Ketamine Clinical Use on the Pediatric Critically Ill Infant: A Global Bibliometric and Critical Review of Literature

The developing central nervous system is vulnerable to several stimuli, especially psychotropic drugs. Sedation procedures during the developmental period are frequent in pediatric intensive care units (PICUs), in which the use of the sedative agent is still a challenge for the PICU team. Ketamine has been indicated for sedation in critically ill children with hemodynamic and ventilatory instabilities, but the possible neurobehavioral consequences related to this use are still uncertain. Here, we performed a bibliometric analysis with conventional metrics and a critical review of clinical findings to reveal a gap in the literature that deserves further investigation. We revealed that only 56 articles corresponded to the inclusion criteria of the study. The United States of America emerges as the main country within the scope of this review. In addition, professional clinical societies play a key role in the publications of scientific clinical findings through the specialist journals, which encourages the sharing of research work. The co-occurrence of keywords evidenced that the terms “sedation”, “ketamine”, and “pediatric” were the most frequent. Case series and review articles were the most prevalent study design. In the critical evaluation, the scarce studies highlight the need of use and post-use monitoring, which reinforces the importance of additional robust clinical studies to characterize the possible adverse effects resulting from ketamine anesthetic protocol in critically ill children.


Introduction
In pediatric critical patients, intensive care units usually use sedation associated with analgesia to change the level of patient consciousness to obtain clinical stabilization or perform specific procedures necessary to support the treatment. Optimal sedation has been described as a state in which the patient is sleepy, responsive to the environment, and without excessive movement [1]. To achieve the optimal level of sedation in critically ill patients, doses of sedatives may be individually titrated to the expected effect. This process has been guided by scores on a variety of observational sedation scales [2].
To perform several procedures that require anesthesia or analgesia in pediatric intensive care unit (PICU) scenarios, the identification of the patient's hemodynamic state has been required. In this context, numerous psychotropic drugs are eligible for this purpose, such as ketamine, which has been claimed as excellent sedation in the intubation procedures in critically ill infants, mainly in the state of hemodynamic instability, which has been referred to as the second-line treatment, according to the Society of Critical Care Medicine Clinical Practice Guidelines (SCCM) [3].

Materials and Methods
To perform this bibliometric analysis, we used the methodology previously described by de Souza Né et al. [14].

Data Source and Collection
A global search was performed on ketamine in the context of pediatric critical care patients in the Web of Science Core Collection (WoS-CC) database. The search strategy applied to retrieve the articles is shown in Figure 1.

Inclusion and Exclusion Criteria
The types of documents selected consisted of original and review articles. No restrictions of language were applied. Finally, the exclusion criteria consisted of conference papers, editorials, letters, papers not available, and publications in which the central theme of the study (ketamine and PICU) was not explored.

Data Selection
To ensure the quality of the selection, two independent researchers searched for articles through the WoS-CC platform. In cases of doubt, a senior researcher was consulted to define the inclusion or exclusion of the study. To optimize the process of extracting articles, two other researchers also participated in the selection phase to collect and compare the number of citations in additional databases (Scopus and Google Scholar). After selecting the articles, a text file generated by the WoS-CC platform was obtained.

Inclusion and Exclusion Criteria
The types of documents selected consisted of original and review articles. No restrictions of language were applied. Finally, the exclusion criteria consisted of conference papers, editorials, letters, papers not available, and publications in which the central theme of the study (ketamine and PICU) was not explored.

Data Selection
To ensure the quality of the selection, two independent researchers searched for articles through the WoS-CC platform. In cases of doubt, a senior researcher was consulted to define the inclusion or exclusion of the study. To optimize the process of extracting articles, two other researchers also participated in the selection phase to collect and compare the number of citations in additional databases (Scopus and Google Scholar). After selecting the articles, a text file generated by the WoS-CC platform was obtained.

Bibliometric Approach
Bibliometrics is a science that explores the measurement of scientific progress [15]. Three principles underlie a bibliometric study: (1) Bradford's Law, which relates the prestige of the journal according to the number of citations; (2) Lotka's Law, which analyzes the scientific productivity of authors; and (3) Zipf's Law, which evaluates the frequency of keywords [15][16][17]. In this review, we retrieved the following data: articles' titles, author's name, number of citations, journal's name, author's keyword, countries, and institutions.
Based on data provided by the WoS-CC database, we used the VOSviewer software

Data Analysis 2.4.1. Bibliometric Approach
Bibliometrics is a science that explores the measurement of scientific progress [15]. Three principles underlie a bibliometric study: (1) Bradford's Law, which relates the prestige of the journal according to the number of citations; (2) Lotka's Law, which analyzes the scientific productivity of authors; and (3) Zipf's Law, which evaluates the frequency of keywords [15][16][17]. In this review, we retrieved the following data: articles' titles, author's name, number of citations, journal's name, author's keyword, countries, and institutions.
Based on data provided by the WoS-CC database, we used the VOSviewer software (version 1.6.16) to obtain interaction networks about co-authorship analysis (considering the amount of publications and citations), occurrence of keywords, and the contribution of institutions. The generated networks must be interpreted as follows: each cluster represents an analysis item (authors, keywords, or institutions); the larger the cluster, the greater the publication/citation of authors, frequency of occurrence of keywords and institutions; the lines between each cluster represent the co-authorship network, connection between keywords, or inter-institutional connection [14]. We also evaluated the relevance of journals, using as a parameter the frequency of publications and visualization of impact factor (considering the JCR 2021) [18]. To assess the worldwide distribution of selected articles, we used the MapChart tool (https://mapchart.net/ accessed on 4 May 2023).

Critical Analysis
In the present review, in addition to the conventional metrics of a bibliometric study, we performed a critical clinical findings analysis. Excel software was used to organize the information needed to construct the critical analysis of knowledge. Thus, all selected articles were submitted to a critical evaluation to collect information about the study design, age/phase of development, the regimen of other psychotropic drugs associated with ketamine, adverse reactions, administration protocol, and the clinical summary. Considering that many articles were not precise regarding the classification of the study design, we adopted the classification defined by Nascimento et al. [19]. This analytical evaluation aims to offer a robust survey regarding the use of ketamine in critically ill pediatric patients. Figure 2 summarizes the methodological strategy adopted in this critical analysis. of journals, using as a parameter the frequency of publications and visualization of impact factor (considering the JCR 2021) [18]. To assess the worldwide distribution of selected articles, we used the MapChart tool (https://mapchart.net/ accessed on 4 May 2023).

Critical Analysis
In the present review, in addition to the conventional metrics of a bibliometric study, we performed a critical clinical findings analysis. Excel software was used to organize the information needed to construct the critical analysis of knowledge. Thus, all selected articles were submitted to a critical evaluation to collect information about the study design, age/phase of development, the regimen of other psychotropic drugs associated with ketamine, adverse reactions, administration protocol, and the clinical summary. Considering that many articles were not precise regarding the classification of the study design, we adopted the classification defined by Nascimento et al. [19]. This analytical evaluation aims to offer a robust survey regarding the use of ketamine in critically ill pediatric patients. Figure 2 summarizes the methodological strategy adopted in this critical analysis.

Bibliometric Analysis
Through the bibliometric survey performed in the WoS-CC, 87 articles were obtained, of which 56 were selected from the reading of the content, which began by reading the title and abstract (when necessary, the articles were read in full) ( Figure 2). A total of 31 articles were excluded for not meeting the established inclusion criteria (Supplementary Materials).
The oldest article was published in 1990 [20] and addressed the use of ketamine in the PICU as a strategy to reduce the use of benzodiazepines. The most recent article,

Bibliometric Analysis
Through the bibliometric survey performed in the WoS-CC, 87 articles were obtained, of which 56 were selected from the reading of the content, which began by reading the title and abstract (when necessary, the articles were read in full) ( Figure 2). A total of 31 articles were excluded for not meeting the established inclusion criteria (Supplementary Materials).
The oldest article was published in 1990 [20] and addressed the use of ketamine in the PICU as a strategy to reduce the use of benzodiazepines. The most recent article, published in 2023, also evaluated the use of ketamine for PICU services and, despite validating the safety and efficacy of the drug, it highlights the importance of studying the long-term effects associated with the use of ketamine in infants [21]. The most cited article consists of a literature review published in 2000 [22], which, at that time, already shed light on the probable negative repercussions of sedoanalgesic procedures during childhood (Table 1).  According to researchers, 287 authors contributed at least 1 article ( Figure 3A). The higher numbers of articles were written by Tobias  According to journals, only 7 journals of a total of 37 periodicals published at least two articles ( Figure 4). Among them, the journal Pediatric Critical Care Medicine (n = 9; JCR impact factor: 3.971) exhibited the highest number of published articles, followed by the journal Critical Care Medicine (n = 4; JCR impact factor: 9.226) and the Journal of Pediatric Intensive Care (n = 4). It is important to highlight that both Critical Care Medicine and Pediatric Critical Care Medicine belong to the Society of Intensive Care Medicine, one of the most important and influential entities in the field of pediatric intensive care.  Keywords represent an important topic of a research article. In this study, a total of 166 keywords were found (authors' keywords), grouped into 20 clusters ( Figure 5A).  Keywords represent an important topic of a research article. In this study, a total of 166 keywords were found (authors' keywords), grouped into 20 clusters ( Figure 5A). Figure 5 also exhibits the co-occurrence of keywords through the lines that interconnect the clusters. The top 10 most frequent keywords were sedation (n = 21), ketamine (n = 16), pediatric (n = 9), analgesia (n = 8), children (n = 8), propofol (n = 6), pediatric intensive care unit (n = 5), pain (n = 4), delirium (n = 4), and anesthesia (n = 4) ( Figure 5B).
The limited scientific production related to the use of ketamine in pediatric critical patients is distributed in a few countries. Figure 6A,B demonstrate that the United States is the country with the highest number of publications (n = 26), followed by Turkey (n = 5) and Spain (n = 4). Israel, Italy, and the Netherlands reached the mark of three publications. In addition, Brazil, Germany, and the United Kingdom contributed two publications. Regarding citations, the United States (n = 867) ranks in first place ( Figure 6C). Next, Israel (n = 190), even with three publications, occupies the second position ( Figure 6C).  is the country with the highest number of publications (n = 26), followed by Turkey (n = 5) and Spain (n = 4). Israel, Italy, and the Netherlands reached the mark of three publications. In addition, Brazil, Germany, and the United Kingdom contributed two publications. Regarding citations, the United States (n = 867) ranks in first place ( Figure 6C). Next, Israel (n = 190), even with three publications, occupies the second position ( Figure 6C).

Critical Analysis
In accordance with the frequency of publication, the period ranging from 2011 to 2020 (n = 28) showed the highest number of productions and citations ( Figure 8A,B). However, the period ranging from 1990 to 2000 exhibited a lower number of publications (n = 5), but a notable number of citations (n = 444). Furthermore, case series study (n = 17) and literature review (n = 14) were the most prevalent studies, with a total of 30 publications. In addition, review articles were the type of study with the highest number of citations (n = 658) ( Figure 8A,B).

Critical Analysis
In accordance with the frequency of publication, the period ranging from 2011 to 2020 (n = 28) showed the highest number of productions and citations ( Figure 8A,B). However, the period ranging from 1990 to 2000 exhibited a lower number of publications (n = 5), but a notable number of citations (n = 444). Furthermore, case series study (n = 17) and literature review (n = 14) were the most prevalent studies, with a total of 30 publications. In addition, review articles were the type of study with the highest number of citations (n = 658) ( Figure 8A,B).   Table 2 shows the clinical findings and other pharmacological issues in the lower number of studies using ketamine on critically ill pediatric patients. Regarding the route of administration, the intravenous route, specifically bolus or continuous infusion, was the principal protocol used. The administration protocols fluctuated between studies, and several of them did not present the dose used. The period of administration also varied between articles, ranging from acute administrations, such as in invasive procedures [33,38], to long-term dosages, such as in cases of patients on mechanical ventilation [11,21,24]. The principal psychotropic drugs associated with ketamine consisted of opioids and benzodiazepines, especially midazolam [11,20,23,24,29,37,40,41,47,63,64,67,68,70,72]. Adverse reactions also varied across the studies, of which dissociative effects, agitation, and cognitive changes compose the main effects described [11,21,22,31,60]. Long-lasting neurobehavioral impairments caused by ketamine have also been reported [11,23]. Regarding comorbidities, respiratory system diseases were the most frequent in these studies [8,11,27,29,40,43,65].   In this study, the authors developed a rotational sedoanalgesia protocol aiming to reduce the incidence of abstinence syndrome. As a result, in which ketamine was associated with propofol, there was a decrease in the risk of adverse reactions, especially those related to the withdrawal syndrome.   This study evaluated a multicenter experience with propofol in critically ill pediatric patients. Among the drugs identified in the psychopharmacotherapy adopted, ketamine was pointed out as responsible for cardiac arrest, without undesirable neurological sequelae. Propofol and ketamine were used concomitantly in 3804 pediatric procedures, however, without specific reports of adverse reactions resulting from this co-administration.
Sinner et al., 2014 [54] Literature review * * * Pediatrics * In this review, the authors highlighted the possibility that anesthetic drugs produce neurotoxicity in the early stages of development. Thus, the authors carried out a survey of preclinical studies that pointed to ketamine as an inducer of brain damage through a mechanism that involved apoptosis of neurons. Furthermore, it is postulated that more clinical studies, especially randomized clinical trials, should be performed to monitor these possible undesirable neurotoxic effects. In this study, the authors evaluated the main adverse reactions associated with tracheal intubation in the variation of site and medications used. The authors claimed that although fentanyl and midazolam were combined in all places, atropine, ketamine, and propofol have been widely used; however, the changes analyzed in the patients would not be associated with this variation in use. In this study, the authors analyzed the impacts of applying a guideline on pain and sedation in clinical practice. The authors report that after the implementation of the guideline, there was a reduction in the infusion of ketamine, which was supposedly related to the application of the guide. In this observational study, the authors applied a questionnaire to evaluate the drugs used as analgesics, muscle relaxants, and sedatives in PICUs in Spain. The authors observed that ketamine was one of the most used drugs as a sedoanalgesic, usually associated with midazolam and used as an anesthetic, mainly in the intubation of asthmatic patients.   This retrospective study reported clinical experiences with sedoanalgesic drugs, in which the authors realized that one of the most used drugs in the clinic was ketamine, especially as an analgesic agent, in addition to highlighting its benefits in sedation protocols.

Discussion
Clinical studies related to the critical pediatric field may support the intensive care services and health professionals in the pharmacological guidelines and procedures in the PICU, such as the sedation and analgesia approach. Thus, this study aims to map the worldwide scientific production presented in the literature about ketamine use in the PICU. The results evidenced the scarcity of publications on this theme, in which the literature review presented a higher number of citations that described the tolerance, physical dependence, and withdrawal of various sedative drugs, including ketamine [22].

Bibliometric Analysis
A bibliometric approach allows mapping the production of scientific knowledge and shedding light on gaps that deserve visibility [73]. Hence, it is necessary to construct a search strategy that is sensitive enough to retrieve all articles related to the study topic. Such a search strategy, in fact, is composed of keywords that represent the subject of the study. Due to the importance of these terms, one of the metrics adopted in this review was based on keyword analysis (Zipf's Law). We identified that the main keywords present in our study were sedation, ketamine, and pediatrics, which are terms that define the central point of this review. This topic emphasizes the importance of carefully selecting the keywords of a scientific paper.
Regarding Lotka's Law, by analyzing the scientific knowledge that has been produced about ketamine in the context of intensive pediatrics, a bibliometric approach provides the tendency in the clinical use of ketamine, as well as maps of which research groups have studied the topic. In this regard, our study showed that few researchers (n = 287) have studied this relevant issue. We observed that an important co-authorship network, led by Nishisaki, A. [36,51,56], presents a significant contribution to the study theme. In fact, this author is a prolific researcher with several publications in the pediatric field. However, despite this, our study also showed the lack of scientific dialogue among most researchers. In summary, the clinical research on ketamine use in the pediatric intensive care context did not present a consistent science network. This is a dangerous fact, given that preclinical research points to the neurotoxic effect of ketamine on the developing central nervous system [74][75][76][77][78][79][80][81]. Although there are limited translational findings of preclinical studies, these data suggest that the use of ketamine, especially in children, should be carefully controlled.
Bradford's law assesses the relevance of journals and establishes that a core of journals has greater specificity on a given subject, being more widely cited and relevant [82,83]. In this review, it was possible to identify that the journal with the highest number of publications was Pediatric Critical Care Medicine, followed by Critical Care Medicine, which includes as references in intensive care pediatrics research with higher scientific prestige. Both journals pertain to the Society of Critical Care Medicine, which reinforces the crucial role of professional societies in the development of knowledge among specialists.
North America was the continent with the most articles published around the theme of this report and with independent institutions. This fact might contribute to the difficulty in the standardization of sedation protocols. The theme involving ketamine is still poorly debated since this review showed only 26 published articles on this subject from the USA. In fact, this country features the top research centers with the highest amount of funding for their investigations [84], which justifies the concentration of the most prolific research institutions. Interestingly, Israel stood out as a country with qualified scientific production on the subject, publishing two robust randomized clinical trials. Our survey, however, suggests that this theme is not yet a priority among the main research centers when analyzing scientific production.

Critical Analysis
The critical evaluation of the articles included in the present study demonstrated several cases reports with no description of follow-up after hospitalization in the PICU and the use of a sedative protocol, which may contribute to the identification of the consequences in children's development. A recent paper published by Sperotto et al. [85] showed that prolonged infusions of ketamine in pediatric critical patients are safe, effective, and reduce the demand for opioids and benzodiazepines. In fact, in clinical practice, there is great concern regarding the use of opioids and benzodiazepines, due to the repercussions generated. Here, we point out that ketamine, despite promoting ideal sedoanalgesia, also needs to be carefully evaluated, especially regarding long-term effects.
The environmental factors (i.e., psychotropic substance exposure) interfere with the brain maturation process, which can provoke central nervous system impairments, as demonstrated previously [13]. In this context, the Society of Critical Care Medicine Clinical Practice Guidelines in 2022 indicated ketamine as a second-choice sedative adjuvant drug in critical care units, mainly in those pediatric patients with hemodynamic instability [3]. Thus, such an anesthetic protocol requires careful and prolonged monitoring of these infants submitted to sedoanalgesia with ketamine, as well as clinical exploitation.
Fundamentally, ketamine consists of a phencyclidine derivative and possesses dissociative properties, with a therapeutic proposal since the 1960s; it pharmacologically blocks the postsynaptic N-methyl-D-aspartate (NMDA) glutamate receptors [86]. This unique mechanism of action alone was enough to induce neurodevelopment brain disorders; however, ketamine exhibits multiple other targets of action, which disturbs normal physiological neurodevelopment, inducing delirium and abstinence syndrome, among other behavioral consequences [11,30].
As mentioned previously, prolonged exposure to ketamine during brain development induces cell death, especially by a mechanism that involves the upregulation of compensation of subunits of the NMDA receptor, triggering intracellular calcium accumulation, increased oxidative stress, and the activation of nuclear factor kappa B (NF-κB) pathway, which promotes more vulnerability for neurons, even after drug withdrawal [87,88]. Furthermore, significant and persistent reductions in cortical and hippocampal volumes occur after psychotropic exposure early in brain development [89]. Changes in the child's brain structure and functions during its development and maturation, especially in the first 4 years of life, are fundamental for the adequate networks of neural connections of cognitive, motor, and sensory functions [12]. These statements reinforce the need for research focused on the long-term evaluation of the infants submitted to sedoanalgesia with ketamine, as well as other psychotropic substances.
There are inconclusive findings regarding the use of ketamine in the critical evaluation of the selected articles. Some studies emphasize the safety and efficacy of the use of ketamine [20,22,32], highlight its use to reduce the use of opioids [32,46], and consider ketamine as a safe choice to treat status epilepticus [28]. On the other hand, some studies highlight behavioral and cognitive alterations and long-term negative repercussions following ketamine administration [11,59]. Some investigations consider that the association of ketamine plus midazolam reduces the incidence of adverse effects [47]; however, other research associates this association with higher clinical complications [64]. In addition, most studies did not address the use of ketamine as the central theme of the study.
It is important to emphasize that although the bibliometric analysis gathers important elements of metrics, it does not allow the authors to evaluate the methodological quality of the chosen articles, nor the certainty of evidence of these articles. The results presented here do not allow for decision making regarding protocol choices and/or clinical safety. The mapping performed in this study motivates the development of new primary research, as well as secondary studies with other designs and objectives, such as systematic reviews and scoping reviews.

Conclusions
It is noteworthy that our investigation demonstrated the limited number of randomized clinical and multicentric studies with a representative sample of infants, specifically evaluating the use of ketamine in the context of pediatric intensive care. In this sense, this bibliometric analysis allows us to point out the need for further studies, with more robust methodological designs that provide better scientific evidence on the use of ketamine in critically ill pediatric patients.

Supplementary Materials:
The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm12144643/s1, Table S1: List of excluded articles.  Data Availability Statement: All data generated in this review are included in this paper. Further enquiries can be directed to the corresponding author.