Intrathecal tetanus immunoglobulins in the management of tetanus
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《美国医学杂志》
Department of Pediatrics, Medical College, Calicut, Kerala, India
Objective. To study the clinical profile, treatment and outcome of tetanus in children treated with intrathecal tetanus immunoglobulin. (TIG) Methods. Retrospective analysis of hospital records of tetaus cases admitted to the pediatric ICU during the five year period between 1999 to 2004 was done. Results. There were 66 cases of tetanus treated with intrathecal TIG. Children below 5 years formed 53% of cases and 47% were above 5 years. Totally unimmunized children constituted 82% of cases and 18% partially immunized children. The portal of entry was otogenic in 58% of cases and injury in30% of cases. The common complications observed included thrombophlebitis, aspiration pneumonia, laryngospasm and autonomic system involvement. There were no complications specific to intrathecal administration of TIG. The mortality due to tetanus was 9%. Discussion. Mortality and morbidity due to tetanus was less in the present study compared to other centers where TIG is given intramuscularly. Conclusion. Intrathecal TIG is effective in the treatment of mild and moderate tetanus. Randomized controlled clinical trials are needed to evaluate the efficacy of intrathecal TIG in the management of severe tetanus.
Keywords: Tetanus; Otogenic; Intrathecal TIG
Tetanus caused by the exotoxin of Clostridium tetani s a scourge among children in many less privileged populations of the world today.[1],[2] This is so in spite of the availability of a cheap and effective vaccine.
Treatment of tetanus consists of administration of tetanus immunoglobulin to neutralize the toxin, drugs to control spasms, antibiotics to eradicate the organism, treatment of complications and meticulous supportive care. Standard textbooks recommend TIG to be given as soon as possible intramuscularly. There is no consensus on the dose of intramuscular TIG. The dose recommended varies from 500IU to 6000 IU. Intrathecal administration of TIG is said to be ineffective or experimental.[3],[4]
A study conducted in our institution in 1982 compared the efficacy of intrathecal TIG with intravenous Anti Tetanus Serum (ATS) and intrathecal ATS. Mortality and morbidity was significantly lower in the intrathecal TIG group.[5] In accordance with the results of this study we have been using intrathecal TIG in the management of tetanus in children for the last two decades.
In this analysis we present the data on tetanus cases managed in our institution during the period of 5 years from 1st January 1999 to 31st December 2004. This is a retrospective analysis of hospital records of tetanus cases managed in the pediatric ICU of the Institute of Maternal and Child Health at Medical College, Calicut.
Materials and Methods
The study included all cases of tetanus admitted to the pediatric ICU during the study period. The admission policy at the department of pediatrics restricts admission to children below the age of 12 years. As a policy, neonatal cases are not admitted to the pediatric ICU and so neonatal tetanus was not included in this analysis. Diagnosis of tetanus was made based on clinical features. (Presence of trismus, risus sardonicus and / or provoked or unprovoked spasms). Details regarding immunization status, portal of entry, incubation period, period of onset, clinical features, treatment, complications and outcome were recorded in the case sheet.
All patients were managed as per protocol. On admission all patients received 250 IU TIG intrathecally after proper relaxation was achieved with intravenous diazepam. All children received crystalline penicillin 1 lakhs U/Kg/day, which was continued for 10 days. Intravenous diazepam, starting with 1 mg/kg/dose 2 hrly and adjusting the dose accordingly depending on the severity of spasms, was used for muscle relaxation. Chlorpromazine in the dose of 0.3 - 0.5 mg/kg/dose 6 hourly was given if spasms were not controlled with diazepam. Supportive therapy included IV fluids, oropharyngeal toilet and nursing care. Ryle's tube feeding was initiated once the spasms were controlled, usually within 48 to 72 hours.
Intravenous diazepam was replaced with oral diazepam in the same dose, once spasms were controlled. Children were discharged when they were free of spasms, able to take oral feeds, and able to walk independently. All children received one dose of tetanus toxoid before discharge from the hospital. The unimmunized or partially immunized siblings were also brought to the hospital and immunized before discharge. Follow up was done at 2 weeks and 4 weeks after discharge and after that as and when required.
Results
There were 92 patients admitted with tetanus during the study period. Of the 92 patients 66 children received 250 IU of TIG intrathecally. 26 children received varying doses of intramuscular TIG, in addition to intrathecal TIG. (This variation in the route and dose of TIG was due to differences in the policy regarding TIG, with some units preferring to give IM TIG in addition to intrathecal TIG). The 66 children who received intrathecal TIG alone were taken up for the final analysis.
There were 32 boys and 34 girls. The youngest was 1.5 yrs and the oldest 12 yrs old. 35 (53%) children were in the 0-5 year age group and 31(47%) were in the 6-12 year age group. Totally unimmunized children constituted 82 % (54) of cases and 11(18%) children were partially immunized. Tetanus occurred in a one year old boy who received 3 doses of DPT.
The portal of entry was otogenic in 38 (58%) cases, injury in 20 (30%) cases and unidentified in 8 children. A difference was noticed in the portal of entry between children in the 0-5 year age group and in the 6-12 year age group. In the 0-5 year age group the portal of entry was CSOM in 27 (77%) cases where as in the older children majority of cases (14; 45%) occurred following injury. This finding emphasizes the need for prompt treatment of ear infection in young children.
In the post injury cases incubation period was 1week or less in 13 (65%) cases and more than 1 week in 7 (35%) cases. Mean incubation period was 4.6 days with maximum 30 days and minimum 2 days. Mean period of onset was 2.1 days with minimum 1 day and maximum 7 days. Clostridium tetani could be isolated in 5 (8%) cases.
As per the modified Patel and Joag criteria[6],[7] 13 (20%) cases were mild, 47 (71%) cases were moderate and 6 (9%) cases were having severe tetanus. Fever at onset was present in 64% (24) of cases.
The common complications observed were thrombophlebitis (27; 41%), aspiration pneumonia (11; 17%), and laryngospasm (4; 6%). Autonomic system involvement in the form of tachycardia and hypertension were present in 8 (12%) children. There were no complications specific to intrathecal administration of TIG per se.
The mean hospital stay was 14 days with maximum 36 days and minimum 3 days. Intubation and mechanical ventilation (with resuscitation bag) was required in 6 (9%) children. Tracheostomy was not done in any of the cases.
Over all mortality due to tetanus in the post neonatal period in our institution was 12% (11) when children who received intramuscular TIG in addition to intrathecal TIG were also included for the analysis. Of the 66 children who were treated with intrathecal TIG alone, 60 (91%) children recovered fully and 6 (9%) children died. Among the children who died, five had severe tetanus and one child had moderate tetanus. Cause of death was uncontrollable spasms resulting in laryngospasm in 4 children and massive aspiration in two children. Among the 7 children who had severe degree of tetanus only one child could be saved.
Discussion
There is no consensus as yet on the route of administration or dosage of tetanus immunoglobulin. Although standard textbooks do not recommend intrathecal administration of TIG, there have been several reports favoring this route of administration of TIG in the management of tetanus.[8],[9],[10] The dose of intramuscular TIG recommended varies from 500 -6000 IU.[3],[4] The disadvantages of intramuscular TIG include high cost and the need for multiple injections due to large volume administered. The benefits of intrathecal TIG are economical advantage, and safety apart from efficacy.
Our institution has been treating tetanus for the last two decades with intrathecal TIG. Although we do not have a well-equipped ICU our results compare favorably with those from other centers in India and abroad with regard to morbidity and mortality. Another center in Kerala where patient parameters, treatment protocol and facilities were similar to ours, and the use of intrathecal TIG is practised reported similar findings (mortality 7.1%; average hospital stay 10 days and only 3 out of 41 required mechanical ventilation) with regard to mortality and morbidity as in our study.[8]
There are also reports from well-equipped hospitals in India using intramuscular TIG where the mortality, morbidity including need for assisted ventilation and hospital stay are not as good as ours [7], [11]. The primary difference, compared to our institution was in the route of administration of TIG. The toxin produced by Cl.tetani binds at the neuromuscular junction then gets transported to the alpha motor neuron by retrograde axonal transport. The toxin exit the motor neuron in the spinal cord and enters the adjacent inhibitory inter neurons where it prevents the release of the neurotransmitter GABA (3). Once the toxin has begun its axonal ascent, it cannot be arrested by systemic administration of TIG. Intrathecal TIG probably acts at this level.
Early tracheostomy, elective paralysis and mechanical ventilation are reported to reduce mortality and morbidity in tetanus.[7] In our experience mild and moderate tetanus cases improved very well without the need for tracheostomy or mechanical ventilation when TIG was used intrathecally. These procedures may be required in treating children with severe tetanus. In our series, cause of death was laryngospasm in five out of six cases and some of these children could have been saved and the mortality would have been less if we were able to provide timely ventilatory support. It is felt that non-availability of sophisticated equipment may not be a major disadvantage in the presence of meticulous nursing care in the ICU when intrathecal TIG is used in the treatment of mild and moderate tetanus.
Conclusion
The last word on the efficacy of intrathecal TIG has not been said. More randomized controlled clinical trials are needed to evaluate the efficacy of intrathecal TIG in the management of tetanus, especially in cases of severe tetanus. We feel that children with tetanus should not be denied the benefits of treatment with intrathecal TIG since it is safe, effective and economical.
Acknowledgement
The authors thank all the staff members of the Department of Pediatrics, Medical College Calicut, who were involved in the management of tetanus cases admitted to the PICU. We also thank Mr. Hakkim Sherif of the medical record library at the Institute of Maternal and Child Health, Calicut for helping in the collection of data.
References
1.Miranda-Filho Dde B, Ximenes RA, Barone AA, Vaz VL, Vieira AG, Albuquerque VM. Randomized controlled trial of tetanus treatment with antitetanus immunoglobulin by the intrathecal or intramuscular route. BMJ 2004; 328: 615 [PUBMED] [FULLTEXT]
2.Omoigberale AI, Abiodun PO. Upsurge in neonatal tetanus in Benin City, Nigeria. East Afr Med J 2005; 82: 98-102. [PUBMED]
3.Arnon SS. Tetanus (Clostridium tetani) In Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Text Book of Pediatrics, 17th Ed. Philadelpha, Saunders 2004; 951-953
4.Abrutyn E. Tetanus. In Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison's Principles of Internal Medicine. 15th Ed. New York; McGraw-Hill. 2001; 918-920.
5.Ramachandran N. A Comparative Study of Different Regimens in the Management of Tetanus with Special Reference to Intrathecal Serotherapy, Thesis for MD Pediatrics, University of Calicut, 1982.
6.Patel JC, Joag GG. Grading of tetanus to evaluate prognosis. Indian J Med Sci 1959; 13 : 834-840. [PUBMED]
7.Tullu MS, Deshmukh CT, Kamat JR. Experience of Pediatric Tetanus Cases from Mumbai. Indian Pediatr 2000; 37: 765-771. [PUBMED] [FULLTEXT]
8.Menon. J, Mathews L. Intrathecal Immunoglobulin in the treatment of Tetanus. Indian Pediatr 2000; 37: 765-771.
9.Agarwal M, Thomas K, peter JV, Jayaseelan L,cherian AM. A randomized double-blind sham-controlled study of intrathecal human anti-tetanus immunoglobulin in the management of tetanus. Natl Med J India 1998; 11: 209-212.
10.Gupta PS, Kapoor R, Goyal S, Batra VK, Jain BK. Intrathecal human tetanus immunoglobulin in early tetanus. Lancet 1980; 2: 439-440 [PUBMED]
11.Patel JC, Mehta BC. Tetanus: study of 8,697 cases. Indian J Med Sci 1999; 53: 393-401s [PUBMED](Geeta MG, Krishnakumar P, Mathews Lulu)
Objective. To study the clinical profile, treatment and outcome of tetanus in children treated with intrathecal tetanus immunoglobulin. (TIG) Methods. Retrospective analysis of hospital records of tetaus cases admitted to the pediatric ICU during the five year period between 1999 to 2004 was done. Results. There were 66 cases of tetanus treated with intrathecal TIG. Children below 5 years formed 53% of cases and 47% were above 5 years. Totally unimmunized children constituted 82% of cases and 18% partially immunized children. The portal of entry was otogenic in 58% of cases and injury in30% of cases. The common complications observed included thrombophlebitis, aspiration pneumonia, laryngospasm and autonomic system involvement. There were no complications specific to intrathecal administration of TIG. The mortality due to tetanus was 9%. Discussion. Mortality and morbidity due to tetanus was less in the present study compared to other centers where TIG is given intramuscularly. Conclusion. Intrathecal TIG is effective in the treatment of mild and moderate tetanus. Randomized controlled clinical trials are needed to evaluate the efficacy of intrathecal TIG in the management of severe tetanus.
Keywords: Tetanus; Otogenic; Intrathecal TIG
Tetanus caused by the exotoxin of Clostridium tetani s a scourge among children in many less privileged populations of the world today.[1],[2] This is so in spite of the availability of a cheap and effective vaccine.
Treatment of tetanus consists of administration of tetanus immunoglobulin to neutralize the toxin, drugs to control spasms, antibiotics to eradicate the organism, treatment of complications and meticulous supportive care. Standard textbooks recommend TIG to be given as soon as possible intramuscularly. There is no consensus on the dose of intramuscular TIG. The dose recommended varies from 500IU to 6000 IU. Intrathecal administration of TIG is said to be ineffective or experimental.[3],[4]
A study conducted in our institution in 1982 compared the efficacy of intrathecal TIG with intravenous Anti Tetanus Serum (ATS) and intrathecal ATS. Mortality and morbidity was significantly lower in the intrathecal TIG group.[5] In accordance with the results of this study we have been using intrathecal TIG in the management of tetanus in children for the last two decades.
In this analysis we present the data on tetanus cases managed in our institution during the period of 5 years from 1st January 1999 to 31st December 2004. This is a retrospective analysis of hospital records of tetanus cases managed in the pediatric ICU of the Institute of Maternal and Child Health at Medical College, Calicut.
Materials and Methods
The study included all cases of tetanus admitted to the pediatric ICU during the study period. The admission policy at the department of pediatrics restricts admission to children below the age of 12 years. As a policy, neonatal cases are not admitted to the pediatric ICU and so neonatal tetanus was not included in this analysis. Diagnosis of tetanus was made based on clinical features. (Presence of trismus, risus sardonicus and / or provoked or unprovoked spasms). Details regarding immunization status, portal of entry, incubation period, period of onset, clinical features, treatment, complications and outcome were recorded in the case sheet.
All patients were managed as per protocol. On admission all patients received 250 IU TIG intrathecally after proper relaxation was achieved with intravenous diazepam. All children received crystalline penicillin 1 lakhs U/Kg/day, which was continued for 10 days. Intravenous diazepam, starting with 1 mg/kg/dose 2 hrly and adjusting the dose accordingly depending on the severity of spasms, was used for muscle relaxation. Chlorpromazine in the dose of 0.3 - 0.5 mg/kg/dose 6 hourly was given if spasms were not controlled with diazepam. Supportive therapy included IV fluids, oropharyngeal toilet and nursing care. Ryle's tube feeding was initiated once the spasms were controlled, usually within 48 to 72 hours.
Intravenous diazepam was replaced with oral diazepam in the same dose, once spasms were controlled. Children were discharged when they were free of spasms, able to take oral feeds, and able to walk independently. All children received one dose of tetanus toxoid before discharge from the hospital. The unimmunized or partially immunized siblings were also brought to the hospital and immunized before discharge. Follow up was done at 2 weeks and 4 weeks after discharge and after that as and when required.
Results
There were 92 patients admitted with tetanus during the study period. Of the 92 patients 66 children received 250 IU of TIG intrathecally. 26 children received varying doses of intramuscular TIG, in addition to intrathecal TIG. (This variation in the route and dose of TIG was due to differences in the policy regarding TIG, with some units preferring to give IM TIG in addition to intrathecal TIG). The 66 children who received intrathecal TIG alone were taken up for the final analysis.
There were 32 boys and 34 girls. The youngest was 1.5 yrs and the oldest 12 yrs old. 35 (53%) children were in the 0-5 year age group and 31(47%) were in the 6-12 year age group. Totally unimmunized children constituted 82 % (54) of cases and 11(18%) children were partially immunized. Tetanus occurred in a one year old boy who received 3 doses of DPT.
The portal of entry was otogenic in 38 (58%) cases, injury in 20 (30%) cases and unidentified in 8 children. A difference was noticed in the portal of entry between children in the 0-5 year age group and in the 6-12 year age group. In the 0-5 year age group the portal of entry was CSOM in 27 (77%) cases where as in the older children majority of cases (14; 45%) occurred following injury. This finding emphasizes the need for prompt treatment of ear infection in young children.
In the post injury cases incubation period was 1week or less in 13 (65%) cases and more than 1 week in 7 (35%) cases. Mean incubation period was 4.6 days with maximum 30 days and minimum 2 days. Mean period of onset was 2.1 days with minimum 1 day and maximum 7 days. Clostridium tetani could be isolated in 5 (8%) cases.
As per the modified Patel and Joag criteria[6],[7] 13 (20%) cases were mild, 47 (71%) cases were moderate and 6 (9%) cases were having severe tetanus. Fever at onset was present in 64% (24) of cases.
The common complications observed were thrombophlebitis (27; 41%), aspiration pneumonia (11; 17%), and laryngospasm (4; 6%). Autonomic system involvement in the form of tachycardia and hypertension were present in 8 (12%) children. There were no complications specific to intrathecal administration of TIG per se.
The mean hospital stay was 14 days with maximum 36 days and minimum 3 days. Intubation and mechanical ventilation (with resuscitation bag) was required in 6 (9%) children. Tracheostomy was not done in any of the cases.
Over all mortality due to tetanus in the post neonatal period in our institution was 12% (11) when children who received intramuscular TIG in addition to intrathecal TIG were also included for the analysis. Of the 66 children who were treated with intrathecal TIG alone, 60 (91%) children recovered fully and 6 (9%) children died. Among the children who died, five had severe tetanus and one child had moderate tetanus. Cause of death was uncontrollable spasms resulting in laryngospasm in 4 children and massive aspiration in two children. Among the 7 children who had severe degree of tetanus only one child could be saved.
Discussion
There is no consensus as yet on the route of administration or dosage of tetanus immunoglobulin. Although standard textbooks do not recommend intrathecal administration of TIG, there have been several reports favoring this route of administration of TIG in the management of tetanus.[8],[9],[10] The dose of intramuscular TIG recommended varies from 500 -6000 IU.[3],[4] The disadvantages of intramuscular TIG include high cost and the need for multiple injections due to large volume administered. The benefits of intrathecal TIG are economical advantage, and safety apart from efficacy.
Our institution has been treating tetanus for the last two decades with intrathecal TIG. Although we do not have a well-equipped ICU our results compare favorably with those from other centers in India and abroad with regard to morbidity and mortality. Another center in Kerala where patient parameters, treatment protocol and facilities were similar to ours, and the use of intrathecal TIG is practised reported similar findings (mortality 7.1%; average hospital stay 10 days and only 3 out of 41 required mechanical ventilation) with regard to mortality and morbidity as in our study.[8]
There are also reports from well-equipped hospitals in India using intramuscular TIG where the mortality, morbidity including need for assisted ventilation and hospital stay are not as good as ours [7], [11]. The primary difference, compared to our institution was in the route of administration of TIG. The toxin produced by Cl.tetani binds at the neuromuscular junction then gets transported to the alpha motor neuron by retrograde axonal transport. The toxin exit the motor neuron in the spinal cord and enters the adjacent inhibitory inter neurons where it prevents the release of the neurotransmitter GABA (3). Once the toxin has begun its axonal ascent, it cannot be arrested by systemic administration of TIG. Intrathecal TIG probably acts at this level.
Early tracheostomy, elective paralysis and mechanical ventilation are reported to reduce mortality and morbidity in tetanus.[7] In our experience mild and moderate tetanus cases improved very well without the need for tracheostomy or mechanical ventilation when TIG was used intrathecally. These procedures may be required in treating children with severe tetanus. In our series, cause of death was laryngospasm in five out of six cases and some of these children could have been saved and the mortality would have been less if we were able to provide timely ventilatory support. It is felt that non-availability of sophisticated equipment may not be a major disadvantage in the presence of meticulous nursing care in the ICU when intrathecal TIG is used in the treatment of mild and moderate tetanus.
Conclusion
The last word on the efficacy of intrathecal TIG has not been said. More randomized controlled clinical trials are needed to evaluate the efficacy of intrathecal TIG in the management of tetanus, especially in cases of severe tetanus. We feel that children with tetanus should not be denied the benefits of treatment with intrathecal TIG since it is safe, effective and economical.
Acknowledgement
The authors thank all the staff members of the Department of Pediatrics, Medical College Calicut, who were involved in the management of tetanus cases admitted to the PICU. We also thank Mr. Hakkim Sherif of the medical record library at the Institute of Maternal and Child Health, Calicut for helping in the collection of data.
References
1.Miranda-Filho Dde B, Ximenes RA, Barone AA, Vaz VL, Vieira AG, Albuquerque VM. Randomized controlled trial of tetanus treatment with antitetanus immunoglobulin by the intrathecal or intramuscular route. BMJ 2004; 328: 615 [PUBMED] [FULLTEXT]
2.Omoigberale AI, Abiodun PO. Upsurge in neonatal tetanus in Benin City, Nigeria. East Afr Med J 2005; 82: 98-102. [PUBMED]
3.Arnon SS. Tetanus (Clostridium tetani) In Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Text Book of Pediatrics, 17th Ed. Philadelpha, Saunders 2004; 951-953
4.Abrutyn E. Tetanus. In Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison's Principles of Internal Medicine. 15th Ed. New York; McGraw-Hill. 2001; 918-920.
5.Ramachandran N. A Comparative Study of Different Regimens in the Management of Tetanus with Special Reference to Intrathecal Serotherapy, Thesis for MD Pediatrics, University of Calicut, 1982.
6.Patel JC, Joag GG. Grading of tetanus to evaluate prognosis. Indian J Med Sci 1959; 13 : 834-840. [PUBMED]
7.Tullu MS, Deshmukh CT, Kamat JR. Experience of Pediatric Tetanus Cases from Mumbai. Indian Pediatr 2000; 37: 765-771. [PUBMED] [FULLTEXT]
8.Menon. J, Mathews L. Intrathecal Immunoglobulin in the treatment of Tetanus. Indian Pediatr 2000; 37: 765-771.
9.Agarwal M, Thomas K, peter JV, Jayaseelan L,cherian AM. A randomized double-blind sham-controlled study of intrathecal human anti-tetanus immunoglobulin in the management of tetanus. Natl Med J India 1998; 11: 209-212.
10.Gupta PS, Kapoor R, Goyal S, Batra VK, Jain BK. Intrathecal human tetanus immunoglobulin in early tetanus. Lancet 1980; 2: 439-440 [PUBMED]
11.Patel JC, Mehta BC. Tetanus: study of 8,697 cases. Indian J Med Sci 1999; 53: 393-401s [PUBMED](Geeta MG, Krishnakumar P, Mathews Lulu)