study	ANESTHESIOLOGY	21368654	229,00	17,615
17	Brambrink, AM	Ketamine-induced Neuroapoptosis in the Fetal and Neonatal Rhesus Macaque Brain	ANESTHESIOLOGY	22222480	226,00	18,833
18	Istaphanous, GK	Comparison of the Neuroapoptotic Properties of Equipotent Anesthetic Concentrations of Desflurane, Isoflurane, or Sevoflurane in Neonatal Mice	ANESTHESIOLOGY	21293251	209,00	16,077
19	Ma, DQ	Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain	ANESTHESIOLOGY	17413912	208,00	12,235
20	Sanders, RD	Dexmedetomidine provides cortical neuroprotection: impact on anesthetic-induced neuroapoptosis in the rat developing brain	ACTA ANAESTHESIOLOGICA SCANDINAVICA	20003127	200,00	14,286
21	Head, BP	Inhibition of p75 Neurotrophin Receptor Attenuates Isoflurane-mediated Neuronal Apoptosis in the Neonatal Central Nervous System	ANESTHESIOLOGY	19293698	192,00	12,800
22	Loepke, AW	The Effects of Neonatal Isoflurane Exposure in Mice on Brain Cell Viability, Adult Behavior, Learning, and Memory	ANESTHESIA AND ANALGESIA	19095836	192,00	12,800
23	Cattano, D	Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain	ANESTHESIA AND ANALGESIA	18499599	190,00	11,875
24	Jevtovic-Todorovic, V	Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar	BRITISH JOURNAL OF ANAESTHESIA	23722106	188,00	17,091
25	Briner, A	Volatile Anesthetics Rapidly Increase Dendritic Spine Density in the Rat Medial Prefrontal Cortex during Synaptogenesis	ANESTHESIOLOGY	20124985	165,00	11,786
26	Liang, G	Isoflurane Causes Greater Neurodegeneration Than an Equivalent Exposure of Sevoflurane in the Developing Brain of Neonatal Mice	ANESTHESIOLOGY	20460994	159,00	11,357
27	Lu, Y	Anesthetic Sevoflurane Causes Neurotoxicity Differently in Neonatal Naive and Alzheimer Disease Transgenic Mice	ANESTHESIOLOGY	20460993	156,00	11,143
28	Wei, HF	The common inhalational anesthetic isoflurane induces apoptosis via activation of inositol 1,4,5-trisphosphate receptors	ANESTHESIOLOGY	18212570	151,00	9438
29	Kodama, M	Neonatal Desflurane Exposure Induces More Robust Neuroapoptosis than Do Isoflurane and Sevoflurane and Impairs Working Memory	ANESTHESIOLOGY	21956042	148,00	11,385
30	Hu, DQ	Association between Exposure of Young Children to Procedures Requiring General Anesthesia and Learning and Behavioral Outcomes in a Population-based Birth Cohort	ANESTHESIOLOGY	28609302	146,00	20,857
31	Sanders, RD	Impact of anesthetics and surgery on neurodevelopment: an update	BRITISH JOURNAL OF ANAESTHESIA	23542078	145,00	13,182
32	Ma, DQ	Neuroprotective and neurotoxic properties of the “inert” gas, xenon	BRITISH JOURNAL OF ANAESTHESIA	12393773	145,00	6591
33	Zheng, H	Sevoflurane Anesthesia in Pregnant Mice Induces Neurotoxicity in Fetal and Offspring Mice	ANESTHESIOLOGY	23314109	144,00	13,091
34	Tang, JXX	Human Alzheimer and Inflammation Biomarkers after Anesthesia and Surgery	ANESTHESIOLOGY	21857497	143,00	11,000
35	Creeley, CE	Isoflurane-induced Apoptosis of Neurons and Oligodendrocytes in the Fetal Rhesus Macaque Brain	ANESTHESIOLOGY	24158051	140,00	14,000
36	Sprung, J	Anesthesia for Cesarean Delivery and Learning Disabilities in a Population-based Birth Cohort	ANESTHESIOLOGY	19602960	140,00	9333
37	Hayashi, H	Repeated administration of ketamine may lead to neuronal degeneration in the developing rat brain	PAEDIATRIC ANAESTHESIA	12519135	139,00	6318
38	Sanchez, V	General Anesthesia Causes Long-term Impairment of Mitochondrial Morphogenesis and Synaptic Transmission in Developing Rat Brain	ANESTHESIOLOGY	21909020	136,00	10,462
39	Anand, KJS	Anesthetic agents and the immature brain: Are these toxic or therapeutic?	ANESTHESIOLOGY	15277935	135,00	6750
40	Raper, J	Multiple Anesthetic Exposure in Infant Monkeys Alters Emotional Reactivity to an Acute Stressor	ANESTHESIOLOGY	26313293	134,00	14,889
41	Johnson, SA	Isoflurane-induced neuroapoptosis in the developing brain of nonhypoglycemic mice	JOURNAL OF NEUROSURGICAL ANESTHESIOLOGY	18157021	134,00	8375
42	Bai, XW	Ketamine Enhances Human Neural Stem Cell Proliferation and Induces Neuronal Apoptosis via Reactive Oxygen Species-Mediated Mitochondrial Pathway	ANESTHESIA AND ANALGESIA	23460563	130,00	11,818
43	Block, RI	Are Anesthesia and Surgery during Infancy Associated with Altered Academic Performance during Childhood?	ANESTHESIOLOGY	22801049	130,00	10,833
44	Stratmann, G	Effect of Hypercarbia and Isoflurane on Brain Cell Death and Neurocognitive Dysfunction in 7-day-old Rats	ANESTHESIOLOGY	19293696	130,00	8667
45	Stratmann, G	Neurotoxicity of Anesthetic Drugs in the Developing Brain	ANESTHESIA AND ANALGESIA	21965351	118,00	9077
46	Hudson, AE	Are anesthetics toxic to the brain?	BRITISH JOURNAL OF ANAESTHESIA	21616941	117,00	9000
47	Amrock, LG	Long-term Effects of Single or Multiple Neonatal Sevoflurane Exposures on Rat Hippocampal Ultrastructure	ANESTHESIOLOGY	25289484	115,00	12,778
48	Berger, M	Best Practices for Postoperative Brain Health: Recommendations From the Fifth International Perioperative Neurotoxicity Working Group	ANESTHESIA AND ANALGESIA	30303868	114,00	19,000
49	Straiko, MMW	Lithium Protects against Anesthesia-induced Developmental Neuroapoptosis	ANESTHESIOLOGY	19293695	113,00	7533
50	Ing, C	Comparative Analysis of Outcome Measures Used in Examining Neurodevelopmental Effects of Early Childhood Anesthesia Exposure	ANESTHESIOLOGY	24694922	110,00	11,000
51	Istaphanous, GK	General anesthetics and the developing brain	CURRENT OPINION IN ANESTHESIOLOGY	19434780	109,00	7267
52	Pearn, ML	Propofol Neurotoxicity Is Mediated by p75 Neurotrophin Receptor Activation	ANESTHESIOLOGY	22198221	107,00	8917
53	Sinner, B	General anesthetics and the developing brain: an overview	ANAESTHESIA	24829066	105,00	10,500
54	Graham, MR	Neurodevelopmental Assessment in Kindergarten in Children Exposed to General Anesthesia before the Age of 4 Years A Retrospective Matched Cohort Study	ANESTHESIOLOGY	27655179	103,00	12,875
55	Davidson, AJ	Anesthesia and neurotoxicity to the developing brain: the clinical relevance	PEDIATRIC ANESTHESIA	21466608	101,00	7769
56	Edwards, DA	Bumetanide Alleviates Epileptogenic and Neurotoxic Effects of Sevoflurane in Neonatal Rat Brain	ANESTHESIOLOGY	20124973	101,00	7214
57	Olney, JW	Anesthesia-induced developmental neuroapoptosis - Does it happen in humans?	ANESTHESIOLOGY	15277906	101,00	5050
58	DiMaggio, C	Pediatric Anesthesia and Neurodevelopmental Impairments: A Bayesian Meta-analysis	JOURNAL OF NEUROSURGICAL ANESTHESIOLOGY	23076225	99,00	8250
59	Perez-Zoghbi, JF	Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats	BRITISH JOURNAL OF ANAESTHESIA	28969317	94,00	13,429
60	O’Leary, JD	A Population-based Study Evaluating the Association between Surgery in Early Life and Child Development at Primary School Entry	ANESTHESIOLOGY	27433745	90,00	11,250
61	Boscolo, A	Early Exposure to General Anesthesia Disturbs Mitochondrial Fission and Fusion in the Developing Rat Brain	ANESTHESIOLOGY	23411726	90,00	8182
62	Lemkuil, BP	Isoflurane Neurotoxicity Is Mediated by p75(NTR)-RhoA Activation and Actin Depolymerization	ANESTHESIOLOGY	21169791	90,00	6923
63	Loepke, AW	The physiologic effects of isoflurane anesthesia in neonatal mice	ANESTHESIA AND ANALGESIA	16368807	89,00	4944
64	Vutskits, L	Clinically relevant concentrations of propofol but not midazolam alter in vitro dendritic development of isolated gamma-aminobutyric acid-positive interneurons	ANESTHESIOLOGY	15851884	88,00	4632
65	Kahraman, S	GABAergic Mechanism of Propofol Toxicity in Immature Neurons	JOURNAL OF NEUROSURGICAL ANESTHESIOLOGY	18812886	83,00	5188
66	Braun, S	Ketamine induces apoptosis via the mitochondrial pathway in human lymphocytes and neuronal cells	BRITISH JOURNAL OF ANAESTHESIA	20659914	81,00	5786
67	Soriano, SG	Ketamine Activates Cell Cycle Signaling and Apoptosis in the Neonatal Rat Brain	ANESTHESIOLOGY	20418696	81,00	5786
68	Creeley, CE	The Young: Neuroapoptosis Induced by Anesthetics and What to Do About It	ANESTHESIA AND ANALGESIA	19955510	78,00	5571
69	Zhao, YL	GABAergic Excitotoxicity Injury of the Immature Hippocampal Pyramidal Neurons’ Exposure to Isoflurane	ANESTHESIA AND ANALGESIA	21918167	76,00	5846
70	Weiss, M	Safe Anesthesia for Every Tot – The SAFETOTS initiative	CURRENT OPINION IN ANESTHESIOLOGY	25887194	75,00	8333
71	Hansen, TG	Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study	PEDIATRIC ANESTHESIA	23863116	75,00	6818
72	Shu, Y	Xenon Pretreatment Attenuates Anesthetic-induced Apoptosis in the Developing Brain in Comparison with Nitrous Oxide and Hypoxia	ANESTHESIOLOGY	20613483	75,00	5357
73	Wang, C	Strategies and experimental models for evaluating anesthetics: Effects on the developing nervous system	ANESTHESIA AND ANALGESIA	18499593	75,00	4688
74	Zhang, B	The Effects of isoflurane and Desflurane on Cognitive Function in Humans	ANESTHESIA AND ANALGESIA	22075020	73,00	6083
75	Wise-Faberowski, L	Isoflurane-induced neuronal degeneration: An evaluation in organotypic hippocampal slice cultures	ANESTHESIA AND ANALGESIA	16115969	73,00	3842
76	Hansen, TG	Anesthesia-related neurotoxicity and the developing animal brain is not a significant problem in children	PEDIATRIC ANESTHESIA	25266176	71,00	7889
77	Zhao, XL	Dual Effects of Isoflurane on Proliferation, Differentiation, and Survival in Human Neuroprogenitor Cells	ANESTHESIOLOGY	23314167	70,00	6364
78	Cattano, D	Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain	CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE	18591700	69,00	4313
79	Bong, CL	The Effects of Exposure to General Anesthesia in Infancy on Academic Performance at Age 12	ANESTHESIA AND ANALGESIA	24132012	67,00	6091
80	Zhen, Y	Nitrous Oxide Plus Isoflurane Induces Apoptosis and Increases beta-Amyloid Protein Levels	ANESTHESIOLOGY	19741497	67,00	4467
81	Alvarado, MC	Visual recognition memory is impaired in rhesus monkeys repeatedly exposed to sevoflurane in infancy	BRITISH JOURNAL OF ANAESTHESIA	28575197	66,00	9429
82	Istaphanous, GK	Characterization and Quantification of Isoflurane-Induced Developmental Apoptotic Cell Death in Mouse Cerebral Cortex	ANESTHESIA AND ANALGESIA	23460572	66,00	6000
83	Stratmann, G	Isoflurane Does Not Affect Brain Cell Death, Hippocampal Neurogenesis, or Long-term Neurocognitive Outcome in Aged Rats	ANESTHESIOLOGY	20098132	65,00	4643
84	Ing, C	Age at Exposure to Surgery and Anesthesia in Children and Association With Mental Disorder Diagnosis	ANESTHESIA AND ANALGESIA	28857799	64,00	9143
85	Twaroski, DM	Down-regulation of MicroRNA-21 Is Involved in the Propofol-induced Neurotoxicity Observed in Human Stem Cell-derived Neurons	ANESTHESIOLOGY	24950164	64,00	6400
86	Deng, M	Brain regional vulnerability to anesthesia-induced neuroapoptosis shifts with age at exposure and extends into adulthood for some regions	BRITISH JOURNAL OF ANAESTHESIA	24431386	64,00	6400
87	Duan, X	Dexmedetomidine provides neuroprotection: impact on ketamine-induced neuroapoptosis in the developing rat brain	ACTA ANAESTHESIOLOGICA SCANDINAVICA	25041263	63,00	6300
88	Yan, J	Dual Effects of Ketamine: Neurotoxicity Versus Neuroprotection in Anesthesia for the Developing Brain	JOURNAL OF NEUROSURGICAL ANESTHESIOLOGY	24275940	63,00	6300
89	Yonamine, R	Coadministration of Hydrogen Gas as Part of the Carrier Gas Mixture Suppresses Neuronal Apoptosis and Subsequent Behavioral Deficits Caused by Neonatal Exposure to Sevoflurane in Mice	ANESTHESIOLOGY	23221861	63,00	5727
90	Noguchi, KK	Isoflurane exposure for 3 hours triggers apoptotic cell death in neonatal macaque brain	BRITISH JOURNAL OF ANAESTHESIA	28969320	62,00	8857
91	Palanisamy, A	Maternal anesthesia and fetal neurodevelopment	INTERNATIONAL JOURNAL OF OBSTETRIC ANESTHESIA	22405978	62,00	5167
92	Cata, JP	Neurological biomarkers in the perioperative period	BRITISH JOURNAL OF ANAESTHESIA	22065690	62,00	4769
93	Guerra, GG	Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy	PEDIATRIC ANESTHESIA	21507125	60,00	4615
94	Soriano, SG	Of mice and men: Should we extrapolate rodent experimental data to the care of human neonates?	ANESTHESIOLOGY	15791124	60,00	3158
95	Zheng, SQ	Sevoflurane causes neuronal apoptosis and adaptability changes of neonatal rats	ACTA ANAESTHESIOLOGICA SCANDINAVICA	23889296	59,00	5364
96	Bittner, EA	Brief review: Anesthetic neurotoxicity in the elderly, cognitive dysfunction and Alzheimer’s disease	CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE	21174183	59,00	4538
97	Jevtovic-Todorovic, V	Exposure of Developing Brain to General Anesthesia: What Is the Animal Evidence?	ANESTHESIOLOGY	29271804	58,00	9667
98	Raper, J	Persistent alteration in behavioral reactivity to a mild social stressor in rhesus monkeys repeatedly exposed to sevoflurane in infancy	BRITISH JOURNAL OF ANAESTHESIA	29576116	58,00	9667
99	Liu, JR	Noxious Stimulation Attenuates Ketamine-induced Neuroapoptosis in the Developing Rat Brain	ANESTHESIOLOGY	22617253	58,00	4833
100	Vutskits, Laszlo; Davidson, Andrew	Update on developmental anesthesia neurotoxicity	CURRENT OPINION IN ANESTHESIOLOGY	28277380	57,00	11,400

4. Discussion

We analyzed the characteristics of most cited 100 publications about anesthesia-induced neurotoxicity in this study. We found that general anesthesia-induced neurotoxicity mostly studied in young age groups and mostly experimental studies were performed. Inhalational anesthetics were the main drug of the investigations. The analysis of top 100 publications in this field showed that USA is the center of studies in this topic and they are mostly featured in the journals published in American continent. We also determined that funding is not much but publishing open access is important to be cited.

Anesthesia induced neurotoxicity is a big concern especially in pediatric anesthesia. After the experimental studies showing neurotoxicity after anesthesia exposure in pediatric age group Food and Drug Administration make a safety announcement about anesthetic use in children younger than 4 years and pregnant women.^[11] Since the first studies that show detrimental effects of anesthetic agents on developing brain predominantly, many articles were published investigating the possible mechanism, affected age periods, brain regions, and potential drugs that can prevent anesthesia-induced neurotoxicity.^[2] There are conflicting results in the literature about anesthesia-induced neurotoxicity.^[4] Especially in clinical trials, it is impossible to ignore the effects and the cause of the surgery. Each day millions of children are exposed to anesthesia drugs for surgery or interventions so it is important to understand the real effects of anesthetics on central nervous system. Cao et al^[12] investigated the articles about neurotoxicity of anesthesia and developing brain and analyzed 414 articles published in 20 years. In this study, we aimed to analyze the most cited 100 articles in the field of anesthesia-induced neurotoxicity. Thus, we holistically investigated the most cited articles in this topic from the first study until today.

In the most cited 100 articles about anesthesia-induced neurotoxicity, the number of the papers make a peak between the years 2010 to 2014. There may be 2 reasons of this finding; first, after the first studies showing anesthesia-induced neurotoxicity in the beginning of 2000s researchers performed many other studies. The other reason may be the period between the years until today that time is also an important issue for the total number of citations. Even though, there is a cluster between 2010 and 2014, mean citation numbers of the articles published between 2005 and 2009 is the highest. These are the articles included in first publications about anesthesia-induced neurotoxicity and latter articles were designed in the light of these studies. There was not any paper in the most cited 100 papers about anesthesia-induced neurotoxicity after 2018. The most likely reason for this finding is Coronavirus Disease-19 (COVID-19) pandemic. After the first detected cases and lock-down most of the research was about COVID-19 until World Health Organization announced the end of the pandemic. A study about citation dynamics showed that after 2020, there was an incredible increase in the number of citations of the studies about COVID-19. This was called as “covidization” by the researchers.^[13] COVID-19 was the main subject of all researchers, so the studies on this topic were mostly read and cited.

The 75 of the most cited 100 papers were articles and most of them were experimental studies. As in all areas of medicine, to search a new finding experimental studies are the first step. Rodents are the mostly studied animals in this area. When the arguments about clinical application of findings from animal studies increased,^[14] monkeys (non-human primates) as study animals were used and clinical studies were conducted. Even though, monkeys are genetically closer to human than rodents the number of studies is limited possibly because of high cost, ethical concerns and difficulty to access these experimental animals.^[15] In clinical practice, it is very hard to define sole effect of anesthesia and it is even harder to find out the effect of a certain anesthetic. Clinical trials are generally retrospective and observational studies. It is unethical to make a randomized controlled trial with a control group without anesthesia even during scanning procedures like magnetic resonance in pediatric age group. This limits the number of clinical studies and their results. Predictably, clinical trials focused on cognition, behavior, attention and school performance after early exposure to general anesthetics while experimental studies focused on pathology, pathways and learning-memory tasks. It is understandable that the percentage of reviews were lower in the first 2 time intervals we choose and got higher in the last 2 periods. Between 2015 and 2019, one third of most cited papers in anesthesia-induced neurotoxicity were reviews.

More than 75% of the most cited papers about anesthesia-induced neurotoxicity were published in the leading journals of anesthesia like Anesthesiology, with the greatest number of papers, Anesthesia and Analgesia and British Journal of Anesthesia. This finding shows 2 important points; anesthesia-induced neurotoxicity is an important topic for anesthetists and researchers in this area mostly read the leading journals and so cite them. Comparable with this finding, journals published in USA has most of the articles in the most cited 100 papers, which was followed by England. Harvard University is the institution of most of the papers. USA seems to be the authority in anesthesia-induced neurotoxicity, owing to the well-known experts in this topic.

Most of the top 100 cited anesthesia-induced papers were about the anesthetic exposure during early ages of life. However, anesthetic drugs also have effects on old brain. Studies showed that there may be a relationship between postoperative cognitive dysfunction, delirium, Alzheimer and anesthesia.^[5,6] However, our findings showed that the researchers in this field have a greater interest on the neurotoxic effects of anesthetic drugs on developing brain since less than 1% of the most cited papers were about older individuals.

Half of the papers in the first 100 papers were funded. We also found that, the total and annual citations of funded papers were significantly higher. Funded articles may investigate mechanisms, pathology or endpoints that are more detailed, which results with higher reader interest and citation. Open access is another important factor for citation according to our findings. Researchers may read and cite the articles that they can reach. Funding is also important to publish an article as open access.

In pediatric anesthesia, inhalational anesthetics, especially sevoflurane, are frequently used.^[16] Therefore, to know the safety of these agents is crucial. In line with this curiosity, more than half of the articles investigated the neurotoxic effects of inhalational anesthetics in the most cited 100 papers. Since it is impossible to perform surgery without anesthesia, protection is an important issue against anesthesia-induced neurotoxicity. However, only 16% of the research papers in the most cited 100 publications investigated the effects of possible protective agents against anesthesia-induced neurotoxicity. The 2 most commonly used agents were dexmedetomidine and xenon. The possible reason these are the most preferred agents is they can be used in anesthesia practice and with their sedative effects, they can lower the anesthetic dosage.

In statistical analysis, we found a weak positive correlation with the page number of the publications and annual citation number. Reviews generally have more pages then research articles. Reviews are usually most read papers since readers can get general opinion and review the literature about a topic. However, before a review is written there should be publications like research articles and case reports about that topic. Therefore, reviews are published after a sum of papers are published. This can be the reason of the correlation between page number and annual citation number but not with total citation number.

The impact factor is a scientometric index that shows mean annual citation number of articles published in a certain journal in the last 2 years. When a journal completes 3 years in publication, an impact factor can be calculated.^[17] A 5-year impact factor is, similar to this definition, mean citation number of the articles published in a certain journal for last 5 years. If a journal publishes higher numbers of review articles it is possible that the impact factor of the journal is higher. The result of our analysis is compatible with the definition of impact factor. Although we could not find a relationship with journals impact factor and citations numbers, there was a weak correlation between 5-year impact factor and annual citation numbers. Since impact factor is a summary of 2 years, 2021 and 2022 for this study, publications about COVID-19 may have changed the impact factors of anesthesia journals. Whereas, 5-year impact factor may reflect the actual impact factor of a journal and can explain the correlation between annual citation numbers. Authors tend to submit their papers to journals with high impact factor. In our study, we found that high impact factor is associated with a significant increase in annual citation.

One of the limitations of this study is, for searching WOS database keys should be used. WOS database gives these keys to the publications and although the rate is very low, sometimes these keys may be incorrect. Therefore, some studies on the searched subject may not be involved in the search results or the studies out of the searched topic may take place in the results. These publications should be evaluated and excluded from the analysis. Another limitation is we only search the WOS database in order to make the top cited 100 publications list. Nevertheless, unfortunately, other databases may not be trustworthy as WOS database and they can give incorrect articles and citation numbers. These limitations are not specific to our study; all studies using this methodology have the same limitation.^[18,19] Third limitation is, recent articles with high impact are not included in this study because it takes time to have enough citations for being in the top cited 100 publication list. The last limitation of this study is, not all of the publications about general anesthesia-induced neurotoxicity were evaluated. However, our aim was to evaluate the most cited 100 publications on this field and analyze their characteristics.

In conclusion, anesthesia-induced neurotoxicity is very important, especially for pediatric anesthetists. This study is the first to conduct a bibliometric analysis of the most cited 100 publications on this field. Our study found that the publications about anesthesia-induced neurotoxicity made a peak in 2014 and mostly the researchers in USA are investigating this topic. Both inhalational and IV anesthetics were studied but inhalational anesthetics have greater interest, possibly they are commonly used in pediatric anesthesia. Although there was a gap in the publications about this topic during the COVID-19 pandemic, we believe that there will be many more publications on anesthesia-induced neurotoxicity since the mechanism, outcome and possible protection methods are still unknown.

Author contributions

Conceptualization: Elvan Ocmen, Hale Aksu Erdost, Volkan Hanci.

Data curation: Elvan Ocmen, Hale Aksu Erdost, Volkan Hanci.

Formal analysis: Volkan Hanci.

Investigation: Elvan Ocmen, Hale Aksu Erdost.

Methodology: Elvan Ocmen, Hale Aksu Erdost, Volkan Hanci.

Software: Volkan Hanci.

Supervision: Volkan Hanci

Writing – original draft: Elvan Ocmen.

Writing – review & editing: Elvan Ocmen, Hale Aksu Erdost, Volkan Hanci.