650 Correspondence Although there is little doubt that the response of young infants to bronchodilators is less good than that of older children, I think that in the acute stage a substantial number of them do benefit and it is worth a trial.
Intrathecal ATS and high dosage diazepam in neonatal tetanus
Sir, We should like to make a few comments about the report Konig, P. (1978). Treatment of severe attacks of asthma in by Khoo et al. (Archives, 1978, 53, 737). Seven of the 19 children with nebulised B2 adrenergic agents. Annals of neonates studied required total paralysis with IPPV for Allergy, 40, 185-188. uncontrolled spasms, 2 died, and 5 more might have died Radford, M. (1975). Effect of salbutamol in infants with but for total paralysis and IPPV. Therefore, it is not wheezy bronchitis. Archives of Disease in Childhood, 50, justified to say that improved survival was due to admini535-538. Rutter, M., Milner, A. D., and Hiller, E. J. (1975). Effect of stration of high doses of diazepam alone. Recently we initiated a study on the efficacy of a bronchodilators on respiratory resistance in infants and young children with bronchiolitis and wheezy bronchitis. regimen consisting of intrathecal administration of antitetanus serum (ATS), and high doses of diazepam (15-30 Archives of Disease in Childhood, 50, 719-722. mg/kg per day) and chlorpromazine (15-30 mg/kg per PETER K6NIG day) intravenously. Between July and October 1978, we studied 10 neonates University of Missouri-Columbia, School of Medicine, (Table). Diagnosis was on clinical grounds, and severity Department of Child Health, was graded using the criteria of Patel and Joag (1959). 7th Floor North, Immediately after admission an IV line was established Columbia, and diazepam administered at the rate of 1 mg/kg per Missouri 65211, minute until the infant was free of spasm and rigidity. USA This was followed by administration of ATS, 250 IU intrathecally, and 1500 IU IV. Penicillin and gentamicin Dr Milner and co-workers comment: (5 mg/kg per day) vere given. Infants were nursed in the We were interested to hear of Dr Konig's experience paediatric ward. The umbilical cord was cleaned with with nebulised salbutamol in children under one year. We spirit, and painted with gentian violet routinely. Pharynaccept that all our studies were carried out during the geal suction was done at regular intervals. recovery phase but we have not found that any child Subsequent muscle relaxation was achieved by alterunder one year has obtained any useful, clinical benefit nate IV administration of 2.5-7.5 mg diazepam and from nebulised salbutamol when administered in the chlorpromazine, each at 2-4 hourly intervals (total daily acute phase. Since our paper was published, two children dose of each drug 15-30 mg/kg). Once spasms had been between the ages of 12 and 18 months have responded controlled, a nasogastric tube was inserted for feeding well, and we have since heard of another who apparently and giving diazepam and chlorpromazine. Sedation was obtained benefit by age 11 months. We still recommend gradually tapered off at a rate of 10-15 % of total dose that salbutamol be given to all wheezing children over administered at intervals of 1-2 days, depending on the one year but think it unlikely that many children younger degree of hypertonia. None of the infants was given that this will respond to this form of treatment. IPPV with total paralysis. Eight neonates recovered completely and 2 died, one A. D. MILNER of fulminant bronchopneumonia and the other with University of Nottingham, aspirant pneumonia. The average duration in hospital for Department of Child Health, the survivors was 20 days, and the average period for IV Medical School, diazepam and chlorpromazine 3.4 days. We observed Queen's Medical Centre, that the shorter the interval between the onset of the Nottingham NG7 2UH tetanus neonatorum and the intrathecal ATS, the quicker References
Table The 10 neonates* studied Case
1 2 3 4 5
6 7 8 9 10
Gestational weight (kg) 2-8 2.6 2-7 3.0 2.0 36 weeks 2.4 2.1 2*8 3-0 2.7
Instrument for cord cutting
Grade
(days) 6 6 5 9 5
Blade Blade Razor Scissors Scissors
7 6 7 7 6
Kitchen knife Blade
Age at onset
*All were term except for Cases 5 and 6.
Spasm
Duration of
controlled (hours)
sedation (days)
V V V IV V
48 48 9 days 24 Not controlled
20 7 25 12 -
-
V V V V V
36 Not controlled 72 48 120
9 19 10 30
20 it 40
Hospital (days)
Outcome
30 13 25 12
Recovered Recovered
10 -
Recovered Recovered Died 50 hours after being admitted Recovered Died Recovered Recovered Recovered
Correspondence 651 was the control of spasm and the shorter the duration in hospital. Besides thrombophlebitis at the site of venepunctures (probably secondary to benzoic acid present in injectable diazepam) a common complication was apnoea, which responded to partial withdrawal of diazepam. At 3-4 months all 6 neonates who returned for follow-up were developmentally normal. We feel a combination of high doses of diazepam and chlorpromazine with intrathecal ATS (given early after onset of tetanus) is effective in reducing mortality. Reference
Patel, J. C., and Joag, C. G. (1959). Grading of tetanus to evaluate prognosis. Indian Journal of Medical Sciences, 13, 834-840.
SUNIT SINGHI AND PRATIBHA SINGHI Department of Paediatrics, JLN Medical College, Ajmer (Rajasthan) 305001, India Dr Khoo and co-workers comment: We did not claim that the low mortality rate in our patients with neonatal tetanus was due to high dose diazepam alone. Other equally important therapeutic measures that contributed to the improved survival rate in our patients included good nursing care, tetanus antitoxins, antibiotics, nutritional support, and the judicious use of sedatives. In our study, the use of continuous high dose IV diazepam (20-40 mg/kg per day) certainly decreased the mortality rate and also the need for artificial ventilation from 77 to 37% (Khoo et al.,
1978). The treatment regimen advocated by Singhi and Singhi is very similar to ours except for the use of intrathecal ATS and the very high dose of chlorpromazine. The role of intrathecal ATS in the management of neonatal tetanus is still controversial (Laurence, 1975). The reason for injecting ATS into the CSF is to neutralise the tetanus toxin that has penetrated the CNS but has not yet begun to act. Besides, ATS given via the IV route penetrates the blood/CNS barrier poorly, and the levels of antitoxin in the CSF are approximately 400 times less than in the blood (Patel et al., 1963; Ildirim et al., 1969). In 1917, Sherrington obtained good results from the use of intrathecal ATS in monkeys with tetanus. It was subsequently tried in man but eventually abandoned because of adverse reactions to the CNS and doubts about its efficacy (Dietrich, 1940; Pratt, 1945). However,
recent reports of the use of intrathecal ATS in tetanus are encouraging (Ildirim, 1970; Sanders et al., 1977; Salimpour, 1978). Ildirim (1970) treated 28 cases of neonatal tetanus with intrathecal ATS and prednisolone mixture and had a low mortality rate of 10 7 %. In another clinical trial on 322 cases of adult-type tetanus, 200 units intrathecal ATS (horse) was found to be an effective adjuvant in reducing the mortality rate from 14.5 to 4.5 % (Sanders et al., 1977). No complication was encountered apart from occasional difficulty in giving ATS intrathecally, while remarkable relaxation was observed in the patients. With the availability of human antitetanus serum, which is relatively free of allergic side effects and less irritating to the CNS, the prospects for intrathecal ATS (human) is promising, but needs further tests before it can be recommended. -
References Dietrich, H. F. (1940). Tetanus in childhood with special
reference to treatment. American Journal of Diseases of Children, 59, 693-710. Ildirim, I. (1970). Intrathecal treatment of tetanus with antitetanus serum and prednisolone mixture. Third International Conference on Tetanus. Pan American Health Organisation, 253, 119-127. Ildirim, I., Meira, A. R., and Furcolow, M. L. (1969). Letter: Tetanus. New England Journal of Medicine, 280, 1243. Khoo, B. H., Lee, E. L., and Lam, K. L. (1978). Neonatal tetanus treated with high dose diazepam. Archives of Disease in Childhood, 53, 737-739. Laurence, D. R. (1975). Therapeutic measures in tetanus. Progress in Drug Research, 19, 323-328. Patel, J. C., Metha, B. C., Nanavati, B. H., Hazra, A. K., Rao, S. S., and Swaminathan, C. S. (1963). Role of serum therapy in tetanus. Lancet, 1, 740-743. Pratt, E. L. (1945). Clinical tetanus: study of fifty-six cases, with special reference to methods of prevention and a plan for evaluating treatment. Journal of the American Medical Association, 129, 1243-1247. Salimpour, R. (1978). Tetanus of the newborn in Tehran. A ten year study of 880 cases. Journal of Tropical Pediatrics and Environmental Child Health, 24, 140-142. Sanders, R. K. M., Martyn, B., Joseph, R., and Peacock, M. L. (1977). Intrathecal antitetanus serum (horse) in the treatment of tetanus. Lancet, 1, 974-977. Sherrington, C. S. (1917). Observations with antitetanus serum in monkeys. Lancet, 2, 964-996. B. H. KHoo, E. L. LEE, AND K. L. LAM
Department of Paediatrics, University Hospital, Kuala Lumpur, Malaysia
Intrathecal ATS and high dosage diazepam in neonatal tetanus
Sir, We should like to make a few comments about the report Konig, P. (1978). Treatment of severe attacks of asthma in by Khoo et al. (Archives, 1978, 53, 737). Seven of the 19 children with nebulised B2 adrenergic agents. Annals of neonates studied required total paralysis with IPPV for Allergy, 40, 185-188. uncontrolled spasms, 2 died, and 5 more might have died Radford, M. (1975). Effect of salbutamol in infants with but for total paralysis and IPPV. Therefore, it is not wheezy bronchitis. Archives of Disease in Childhood, 50, justified to say that improved survival was due to admini535-538. Rutter, M., Milner, A. D., and Hiller, E. J. (1975). Effect of stration of high doses of diazepam alone. Recently we initiated a study on the efficacy of a bronchodilators on respiratory resistance in infants and young children with bronchiolitis and wheezy bronchitis. regimen consisting of intrathecal administration of antitetanus serum (ATS), and high doses of diazepam (15-30 Archives of Disease in Childhood, 50, 719-722. mg/kg per day) and chlorpromazine (15-30 mg/kg per PETER K6NIG day) intravenously. Between July and October 1978, we studied 10 neonates University of Missouri-Columbia, School of Medicine, (Table). Diagnosis was on clinical grounds, and severity Department of Child Health, was graded using the criteria of Patel and Joag (1959). 7th Floor North, Immediately after admission an IV line was established Columbia, and diazepam administered at the rate of 1 mg/kg per Missouri 65211, minute until the infant was free of spasm and rigidity. USA This was followed by administration of ATS, 250 IU intrathecally, and 1500 IU IV. Penicillin and gentamicin Dr Milner and co-workers comment: (5 mg/kg per day) vere given. Infants were nursed in the We were interested to hear of Dr Konig's experience paediatric ward. The umbilical cord was cleaned with with nebulised salbutamol in children under one year. We spirit, and painted with gentian violet routinely. Pharynaccept that all our studies were carried out during the geal suction was done at regular intervals. recovery phase but we have not found that any child Subsequent muscle relaxation was achieved by alterunder one year has obtained any useful, clinical benefit nate IV administration of 2.5-7.5 mg diazepam and from nebulised salbutamol when administered in the chlorpromazine, each at 2-4 hourly intervals (total daily acute phase. Since our paper was published, two children dose of each drug 15-30 mg/kg). Once spasms had been between the ages of 12 and 18 months have responded controlled, a nasogastric tube was inserted for feeding well, and we have since heard of another who apparently and giving diazepam and chlorpromazine. Sedation was obtained benefit by age 11 months. We still recommend gradually tapered off at a rate of 10-15 % of total dose that salbutamol be given to all wheezing children over administered at intervals of 1-2 days, depending on the one year but think it unlikely that many children younger degree of hypertonia. None of the infants was given that this will respond to this form of treatment. IPPV with total paralysis. Eight neonates recovered completely and 2 died, one A. D. MILNER of fulminant bronchopneumonia and the other with University of Nottingham, aspirant pneumonia. The average duration in hospital for Department of Child Health, the survivors was 20 days, and the average period for IV Medical School, diazepam and chlorpromazine 3.4 days. We observed Queen's Medical Centre, that the shorter the interval between the onset of the Nottingham NG7 2UH tetanus neonatorum and the intrathecal ATS, the quicker References
Table The 10 neonates* studied Case
1 2 3 4 5
6 7 8 9 10
Gestational weight (kg) 2-8 2.6 2-7 3.0 2.0 36 weeks 2.4 2.1 2*8 3-0 2.7
Instrument for cord cutting
Grade
(days) 6 6 5 9 5
Blade Blade Razor Scissors Scissors
7 6 7 7 6
Kitchen knife Blade
Age at onset
*All were term except for Cases 5 and 6.
Spasm
Duration of
controlled (hours)
sedation (days)
V V V IV V
48 48 9 days 24 Not controlled
20 7 25 12 -
-
V V V V V
36 Not controlled 72 48 120
9 19 10 30
20 it 40
Hospital (days)
Outcome
30 13 25 12
Recovered Recovered
10 -
Recovered Recovered Died 50 hours after being admitted Recovered Died Recovered Recovered Recovered
Correspondence 651 was the control of spasm and the shorter the duration in hospital. Besides thrombophlebitis at the site of venepunctures (probably secondary to benzoic acid present in injectable diazepam) a common complication was apnoea, which responded to partial withdrawal of diazepam. At 3-4 months all 6 neonates who returned for follow-up were developmentally normal. We feel a combination of high doses of diazepam and chlorpromazine with intrathecal ATS (given early after onset of tetanus) is effective in reducing mortality. Reference
Patel, J. C., and Joag, C. G. (1959). Grading of tetanus to evaluate prognosis. Indian Journal of Medical Sciences, 13, 834-840.
SUNIT SINGHI AND PRATIBHA SINGHI Department of Paediatrics, JLN Medical College, Ajmer (Rajasthan) 305001, India Dr Khoo and co-workers comment: We did not claim that the low mortality rate in our patients with neonatal tetanus was due to high dose diazepam alone. Other equally important therapeutic measures that contributed to the improved survival rate in our patients included good nursing care, tetanus antitoxins, antibiotics, nutritional support, and the judicious use of sedatives. In our study, the use of continuous high dose IV diazepam (20-40 mg/kg per day) certainly decreased the mortality rate and also the need for artificial ventilation from 77 to 37% (Khoo et al.,
1978). The treatment regimen advocated by Singhi and Singhi is very similar to ours except for the use of intrathecal ATS and the very high dose of chlorpromazine. The role of intrathecal ATS in the management of neonatal tetanus is still controversial (Laurence, 1975). The reason for injecting ATS into the CSF is to neutralise the tetanus toxin that has penetrated the CNS but has not yet begun to act. Besides, ATS given via the IV route penetrates the blood/CNS barrier poorly, and the levels of antitoxin in the CSF are approximately 400 times less than in the blood (Patel et al., 1963; Ildirim et al., 1969). In 1917, Sherrington obtained good results from the use of intrathecal ATS in monkeys with tetanus. It was subsequently tried in man but eventually abandoned because of adverse reactions to the CNS and doubts about its efficacy (Dietrich, 1940; Pratt, 1945). However,
recent reports of the use of intrathecal ATS in tetanus are encouraging (Ildirim, 1970; Sanders et al., 1977; Salimpour, 1978). Ildirim (1970) treated 28 cases of neonatal tetanus with intrathecal ATS and prednisolone mixture and had a low mortality rate of 10 7 %. In another clinical trial on 322 cases of adult-type tetanus, 200 units intrathecal ATS (horse) was found to be an effective adjuvant in reducing the mortality rate from 14.5 to 4.5 % (Sanders et al., 1977). No complication was encountered apart from occasional difficulty in giving ATS intrathecally, while remarkable relaxation was observed in the patients. With the availability of human antitetanus serum, which is relatively free of allergic side effects and less irritating to the CNS, the prospects for intrathecal ATS (human) is promising, but needs further tests before it can be recommended. -
References Dietrich, H. F. (1940). Tetanus in childhood with special
reference to treatment. American Journal of Diseases of Children, 59, 693-710. Ildirim, I. (1970). Intrathecal treatment of tetanus with antitetanus serum and prednisolone mixture. Third International Conference on Tetanus. Pan American Health Organisation, 253, 119-127. Ildirim, I., Meira, A. R., and Furcolow, M. L. (1969). Letter: Tetanus. New England Journal of Medicine, 280, 1243. Khoo, B. H., Lee, E. L., and Lam, K. L. (1978). Neonatal tetanus treated with high dose diazepam. Archives of Disease in Childhood, 53, 737-739. Laurence, D. R. (1975). Therapeutic measures in tetanus. Progress in Drug Research, 19, 323-328. Patel, J. C., Metha, B. C., Nanavati, B. H., Hazra, A. K., Rao, S. S., and Swaminathan, C. S. (1963). Role of serum therapy in tetanus. Lancet, 1, 740-743. Pratt, E. L. (1945). Clinical tetanus: study of fifty-six cases, with special reference to methods of prevention and a plan for evaluating treatment. Journal of the American Medical Association, 129, 1243-1247. Salimpour, R. (1978). Tetanus of the newborn in Tehran. A ten year study of 880 cases. Journal of Tropical Pediatrics and Environmental Child Health, 24, 140-142. Sanders, R. K. M., Martyn, B., Joseph, R., and Peacock, M. L. (1977). Intrathecal antitetanus serum (horse) in the treatment of tetanus. Lancet, 1, 974-977. Sherrington, C. S. (1917). Observations with antitetanus serum in monkeys. Lancet, 2, 964-996. B. H. KHoo, E. L. LEE, AND K. L. LAM
Department of Paediatrics, University Hospital, Kuala Lumpur, Malaysia
