High-Impact Clinical Studies That Fomented New Developments in Anesthesia: History of Achievements, 1966-2015.

The aim of this work is to identify the most influential initial clinical studies that fomented important developments in anesthesiology over the past 50 years. Studies fomenting new development can be selected using vastly different approaches and, therefore, might provide diverse outcomes. In the present work, two basic aspects of study assessments - the stage of development (eg, generation of idea, preclinical studies, clinical trials) and the method of selection (eg, committee vote, various types of citation analysis, method of finding the invention disclosure) - were chosen according to the following model. The stage of development: the initial clinical studies demonstrating the basic advantage of an innovation for providing anesthesia. The method: a combination of two factors - the study priority in terms of the time of its publication and the degree of its acknowledgement in the form of citation impact; the time of study publication was regarded as a primary factor, but only if the study's citation count was =/>20. The initial high-impact studies were selected for 16 drug-related topics (ketamine, isoflurane, etomidate, propofol, midazolam in anesthesia, vecuronium, alfentanil, atracurium, sevoflurane, sufentanil, rocuronium, desflurane, ropivacaine, remifentanil, dexmedetomidine in anesthesia, and sugammadex), and 9 technique-related topics (ultrasound-guided peripheral nerve block, capnography in anesthesia, target-controlled intravenous anesthesia, pulse oximetry in anesthesia, total intravenous anesthesia, transesophageal echocardiography in anesthesia, combined spinal-epidural anesthesia, and bispectral index). Twenty-five studies were designated the first high-impact studies (one for each topic); 16 are drug-related and 9 are technique-related. Half of the first high-impact studies had a citation count of =/>100, (range: 100 to 555). The citation count of the other half of high-impact studies did not reach the 100-citation threshold (range: 41 to 97). If a selected first high-impact study had a citation count <100, a next-on-timeline, additional study with citation count =/>100 was also selected; (range: 100 to 344). The present results show that an initial high-impact clinical study on a new development in anesthesiology can be determined and that related citations usually vary from one hundred to five hundred.

Introduction

In a previous study,1 we analyzed important new developments in anesthesiology over the past 50 years. The topics for such developments were selected using an objective indicator – the degree to which the number of academic articles on a topic increased. More than 20 such topics were identified. The aim of this study was to determine for each of these topics the most influential initial clinical studies, also using an objective indicator – the number of citations generated by the study’s publication.

In science, priority rule is the credit given to the person who first published a new finding or proposed a theory.2,3 Determining priority of discovery is a two-step process that includes its disclosure and validation.4 The validation reflects the scientific community’s response to a disclosure centered on two questions: Is a new finding correct, and is it of sufficient interest to merit attention and further development? In practice, this acknowledgement usually comes in the form of citations in papers by other scientists, which can accumulate over time. Unlike disclosure (eg, publication), which is an event with a definite time stamp, validation can take a variable amount of time.4

The chain of accomplishments leading to any important new development has many links. Among the main ones are disclosure(s) of a new idea (eg, patents), definitive bench and/or animal studies, and human studies leading to the formal approval of a drug or technique for use in clinical practice. The aim of the current study is to assess only one of these links – initial clinical studies that prominently contributed to the acceptance of a new development by the scientific community. We sought to assess the contribution of initial clinical studies to the success of a new development by combining two factors: the time of the study publication and its acknowledgement by the scientific community in the form of total citation impact. For this, we identified initial studies that proved the effectiveness of a drug (or technique) in achieving a specific aim in anesthesia, and were the first to have an impressive citation impact.

Methods

On Topics of New Developments

The selection of the topics of new developments was based on the results of the previous study, in which the degree of increase in the number of academic articles on a topic was used for selection.1 The main tool for selection was popularity index (PI),5 the percentage of articles on the topic among all articles related to the PubMed (MeSH) term “Anesthesia” over the same 5-year period. A topic was selected if it had reached a PI =/> 0.5 during any 5-year period from 1966 to 2015, or the total number of articles on the topic reached at least 500 articles.1 There were 27 such topics, 19 of them were drug-related (ketamine, isoflurane, enflurane, etomidate, propofol, midazolam in anesthesia, vecuronium, alfentanil, atracurium, sevoflurane, sufentanil, mivacurium, rocuronium, desflurane, ropivacaine, remifentanil, dexmedetomidine in anesthesia, levobupivacaine, and sugammadex) and 9 technique-related (ultrasound-guided peripheral nerve block, capnography in anesthesia, target-controlled intravenous anesthesia, pulse oximetry in anesthesia, total intravenous anesthesia, transesophageal echocardiography in anesthesia, combined spinal-epidural anesthesia, bispectral index, and transversus abdominis plane block). In the present study, we excluded from the list of drugs three agents that were discontinued in the USA in 2020 – enflurane, mivacurium, and levobupivacaine; the list of technique-related topics was not modified. Basic search details on these topics are presented in Table 1.

Table 1

Search Details on Initial High-Impact Clinical Studies

(A) Drugs
#	Topic	Patent		Search Timespan	Search Terms	Additional MeSH Headingsb
		Yeara	Inventors
1	Ketamine	1963	Stevens CL	1963–1972	Ketamine, CI-581, Ketalar	Anesthesia, Humans
2	Isoflurane	1969	Terrell RC	1969–1976	Isoflurance, Forane	Anesthesia, Humans
3	Etomidate	1964	Fred GE, Eijcken CAMV	1964–1976	Etomidate, R26490	Anesthesia, Humans
4	Propofol	1974	Glen JB, James R	1976–1984	Propfol, ICI 35868, Diprivan	Anesthesia, Humans
5	Midazolam in anesthesia	1973	Fryer RI, Walser A	1973–1981	Midazolam, RO 21–3981	Anesthesia, Humans
6	Vecuronium	1974	Hewett CL, Savage DS	1974–1982	Vecuronium, ORG NC45	Anesthesia, Humans
7	Alfentanil	1978	Janssens FPB	1978–1986	Alfentanil, R-39209	Anesthesia, Humans
8	Atracurium	1975	Stenlake JB, Waigh RO, Dewar CH	1975–1983	Atracurium, 33A74	Anesthesia, Humans
9	Sevoflurane	1969	Terrell RC	1969–1987	Sevoflurane	Anesthesia, Humans
10	Sufentanil	1976	Janssen PAJ, Van Daele GHP	1976–1984	Sufentanil, R30730	Anesthesia, Humans
11	Rocuronium	1990	Sleigh T, Carlye IC, Muir AW	1990–1996	Rocuronium, ORG9426	Anesthesia, Humans
12	Desflurane	1987	Terrell RC	1987–1992	Desflurane, I-653	Anesthesia, Humans
13	Ropivacaine	1986	Sandberg RV	1986–1992	Ropivacaine	Anesthesia, Humans
14	Remifentanil	1989	Feldman PL, James MK, Brackeen MR, et al.	1989–1998	Remifentanil	Anesthesia, Humans
15	Dexmedetomidine in anesthesia	1988	Karjalainen AJ, Virtanen RE, Savolainen EJ	1988–2003	Dexmedotomidine	Anesthesia, Humans
16	Sugammadex	2000	Zhang M, Palin R,Bennett J	2000–2008	Sugammadex, ORG 25969	Anesthesia, Humans
(B) Techniques
#	Topic	Patent		Search Timespan	Search Terms	Additional MeSH Headingsb
		Yeara	Inventors
1	Ultrasound-guided peripheral nerve block	-	-	1977–1995	“Ultrasound-guided AND Nerve Block NOT Biopsy”	Anesthesia, Humans
2	Capnography in anesthesia	-	-	1982–1989	“Capnography OR Capnometry OR End-tidal PCO2”	Anesthesia, Humans
3	Target-controlled intravenous anesthesia	-	-	1982–1993	“Target-controlled intravenous anesthesia OR Target-controlled infusion”	Anesthesia, Humans
4	Pulse oximetry in anesthesia	1979	Aoyagi T, Kobayashi N, Sasaki T	1982–1989	“Pulse oximetry”	Anesthesia, Humans
5	Total intravenous anesthesia	-	-	1985–1997	“Total intravenous anesthesia OR TIVA”	Anesthesia, Humans
6	Transesophageal echocardiography in anesthesia	-	-	1986–1996	“Transesophageal echocardiography OR TEE”	Anesthesia, Humans
7	Combined spinal- epidural anesthesia	-	-	1982–1989	“Combined spinal- epidural OR Combined subarachnoid and epidural”	Anesthesia, Humans
8	Bispectral index			1994–2000	“Bispectral index OR BIS”	Anesthesia, Humans
9	Transversus abdominis plane block			2005–2008	“Transversus abdominis plane block”	Anesthesia, Humans

Notes: aYear of worldwide patent application (Google Patent); bMeSH (Medical Subject Headings) vocabulary of Medline database.

Requirements for Selection of Initial High-Impact Studies

General Requirements

The selection of initial high-impact studies was based on the following general requirements: 1) the principal aim of the study should be the assessment of the effectiveness of a new agent (or technique) in achieving a specific aim in anesthesia; 2) the study should be published as an original research article; 3) the study should be one of the initial clinical studies on a topic; 4) the study should have an impressive citation impact (the Thomson Reuters Web of Science Database),6 preferably more than 100, but not fewer than 20 citations, most importantly, it should be published before other clinical studies on the topic with citation records =/> 20. If the study had a citation record =/> 20, but not =/> 100, an additional study with =/> 100 citations was also selected, on condition that it was published the next on the timeline after the first study. As a result, there were two types of initial studies with =/> 100 citations: the first high-impact studies with =/> 100 citations and the additional high-impact studies with =/> 100 citations. The choice of the number of citations thresholds (20 and 100) was a voluntary one.

Specific Requirements

Specific requirements for the selection of studies with 20-citation threshold: If several studies with =/> 20 citations were published almost simultaneously (within six-month period), all of them were identified, unless they had <30% of the number of citations of the study with the highest citation rate.

Specific requirements for the selection of additional studies with 100-citation threshold: 1) If the =/> 100 citations study is an additional one, its date of publication should be closest to that of the first study with <100 citations (but >20 citations). 2) If several studies with the =/>100 citation count were published during the same six-month period, all were listed according to their publication dates. Any of these studies with fewer than 30% of the citations of the first study were excluded.

Results

Table 2 presents data on studies according to the number of citations they elicited as well as their publication dates (year and month), which are the principal criteria for the assessment of their priority. The table indicates the first authors of the articles, all other authors (along with the article titles, journal names, and other publication details). The review's list of selected studies as systemized in Table 2 can be viewed in . In Table 2 studies are divided into two categories: those which crossed only =/> 20 citation-threshold and those which crossed a higher threshold, =/> 100 citations. The selected studies were prioritized based on publication date, but only if their citation count was =/> 20. Subject to a number of specifications (presented in the Methods), one study for each topic was designated as the first high-impact study. If the first high-impact study did not reach the 100 citation-threshold, the study next to it on the timeline was also selected; it was designated as the additional high-impact study – published at a later date, but having a higher citation count. As a result, there were two types of initial studies with =/>100 citations: the first studies with =/> 100 citations and additional studies with =/>100 citations; both of them are presented in Table 2. They are listed separately in Table 3.

Table 2

Initial High-Impact Clinical Studies in Major Anesthesia Developments Since 1965

(A) Drugs
#	Topic	Studies According to Number of Citations
		≥20 Thresholda			≥100 Threshold
		First Author and Journal	Time of Publication	Number of Citations	First Author and Journal	Time of Publication		Number of Citations
1	Ketamine	–	–	–	Domino EF7Clin Pharmacol Ther	1965 (May -Jun)		555
2	Isoflurane	Dobkin AB8Can Anaeth Soc J	1971 (May)	43	Stevens WC9Anesthesiology	1971 (Jul)		344
3	Etomidate	Doenicke A10Anaesthetist	1973 (Aug)	72	Holdcroft A11Br J Anaesth	1976 (Mar)		100
4	Propofol	-	-	-	Kay B12Acta Anaesth Belg	1977 (Feb)		122
5	Midazolam in anesthesia	-	-	-	Conner JT13Anesth Analg	1978 (Jan -Feb)		106
					Reves JG14Can Anaesth Soc J	1978 (May)		118
					Fragen RJ15Anesthesiology	1978 (Jul)		128
6	Vecuronium	-	-	-	Agoston S116Br J Anaesth	1980 (Jun)		125
					Krieg N17Br J Anaesth	1980 (Aug)		95
7	Alfentanil	Kay B18Anaesthesia	1980 (Dec)	41	Ausems ME19Anesthesiology	1986 (Oct)		210
8	Atracurium	-	-	-	Payne JP20Br J Anaesth	1981 (Jan)		212
9	Sevoflurane	-	-	-	Holaday DA21Anesthesiology	1981 (Feb)		194
					Katoh T22Anesthesiology	1987 (Mar)		229
10	Sufentanil	Bovill JG23Br J Anaesth	1982 (Jan)	48	de Lange S24Anesthesiology	1982 (Feb)		143
11	Rocuronium	-	-	-	Wierda JM25Br J Anaesth	1990 (Apr)		132
12	Desflurane	Jones RM26Anesth Analg	1990 (Jan)	76	Rampil IJ27Anesthesiology	1991 (Mar)		169
13	Ropivacaine	Katz JA28Anesth Analg	1990 (Jan)	70	Brockway MS31Br J Anaesth	1991 (Jan)		146
		Concepcion M29Anesth Analg	1990 (Jan)	63
		Brown DL30Anesthesiology	1990 (Apr)	74
14	Remifentanil	Dershwitz M32Anesth Analg	1995 (Sep)	97	Hogue CW Jr33Anesth Analg	1996 (Aug)		161
					Lang E34Anesthesiology	1996 (Oct)		165
15	Dexmedetomidine in anesthesia	Aantaa RE35Anesth Analg	1990 (Apr)	67	Aantaa R36Anesthesiology	1990 (Aug)		175
16	Sugammadex	-	-	-	Gijsenbergh F37Anesthesiology	2005 (Oct)		179
					Shields M38Br J Anaesth	2006 (Jan)		118
(B) Techniques
#	Topic	Studies According to Number of Citations
		≥20 Thresholda			≥100 Threshold
		First Author and Journal	Time of Publication	Number of Citations	First Author and Journal	Time of Publication	Number of Citations
1	Ultrasound-guided peripheral nerve block	La Grange P39Br J Anaesth	1978 (Sep)	65	Kapral S40Anesth Analg	1994 (Mar)	219
2	Capnography in anesthesia	-		-	Linko K41Acta Anaesth Scand	1983 (Jun)	102
3	Target-controlled intravenous anesthesia	Schuttler J42Anaesthesia		65	Schwilden H43Anesthesiology	1987 (Sen)	226
4	Pulse oximetry in anesthesia	-	-	-	Yelderman M44Anesthesiology	1983 (Oct)	364
5	Total intravenous anesthesia	de Grood PM45Postgrad Med J	1985 (Jan)	46	Hogue CW Jr33Anesth Analg	1996 (Aug)	162
6	Transesophageal echocardiography in	-	-	-	Roizen MF46J Vasc Surg	1984 (Mar)	140
7	Combined spinal-epidural anesthesia	-	-	-	Rawal N47Acta Anaesth Scand	1988 (Jan)	125
8	Bispectral index	Kearse LA48 Electroenceph Clin Neurophysiol	1994 (Mar)	50	Kearse LA49Anesthesiology	1994 (Dec)	133
					Vernon JM50Anesth Analg	1995 (Apr)	163
9	Transversus abdominis plane block	-	-	-	McDonnell JG51Anesth Analg	2007 (Jan)	421

Notes: aHigh-impact study crossing threshold of ≥20 citations, but not threshold of ≥100 citations; The numeral at the name of first author represents the reference number in the list of references.

Table 3

Number of Citations Generated by Initial High-Impact Clinical Studies

(A) Drugs
#	Topic	First Studya		Additional Studyb
		Citation Impact	First Author	Citation Impact	First Author
1	Ketamine	555	Domino EF7	–	–
2	Isoflurane	43	Dobkin AB8	344	Stevens WC9
3	Etomidate	72	Doenicke A10	100	Holdcroft A11
4	Propofol	122	Kay B12	–	–
5	Midazolam in anesthesia	106	Conner JT13	–	–
6	Vecuronium	125	Agoston S16	–	–
7	Alfentanil	41	Kay B18	210	Ausems ME19
8	Atracurium	212	Payne JP20	–	–
9	Sevoflurane	194	Holaday DA21	–	–
10	Sufentanil	48	Bovill JG23	144	DeLange S24
11	Rocuronium	132	Wierda JM25	–	–
12	Desflurane	76	Jones RM26	169	Rampil IJ27
13	Ropivacaine	70	Katz JA28	146	Brockway MC31
		63	Conceptcion29
14	Remifentanil	97	Dershwitz M32	161	Hogue GW Jr33
15	Dexmedetomidi ne in anesthesia	67	Aantaa R35	175	Aantaa R36
16	Sugammadex	179	GijsenberghF37	–	–
(B) Techniques
#	Topic	Initial Studya		Additional Studyb
		Citation Impact	First Author	Citation Impact	First Author
1	Ultrasound-guided peripheral nerve block	65	La Grange P39	219	Kapral S40
2	Capnography in anesthesia	201	Linko K41	-	-
3	Target-controlled intravenous anesthesia	65	Schuttler J42	226	Schwilden H43
4	Pulse oximetry in anesthesia	364	Yelderman M44	-	-
5	Total intravenous anesthesia	46	de Grood PM45	162	Hogue CW Jr33
6	Transesophageal echocardiography in anesthesia	140	Roizen MF46	-	-
7	Combined spinal- epidural anesthesia	125	Rawal N47	-	-
8	Bispectral index	50	Kearse LA48	133	Kearse LA49
9	Transversus abdominis plane block	421	McDonnell JG51	-

Notes: aFirst study with citation impact ≥20; bIf the first study had <100 citation, the next-on-timeline study with ≥100 citations was added.

Overall, 25 studies were designated as first high-impact studies, 16 of which are drug-related and 9 technique-related. Only half of the first high-impact studies had a citation count of =/>100: 8 of 16 with drug-related topics, from 106 to 555 citations; and 4 of 9 with technique-related topics, from 102 to 421 citations. The other half of the first high-impact studies did not reach the 100-citation threshold: for drug-related topics their counts were from 41 to 97, and for technique-related topics – 46 to 65. There were no citation counts below 40 with any topic, although citation rates from 20 to 40 were searched for. Given the principles for selection, all additional high-impact studies had =/>100 citations (Table 3, right column): with eight drug-related topics the citations count varied from 100 to 344, and with four technique-related topics – from 133 to 219.

The selection of the first high-impact study (or the additional high-impact study) was often made more difficult by the presence of several studies with very close dates of publication and similar citation counts. The greatest difficulties in this respect were with five drug-related topics: midazolam, vecuronium, sevoflurane, ropivacaine, and sugammadex. This can be seen when dates of publication and citation counts of several similar high-impact studies (Table 2) are compared with those of a single study presented as the final choice (Table 3). For example, there were three studies on the use of midazolam for anesthesia published in 1978: Conner13 in January–February, Reves14 in May, and Fragen15 in July; the citation counts for all three studies varied only from 106 to 128. The choice of Conner’s study (Table 3) was based on several months earlier publication. Another example is the three studies on ropivacaine published in 1990: Katz28 in January, Concepcion29 in January, and Brown30 in April. In this case, two studies (Katz and Concepcion) were published in the same issue of Anesthesia & Analgesia and had similar citation counts – 70 and 63, respectively (Table 2). Both studies are placed in Table 3 as the first high-impact study, as an exception to the rule of one study per topic.

Discussions

In this review, we identified the initial high-impact clinical studies which fomented new developments in anesthesiology over the past 50 years. These studies were assessed by combining two factors: the study’s publication date and the degree of its acknowledgement by the scientific community in the form of citations. As a result, twenty-five studies were designated the first high-impact studies (one for each topic); 16 are drug-related and 9 are technique-related. Half of the first high-impact studies had a citation count of =/>100, (range: 100 to 555). The citation count of the other half of high-impact studies did not reach the 100-citation threshold (range: 41 to 97). If a selected first high-impact study had a citation count <100, a next-on-timeline, additional study with citation count =/>100 was also selected (range: 100 to 344).

These studies represent 25 topics of the most meaningful developments in anesthesiology. What is a meaningful development? According to Helmer,52 one of the most important conditions for meaningful research is a practically useful impact on society. In this review, due to the retrospective view of developments whose usefulness was confirmed during many decades of clinical practice, research studies with impact on these developments were historically shown to be practically useful. They include the following topics which are well known to any anesthesiologist. Sixteen drug-related topics: ketamine, isoflurane, etomidate, propofol, midazolam in anesthesia, vecuronium, alfentanil, atracurium, sevoflurane, sufentanil, rocuronium, desflurane, ropivacaine, remifentanil, dexmedetomidine in anesthesia, and sugammadex; and also nine technique-related topics: ultrasound-guided peripheral nerve block, capnography in anesthesia, target-controlled intravenous anesthesia, pulse oximetry in anesthesia, total intravenous anesthesia, transesophageal echocardiography in anesthesia, combined spinal-epidural anesthesia, and bispectral index.

It is important to underline that all selected studies had two specific features. First, only original research articles, in which the principle goal was the assessment of possible use of a new agent or technique for achieving a specific aim in anesthesia, were selected. Studies beyond the initial question of the basic advantage of a new drug (or technique) for anesthesia, such as drug’s formulation, the general characteristic of drug’s pharmacokinetics, or possible additional clinical indications, were not selected as the initial high-impact studies.

Second, only initial clinical studies were selected. Their impact on the opinion of the scientific community was sufficient to convince it that a new agent or technique is of interest for further development, indicating that the previous chain of events, from conceiving an idea (eg, patent) to bench or/and animal experiments, and finally to clinical trial, had real promise. The high citation impact of the initial clinical study elevates a new agent, following multiple study-steps on various aspects of the agent’s action, to its destination – formal approval for use in clinical practice. In the long life of an introduced drug or technique, significant new research findings may change the drug’s role in clinical practice. This assessment concentrated only on initial clinical studies that gave birth to new developments.

Among limitations of this review is, described in the methods, voluntary choice of the number of citations thresholds for selecting the studies. The other limitation is associated with the preselected aspects of the review, which requires the following explanation. The presented analysis of the studies has two aspects: 1) Which stage of development to analyze, and 2) What method to use. With the first aspect, each new development has a number of stages, such as the generation of a novel idea, its disclosure in a patent, definitive bench or/and animal studies, initial clinical studies, and advanced clinical studies leading to formal approval for general use in clinical practice. The aim of present assessment was to analyze only initial clinical studies. The second aspect, related to the methods of comparative assessment of the studies on a new development, could be based on a list established by academic leaders or through committee vote;53 another more objective one is based on various methods derived from raw citation data;54 the most important factor in discovery assessment is associated with the date of disclosure.3 In the present assessment, a combination of two factors was used: the study’s priority in terms of the time of its publication and the degree of its acknowledgement by the academic community in the form of citations. With different approaches to these two aspects of analysis – what stage to analyze and what method to apply for the study selection – various outcomes are possible. This may be regarded as a potential limitation of the current review. For example, our approach, based on initial clinical studies, is not directed toward the most important element of any new development – the generation of a new idea including its disclosure (eg, patent). At the same time, it was centered on the most critical consideration in the development of a new idea – is it clinically useful? Thus, with different approaches the importance of different studies could be assessed quite differently; therefore, our results should be regarded only as an initial attempt in the selection of high-impact studies that fomented new developments in anesthesia.

In conclusion, the present results show that an initial high-impact clinical study on a new development in anesthesiology can be determined and that related citations usually vary from one hundred to five hundred. The review’s List of Selected Studies. These initial clinical studies fomented the most important development in anesthesiology over the past 50 years.