Randomised controlled trial of tetanus treatment with antitetanus immunoglobulin by the intrathecal or intramuscular route
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《英国医生杂志》
1 Department of Clinical Medicine, Faculty of Medical Sciences, University of Pernambuco, Santo Amaro, 50100.130, Recife, Pernambuco, Brazil, 2 Institute of Tropical Medicine Faculty of Medicine, University of S?o Paulo, 05.403-000, S?o Paulo, SP, Brazil, 3 Oswaldo Cruz University Hospital, University of Pernambuco
Correspondence to: D B Miranda-Filho, Rua Cosme Bezerra, 85/107, Iputinga, 50.670.310, Recife, Pernambuco, Brazil demofilho@uol.com.br
Abstract
Tetanus is a universal public health problem, with around one million cases a year and a mortality between 6% and 60%.1 Over the past 30 years only nine randomised controlled trials have studied the prevention and treatment of tetanus.2 Recent advances in treating tetanus are ascribed to the more frequent and effective use of aggressive treatments that utilise tracheotomy, artificial paralysis, and artificial respiration.2-4
Treating tetanus by neutralising the toxin is still controversial, especially dosage and route of administration.5-15 A meta-analysis of intrathecal therapy was inconclusive in adults.16 We evaluated the effect of such therapy on clinical progression of and mortality from tetanus.
Methods
From July 1997 to July 2001 we recruited 120 patients; 58 were allocated to the treatment group and 62 to the control group (figure). Potential confounders were similarly distributed between the groups (table 1).
Trial profile
Table 1 Baseline characteristics of patients treated for tetanus by the intramuscular route (control group) or intrathecal route
Three patients refused to participate. They were treated in accordance with normal routine and were eventually discharged from hospital. In two patients it proved technically difficult to achieve suboccipital or lumbar puncture; they received treatment by the intramuscular route only, but for analyses they were considered in the intrathecal group. We excluded one patient randomised to each group owing to misclassification of diagnosis: one had herpes virus meningitis and the other muscular rigidity due to metoclopramide.
The treatment group showed better clinical progression than the control group (2 for trend 7.82, P = 0.0052; table 2). Most of the participants were classified with either grade I or II disease. Up to 10 days after admission most patients in the treatment group had grade I or II disease and most patients in the control group had grade III or IV disease (table 3).
Table 2 Clinical progression of patients treated for tetanus by the intramuscular route (control group) or intrathecal route
Table 3 Severity of tetanus within 10 days of admission. Values are numbers (percentages) of patients
We excluded 23 patients on the basis of spasms: 17 had none during hospital stay, five died during the period that spasms occurred, and in one the record of daily spasms was mislaid. The study group had shorter duration of occurrence of spasms (2 for trend 14.96, P = 0.0001; table 4). Among the 106 patients who survived, duration of hospital stay varied from 2 to 80 days. The treatment group had a shorter duration of hospital stay (4.56, 0.03; table 4); a smaller proportion had complications during this time, although the difference was not significant (P = 0.071; table 5).
Table 4 Duration of occurrence of spasms and hospital stay and need for respiratory assistance in patients treated for tetanus by the intramuscular route (control group) or intrathecal route
Table 5 Complications and mortality in patients treated for tetanus by the intramuscular route (control group) or intrathecal route
Respiratory infection was the most common complication. It occurred less frequently in the treatment group, although the difference was not significant (P = 0.073; table 5). The relative risk of patients developing respiratory failure that required artificial respiration was smaller in the treatment group than in the control group, but the difference was not significant (P = 0.094; table 5). However, the difference in the duration of respiratory assistance among 50 patients in both groups (six died during respiratory assistance) was significant (2 for trend 6.56, P = 0.01; see table 4).
The relative risk of death was smaller among patients in the treatment group, although the difference was not significant (P = 0.2). The wide confidence interval (0.78 to 7.05) suggests that the sample size was too small to detect a difference of this magnitude (table 5).
In general, all results showed improvement among patients in the treatment group. Differences were not significant for mortality and complications only.
Five patients had mild headache during the intrathecal procedure. In only one did this continue after the flow rate of the drug was reduced and the procedure finished; the headache stopped after 500 mg dipirona was given intravenously. We observed no meningeal irritation or meningitis among patients given intrathecal therapy. Among the 106 patients who were discharged, 64 returned to the outpatient clinic for a check up, in accordance with the study protocol. Of these, 37 belonged to the treatment group; they had no side effects.
Fourteen patients died during the study. The cause of death was not determined in seven, four died from septicaemia or septic shock, one died in an anoxic coma after prolonged cardiorespiratory arrest, one died from respiratory infection, and one died from acute respiratory failure. Half of these patients died within 10 days of admission. The others died between days 16 and 89. No particular pattern was observed for deaths.
Discussion
Bleck TP. Clostridium tetani (tetanus). In: Mandell GL, Bennett JE, Dolin R, eds. Man-dell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia: Churchill Livingstone, 2000: 2537-43.
Thwaites CL, Farrar JJ. Preventing and treating tetanus. The challenge continues in the face of neglect and lack of research. BMJ 2003;326: 117-8.
Edmondson RS, Flowers MW. Intensive care in tetanus: management, complications and mortality in 100 cases. BMJ 1979;1: 1401-4.
Harding-Goldson HE, Hanna WJ. Tetanus: a recurring intensive care problem. J Trop Med Hyg 1995;98: 179-84.
Sanders RKM, Martyn B, Joseph R, Peacock ML. Intrathecal antitetanus serum (horse) in the treatment of tetanus. Lancet 1977;1: 974-7.
Vakil BJ, Armitage P, Clifford RE, Laurence DR. Therapeutic trial of intracisternal human tetanus immunoglobulin in clinical tetanus. Trans R Soc Trop Med Hyg 1979;73: 579-83.
Gupta PS, Goyal S, Kapoor R, Batra VK, Jain BK. Intrathecal human tetanus immunoglobulin in early tetanus. Lancet 1980;2: 439-40.
Keswani NK, Singh AK, Upadhyana KD. Intrathecal tetanus anti-toxin in moderate and severe tetanus. J Indian Med Assoc 1980;75: 67-9.
Rossano C, Giugliano F. Prime esperienze e risultati terapeutici con immunoglobuline umane antitetaniche per via subaracnoidea. Minerva Anestesiol 1970;36: 725-7.
Ildirim I. Intrathecal treatment of tetanus with antitetanus serum and prednisolone mixture. In: International Conference on Tetanus, S?o Paulo. Pan American Health Organisation - Scient public 1972;253: 119-26.
Veronesi R, Bizzini B, Hutzler RU, Focaccia R, Mazza CC, Feldman C, et al. Eficácia do tratamento do tétano com antitoxina tetanica por via raquideana e/ou venosa. Estudo de 101 casos, com pesquisa sobre a permanência da gamaglobulina humana - F(ab)2 no1íqüor e no sangue. Revista brasileira Clínica e Terapêutica 1980;9: 301-19.
Sun KO, Chan YW, Cheung RTF, So PC, Yu YL, Li PCK. Management of tetanus: a review of 18 cases. J R Soc Med 1994;87: 135-7.
Gallais, H. Intérêt de l'administration intrathécale de sérum antitétanique et de cortico?des pour le treatment du tétanos déclaré. La Nouvelle Presse médicale 1977;6: 571.
List WF. The immediate treatment of tetanus with high doses of human tetanus antitoxin. Notfallmedizin 1981;7: 731-3.
Thomas PP, Crowell EB, Mathew M. Intrathecal anti-tetanus serum (ATS) and parenteral betamethasone in treatment of tetanus. Trans R Soc Trop Med Hyg 1982;76: 620-3.
Abrutyn E, Berlin JA. Intrathecal therapy in tetanus, a meta-analysis. JAMA 1991;266: 2262-7.
Friedman LM, Furberg CD, Demets DL. Fundamentals of clinical trials, 3rd ed. St Louis, MI: Mosby, 1996.
Miranda Filho DB, Ximenes RAA, Bernardino SN, Escari?o AG. Caracteriza??o epidemiológica do tétano no estado de Pernambuco no período de 1981 a 1995. Resumos do IX Congresso Brasileiro de Infectologia; 1996; Aug 25-9; Recife. Sociedade Brasileira de Infectologia.
Miranda Filho D, Ximenes R, Barone A, Vaz V, Vieira. Classifica??o clínica de pacientes com tétano para monitoramento da resposta a medidas terapêuticas. Braz J Infect Dis 2003;7(suppl 1): S18.
Armitage P, Clifford R. Prognosis in tetanus: use of data from therapeutic trial. J Infect Dis 1978;138: 1-8.
Miranda Filho DB, Ximenes RAA, Bernardino SN, Escari?o AG. Identification of risk factors for death from tetanus in Pernambuco, Brazil. A case control study. Rev Inst Med Trop Sao Paulo 2000;42: 333-9.
Agarwal M, Thomas K, Peter JV, Jeyaseelan L, Cherian AM. A randomised double-blind sham controlled study of intrathecal human anti-tetanus immunoglobulin in the management of tetanus. Natl Med J India 1998;11: 209-12.
Barone AA, Raineri HC, Ferreira JM. Tétano: aspectos epidemiológicos, clínicos e terapêuticos. Análise de 461 casos. Rev Hosp Clin Fac Med Sao Paulo 1976;31: 215-25.
Udwadia FE, Lall A, Udwadia ZF, Sekhar M, Vora A. Tetanus and its complications: intensive care and management experience in 150 Indian patients. Epidemiol Infect 1987;99: 675-84.(Demócrito de Barros Miran)
Correspondence to: D B Miranda-Filho, Rua Cosme Bezerra, 85/107, Iputinga, 50.670.310, Recife, Pernambuco, Brazil demofilho@uol.com.br
Abstract
Tetanus is a universal public health problem, with around one million cases a year and a mortality between 6% and 60%.1 Over the past 30 years only nine randomised controlled trials have studied the prevention and treatment of tetanus.2 Recent advances in treating tetanus are ascribed to the more frequent and effective use of aggressive treatments that utilise tracheotomy, artificial paralysis, and artificial respiration.2-4
Treating tetanus by neutralising the toxin is still controversial, especially dosage and route of administration.5-15 A meta-analysis of intrathecal therapy was inconclusive in adults.16 We evaluated the effect of such therapy on clinical progression of and mortality from tetanus.
Methods
From July 1997 to July 2001 we recruited 120 patients; 58 were allocated to the treatment group and 62 to the control group (figure). Potential confounders were similarly distributed between the groups (table 1).
Trial profile
Table 1 Baseline characteristics of patients treated for tetanus by the intramuscular route (control group) or intrathecal route
Three patients refused to participate. They were treated in accordance with normal routine and were eventually discharged from hospital. In two patients it proved technically difficult to achieve suboccipital or lumbar puncture; they received treatment by the intramuscular route only, but for analyses they were considered in the intrathecal group. We excluded one patient randomised to each group owing to misclassification of diagnosis: one had herpes virus meningitis and the other muscular rigidity due to metoclopramide.
The treatment group showed better clinical progression than the control group (2 for trend 7.82, P = 0.0052; table 2). Most of the participants were classified with either grade I or II disease. Up to 10 days after admission most patients in the treatment group had grade I or II disease and most patients in the control group had grade III or IV disease (table 3).
Table 2 Clinical progression of patients treated for tetanus by the intramuscular route (control group) or intrathecal route
Table 3 Severity of tetanus within 10 days of admission. Values are numbers (percentages) of patients
We excluded 23 patients on the basis of spasms: 17 had none during hospital stay, five died during the period that spasms occurred, and in one the record of daily spasms was mislaid. The study group had shorter duration of occurrence of spasms (2 for trend 14.96, P = 0.0001; table 4). Among the 106 patients who survived, duration of hospital stay varied from 2 to 80 days. The treatment group had a shorter duration of hospital stay (4.56, 0.03; table 4); a smaller proportion had complications during this time, although the difference was not significant (P = 0.071; table 5).
Table 4 Duration of occurrence of spasms and hospital stay and need for respiratory assistance in patients treated for tetanus by the intramuscular route (control group) or intrathecal route
Table 5 Complications and mortality in patients treated for tetanus by the intramuscular route (control group) or intrathecal route
Respiratory infection was the most common complication. It occurred less frequently in the treatment group, although the difference was not significant (P = 0.073; table 5). The relative risk of patients developing respiratory failure that required artificial respiration was smaller in the treatment group than in the control group, but the difference was not significant (P = 0.094; table 5). However, the difference in the duration of respiratory assistance among 50 patients in both groups (six died during respiratory assistance) was significant (2 for trend 6.56, P = 0.01; see table 4).
The relative risk of death was smaller among patients in the treatment group, although the difference was not significant (P = 0.2). The wide confidence interval (0.78 to 7.05) suggests that the sample size was too small to detect a difference of this magnitude (table 5).
In general, all results showed improvement among patients in the treatment group. Differences were not significant for mortality and complications only.
Five patients had mild headache during the intrathecal procedure. In only one did this continue after the flow rate of the drug was reduced and the procedure finished; the headache stopped after 500 mg dipirona was given intravenously. We observed no meningeal irritation or meningitis among patients given intrathecal therapy. Among the 106 patients who were discharged, 64 returned to the outpatient clinic for a check up, in accordance with the study protocol. Of these, 37 belonged to the treatment group; they had no side effects.
Fourteen patients died during the study. The cause of death was not determined in seven, four died from septicaemia or septic shock, one died in an anoxic coma after prolonged cardiorespiratory arrest, one died from respiratory infection, and one died from acute respiratory failure. Half of these patients died within 10 days of admission. The others died between days 16 and 89. No particular pattern was observed for deaths.
Discussion
Bleck TP. Clostridium tetani (tetanus). In: Mandell GL, Bennett JE, Dolin R, eds. Man-dell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia: Churchill Livingstone, 2000: 2537-43.
Thwaites CL, Farrar JJ. Preventing and treating tetanus. The challenge continues in the face of neglect and lack of research. BMJ 2003;326: 117-8.
Edmondson RS, Flowers MW. Intensive care in tetanus: management, complications and mortality in 100 cases. BMJ 1979;1: 1401-4.
Harding-Goldson HE, Hanna WJ. Tetanus: a recurring intensive care problem. J Trop Med Hyg 1995;98: 179-84.
Sanders RKM, Martyn B, Joseph R, Peacock ML. Intrathecal antitetanus serum (horse) in the treatment of tetanus. Lancet 1977;1: 974-7.
Vakil BJ, Armitage P, Clifford RE, Laurence DR. Therapeutic trial of intracisternal human tetanus immunoglobulin in clinical tetanus. Trans R Soc Trop Med Hyg 1979;73: 579-83.
Gupta PS, Goyal S, Kapoor R, Batra VK, Jain BK. Intrathecal human tetanus immunoglobulin in early tetanus. Lancet 1980;2: 439-40.
Keswani NK, Singh AK, Upadhyana KD. Intrathecal tetanus anti-toxin in moderate and severe tetanus. J Indian Med Assoc 1980;75: 67-9.
Rossano C, Giugliano F. Prime esperienze e risultati terapeutici con immunoglobuline umane antitetaniche per via subaracnoidea. Minerva Anestesiol 1970;36: 725-7.
Ildirim I. Intrathecal treatment of tetanus with antitetanus serum and prednisolone mixture. In: International Conference on Tetanus, S?o Paulo. Pan American Health Organisation - Scient public 1972;253: 119-26.
Veronesi R, Bizzini B, Hutzler RU, Focaccia R, Mazza CC, Feldman C, et al. Eficácia do tratamento do tétano com antitoxina tetanica por via raquideana e/ou venosa. Estudo de 101 casos, com pesquisa sobre a permanência da gamaglobulina humana - F(ab)2 no1íqüor e no sangue. Revista brasileira Clínica e Terapêutica 1980;9: 301-19.
Sun KO, Chan YW, Cheung RTF, So PC, Yu YL, Li PCK. Management of tetanus: a review of 18 cases. J R Soc Med 1994;87: 135-7.
Gallais, H. Intérêt de l'administration intrathécale de sérum antitétanique et de cortico?des pour le treatment du tétanos déclaré. La Nouvelle Presse médicale 1977;6: 571.
List WF. The immediate treatment of tetanus with high doses of human tetanus antitoxin. Notfallmedizin 1981;7: 731-3.
Thomas PP, Crowell EB, Mathew M. Intrathecal anti-tetanus serum (ATS) and parenteral betamethasone in treatment of tetanus. Trans R Soc Trop Med Hyg 1982;76: 620-3.
Abrutyn E, Berlin JA. Intrathecal therapy in tetanus, a meta-analysis. JAMA 1991;266: 2262-7.
Friedman LM, Furberg CD, Demets DL. Fundamentals of clinical trials, 3rd ed. St Louis, MI: Mosby, 1996.
Miranda Filho DB, Ximenes RAA, Bernardino SN, Escari?o AG. Caracteriza??o epidemiológica do tétano no estado de Pernambuco no período de 1981 a 1995. Resumos do IX Congresso Brasileiro de Infectologia; 1996; Aug 25-9; Recife. Sociedade Brasileira de Infectologia.
Miranda Filho D, Ximenes R, Barone A, Vaz V, Vieira. Classifica??o clínica de pacientes com tétano para monitoramento da resposta a medidas terapêuticas. Braz J Infect Dis 2003;7(suppl 1): S18.
Armitage P, Clifford R. Prognosis in tetanus: use of data from therapeutic trial. J Infect Dis 1978;138: 1-8.
Miranda Filho DB, Ximenes RAA, Bernardino SN, Escari?o AG. Identification of risk factors for death from tetanus in Pernambuco, Brazil. A case control study. Rev Inst Med Trop Sao Paulo 2000;42: 333-9.
Agarwal M, Thomas K, Peter JV, Jeyaseelan L, Cherian AM. A randomised double-blind sham controlled study of intrathecal human anti-tetanus immunoglobulin in the management of tetanus. Natl Med J India 1998;11: 209-12.
Barone AA, Raineri HC, Ferreira JM. Tétano: aspectos epidemiológicos, clínicos e terapêuticos. Análise de 461 casos. Rev Hosp Clin Fac Med Sao Paulo 1976;31: 215-25.
Udwadia FE, Lall A, Udwadia ZF, Sekhar M, Vora A. Tetanus and its complications: intensive care and management experience in 150 Indian patients. Epidemiol Infect 1987;99: 675-84.(Demócrito de Barros Miran)