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  • Research
  • Open Access

The 100 most influential publications in paracetamol poisoning treatment: a bibliometric analysis of human studies

  • 1, 2, 3Email author,
  • 4,
  • 2,
  • 5 and
  • 3
SpringerPlus20165:1534

https://doi.org/10.1186/s40064-016-3240-z

  • Received: 30 April 2016
  • Accepted: 6 September 2016
  • Published:

Abstract

Background

Analysis of the most influential publications within paracetamol poisoning treatment can be helpful in recognizing main and novel treatment issues within the field of toxicology. The current study was performed to recognize and describe the most highly cited articles related to paracetamol poisoning treatment.

Methods

The 100 most highly cited articles in paracetamol poisoning treatment were identified from the Scopus database in November 2015. All eligible articles were read for basic information, including total number of citations, average citations per year, authors’ names, journal name, impact factors, document types and countries of authors of publications.

Results

The median number of citations was 75 (interquartile range 56–137). These publications were published between 1974 and 2013. The average number of years since publication was 17.6 years, and 45 of the publications were from the 2000s. A significant, modest positive correlation was found between years since publication and the number of citations among the top 100 cited articles (r = 0.316; p = 0.001). A total of 55 journals published these 100 most cited articles. Nine documents were published in Clinical Toxicology, whereas eight documents were published in Annals of Emergency Medicine. Citations per year since publication for the top 100 most-cited articles ranged from 1.5 to 42.6 and had a mean of 8.5 citations per year and a median of 5.9 with an interquartile range of 3.75–10.35. In relation to the origin of the research publications, they were from 8 countries. The USA had the largest number of articles, 47, followed by the UK and Australia with 38 and nine articles respectively.

Conclusions

This study is the first bibliometric assessment of the top 100 cited articles in toxicology literature. Interest in paracetamol poisoning as a serious clinical problem continues to grow. Research published in high-impact journals and from high income countries is most likely to be cited in published paracetamol research.

Keywords

  • Paracetamol
  • Acetaminophen
  • N-acetylcysteine
  • Bibliometric
  • Citations
  • Scopus
  • Poisoning

Background

N-acetylcysteine (NAC) is a well-established antidote for a paracetamol (acetaminophen) overdose and is highly effective in minimising liver injury if administered promptly. However, NAC is associated with a number of adverse effects, including nausea, vomiting and non-immunoglobulin E anaphylactic (anaphylactoid) reactions (Zyoud et al. 2010c). A number of methods have been applied in clinical practice for risk stratification, such that NAC is administered to patients thought to be at significant risk of paracetamol-induced liver injury. Most prominently, the extent of paracetamol exposure may be estimated from a measured serum concentration at a known interval after ingestion. However, there are difficulties in relying on patient reporting, and errors may occur concerning the reported drug name, dose and timing of ingestion (Zyoud et al. 2012; Hewett et al. 2013; Rutter et al. 2013). A history of acute or chronic alcohol ingestion and biochemical tests of malnutrition have been explored as means of detecting an increased susceptibility to paracetamol liver toxicity; however, none of these are sufficiently reliable for routine clinical application (Waring et al. 2008a, b, d; Zyoud et al. 2011).

The original NAC infusion regimen described by Prescott in the late 1970s gives rise to very high initial blood concentrations, which are associated with the development of adverse effects; a number of alternative regimens have been described, which incorporate a slower initial rate of infusion (Prescott et al. 1977; Zyoud et al. 2010a, b; Waring 2012). Novel NAC infusion regimens are associated with a lower rate of occurrence of adverse effects, but too few data are currently available for a comparison of efficacy in preventing paracetamol-induced liver injury (Chiew et al. 2016). Nonetheless, the regulatory authorities in the UK made substantial changes to the NAC Marketing Authorisation in September 2012, incorporating a slower delivery of the initial loading dose of 150 mg per kg, extended from 15 to 60 min. At the same time, amendments were made to the criteria for NAC so that treatment should be considered for any patient that ingests more paracetamol than 75 mg per kg of body weight or has a measured paracetamol concentration higher than the 100-line nomogram that was formerly used for “high risk” patients only. Other countries have followed suit and incorporated these amendments into local policy. At present, few data exist concerning the impact on rates of occurrence of liver injury or adverse acetylcysteine effects. Early reports from the UK indicate that, since September 2012, there have been increased numbers of patients receiving acetylcysteine, increased hospitalisation and a substantial financial burden (Thompson et al. 2013; Bateman et al. 2014a).

Other novel therapeutic approaches have been examined in patients receiving an intravenous NAC antidote after paracetamol poisoning. For example, co-administration of cimetidine has been found to have no significant effect on patient outcome (Ebrahimi et al. 2015). Co-administration of ondansetron is highly effective in reducing the adverse effects associated with NAC administration, and this might be considered for routine administration in patients at high risk of anaphylactoid reactions, for example those with a history of asthma or previous adverse effects after NAC (Bateman et al. 2014b).

While numerous bibliometric reports have been performed to investigate factors related to research output in the toxicology field (Zyoud et al. 2010b, 2014a, 2015a, b, c, d), to our knowledge, no study has attempted to evaluate the most influential publications within a particular subspecialty in toxicology. The main aim of our study was to identify the 100 most frequently cited articles related to paracetamol poisoning treatment. Therefore, a bibliometric evaluation of scientific literature in a particular field may be used to recognize the impact of influential scholarly work, authors, subjects, countries, etc. The total number of citations that a published article has achieved indicates the importance that published article has on that area of practice. Analysis of the most influential publications within paracetamol poisoning treatment can be helpful in recognizing main and novel treatment issues within the field of toxicology.

Methods

Data acquisition

In November 2015, we used the Scopus database to retrieve the most frequently cited articles on paracetamol poisoning treatment. Scopus is the largest electronic scientific database. It is larger than either MEDLINE or Web of Science and is more accurate than Google Scholar. Furthermore, Scopus is accessible and allows researchers to obtain information and do analysis that might not be readily achievable in MEDLINE or Google Scholar.

The search terms used to retrieve articles related to paracetamol poisoning treatment were elected from previous bibliometric studies related to paracetamol (Robert et al. 2009; Zyoud et al. 2015a, d). The articles entitled with the terms “acetaminophen” or “paracetamol” or “acetamidophenol” or “hydroxyacetanilide” or “tylenol” or “n-acetyl-p-aminophenol” or “panadol” or “APAP” or “acephen” were included in the research. Then, the following keywords were entered as terms in the article title or abstract: “poison*” or “overdose*” or “*toxic*”. All the previous terms were followed by “treat*” or “antidot*” or “detoxification” or “intervention” or “manag*”. To include all possible publications related to paracetamol treatment, we included the following strategy in addition to the previous one. The following keywords, “NAC” or “acetylcysteine” or “N-acetyl-l-cysteine”, were entered as terms in the article title or abstract and followed by the following terms: “acetaminophen” or “paracetamol” or “acetamidophenol” or “hydroxyacetanilide” or “tylenol” or “n-acetyl-p-aminophenol” or “panadol” or “APAP” or “acephen”. The Scopus search was conducted by applying the previous strategies of search for all previous years. No limits were placed on the time period for this search. Furthermore, all documents related to paracetamol, with no language restriction, were searched in Scopus database. Wildcard characters were used to include variations of a word by using an asterisk (*) to make our search strategy simpler. For example, in the Scopus search engine, when we entered “*toxic*”, it offered a wildcard character capability, and we got results for toxic, toxicity, toxicant, toxicities, intoxication—briefly, any possible word that might include the five letters (i.e. toxic).

Data analysis

We sorted the extracted results from the largest number of citations to the lowest. The results were then evaluated by two independent researchers to extract only the top 100 cited articles related to paracetamol poisoning treatment in human research subjects. Total numbers of citations, average citations per year, authors’ names, journal name, impact factors (IF), document types, countries of publication, and number of authors for only the top 100 cited articles were noted. The impact factor was obtained from 2014 Journal Citation Reports® (Thomson Reuters, New York, NY, USA) (Thomson Reuters 2015) for all journals that published the top 100 cited articles. This is useful in clarifying the significance of absolute citation frequencies. This search used the electronic version of this database by ranking the top 100 cited publications using the standard competition ranking (SCR). It is possible that some articles were cited more frequently than others because of the long time elapsed since their publication. Therefore, a citation index was calculated for each article to avoid the bias created by the time elapsed since publication. Citation index is calculated as the average number of citations divided by number of years elapsed since the article was initially published. A Pearson’s correlation coefficient test was applied to assess the correlation between the impact factor of the journal or years since publication or citation index and the number of citations for the top 100 cited articles included in the study. This was carried out using Statistical Package for Social Sciences (SPSS) Version 15.0. Descriptive statistics were presented as frequencies, medians and interquartile ranges or averages. p values <0.05 were considered statistically significant for all the comparisons.

Results

Citation count and publication year

The number of citations for the top 100 cited articles in paracetamol poisoning treatment ranged from 44 to 553 (Mitchell et al. 1974; Gazzard et al. 1975; Prescott et al. 1976, 1977, 1979, 1989; Rumack and Peterson 1978; Prescott 1981, 1983; Rumack et al. 1981; Forrest et al. 1982; Prescott and Critchley 1983; Black 1984; Mant et al. 1984; Rumack 1984, 1986; Seeff et al. 1986; Slattery et al. 1987; Lauterburg and Velez 1988; Smilkstein et al. 1988; Ziment 1988; Burgunder et al. 1989; Dawson et al. 1989; Riggs et al. 1989; Harrison et al. 1990; Murphy et al. 1990; Underhill et al. 1990; Flanagan and Meredith 1991; Harrison et al. 1991; Holdiness 1991; Keays et al. 1991; O’Grady et al. 1991; Penna and Buchanan 1991; Smilkstein et al. 1991; Bray et al. 1992; Jones and Vale 1993; Thomas 1993; Mutimer et al. 1994; Makin et al. 1995; Eguia and Materson 1997; Makin and Williams 1997; Bernal et al. 1998; Jones 1998; Kelly 1998; Mitchell et al. 1998; Perry and Shannon 1998; Anderson et al. 1999; Buckley et al. 1999a, b; Detry et al. 1999; McClain et al. 1999; Prescott 2000; Prince et al. 2000; Whyte et al. 2000; Woo et al. 2000; Ferner et al. 2001; Schmidt and Dalhoff 2001; Ward et al. 2001; Appelboam et al. 2002; Gyamlani and Parikh 2002; Rumack 2002; Schiodt et al. 2002; Schmidt et al. 2002; Wallace et al. 2002; James et al. 2003; Kao et al. 2003; Kozer et al. 2003; Daly et al. 2004; Lee 2004; Lynch and Robertson 2004; Benson et al. 2005; Kerr et al. 2005; Marzullo 2005; Prescott 2005; Sivilotti et al. 2005; Aitio 2006; Dart et al. 2006; Kanter 2006; Mahadevan et al. 2006; Nourjah et al. 2006; Atkuri et al. 2007; Larson 2007; Daly et al. 2008; Dodd et al. 2008; Fontana 2008; Heard 2008; Kortsalioudaki et al. 2008; Mazer and Perrone 2008; Pakravan et al. 2008; Waring et al. 2008c; Chun et al. 2009; James et al. 2009; Lee et al. 2009; Millea 2009; Sandilands and Bateman 2009; Yarema et al. 2009; Winnike et al. 2010; Ferner et al. 2011; Khandelwal et al. 2011; Antoine et al. 2013; Samuni et al. 2013) (see Table 1 for the top 100 cited publications in paracetamol poisoning treatment ranked in descending order of the number of citations). The median number of citations was 75 (interquartile range 56–137). These publications were published between 1974 and 2013. The average number of years since publication was 17.6 years, and 45 of the publications were from the 2000s. A significant, modest positive correlation was found between years since publication and the number of citations among the top 100 cited articles (r = 0.316; p = 0.001). The earliest article was written by Mitchell et al. (1974) almost 41 years ago in Clinical Pharmacology and Therapeutics, and the most recent were published about 2 years ago (2013) by Samuni et al. (2013) and Antoine et al. (2013) in Biochimicaet Biophysica ActaGeneral Subjects and Hepatology respectively.
Table 1

The top 100 cited publications in paracetamol poisoning treatment ranked in descending order of the number of citations

SCR

Authors

Title

Year

Source title

Cited by

Document type

IFa

Citation index

Country of corresponding author

Collaboration country

1st

Smilkstein et al. (1988)

Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the National Multicenter Study (1976 to 1985)

1988

New England Journal of Medicine

553

Article

55.873

20.5

USA

 

2nd

James et al. (2003)

Acetaminophen-induced hepatotoxicity

2003

Drug Metabolism and Disposition

511

Review

3.252

42.6

USA

 

3rd

Prescott et al. (1979)

Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning

1979

British Medical Journal

419

Article

17.445

11.6

UK

 

4th

Harrison et al. (1991)

Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure

1991

New England Journal of Medicine

340

Article

55.873

14.2

UK

 

5th

Kelly (1998)

Clinical applications of N-acetylcysteine

1998

Alternative Medicine Review

297

Article

3.833

17.5

USA

 

6th

Keays et al. (1991)

Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial

1991

British Medical Journal

275

Article

17.445

11.5

UK

 

7th

Mitchell et al. (1974)

Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy

1974

Clinical Pharmacology and Therapeutics

258

Article

7.903

6.3

USA

 

8th

Seeff et al. (1986)

Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure

1986

Annals of Internal Medicine

252

Review

17.810

8.7

USA

 

9th

Lee (2004)

Acetaminophen and the US acute liver failure study group: lowering the risks of hepatic failure

2004

Hepatology

250

Review

11.055

22.7

USA

 

10th

Rumack et al. (1981)

Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment

1981

Archives of Internal Medicine

245

Article

17.333

7.2

USA

 

11th

Harrison et al. (1990)

Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine

1990

The Lancet

239

Article

45.217

9.6

UK

 

12th

Makin et al. (1995)

A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987–1993)

1995

Gastroenterology

237

Article

16.716

11.9

UK

 

13th

Forrest et al. (1982)

Clinical pharmacokinetics of paracetamol

1982

Clinical Pharmacokinetics

221

Review

5.053

6.7

UK

 

14th

Prescott (1983)

Paracetamol overdosage. Pharmacological considerations and clinical management

1983

Drugs

219

Review

4.343

6.8

UK

 

15th

Atkuri et al. (2007)

N-acetylcysteine—a safe antidote for cysteine/glutathione deficiency

2007

Current Opinion in Pharmacology

211

Review

4.595

26.4

USA

 

16th

Lee et al. (2009)

Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure

2009

Gastroenterology

180

Article

16.716

30.0

USA

 

17th

Black (1984)

Acetaminophen hepatotoxicity

1984

Annual Review of Medicine

178

Review

12.928

5.7

USA

 

18th

Prescott et al. (1977)

Treatment of paracetamol (acetaminophen) poisoning with n-acetylcysteine

1977

The Lancet

175

Article

45.217

4.6

UK

 

19th

Holdiness (1991)

Clinical pharmacokinetics of N-acetylcysteine

1991

Clinical Pharmacokinetics

172

Review

5.053

7.2

USA

 

19th

Smilkstein et al. (1991)

Acetaminophen overdose: a 48-h intravenous N-acetylcysteine treatment protocol

1991

Annals of Emergency Medicine

172

Article

4.676

7.2

USA

 

21st

Burgunder et al. (1989)

Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration

1989

European Journal of Clinical Pharmacology

163

Article

2.966

6.3

Switzerland

 

22nd

Lauterburg and Velez (1988)

Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity

1988

Gut

159

Article

14.660

5.9

Switzerland

USA

23rd

Larson (2007)

Acetaminophen hepatotoxicity

2007

Clinics in Liver Disease

158

Review

3.660

19.8

USA

 

24th

Rumack(2002)

Acetaminophen hepatotoxicity: the first 35 years

2002

Journal of ToxicologyClinical Toxicology

148

Conference Paper

3.673

11.4

USA

 

25th

Thomas (1993)

Paracetamol (acetaminophen) poisoning

1993

Pharmacology and Therapeutics

141

Article

9.723

6.4

UK

 

26th

Bernal et al. (1998)

Use and outcome of liver transplantation in acetaminophen-induced acute liver failure

1998

Hepatology

134

Article

11.055

7.9

UK

 

27th

Dodd et al. (2008)

N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility

2008

Expert Opinion on Biological Therapy

133

Review

3.743

19.0

Australia

 

28th

Heard (2008)

Acetylcysteine for acetaminophen poisoning

2008

New England Journal of Medicine

130

Article

55.873

18.6

USA

 

29th

Chun et al. (2009)

Acetaminophen hepatotoxicity and acute liver failure

2009

Journal of Clinical Gastroenterology

121

Review

3.498

20.2

USA

 

30th

Flanagan and Meredith (1991)

Use of N-acetylcysteine in clinical toxicology

1991

The American Journal of Medicine

117

Article

5.003

4.9

UK

 

31st

Mant et al. (1984)

Adverse reactions to acetylcysteine and effects of overdose

1984

British Medical Journal

115

Article

17.445

3.7

UK

 

32nd

Prescott et al. (1989)

The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage

1989

European Journal of Clinical Pharmacology

114

Article

2.966

4.4

UK

 

33rd

Daly et al. (2008)

Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration

2008

Medical Journal of Australia

109

Article

4.089

15.6

Australia

New Zealand

34th

Nourjah et al. (2006)

Estimates of acetaminophen (paracetamol)-associated overdoses in the United States

2006

Pharmacoepidemiology and Drug Safety

103

Article

2.939

11.4

USA

 

34th

Schmidt et al. (2002)

Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity

2002

Hepatology

103

Article

11.055

7.9

Denmark

 

36th

Rumack and Peterson (1978)

Acetaminophen overdose: incidence, diagnosis, and management in 416 patients

1978

Pediatrics

102

Article

5.473

2.8

USA

 

37th

Mazer and Perrone(2008)

Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management.

2008

Journal of Medical Toxicology: Official Journal of the American College of Medical Toxicology

96

Review

NA

13.7

USA

 

38th

Jones (1998)

Mechanism of action and value of N-acetylcysteine in the treatment of early and late acetaminophen poisoning: a critical review

1998

Journal of ToxicologyClinical Toxicology

94

Review

3.673

5.5

UK

 

39th

Ward et al. (2001)

Acetaminophen toxicity in children

2001

Pediatrics

93

Review

5.473

6.6

USA

Canada

39th

Prescott et al. (1976)

Cysteamine, methionine, and penicillamine in the treatment of paracetamol poisoning

1976

The Lancet

93

Article

45.217

2.4

UK

 

41st

Penna and Buchanan (1991)

Paracetamol poisoning in children and hepatotoxicity

1991

British Journal of Clinical Pharmacology

92

Review

3.878

3.8

Australia

 

42nd

Prescott and Critchley (1983)

The treatment of acetaminophen poisoning

1983

Annual Review of Pharmacology and Toxicology

90

Review

18.365

2.8

UK

 

43rd

Prescott (2000)

Paracetamol: past, present, and future

2000

American Journal of Therapeutics

89

Article

1.129

5.9

UK

 

44th

Buckley et al. (1999b)

Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning?

1999

Journal of ToxicologyClinical Toxicology

88

Article

3.673

5.5

Australia

 

45th

Antoine et al. (2013)

Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital

2013

Hepatology

84

Article

11.055

42.0

UK

Switzerland

46th

Mitchell et al. (1998)

Earlier identification of patients at risk from acetaminophen-induced acute liver failure

1998

Critical Care Medicine

83

Article

6.312

4.9

UK

 

46th

Slattery et al. (1987)

Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in humans

1987

Clinical Pharmacology and Therapeutics

83

Article

7.903

3.0

USA

 

48th

Millea (2009)

N-acetylcysteine: multiple clinical applications

2009

American Family Physician

79

Review

2.175

13.2

USA

 

49th

Samuni et al. (2013)

The chemistry and biological activities of N-acetylcysteine

2013

Biochimica et BiophysicaActaGeneral Subjects

76

Review

4.381

38.0

Australia

Israel

50th

Winnike et al. (2010)

Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans

2010

Clinical Pharmacology and Therapeutics

75

Article

7.903

15.0

USA

 

50th

Rumack (1984)

Acetaminophen overdose in young children: treatment and effects of alcohol and other additional ingestants in 417 cases

1984

American Journal of Diseases of Children

75

Article

Stop

2.4

USA

 

52nd

Kerr et al. (2005)

The Australasian clinical toxicology investigators collaboration randomized trial of different loading infusion rates of N-acetylcysteine

2005

Annals of Emergency Medicine

74

Article

4.676

7.4

Australia

 

53rd

Aitio(2006)

N-acetylcysteine—passe-partout or much ado about nothing?

2006

British Journal of Clinical Pharmacology

73

Review

3.878

8.1

Switzerland

 

53rd

Detry et al. (1999)

Clinical use of a bioartificial liver in the treatment of acetaminophen-induced fulminant hepatic failure

1999

American Surgeon

73

Article

0.818

4.6

USA

 

55th

Dart et al. (2006)

Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management

2006

Clinical Toxicology

72

Review

3.673

8.0

USA

 

56th

Eguia and Materson (1997)

Acetaminophen-related acute renal failure without fulminant liver failure

1997

Pharmacotherapy

71

Article

2.662

3.9

USA

 

56th

Dawson et al. (1989)

Adverse reactions to N-acetylcysteine during treatment for paracetamol poisoning

1989

Medical Journal of Australia

71

Article

4.089

2.7

Australia

 

58th

Schmidt and Dalhoff (2001)

Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning

2001

British Journal of Clinical Pharmacology

70

Article

3.878

5.0

DenmarK

 

59th

Woo et al. (2000)

Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose

2000

Annals of Emergency Medicine

68

Article

4.676

4.5

USA

 

60th

Buckley et al. (1999a)

Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose

1999

Journal of ToxicologyClinical Toxicology

67

Article

3.673

4.2

Australia

 

61st

Ziment (1988)

Acetylcysteine: a drug that is much more than a mucokinetic

1988

Biomedicine and Pharmacotherapy

66

Review

2.023

2.4

USA

 

62nd

James et al. (2009)

Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure

2009

Drug Metabolism and Disposition

64

Article

3.252

10.7

USA

 

62nd

Fontana (2008)

Acute liver failure including acetaminophen overdose

2008

Medical Clinics of North America

64

Review

2.607

9.1

USA

 

64th

Benson et al. (2005)

The therapeutic use of acetaminophen in patients with liver disease

2005

American Journal of Therapeutics

63

Review

1.129

6.3

USA

 

64th

Bray et al. (1992)

Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure

1992

Human and Experimental Toxicology

63

Article

1.747

2.7

Denmark

 

66th

Prescott (2005)

Oral or intravenous N-acetylcysteine for acetaminophen poisoning?

2005

Annals of Emergency Medicine

61

Editorial

4.676

6.1

UK

 

66th

Perry and Shannon (1998)

Efficacy of oral versus intravenous N-acetylcysteine in acetaminophen overdose: results of an open-label, clinical trial

1998

Journal of Pediatrics

61

Article

3.790

3.6

USA

 

68th

Sandilands and Bateman (2009)

Adverse reactions associated with acetylcysteine Adverse reactions associated with acetylcysteine

2009

Clinical Toxicology

60

Review

3.673

10.0

UK

 

68th

Ferner et al. (2001)

Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example

2001

British Journal of Clinical Pharmacology

60

Article

3.878

4.3

UK

 

68th

O’Grady et al. (1991)

Liver transplantation after paracetamol overdose

1991

British Medical Journal

60

Article

17.445

2.5

UK

 

71st

Kanter (2006)

Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning

2006

American Journal of Health-System Pharmacy

59

Review

1.882

6.6

USA

 

72nd

Appelboam et al. (2002)

Fatal anaphylactoid reaction to N-acetylcysteine: caution in patients with asthma

2002

Emergency Medicine Journal

58

Article

1.843

4.5

UK

 

72nd

Gazzard et al. (1975)

Early changes in coagulation following a paracetamol overdose and a controlled trial of fresh frozen plasma therapy

1975

Gut

58

Article

14.660

1.5

UK

 

74th

Kortsalioudaki et al. (2008)

Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure

2008

Liver Transplantation

57

Article

4.241

8.1

UK

 

74th

Mutimer et al. (1994)

Serious paracetamol poisoning and the results of liver transplantation

1994

Gut

57

Article

14.660

2.7

UK

 

74th

Jones and Vale (1993)

Paracetamol poisoning and the kidney

1993

Journal of Clinical Pharmacy and Therapeutics

57

Review

1.668

2.6

UK

 

77th

Kao et al. (2003)

What Is the rate of adverse events after oral N-acetylcysteine Administered by the intravenous route to patients with suspected acetaminophen poisoning?

2003

Annals of Emergency Medicine

56

Review

4.676

4.7

US

 

77th

Wallace et al. (2002)

Paracetamol overdose: an evidence based flowchart to guide management

2002

Emergency Medicine Journal

56

Article

1.843

4.3

UK

 

79th

McClain et al. (1999)

Acetaminophen hepatotoxicity: an update

1999

Current gastroenterology reports

55

Review

NA

3.4

USA

 

79th

Makin and Williams (1997)

Acetaminophen-induced hepatotoxicity: predisposing factors and treatments

1997

Advances in internal medicine

55

Review

NA

3.1

UK

 

79th

Prescott (1981)

Treatment of severe acetaminophen poisoning with intravenous acetylcysteine

1981

Archives of Internal Medicine

55

Article

17.333

1.6

UK

 

82nd

Murphy et al. (1990)

Severe acetaminophen toxicity in a patient receiving isoniazid

1990

Annals of Internal Medicine

53

Article

17.810

2.1

USA

 

83rd

Daly et al. (2004)

Prospective evaluation of repeated supratherapeutic acetaminophen (paracetamol) ingestion

2004

Annals of Emergency Medicine

52

Article

4.676

4.7

USA

 

83rd

Kozer et al. (2003)

Glutathione, glutathione-dependent enzymes and antioxidant status in erythrocytes from children treated with high-dose paracetamol

2003

British Journal of Clinical Pharmacology

52

Article

3.878

4.3

Israel

 

83rd

Prince et al. (2000)

Reduction in incidence of severe paracetamol poisoning

2000

The Lancet

52

Note

45.217

3.5

UK

 

83rd

Riggs et al. (1989)

Acute acetaminophen overdose during pregnancy

1989

Obstetrics and Gynecology

52

Article

5.175

2.0

USA

 

87th

Khandelwal et al. (2011)

Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure

2011

Hepatology

51

Article

11.055

12.8

USA

 

87th

Yarema et al. (2009)

Comparison of the 20-h intravenous and 72-h oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning

2009

Annals of Emergency Medicine

51

Article

4.676

8.5

Canada

USA

87th

Lynch and Robertson (2004)

Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study

2004

Accident and Emergency Nursing (Continue as International Emergency Nursing)

51

Article

0.703

4.6

UK

 

90th

Ferner et al. (2011)

Management of paracetamol poisoning

2011

British Medical Journal

50

Review

17.445

12.5

UK

 

90th

Mahadevan et al. (2006)

Paracetamol induced hepatotoxicity

2006

Archives of Disease in Childhood

50

Review

2.899

5.6

UK

 

90th

Gyamlani and Parikh (2002)

Acetaminophen toxicity: suicidal versus accidental

2002

Critical Care

50

Article

4.476

3.8

USA

 

90th

Underhill et al. (1990)

A comparison of the efficacy of gastric lavage, ipecacuanha and activated charcoal in the emergency management of paracetamol overdose

1990

Archives of Emergency Medicine (Continue as Emergency Medicine Journal)

50

Article

1.843

2.0

UK

 

94th

Waring et al. (2008c)

Lower incidence of anaphylactoid reactions to N-acetylcysteine in patients with high acetaminophen concentrations after overdose

2008

Clinical Toxicology

49

Article

3.673

7.0

UK

 

94th

Whyte et al. (2000)

Acetaminophen causes an increased international normalized ratio by reducing functional factor VII

2000

Therapeutic Drug Monitoring

49

Article

2.376

3.3

Australia

 

94th

Anderson et al. (1999)

Predicting concentrations in children presenting with acetaminophen overdose

1999

Journal of Pediatrics

49

Article

3.790

3.1

New Zealand

 

97th

Rumack (1986)

Acetaminophen overdose in children and adolescents

1986

Pediatric Clinics of North America

48

Article

2.120

1.7

USA

 

98th

Marzullo (2005)

An update of N-acetylcysteine treatment for acute acetaminophen toxicity in children

2005

Current Opinion in Pediatrics

47

Review

2.528

4.7

USA

 

99th

Sivilotti et al. (2005)

A risk quantification instrument for acute acetaminophen overdose patients treated with n-acetylcysteine

2005

Annals of Emergency Medicine

44

Article

4.676

4.6

Canada

USA

99th

Schiodt et al. (2002)

Influence of acute and chronic alcohol intake on the clinical course and outcome in acetaminophen overdose

2002

Alimentary Pharmacology and Therapeutics

44

Article

5.727

3.5

Denmark

USA

99th

Pakravan et al. (2008)

Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose

2008

Clinical Toxicology

44

Article

3.673

6.3

UK

 

Equal articles have the same ranking number, and then a gap is left in the ranking numbers

SCR standard competition ranking

aThe impact factor was reported according to the Institute for Scientific Information (ISI) journal citation reports (JCR) 2014

Average number of citations per year

Average number of citations per year for the top 100 cited articles ranged from 1.5 to 42.6 with a mean of 8.5 citations per year and a median of 5.9 (interquartile range 3.75–10.35). Table 2 ranks the top 10 publications based on the highest average number of citations per year. Nine of the articles in the list were published after year 2000. The top three articles based on average number of citations per year were the followings: “Acetaminophen-induced hepatotoxicity” with 42.6 average number of citations per year, “Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital” with 42.0 average number of citations per year and “The chemistry and biological activities of N-acetylcysteine” with 38.6 average number of citations per year. Interestingly, the total number of citations was significantly correlated with citation index (r = 0.485, p < 0.001).
Table 2

Ranking the top 10 articles in paracetamol poisoning treatment based on average citations per year

SCR

Authors

Title

Year

Source title

Cited by

Document type

IFa

Citation index

Country of corresponding author

Collaboration country

1st

James et al. (2003)

Acetaminophen-induced hepatotoxicity

2003

Drug Metabolism and Disposition

511

Review

3.252

42.6

USA

 

2nd

Antoine et al. (2013)

Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital

2013

Hepatology

84

Article

11.055

42.0

UK

Switzerland

3rd

Samuni et al. (2013)

The chemistry and biological activities of N-acetylcysteine

2013

Biochimica et BiophysicaActa - General Subjects

76

Review

4.381

38.0

Australia

Israel

4th

Lee et al. (2009)

Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure

2009

Gastroenterology

180

Article

16.716

30.0

USA

 

5th

Atkuri et al. (2007)

N-acetylcysteine—a safe antidote for cysteine/glutathione deficiency

2007

Current Opinion in Pharmacology

211

Review

4.595

26.4

USA

 

6th

Lee (2004)

Acetaminophen and the US acute liver failure study group: lowering the risks of hepatic failure

2004

Hepatology

250

Review

11.055

22.7

USA

 

7th

Smilkstein et al. (1988)

Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the National Multicenter Study (1976–1985)

1988

New England Journal of Medicine

553

Article

55.873

20.5

USA

 

8th

Chun et al. (2009)

Acetaminophen hepatotoxicity and acute liver failure

2009

Journal of Clinical Gastroenterology

121

Review

3.498

20.2

USA

 

9th

Larson (2007)

Acetaminophen hepatotoxicity

2007

Clinics in Liver Disease

158

Review

3.660

19.8

USA

 

10th

Dodd et al. (2008)

N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility

2008

Expert Opinion on Biological Therapy

133

Review

3.743

19.0

Australia

 

SCR standard competition ranking

aThe impact factor was reported according to the Institute for Scientific Information (ISI) journal citation reports (JCR) 2014

Authorship

The total number of authors for the top 100 cited articles was 419, for an average of 4.15 authors per paper. Authors per paper ranged from 1 to 23, and 20 articles were written by one author. Table 3 ranks the top 10 most prolific authors, who have published at least four publications among the 100 most cited publications.
Table 3

The top 10 ranking of prolific authors who published most frequently cited publications, with their affiliations

SCR

Author

No. of publications

Affiliation

1st

Prescott, L.

10

University of Edinburgh, Edinburgh, Scotland, UK

1st

Williams, R.

10

Foundation for Liver Research, Institute of Hepatology, London, UK

3rd

Rumack, B. H.

9

Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA

4th

Wendon, J.

6

Institute of Liver Studies at King’s College School of Medicine at King’s College Hospital, London, UK

5th

Bateman, D. N.

5

University of Edinburgh, Edinburgh, UK

5th

Buckley, N.

5

Department of Pharmacology, School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia

5th

Dawson, A.

5

NSW Poisons Information Center, Westmead Children’s Hospital Sydney, Australia

5th

Lee, W. M.

5

Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center at Dallas, 5959 Harry Hines Boulevard, Suite 420, Dallas, TX 75390-8887, USA

9th

Alexander, G.J.M.

4

Institute of Liver Studies, King’s College School of Medicine and Dentistry, London, UK

9th

Harrison, P.M.

4

Institute of Liver Studies, King’s College Hospital, Denmark Hill, London, UK

9th

Whyte, I.M.

4

Calvary Mater Newcastle, Newcastle, NSW, Australia

SCR standard competition ranking

Journals

A total of 55 journals published these top 100 cited articles. Nine documents were published in Clinical Toxicology, whereas eight documents were published in Annals of Emergency Medicine and five documents each were published in British Journal of Clinical Pharmacology, Hepatology and British Medical Journal. The impact factor for journals containing the top 100 cited paracetamol poisoning treatment articles ranged from 0.703 to 55.873. Twenty-eight documents were published in the ten journals with an IF >10. Only three journals for the top 100 cited articles were without IF. A significant, modest positive correlation was found between the journal impact factor and the number of citations among the top 100 cited articles (r = 0.426; p < 0.001).

Origins and publication type

In relation to the origin of the research publications for the highly cited articles, they were from eight countries. The USA had the largest number of articles with 47 articles. The UK and Australia published 38 and nine articles respectively, whereas Denmark, Switzerland, Canada, New Zealand and Israel published four, four, three, two and two articles respectively. In the terms of “collaboration with other countries”, we found that eight articles were published and co-authored by researchers from multiple countries. Sixty-six articles were original articles, 32 articles were review articles and three were other types of publications, including conference papers, editorials and notes.

Discussion

The present study was designed to rank and characterize the top 100 cited publications in the field of paracetamol poisoning treatment. The most obvious finding to emerge from this study is that results of this study may explain how developments in this area of clinical toxicology have progressed over time. It becomes obvious which key publications and authors have made exceptional contributions that have played an integral role in shaping the guidelines related to the treatment of paracetamol. Furthermore, the results of this study enhance our understanding about the leading publications that have contributed to the development of this field of toxicology.

Common treatment guidelines for paracetamol poisoning that are currently in use include Australian and New Zealand guideline by Daly et al. (2008), USA guideline by Dart et al. (2006) and UK guideline by Wallace et al. (2002). These guidelines ranked 33rd, 55th and 77th respectively. Furthermore, these common guidelines were based on several articles in the top 100 cited publications such as Smilkstein et al. (1988), Prescott et al. (1979), Keays et al. (1991), Prescott et al. (1977), Rumack (2002), and Smilkstein et al. (1991).

The top 100 cited studies in our study were published from 1974 to 2013 with a citation range of 44–553 times since publication. Compared to citations in other medical fields, this occupies a low position; in tuberculosis, the number of citations for top-cited studies ranged from 366 to 4443 (Chen et al. 2015), compared to 582–7248 for hypertension (Oh and Galis 2014). The difference in the total number of citations in each area reveals the number of researchers working in each area (Chen et al. 2015). It is also well known that editors for the main journals with high IFs consider articles with a high citation rate to sustain the IF progress of their journals (Zyoud et al. 2014a, b, 2015a, b, d). Furthermore, since the toxicology field is considered as a very narrow field with a very small readership and number of researchers, it should not be surprising for toxicology topics or toxicology journals to have a small numbers of citations (Bird 2008; Zyoud et al. 2014b). Our results confirm that there was a modest relationship between the number of years elapsed since the time of publication and the number of citations. These results support previous findings which reported that older articles attained more citations because their citable period was longer (Loonen et al. 2008; Lefaivre et al. 2011; Aminian et al. 2014; Joyce et al. 2014; Lee et al. 2015). The annual total number of citations for any article fluctuates with time and for some articles the total annual number of citations might decrease with time while for other articles, the total annual number of citations might increase or remain steady with time. In our study, the low correlation between the total citations and citation index seems to be related to papers that have many citations when they are first published but then drop off in later years because researchers might be tended to preferentially cite the most recent studies (Azer and Azer 2016). Our study showed that the average number of citations per year for articles published after year 2000 was higher than those published before 2000. This finding may be due to the tendency of authors to cite recent papers which is a common practice among authors (Van Noorden et al. 2014).

The most influential article in paracetamol poisoning treatment was conducted by Smilkstein and experts from the USA (Smilkstein et al. 1988) and was published in 1988 in New England Journal of Medicine. This article described the final outcomes of 2540 patients with paracetamol overdose treated with a loading dose of 140 mg per kg of oral NAC followed by 70 mg per kg given every 4 h for an additional 17 doses. It was concluded that NAC treatment should be started within 8 h of an paracetamol overdose (Smilkstein et al. 1988). In contrast to earlier findings, recently, in the last decade, described novel NAC infusion regimens offer different rates of intravenous NAC administration in both the loading and maintenance doses, and this is associated with a lower rate of the occurrence of adverse effects (Pakravan et al. 2008; Waring et al. 2008c). These studies were in the list of influential papers in the top 100 cited articles.

The first paper for paracetamol poisoning treatment was cited only 25 times and was published by Maclean et al. (1968) in 1968 in The Lancet. This article recommended immediate gastric lavage, intravenous hydrocortisone, forced diuresis and antihistamine for paracetamol poisoning treatment. This article achieved a low rate of citation to be listed in the top 100 cited publications in the field of paracetamol poisoning treatment because it was based on treatment regimens, which limited recommendations for the treatment of such cases. The two pioneering publications in the field of general paracetamol poisoning were conducted by Mitchell et al. (1973a, b). They explained the mechanism of paracetamol hepatotoxicity, were published in Journal of Pharmacology and Experimental Therapeutics and are considered as remarkable papers in paracetamol poisoning (Rumack and Bateman 2012). These two publications achieved higher citations in the field of general paracetamol poisoning than in the field of paracetamol poisoning treatment, 1052 and 904 citations each respectively (data not shown), but did not appear in our list because they involved animal research. What is surprising is that this group was in our list and got an advanced position (i.e. the seventh most frequently cited paper) by providing a rationale for therapy in humans by indicating that cysteamine could prevent hepatotoxicity (Mitchell et al. 1974). Prescott et al. (1974) reported the successful treatment of patients with severe paracetamol overdose with cysteamine, but this article was not among the top 100 cited articles. This might be due to the adverse effects in patients making it a less than ideal antidote and of low interest to researchers. Surprisingly, Prescott et al. (1979) were found to be in the list of the top 100 cited articles for a different article, which achieved the third position in the list. They reported that intravenous NAC was more effective in the treatment of paracetamol poisoning than cysteamine and methionine and was markedly free from adverse effects (Prescott et al. 1979). Furthermore, it is somewhat surprising that Prescott and his colleagues in Edinburgh published a series of influential papers in the top 100 cited articles (Prescott et al. 1976, 1977, 1989; Prescott 1983, 2000, 2005; Prescott and Critchley 1983).

One of the pioneering article in the field of general paracetamol poisoning was written by Rumack and Matthew (1975). This article is considered as one of the highly cited articles in the field of general paracetamol poisoning, rather than in the field of paracetamol poisoning treatment. It achieved 303 citations (data not shown) but did not appear in our list. Contrary to expectations, several studies (Schiodt et al. 1997; Larson et al. 2005) were dropped from the list of the top 100 cited articles in the field of paracetamol poisoning treatment because these studies did not mention paracetamol poisoning related treatment terms in their titles or abstract. The most obvious finding to emerge from our study is that Rumack published a series of influential papers in the top 100 cited articles (Rumack and Peterson 1978; Rumack et al. 1981; Rumack 1984, 1986, 2002).

In the present study, 28 documents were published in the ten journals with an IF >10, including New England Journal of Medicine, The Lancet, Annual Review of Pharmacology and Toxicology, Annals of Internal Medicine, British Medical Journal, Archives of Internal Medicine, Gastroenterology, Gut, Annual Review of Medicine and Hepatology. Our results confirm the modes relationship between the journal impact factor and the number of citations among the top 100 cited articles. These results seem to be consistent with other research, which found that the most cited articles in the field of tuberculosis are often published in journals that top the impact factor list (Chen et al. 2015). The results of our study show that more than half of the publications originated from the USA, followed by the UK. These results match those observed in earlier studies (Loonen et al. 2008; Joyce et al. 2014; Oh and Galis 2014; Chen et al. 2015; Dolan et al. 2015). Research activity in these countries is most likely due to their economic strength (Li et al. 2013; Yun et al. 2015), or numerous large poison centers (Forrester 2016), or the number of researchers or general research activity in this scientific field (Zyoud et al. 2015a, d), or number of poisoning incidents in these countries (Bateman 2014; Mowry et al. 2015).

There are several limitations of this study. First, our analysis to choose publications with a primary focus on paracetamol poisoning treatment research likely excluded articles that had otherwise notably influenced thinking in the field, including some of the highly cited articles that refer to investigations of paracetamol poisoning in animals or in vitro. Second, it was based on the Scopus database alone; Scopus does not index all journals, and we may have missed journals that figure in other databases such as Google Scholar. Third, articles published in recent years had less of a chance to be among the top 100 cited articles because less time has elapsed since the date of publication to allow citation. Another limitation is that some publications did not mention paracetamol poisoning related treatment terms in their titles or abstract, so it is possible that not all publications about paracetamol were considered. The present study design means that we are unable to include some clinicians that have influenced the treatment of paracetamol poisoning through other means, including unpublished research work, presentations at scientific meetings, and pioneering clinical practice. For example, many influential toxicologists, such as Matthew H., Jaeschke H., Piperno E. and Khairallah E.A. (Rumack 2002; Proudfoot and Prescott 2009; Rumack and Bateman 2012), were not identified in our study.

In conclusion, we carried out a bibliometric analysis of the most cited publications focused on paracetamol poisoning research, revealing a number of characteristics related to these influential publications, including the country of origin, type of study, journal and authorship. This study is the first bibliometric assessment of the top 100 cited articles in toxicology literature. The most influential report in paracetamol poisoning treatment research appears to be conducted by Smilkstein et al. from the USA and was published by in 1988 in New England Journal of Medicine. Interest in paracetamol poisoning as a serious clinical problem continues to grow. Research published in high-impact journals and from high income countries is most likely to be cited in published paracetamol research.

Abbreviations

NAC: 

N-acetylcysteine

SPSS: 

Statistical Package for Social Sciences

ISI: 

Institute for Scientific Information

JCR: 

Journal Citation Reports

IFs: 

impact factors

SCR: 

standard competition ranking

Declarations

Authors’ contributions

SZ led the study design, data collection, statistical analysis, and drafting of the manuscript, SA, WS and RA participated in the study design, and revised the article for important intellectual content, and WW wrote part of the article and revised the article for important intellectual content. All authors read and approved the final manuscript.

Competing interests

The author declares that they have no competing interests.

Ethics approval and consent to participate

As a bibliometric study, as there were no patients involved in this type of analysis, there was no need for Institutional Review Board approval and it was exempted based upon the design of this study.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors’ Affiliations

(1)
Poison Control and Drug Information Center (PCDIC), College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine
(2)
Department of Clinical and Community Pharmacy, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine
(3)
WHO Collaborating Centre for Drug Information, National Poison Centre, Universiti Sains Malaysia (USM), 11800 Pulau Pinang, Penang, Malaysia
(4)
Acute Medical Unit, York Teaching Hospitals NHS Foundation Trust, Wigginton Road, York, YO31 8HE, UK
(5)
Department of Pharmacology and Toxicology, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine

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