Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial

D Nicholas Bateman, James W Dear, H K Ruben Thanacoody, Simon H L Thomas, Michael Eddleston, Euan A Sandilands, Judy Coyle, Jamie G Cooper, Aryelly Rodriguez, Isabella Butcher, Steff C Lewis, A D Bastiaan Vliegenthart, Aravindan Veiraiah, David J Webb, Alasdair Gray

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Abstract

BACKGROUND: Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both.

METHODS: We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270).

FINDINGS: Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13-0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12-0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20-1·83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111; 3·30, 1·01-10·72; p=0·024).

INTERPRETATION: In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen.

FUNDING: Chief Scientist Office of the Scottish Government.

Original languageEnglish
Pages (from-to)697-704
Number of pages8
JournalThe Lancet
Volume383
Issue number9918
DOIs
Publication statusPublished - 22 Feb 2014

Fingerprint

Acetylcysteine
Acetaminophen
Poisoning
Randomized Controlled Trials
Antiemetics
Ondansetron
Vomiting
Therapeutics
Odds Ratio
Random Allocation
Alanine Transaminase
Placebos
Intention to Treat Analysis
Internet
Appointments and Schedules
Glucose

Keywords

  • Acetaminophen
  • Acetylcysteine
  • Adult
  • Aged
  • Alanine Transaminase
  • Antiemetics
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • Great Britain
  • Humans
  • Infusions, Intravenous
  • Liver Failure, Acute
  • Male
  • Middle Aged
  • Nausea
  • Ondansetron
  • Poisoning
  • Treatment Outcome
  • Vomiting

Cite this

Bateman, D. N., Dear, J. W., Thanacoody, H. K. R., Thomas, S. H. L., Eddleston, M., Sandilands, E. A., ... Gray, A. (2014). Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. The Lancet, 383(9918), 697-704. https://doi.org/10.1016/S0140-6736(13)62062-0

Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning : a randomised controlled trial. / Bateman, D Nicholas; Dear, James W; Thanacoody, H K Ruben; Thomas, Simon H L; Eddleston, Michael; Sandilands, Euan A; Coyle, Judy; Cooper, Jamie G; Rodriguez, Aryelly; Butcher, Isabella; Lewis, Steff C; Vliegenthart, A D Bastiaan; Veiraiah, Aravindan; Webb, David J; Gray, Alasdair.

In: The Lancet, Vol. 383, No. 9918, 22.02.2014, p. 697-704.

Research output: Contribution to journalArticle

Bateman, DN, Dear, JW, Thanacoody, HKR, Thomas, SHL, Eddleston, M, Sandilands, EA, Coyle, J, Cooper, JG, Rodriguez, A, Butcher, I, Lewis, SC, Vliegenthart, ADB, Veiraiah, A, Webb, DJ & Gray, A 2014, 'Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial', The Lancet, vol. 383, no. 9918, pp. 697-704. https://doi.org/10.1016/S0140-6736(13)62062-0
Bateman, D Nicholas ; Dear, James W ; Thanacoody, H K Ruben ; Thomas, Simon H L ; Eddleston, Michael ; Sandilands, Euan A ; Coyle, Judy ; Cooper, Jamie G ; Rodriguez, Aryelly ; Butcher, Isabella ; Lewis, Steff C ; Vliegenthart, A D Bastiaan ; Veiraiah, Aravindan ; Webb, David J ; Gray, Alasdair. / Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning : a randomised controlled trial. In: The Lancet. 2014 ; Vol. 383, No. 9918. pp. 697-704.
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abstract = "BACKGROUND: Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both.METHODS: We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5{\%} dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50{\%} increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270).FINDINGS: Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5{\%} CI 0·13-0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5{\%} CI 0·12-0·43; p<0·0001). The proportion of patients with a 50{\%} increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens (adjusted odds ratio 0·60, 97·5{\%} CI 0·20-1·83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111; 3·30, 1·01-10·72; p=0·024).INTERPRETATION: In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen.FUNDING: Chief Scientist Office of the Scottish Government.",
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note = "Copyright {\circledC} 2014 Bateman et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved. The trial was funded by Chief Scientist Office, Scotland (award CZB/4/722).",
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T1 - Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning

T2 - a randomised controlled trial

AU - Bateman, D Nicholas

AU - Dear, James W

AU - Thanacoody, H K Ruben

AU - Thomas, Simon H L

AU - Eddleston, Michael

AU - Sandilands, Euan A

AU - Coyle, Judy

AU - Cooper, Jamie G

AU - Rodriguez, Aryelly

AU - Butcher, Isabella

AU - Lewis, Steff C

AU - Vliegenthart, A D Bastiaan

AU - Veiraiah, Aravindan

AU - Webb, David J

AU - Gray, Alasdair

N1 - Copyright © 2014 Bateman et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved. The trial was funded by Chief Scientist Office, Scotland (award CZB/4/722).

PY - 2014/2/22

Y1 - 2014/2/22

N2 - BACKGROUND: Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both.METHODS: We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270).FINDINGS: Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13-0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12-0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20-1·83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111; 3·30, 1·01-10·72; p=0·024).INTERPRETATION: In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen.FUNDING: Chief Scientist Office of the Scottish Government.

AB - BACKGROUND: Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both.METHODS: We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270).FINDINGS: Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13-0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12-0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20-1·83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111; 3·30, 1·01-10·72; p=0·024).INTERPRETATION: In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen.FUNDING: Chief Scientist Office of the Scottish Government.

KW - Acetaminophen

KW - Acetylcysteine

KW - Adult

KW - Aged

KW - Alanine Transaminase

KW - Antiemetics

KW - Double-Blind Method

KW - Drug Administration Schedule

KW - Drug Therapy, Combination

KW - Female

KW - Great Britain

KW - Humans

KW - Infusions, Intravenous

KW - Liver Failure, Acute

KW - Male

KW - Middle Aged

KW - Nausea

KW - Ondansetron

KW - Poisoning

KW - Treatment Outcome

KW - Vomiting

U2 - 10.1016/S0140-6736(13)62062-0

DO - 10.1016/S0140-6736(13)62062-0

M3 - Article

C2 - 24290406

VL - 383

SP - 697

EP - 704

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9918

ER -