Human versus equine intramuscular antitoxin, with or without human intrathecal antitoxin, for the treatment of adults with tetanus: a 2 × 2 factorial randomised controlled trial.
Abstract: Intramuscular antitoxin is recommended in tetanus treatment, but there are few data comparing human and equine preparations. Tetanus toxin acts within the CNS, where there is limited penetration of peripherally administered antitoxin; thus, intrathecal antitoxin administration might improve clinical outcomes compared with intramuscular injection. In a 2 × 2 factorial trial, all patients aged 16 years or older with a clinical diagnosis of generalised tetanus admitted to the intensive care unit of the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, were eligible for study entry. Participants were randomly assigned first to 3000 IU human or 21 000 U equine intramuscular antitoxin, then to either 500 IU intrathecal human antitoxin or sham procedure. Interventions were delivered by independent clinicians, with attending clinicians and study staff masked to treatment allocations. The primary outcome was requirement for mechanical ventilation. The analysis was done in the intention-to-treat population. The study is registered at ClinicalTrials.gov, NCT02999815; recruitment is completed. 272 adults were randomly assigned to interventions between Jan 8, 2017, and Sept 29, 2019, and followed up until May, 2020. In the intrathecal allocation, 136 individuals were randomly assigned to sham procedure and 136 to antitoxin; in the intramuscular allocation, 109 individuals were randomly assigned to equine antitoxin and 109 to human antitoxin. 54 patients received antitoxin at a previous hospital, excluding them from the intramuscular antitoxin groups. Mechanical ventilation was given to 56 (43%) of 130 patients allocated to intrathecal antitoxin and 65 (50%) of 131 allocated to sham procedure (relative risk [RR] 0·87, 95% CI 0·66-1·13; p=0·29). For the intramuscular allocation, 48 (45%) of 107 patients allocated to human antitoxin received mechanical ventilation compared with 48 (44%) of 108 patients allocated to equine antitoxin (RR 1·01, 95% CI 0·75-1·36, p=0·95). No clinically relevant difference in adverse events was reported. 22 (16%) of 136 individuals allocated to the intrathecal group and 22 (11%) of 136 allocated to the sham procedure experienced adverse events related or possibly related to the intervention. 16 (15%) of 108 individuals allocated to equine intramuscular antitoxin and 17 (16%) of 109 allocated to human antitoxin experienced adverse events related or possibly related to the intervention. There were no intervention-related deaths. We found no advantage of intramuscular human antitoxin over intramuscular equine antitoxin in tetanus treatment. Intrathecal antitoxin administration was safe, but did not provide overall benefit in addition to intramuscular antitoxin administration. The Wellcome Trust.
Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Publication Date: 2022-05-14 PubMed ID: 35561721PubMed Central: PMC9115864DOI: 10.1016/S2214-109X(22)00117-6Google Scholar: Lookup
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- Journal Article
- Randomized Controlled Trial
- Research Support
- Non-U.S. Gov't
Summary
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This research study investigated the effectiveness of two types of antitoxin (human and equine) and two methods of administration (intramuscular and intrathecal) for the treatment of tetanus in adults. The results showed no significant advantage of one type of antitoxin or administration method over the other.
Study Design
- The study was a 2×2 factorial randomised controlled trial conducted at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam.
- Participants aged 16 years or older with a clinical diagnosis of generalized tetanus were enrolled in the study.
- Participants were first randomly assigned to 3000 IU human or 21 000 IU equine intramuscular antitoxin, and then to either 500 IU intrathecal human antitoxin or a sham procedure.
- The treatment allocations were masked to the attending clinicians and study staff.
- The main outcome measured was the requirement for mechanical ventilation.
Results
- Between January 8, 2017, and September 29, 2019, 272 adults were randomly assigned to interventions and followed up until May 2020.
- In the intrathecal allocation, 43% of patients allocated to antitoxin and 50% of those given a sham procedure required mechanical ventilation. These results were not statistically significant.
- In the intramuscular allocation, 45% of patients given human antitoxin and 44% of those given equine antitoxin required mechanical ventilation. There was no statistically significant difference between these groups.
- Adverse events related to the antitoxin were experienced by 16% of individuals in the intrathecal group and 15% of those in the equine intramuscular group, and 16% in the human antitoxin group. Again, these differences were not statistically significant.
- No deaths resulted from the intervention.
Conclusions
- The study revealed no advantage of human antitoxin over equine antitoxin, or of intramuscular administration over intrathecal administration, in the treatment of adult tetanus.
- The authors concluded that intrathecal administration of antitoxin was safe, but did not provide an overall benefit in addition to intramuscular administration.
- The research was funded by The Wellcome Trust.
Cite This Article
APA
Van Hao N, Loan HT, Yen LM, Kestelyn E, Hong DD, Thuy DB, Nguyen NT, Duong HTH, Thuy TTD, Nhat PTH, Khanh PNQ, Dung NTP, Phu NH, Phong NT, Lieu PT, Tuyen PT, Hanh BTB, Nghia HDT, Oanh PKN, Tho PV, Tan Thanh T, Turner HC, van Doorn HR, Van Tan L, Wyncoll D, Day NP, Geskus RB, Thwaites GE, Van Vinh Chau N, Thwaites CL.
(2022).
Human versus equine intramuscular antitoxin, with or without human intrathecal antitoxin, for the treatment of adults with tetanus: a 2 × 2 factorial randomised controlled trial.
Lancet Glob Health, 10(6), e862-e872.
https://doi.org/10.1016/S2214-109X(22)00117-6 Publication
Researcher Affiliations
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- MRC Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College London, London, UK.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford, Oxford, UK.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Guy's and St Thomas' Hospitals NHS Trust, London, UK.
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford, Oxford, UK; Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford, Oxford, UK.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford, Oxford, UK.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
- Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford, Oxford, UK. Electronic address: lthwaites@oucru.org.
MeSH Terms
- Animals
- Antitoxins / therapeutic use
- Horses
- Humans
- Injections, Intramuscular
- Intensive Care Units
- Tetanus / drug therapy
- Treatment Outcome
Grant Funding
- Wellcome Trust
- 204904/Z/16/Z / Wellcome Trust
- 107367/Z/15/Z / Wellcome Trust
- MR/R015600/1 / Medical Research Council
Conflict of Interest Statement
Declaration of interests All authors declare no competing interests.
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Citations
This article has been cited 3 times.- Deniz M, Erat T. Generalized tetanus: a pediatric case report and literature review.. Rev Inst Med Trop Sao Paulo 2023;65:e40.
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