What Is Known about Midazolam? A Bibliometric Approach of the Literature

Midazolam is a drug with actions towards the central nervous system producing sedative and anticonvulsants effects, used for sedation and seizures treatments. A better understanding about its effects in the different scenarios presented in the literature could be helpful to gather information regarding its clinical indications, pharmacological interactions, and adverse events. From this perspective, the aim of this study was to analyze the global research about midazolam mapping, specifically the knowledge of the 100 most-cited papers about this research field. For this, a search was executed on the Web of Science-Core Collection database using bibliometric methodological tools. The search strategy retrieved 34,799 articles. A total of 170 articles were evaluated, with 70 articles being excluded for not meeting the inclusion criteria. The 100 most-cited articles rendered 42,480 citations on WoS-CC, ranging from 253 to 1744. Non-systematic review was the most published study type, mainly from North America, during the period of 1992 to 2002. The most frequent keywords were midazolam and pharmacokinetics. Regarding the authors, Thummel and Kunze were the ones with the greatest number of papers included. Our findings showed the global research trends about midazolam, mainly related to its different effects and uses throughout the time.


Introduction
Midazolam is a drug from the benzodiazepine class with anxiolytic, sedative, myorelaxant, anticonvulsant, and amnesic pharmacological properties [1]. It enhances the neural-inhibitory actions of the amino-acid neurotransmitter gamma-aminobutyric acid (GABA) on GABA A receptors [2]. It can be administered by several routes, and has a short elimination period and a small period of action, making it the first option for sedation and analgesia, compared to other drugs with the same pharmacological actions, such as other benzodiazepines [3].
These drug indications are mainly related to the reduction of anxiety, sedation, and analgesic action [4]. It is important to remember that benzodiazepines can be administered in combination with other drugs, especially in surgical procedures [5]. However, considering the rapid effects after administration and its already-cited short duration of action, Midazolam has been used in non-surgical procedures, such as outpatient examinations and in dentistry [6].
In addition, this drug has also been playing important roles in the treatment of seizures and epileptic events [7,8]. A meta-analysis showed that midazolam is one of the most successful drugs in achieving seizure cessation [9]. In face of this, it is necessary to compile data about the use of midazolam and its clinical applicability. In Table 1, it is possible to observe the retrieved studies according to the search string used. We categorized them in descending order of citation density. The study with the highest citation density on WoS-CC was Glauser et al., [13] with 95.20 (citations per year) and the lowest was Dundee et al., [7] with 8.08. However, when we consider the total number of citations on WoS-CC, the study conducted by Kress et al., [14] was the most cited when compared to the other studies, while the least-cited paper had 1744 citations. In Table 1, it is possible to observe the retrieved studies according to the search string used. We categorized them in descending order of citation density. The study with the highest citation density on WoS-CC was Glauser et al. [13] with 95.20 (citations per year) and the lowest was Dundee et al. [7] with 8.08. However, when we consider the total number of citations on WoS-CC, the study conducted by Kress et al. [14] was the most cited when compared to the other studies, while the least-cited paper had 1744 citations.   Table 2).  The oldest article on the list was published in 1981 by Allonen et al. [110], entitled "Midazolam Kinetics", in Clinical Pharmacology & Therapeutics. The aim of the article was to review its pharmacodynamics and pharmacokinectics. The most recent article on the list was published in 2016 by Glauser et al. [13], titled "Evidence-Based Guidelines: Treatment of Epileptic Status in Children and Adults: American Epilepsy Society Guidelines Committee Report by Epilepsy Current ". The aim of the article was to compare drugs (diazepam, phenobarbital, midazolam, and lorazepam) in terms of efficacy, tolerability, and safety for the treatment of epileptic episodes in children and adults. The most frequent type of study among the 100 articles was non-systematic reviews (n = 21), followed by cohort (n = 14), randomized (n = 13) and non-randomized (n = 13) clinical trial studies ( Table 2).
The articles selected in this study were published in 49 different journals. The top seven journals were: Clinical Pharmacology & Therapeutics (n = 10), Anesthesiology (n = 7), New England Journal of Medicine (n = 6), Drug Metabolism and Disposition (n = 6), Clinical Pharmacokinetics (n = 5), Molecular Pharmacology (n = 5), and Lancet (n = 5). In addition to having the highest number of publications, they are among the journals with the highest number of citations. A total of 33% of journals had only one article published and 15% of the articles were published in journals with high impact factors in health sciences, such as New England Journal of Medicine (n = 6; 3747 citations), Lancet (n = 5; 1683 citations), and Drugs (n = 4; 1429 citations). The Journal of Neuroscience had the highest citation ratio, despite having only one article published out of 100 selected in this study ( Table 2).
The continent with the most articles on the list was North America (n = 65), followed by the European continent (n = 30), while Asia and Oceania both presented the same number of articles (n = 3). South America only published one, while Africa and Central America did not contribute to any article on the list. Specifically, USA was the country with the most appearances on the list (n = 59), followed by England (n = 11), and Canada (n = 6) ( Figure 2). spite having only one article published out of 100 selected in this study ( Table 2).
The continent with the most articles on the list was North America (n = 65), followed by the European continent (n = 30), while Asia and Oceania both presented the same number of articles (n = 3). South America only published one, while Africa and Central America did not contribute to any article on the list. Specifically, USA was the country with the most appearances on the list (n = 59), followed by England (n = 11), and Canada (n = 6) ( Figure 2). The list of the 100 most-cited articles on Midazolam composed of 556 authors. Based on the ranking of most-cited articles, it was observed that almost 50% of the papers had more than six authors (n = 44), while 24 papers with 3-4 authors appeared on the list, followed by 20 articles with 5-6 authors and 13 articles with 1-2 authors ( Table 2)  The list of the 100 most-cited articles on Midazolam composed of 556 authors. Based on the ranking of most-cited articles, it was observed that almost 50% of the papers had more than six authors (n = 44), while 24 papers with 3-4 authors appeared on the list, followed by 20 articles with 5-6 authors and 13 articles with 1-2 authors ( Table 2) = 4; 1241). The other authors appeared in less than four articles on the list: a total of 16 authors contributed in three articles, 37 authors contributed in two articles, and 497 authors contributed in only one article. Figure 3 shows the clusters created with the network between the authors on the publication of papers on midazolam-related topics.
Healthcare 2022, 10, x FOR PEER REVIEW 12 of 24 3 shows the clusters created with the network between the authors on the publication of papers on midazolam-related topics. Among a total of 145 author-keywords, grouped into 17 clusters, the keywords with the highest occurrence in the 100 most-cited articles were midazolam (n = 5), cytochrome p450 (n = 5), pharmacokinetics (n = 4), drug metabolism (n = 4), CYP3A4 (n = 4), sedation (n = 3), critical care (n = 3), mechanical ventilation (n = 3), and anesthesia (n = 3) (Figure 3). The first three words were also the ones that had the greatest binding strength with a total link strength of 33, 23, and 20, respectively. The words had a diverse frequency in the periods of time, with the words 'midazolam' and 'cytochrome p450′ being frequently featured in the period of 1992-2002. Not all studies had author-keywords (Table 3).  Among a total of 145 author-keywords, grouped into 17 clusters, the keywords with the highest occurrence in the 100 most-cited articles were midazolam (n = 5), cytochrome p450 (n = 5), pharmacokinetics (n = 4), drug metabolism (n = 4), CYP3A4 (n = 4), sedation (n = 3), critical care (n = 3), mechanical ventilation (n = 3), and anesthesia (n = 3) (Figure 3). The first three words were also the ones that had the greatest binding strength with a total link strength of 33, 23, and 20, respectively. The words had a diverse frequency in the periods of time, with the words 'midazolam' and 'cytochrome p450 being frequently featured in the period of 1992-2002. Not all studies had author-keywords (Table 3). From 1981 to 1991, eight studies were published, among them three articles addressed the clinical use of midazolam for sedative purposes, two articles investigated pharmacovigilance parameters (one evaluated the safety and efficacy of midazolam, and the other analyzed side effects), two studies were related to pharmacokinetics and pharmacodynamics of this drug, and one study presented the pharmacological properties and therapeutic use of midazolam.
In the mapping period from 1992 to 2002, 52 published articles were found: a total of 30 studies showed the pharmacodynamics and pharmacokinetics of midazolam; 13 articles published, as its main objective, discussed the sedative effect of this drug; and 9 articles highlighted its analgesic, anxiolytic, and antiepileptic effects.
During the period of 2003 to 2013, 39 articles were published: a total of 12 studies addressed the sedative effects of midazolam, five evaluated its use as a therapeutic alternative for epilepsy treatments, four articles evaluated pharmacovigilance parameters investigating the side effects from the use of midazolam, four studies evaluated the anesthetic effect (in which two studies evaluated the level of neurodegeneration), three studies showed results of its effects as analgesic, three studies presented pharmacodynamic steps, such as drug interactions with other drugs, seven articles addressed its pharmacokinetics, showing its mechanism of action through CYP-isoenzymes-promoting chemical modification of several exogenous molecules, and lastly, one article evaluated midazolam for severe-condition treatments.
Finally, in the last period mapped, during the years 2014 to 2016, one article on the use of midazolam for epilepsy treatments was published in which the authors evaluated the efficacy, tolerability, and safety data for anticonvulsant treatment of children and adults with convulsive epilepsy, and used this analysis to develop an evidence-based treatment algorithm to prescribe midazolam.

Discussion
This review mapped the produced knowledge found on the most cited-studies about the use of midazolam. A total of 100 studies with different levels of evidence were analyzed, and they included many experimental designs with a predomination of non-systematic reviews, randomized clinical trials, and non-randomized clinical trials. Because of the bibliometric approach performance, it was possible to gather metric information about these articles and extract the main findings considering the follow-up of trends in the use of midazolam.
Experimental designs determine evidence-based practice that supports the work of health professionals [95]. The designs with the highest levels of evidence are systematic reviews and meta-analyses, followed by randomized clinical trials and cohort studies [111]. The experimental design with the highest appearance in the list of the 100 most-cited articles were non-systematic reviews with the main objective of discuss the effects of midazolam, including sedation, analgesia, metabolism, and mechanisms of action, compared to other drugs. Non-systematic reviews provide readers with a current and ordered view of the literature on a specific topic. This type of study can be a very important explanatory space for beginning readers. However, there are positive and negative points that arise from the methods chosen for its development, for example, the selection of articles with low scientific evidence [112].
Among the journals with the highest number of publications, Clinical Pharmacology & Therapeutics (n = 10) and Anesthesiology (n = 7) were the ones with the most articles. The first journal addresses the clinical application of drugs while the second is a journal that approaches the main clinical application associating the sedation-anesthesia aspects. In addition, a prevalence of journals that essentially address molecular aspects of drugs and medications, with papers that evidence midazolam mechanism of actions, pharmacokinetics, and pharmacodynamics.
Midazolam is a hypnotic-sedative drug with anxiolytic properties capable of inducing amnesia and reliable hypnosis in the benzodiazepine group, more specifically the subfamily of imidazobenzodiazepines, with properties distinct from other benzodiazepines; Midazolam has rapid onset (2 to 3 min), is short duration (45 to 60 min), and has high hepatic metabolic clearance, when compared to other drugs in the group [7,60,67].
This drug is used clinically in the treatment of convulsive-epileptic status in children and adults [13,23,48], and as a sedative in colonoscopy [40], endoscopy [45,93] intubation, and extubation of mechanically ventilated patients [3]. In addition, it is used in palliativesedation therapy to relieve refractory symptoms by reducing consciousness in terminally ill patients [62].
Among the 100 most-cited studies retrieved by our search, the most-cited non-systematic review addressed the relationship between the interaction of drugs, like midazolam, with systematic effects mediated by the consumption of grapefruits, such as modulation on the expression of cytochrome P450 [52]. Midazolam is metabolized by cytochrome P450 3A isoenzymes and the inhibition of this molecule is associated with an increase in midazolam bioavailability [66,102]. Thus, the consumption of grapefruits inhibits cytochrome P450 34A molecules, delaying absorption, reducing first-pass effect of the drug, and increasing blood plasma levels of midazolam, resulting in possible excessive levels of its effects, mainly related to sedation [112].
In addition to this part of the debate, our metrics revealed that Kenneth Thummel is the author with the most publications and citations on the 100 most-cited ranking. He obtained his PhD in pharmaceutical sciences at the University of Washington in 1987, became a postdoctoral fellow in pharmacology at the Center for Health Sciences at the University of Connecticut (USA), and later a professor at the University of Washington's School of Pharmacy. He investigates the kinetic of drug metabolism, first-pass intestinal metabolism mediated by cytochrome P4503A, mechanism of metabolic clearance of drugs, and genetic modifiers of the responses to drug specializations in drug metabolism. All of his work presented in our ranking built a solid consensus about midazolam metabolization by cytochrome P450 3A, demonstrating to the scientific community the importance of pharmaco-interactions with this molecule and midazolam administration [25,42,69,77].
His evidences are the ones that elucidate the intestinal and hepatic metabolism in the oral first-pass elimination of a CYP3A substrate using midazolam [66]. Thummel and his co-workers created links with other authors, such as Wrighton, S.A., in order to investigate even more about this important enzyme of midazolam elimination [96]. With this, a network was created with other groups of authors (Hall, S.D. and Gorski C.), which investigated the influence of on CYP expression/inhibition, making the drug a standard substrate to the CYP3A subunit. Their work even recognized other interactors on CYP expression using midazolam as a positive control, highlighting the inhibition of CYP subunits by midazolam hydroxylation [90]. Furthermore, our analysis showed that this group of authors collaborated with Huang, S.M., Lesko, L.J., and Madani, S., investigating the potential effects between midazolam interaction and other drugs. The data shown in Figure 3 infer that the research field on midazolam has been related to the understanding of the molecules involved in drug pharmacokinetics, especially, the correlation between specific enzymes in the process and drugs interaction, bringing to the readership a broader perspective on the simultaneous use of midazolam with other substances, guiding new perspectives and raising questions about the topic. In this way, midazolam is an important player to systemic metabolism [25,66]. In this sense, the elderly need special attention, given the reduction of liver mass and/or reduction of perfusion, and therefore, have a lower ability to metabolize drugs [27].
Cytochrome P450, drug metabolism, and pharmacokinetics are connected keywords revealed by our bibliometric analysis (Figure 4). Keywords work as codes for indexing articles in databases and, when used in search of articles, they present more significant results in comparison to phrases. In addition, keywords can illustrate the field of research in a given subject [112]. Other keywords that occurred frequently among the 100 most-cited articles are midazolam, cytochrome p450, pharmacokinetics, drug metabolism, cyp3a4, sedation, critical care, and mechanical ventilation, suggesting that fields of investigation associated with these keywords are an important part of the discussion related to the use of this drug, since most of them reported on the importance of cytochrome p450 protein in the metabolization of midazolam. Furthermore, it is possible to relate it to its clinical applicability both in outpatient and intensive-care settings.
Healthcare 2022, 10, x FOR PEER REVIEW 15 of 24 cited articles are midazolam, cytochrome p450, pharmacokinetics, drug metabolism, cyp3a4, sedation, critical care, and mechanical ventilation, suggesting that fields of investigation associated with these keywords are an important part of the discussion related to the use of this drug, since most of them reported on the importance of cytochrome p450 protein in the metabolization of midazolam. Furthermore, it is possible to relate it to its clinical applicability both in outpatient and intensive-care settings. A direct link found in the analysis of the keywords was the relation between midazolam and epilepsy. Status epilepticus is a condition where the patient has continuous or rapidly repeating seizures [113]. Benzodiazepines remain the first-choice drugs for the management of epilepsy and seizures, and from this class, midazolam is the only watersoluble drug available [53]. For status-epilepticus treatment, midazolam can be administered via intramuscular, intravenous, and buccally and nasally [114,115]. Clinical trials A direct link found in the analysis of the keywords was the relation between midazolam and epilepsy. Status epilepticus is a condition where the patient has continuous or rapidly repeating seizures [113]. Benzodiazepines remain the first-choice drugs for the management of epilepsy and seizures, and from this class, midazolam is the only water-soluble drug available [53]. For status-epilepticus treatment, midazolam can be administered via intramuscular, intravenous, and buccally and nasally [114,115]. Clinical trials comparing midazolam and diazepam efficacy in children showed better results in the cases using midazolam [3,75,115]. Buccal midazolam was able to reduce the number of seizure episodes and the time to stop seizing in treated children with a decrease of respiratory depression requiring interventional need [75].
Furthermore, a systematic review performed in 2002 suggested that the treatment of refractory-status epilepticus using pentobarbital was better than using midazolam or propofol [63]. However, after 10 years, a study reviewing the outcome data reported by 121 studies published since 1981, indicated that midazolam presented better results in comparison to thiopental/pentobarbital and propofol in the control of seizures [85]. These findings point to the fact that science is continuous, and the interpretation of the literature data must occur with caution to details and related factors, such as methodology and year of publication. Most recent articles are essential for updating protocols, advancing diagnosis and knowledge of the current and scientific clinical scenario, and helping researchers to study, investigate, and advance future issues [10].
The most recent article on our ranking is 'Evidence-based guideline: treatment of epileptic convulsive status in children and adults: Report of the Guideline Committee of the American Epilepsy Society', published in 2016 [13]. It was a randomized clinical trial that analyzed data on the efficacy, tolerability, and safety of Midazolam IM, Fenobarbital IV, Diazepam IV, and Lorazepam IV drugs for seizure treatments in children and adults to propose a possible algorithm-based treatment guideline. In this study, it was observed that in adult patients, Midazolam administered via intramuscular, presented superior efficacy, when compared to Lorazepam. However, in the infant population, there were not satisfactory analyses to reach a more reliable conclusion.
Another important scientific metric is the number of citation of an article. Articles with 100 or more citations can be considered classic, depending on the research area. Classical articles influence the development of scientific knowledge and clinical practices [116]. For a better evaluation about citations, the WoS-CC database was chosen for our bibliometric analysis. This database allows the retrieval of publications since 1945 and has high-quality journals indexed from all over the world [117,118]. However, we also performed searches on Scopus and Google Scholar databases to compare this citation index. We chose Scopus because of its high recognition, credibility, and innovative scope in the field of bibliometrics, and Google Scholar because of its accessibility in many countries [119,120]. Still reflecting on citations, the density of citation, i.e., the number of citations per year after publication, can provide insights into the scientific knowledge presented in the studies. Our bibliometric review revealed that although [13] is the most recent study in the top 100 most-cited articles about midazolam, it has already obtained the highest citation density in this field, reflecting that the guidelines about the treatment of epilepticus status is possibly an emerging trend related this drug, as this article accumulates a considerable number of citations in a short period of time.
The most-cited article found in our bibliometric analysis was 'Daily Interruption of Sedatives in critically ill patients' mechanical ventilation' [14], which had 1744 citations. It was a randomized clinical study that evaluated the impact of continuously sedative administration in patients hospitalized in intensive care, and its possible adverse events, such as changes in mental status and the length of stay of patients in hospitals.
Guidelines for sedation of patients hospitalized in intensive-care units have recommended the use of γ-aminobutyric acid (GABA) receptor agonists, such as midazolam, despite the risks associated to its prolonged use [16]. Regarding adverse effects, it was demonstrated in a randomized controlled trial that continuous infusion of midazolam in patients undergoing mechanical ventilation had a longer length of stay in the intensivecare unit and a longer need for mechanical ventilation when compared to patients who had a daily interruption of midazolam infusions [3,14]. This fact was also observed in a prospective-observational cohort study [49], where patients with continuous sedation had 13.5 ± 33.7 days of hospitalization, compared to 4.8 ± 4.1 days of patients with an interruption of sedation.
In another prospective cohort study [44], the safety and efficacy of dexmedetomidine were compared to midazolam's. An association between time of delirium and death of patients admitted to the intensive-care unit on mechanical ventilation was observed. Patients with one day of delirium had a risk of death of 1.70, while two days of delirium had a rate of 2.69 and three days or more of delirium had a rate of 3.37. In addition, ventilation time and hospital stay were relevant variables even after dose adjustment.
Anesthesia and sedation were the most popular clinical applications of midazolam [3]. Out of the 100 most-cited studies about the drug, more than a quarter of the articles (n = 37) had these as study objects, which indicates the importance of this field of investigation. Midazolam can be effectively used for mild and deep sedation. It was preferred over other benzodiazepines because of its short duration and fewer emergency complications [60]. In comparison to other drugs, such as propofol, midazolam showed worse performance in parameters evaluated on the moderate-sedation-of-routine-endoscopic procedures. A systematic review and meta-analysis retrieved in our bibliometric search evaluating the efficacy, safety, and efficiency of sedative agents revealed that midazolam had a longer sedation and recovery time than propofol. In addition, the data of the study showed that 34% of patients had at least some memories of the procedure [45]. Besides, another systematic review evidenced that dexmedetomidine provided more comfort to the patient and clinician during procedural sedation than midazolam, even though the safety profiles were similar [121].
Perhaps, midazolam use in the sedation of patients in the intense-care unit is the commonest use of the drug. Sedation in this case is employed to achieve comfort and analgesia at the invasive-mechanical ventilation; it also relieves anxiety and reduces stress [122]. Midazolam is widely used in this case, even though the Clinical Practice Guidelines for The Management of Pain, Agitation, and Delirium in Adult Patients in The Intensive Care Unit recommends sedation with non-benzodiazepines in association with analgesic agents [123]. However, it is important to note that patients admitted to the intensive-care unit have different reasons to be there. For example, patients undergoing elective surgeries who will need mechanical ventilation for a short period and critically ill patients who will stay intubated for longer periods. The protocols for each case must be considered individually.
Midazolam showed good results in short-period sedations [124]. However, studies correlated the continuous use of midazolam to depression of the respiratory system, oversedation, neurological impairment, and delayed extubation [125]. With this in mind, many studies proposed interruption protocols of sedative infusions in critical patients undergoing mechanical ventilation, attempting to verify if sedative drugs were associated with longer mechanical-ventilation needs [14,29].
Moreover, the literature reported other adverse side events of midazolam use. Those effects were mainly related to patients undergoing longer use of the drug, as the ones in the intensive-care unit. Three studies on our 100 most-cited list in the field associated midazolam with delirium development. Two of them evidenced potential risk of transition of patients with mechanical ventilation to delirium [37,44], while the other one showed that the incidence of patients who developed postoperative delirium experiences after undergoing cardiac-valve procedures was higher in patients who used midazolam in the sedative protocol than patients who used dexmedetomidine [35]. Unfortunately, none of them elucidated the possible mechanisms related with this apparent relationship.
North America directs important financial resources to research and are home of many major research centers for the diagnosis, treatment, and follow-up of clinical cases [10]. Our bibliometric analysis revealed that the USA is the country with most articles among the 100 most-cited studies in the field of Midazolam research. A great number of the studies investigates drug metabolism; this growing interest in USA in investigating midazolam may be due to the clarification of the mechanism of action and its adverse events with interaction associated with other substances.
Through this set of information extracted from these 100 studies, it is possible to see the main authors, countries, and keywords with the search strategy developed. However, it is important to emphasize that only the study ranking on the WOS database was considered, i.e., the positions of the studies may change in other databases. Another point is that the elaboration of the search strategy aims to retrieve a greater number of studies on the subject, but this recovery depends directly on the keywords used in the search strategy and that this process may present weaknesses, such as the non-retrieval of some studies.

Conclusions
The present study identified the 100 most-cited articles on midazolam, and highlighted the quantity and quality of research and the evolution of scientific knowledge about midazolam. The bibliometric results highlighted the knowledge presented by older articles, such as the pharmacokinetics, metabolism, and bioavailability of midazolam, while the most recent ones indicated the use of midazolam for the treatment of seizures in adults and children. The USA stood out with the largest number of articles and also as the headquarters of journals with the largest number of publications on the list. It indicated the large number of researchers from the USA working in the area of pharmacokinetics and clinical pharmacology involving this drug, which has different therapeutic actions, such as anesthetic, sedative, and anxiolytic, demonstrated mainly in the non-systematic review articles that are part of the list of the 100 most-cited articles.