Evaluation of diazepam alone and in combination with chlorpromazine or propranolol in the therapy of tetanus.
Severity of spasms contribute considerably to mortality in tetanus and need for a reliable and safe anticonvulsant still exists. Diazepam, chlorpromazine, paraldehyde and phenobarbitone have been used for controlling spasms either singly or in combination in severe cases. The combinations are made empirically with a hope to achieve synergistic therapeutic effect.,  , ,
Increased sympathetic overactivity has been observed in some patients with tetanus and this may complicate the outcome of the disease. It is claimed that adrenergic beta blockers may help to reduce mortality in such cases.,  The present study was undertaken to evaluate the usefulness of diazepam, chlorpromazine and beta adrenergic Mocker propranolol, used alone or in combination, in patients with tetanus.
A total of 92 cases of tetanus admitted to the tetanus ward of a general hospital, was studied. The age of the patients varied between 13 and 70 years. Seventyfive cases were males and 17 females.
On admission, they were examined clinically in detail and the data recorded in a proforma. After a sensitivity test, antitetanus serum 20,000 I.U. was injected intravenously in 50 ml of 5% glucose. All patients received procaine penicillin 600,000 units intramuscularly daily. Fluid and electrolyte therapy was regulated by noting the clinical condition, urine output and serum electrolyte values. Patients with evidence of respiratory distress and cyanosis were given oxygen and tracheostomy was performed only in a few cases as an emergency.
In addition to this standard regimen, patients also received anticonvulsant drugs. For this purpose, they were divided into 3 treatment groups in accordance with a randomization chart and allotted one of the drug regimes as follows:
Group A received diazepam alone. The dose of diazepam varied from 20-240 mg daily in 4-6 divided doses. The Drug was given orally wherever possible. In other cases it was given intravenously or intramuscularly every 4 to 6 hours.
Group B received chlorpromazine in doses from 75-150 mg daily intramuscularly in 3 divided doses in addition to diazepam as in Group A.
Group C received diazepam as in Group A and also propranolol in the dose ranging from 20-120 mg daily in four divided doses orally; in a few cases it was given intravenously.
The spasms were recorded as mild, moderate and severe according to preset criteria. Particular attention was given to the presence of sympathetic overactivity characterized clinically as tachycardia with a pulse rate of over 100 beats per minute, fluctuating blood pressure of more than 140/90 mm of Hg., excessive sweating and raised axillary temperature over 100°F.10 ECG was taken routinely on admission and at discharge; in some, it was repeated during the course of the disease when cardiac abnormality was suspected.
For the purpose of statistical comparison the severity of the disease was graded according to the criteria of Patel and Joag, except that the grades IV and V, were graded together as grade IV only as there were only a few cases in grade V. Statistical analysis was carried out by using the Chi-square test.
Distribution of cases in various groups is shown in [Table - 1]. The total mortality in this series of 92 patients was 24%. This did not differ significantly from the overall mortality in each group receiving different drug regimens. The highest mortality was observed in the grade IV cases in all the three groups. Statistical comparison of the mortality rates between the groups of serious cases in the 3 regimes showed no significant difference. Similarly mortality rates were similar even in the milder cases belonging to three different groups.
Among the 92 subjects studied, 29 showed some evidence of sympathetic overactivity. Of these, 10 received diazepam alone as an anticonvulsant, 8 had diazepam + chlorpromazine combination and the remaining 11 received diazepam + propranolol combination. The results are presented in [Table - 2]. In the diazepam group 50% of cases had grade IV tetanus, 2 belonged to grade II and only 1 belonged to grade I. In 4 out of the grade IV cases with sympathetic overactivity the pulse rate showed a rise ranging from 10 to 34 beats per minute after 48 hours of treatment. Only in one grade IV case the pulse rate showed, a drop of beats per minute. The overall mortality in this group was 50%.
In patients who received the diazepam + chlorpromazine combination, 8 subjects had evidence of sympathetic overactivity. Of these, 5 patients had grade IV severity tetanus and 3 had grade III severity tetanus. Out of the 5 grade IV cases, one case had a pulse rate of 116 per minute; this patient expired due to cardiorespiratory failure within 24 hours. In 3 other grade IV cases, the pulse went up by 40 to 70 beats per minute while in the remaining one grade IV case the pulse was 100, per minute and remained the same after 48 hours. Out of these 8 cases 3 died, the overall mortality being 37%.
In the diazepam + propranolol group sympathetic overactivity was evident in 11 subjects. Of these, 3 cases belonged to grade IV and 7 to grade III. Only one case was graded as II. In 3 cases of grade IV, the pulse rates on admission were 106, 104 and 100 per minute respectively and after 48 hours' treatment, the pulse rates remained similar in two and showed a rise of only 10-15 beats per minute in the third. From the remaining 7 cases, in 2 cases the pulse rate showed a drop while in 4 it remained unchanged following propranolol. Only in one case it showed a rise. The overall mortality in this group, however, was 44.5%. The statistical comparison of mortality between the groups with sympathetic overactivity receiving three different drug regimens showed no significant difference.
Usually the duration of hospitalisation is proportionate to the severity of the disease and recovery process, and may give some indication regarding the beneficial effects of therapy. The comparison of the data revealed no significant difference in the 3 groups in this respect.
An ideal anticonvulsant drug should be one that relieves muscle spasms without interfering with respiration and circulation and should induce prompt sedation without loss of consciousness and serious side effects. Since no anticonvulsant can be considered as ideal, various anticonvulsants have been tried singly or in combination in the treatment of tetanus.,  To evaluate any anticonvulsant regimen in tetanus one of the difficulties encountered is the marked variability of the disease from one patient to another and in the same patient from time to time. For example, in an otherwise, relatively mild case sudden onset of laryngeal spasm may cause death. In order to overcome this problem, tetanus has been graded in different groups of severity, according to the preset criteria., , ,  It was observed that the mortality rate increases with the severity of the disease. Therefore, evaluation of anticonvulsants becomes more meaningful if the data is analysed in relation to the grade of severity.
Earlier use of chlorpromazine in the treatment of tetanus was reported in 6 cases by Cole and Robertson. Initial studies with chlorpromazine alone or with other drugs have demonstrated that chlorpromazine is useful in the treatment of tetanus., , ,  However, these results are not confirmed by controlled trials., ,  Chlorpromazine, on its own does not seem to be an effective anticonvulsant. In fact, larger doses of chlorpromazine may facilitate spasms.
Presently, diazepam is considered an anticonvulsant of choice in the treatment of tetanus because of its wider margin of safety and less effect on vital centres as compared to other older drugs.,  Our results confirmed that diazepam used alone is a useful anticonvulsant in the treatment of tetanus. Since the mechanism of action of diazepam and chlorpromazine are different, addition of chlorpromazine to diazepam may improve the therapy in severe cases. However, in this study diazepam and chlorpromazine combination did not improve the mortality in various grades of tetanus as compared to the group that received diazepam alone. Since diazepam is a safer drug, there seems to be no justification for adding chlorpromazine to diazepam.
It is known that some patients with tetanus develop a syndrome characterised by labile hypertension, peripheral vasoconstriction, tachycardia, arrhythmias, sweating and pyrexia associated with an increased catecholamine excretion. This is probably due to the overactivity of the sympathetic nervous system probably brought on by the action of tetanus toxin on the brain stem. It is suggested that such increased sympathetic overactivity may contribute to the mortality in tetanus and treatment with adrenergic blockers could improve the survival rate. Propranolol, a beta adrenergic blocking agent in addition to its adrenergic blocking activity possesses anticonvulsant properties in mice. It was considered logical, therefore, to evaluate the combination of diazepam and propranolol in controlling the spasms.
In the present study, 29 cases showed evidence of some sympathetic overactivity. Of these, 10 received diazepam alone, 8 received diazepam + chlorpromazine combination and 11 received diazepam + propranolol combination. Although addition of propranolol did control the pulse rate, no significant difference in mortality was observed between the 3 groups when analysed according to severity of grade. The dose of propranolol ranged from 20-120 mg daily. It is possible that larger doses of propranolol may be useful. However, a caution was exercised in using propranolol because of its major actions on the heart.
Diazepam in addition to its potent anticonvulsant properties also possesses selective inhibitory action on central sympathetic stimulation. The drug has been shown to depress centrally elicited cardiovascular stimulation. It appears that addition of chlorpromazine or propranolol to diazepam is not likely to produce any additional benefit in the treatment of convulsions in tetanus.