Experience of use of magnesium sulfate in the treatment of tetanus in a tertiary referral Infectious Disease Hospital, Kolkata, India

Background: Tetanus is still a public health problem in developing countries with high morbidity and mortality. Aims and Objectives: To evaluate the effects of magnesium sulfate in the treatment of moderate to very severe tetanus cases. Patients and Methods: Eighty-six patients suffering from of moderate to very severe tetanus, treated with injection magnesium sulphate in combination with injection diazepam were evaluated and compared to the tetanus patients from the hospital record (treated with only diazepam) regarding outcomes. Results: The average duration of reflex spasm was 12 vs. 8 days in moderate group, 18 vs. 15 days in severe group and 21 vs. 17 days in very severe group in the previous and study year respectively. Average duration of hospital stay was 20 vs. 17 days in moderate group, 27 vs. 22 days in severe group and 36 vs. 30 days in very severe group in the previous and study year respectively. It had been observed that in both severe and very severe tetanus cases, occurrence of autonomic instability, respiratory depression, aspiration pneumonia, cardiac arrhythmia and total death – all were decreased in the study period than previous year. Conclusion: Magnesium sulfate in combination with diazepam may be a better option in the treatment of tetanus particularly in developing countries with limited intensive care facility because of morbidity and mortality benefits.

Keywords: Autonomic insufficiency, magnesium sulfate, tetanus, outcomes

Tetanus is still a significant public health problem in many developing countries including India, despite the availability of a highly effective vaccine and mortality still remains higher among the neonates, pregnant women and elderly. In India high incidence of tetanus is probably due to inadequate vaccination coverage (including booster doses), high occupational exposure (injuries in farmers, industrial workers) and lack of proper wound care. Worldwide the annual death due to tetanus was estimated to be approximately 800,000 to 1000,000 cases with case fatality rate 20%-50%, but with the introduction of modern intensive care unit (ICU) management mortality had been reduced significantly (from 44% to 15%). ^[1],[2] Tetanus may be complicated by autonomic nervous system (ANS) instability and thought to be precipitated by a combination of high catecholamines due to the sympathetic nervous system overactivity and also due to direct effect of the tetanus toxin on the myocardium, whereas parasympathetic dysfunction is probably due to direct damage to the vagal nucleus by the tetanus toxin. ^[3],[4],[5] The features of autonomic insufficiency in tetanus may be – sinus tachycardia/bradycardia, excess/diminished sweating or oro-tracheal secretion, urinary retention, whereas serious ANS dysfunctions may be- hyperpyrexia, persistent hypertension, cardiac arrhythmias, and ”autonomic storms”(marked cardiovascular instability leading to sudden cardiac death) ^[6] Now a days magnesium sulfate is increasingly being utilized as part of multimodal therapy in the treatment of tetanus patients because of its multidisciplinary actions (besides its anti spasmodic property). This drug blocks pre-synaptic neuromuscular excitation, prevents the release of catecholamines from nerves and adrenal medulla, reduces the responsiveness of the receptors to already released catecholamines. ^[7],[8],[9] As per the WHO guidelines for the management of tetanus patients, magnesium sulphate may be used alone or in combination with benzodiazepines to control both spasm and ANS dysfunctions. ^[10] Besides low cost and ease of administration of this drug are really beneficial particularly in the developing countries with high case prevalence and limited ICU facility. In addition it would be cost-effective as there may be fewer requirements of ventilatory support and also other complications like deep venous thrombosis, barotraumas, respiratory infections. ^[8]

The objectives of this study were to evaluate the effects of magnesium sulfate in moderate, to very severe tetanus patients in respect to morbidity and mortality outcomes.

Eighty-six (n = 86) tetanus patients admitted in the Infectious Disease hospital, Kolkata, India from January 2011 to March 2012 were included in this study. The inclusion criteria were-moderate to very severe tetanus cases (Ablett’s clinical classification), age between 15 and 45 years and exclusion criteria were diabetes, hypertension, chronic airway pulmonary disease, pregnancy, preexisting heart diseases or neurological disorders. All these patients were treated with intravenous diazepam (maximum up to 50 mg/day) in combination with intravenous magnesium sulfate (WHO guidelines, January 2010). ^[10] Patients were monitored closely in respect to pulse, blood pressure, respiratory rate, reflex spasm, knee jerk, urine output, and features of autonomic insufficiency (sweating, excessive oro-tracheal secretion, persistent bradycardia/tachycardia or hypotension/hypertension, urinary retention, etc.). Blood biochemistry including electrocardiography in 12 leads, arterial blood gas analysis, chest x-ray, and wound swab/culture were done where indicated. From the hospital records of the previous years (January 2009 to March 2010), same number of tetanus cases (n=86) who were treated with only intravenous diazepam (maximum dose required up to 200 mg/day) as a sole muscle relaxant, were randomly selected as per the study criteria and compared with study group regarding the duration of reflex spasm, complications, duration of hospital stay and outcomes.

Among 86 tetanus patients of both the study group and previous year, 24 had moderate, 42 had severe and 20 had very severe forms of tetanus [Table 1]. In the moderate group the mean duration of spasm were about 12 days vs. 8 days whereas duration of hospital stays were about 20 days vs. 17 days in the previous year and study group respectively [Figure 1] and [Figure 2]. Autonomic insufficiency were found in 4 and 2 cases in previous year and study group respectively though serious autonomic insufficiency were not detected in either group [Figure 3]. Complete and partial recovery (with some rigidity) were observed in 14 patients and 5 patients in the previous year whereas these were 19 patients and 10 patients in the study group. In the severe group duration of spasm and hospital stay were about 18 days and 27 days in the previous year whereas these were 15 days and 22 days in the study group. Serious ANS involvement was observed in 4 cases and 3 cases in the previous year and the study group respectively. Respiratory depression and aspiration pneumonia were observed in 3 and 4 patient in previous year whereas these were one and two patients in the study group. Complete recovery and partial recovery were observed in 22 and 17 patients in previous year whereas these were 30 and 11 patients in the study group. In this severe group death occurred in 3 cases in previous year (2 patients died due to cardiac arrhythmia and one patient due to aspiration pneumonia) but only one patient died due to cardiac arrhythmia in the study group. In very severe cases the mean duration of spasm and duration of hospital stay were 21 and 36 days in previous year whereas these were 17 and 30 days in the study group. Serious ANS involvement occurred in 6 patients in previous year but 4 patients in study group. Respiratory depression and aspiration pneumonia occurred in 7 and 5 patient in previous year whereas these were one and two patients respectively in the study group. Complete and partial recovery were observed in 10 and 7 patients respectively in previous year whereas these were 5 and 9 patients in the study group. Death occurred in 6 patients in previous year (3 patient died due to cardiac arrhythmia and 3 patient due to aspiration pneumonia) whereas 3 patients died in the study group (2 patient due to cardiac arrhythmia and one due to aspiration pneumonia). Myocarditis though rare in tetanus, was observed in 2 patients in the previous year but detected in only one patient in the study group. Ten patients required ventilator support in the previous year whereas in current year only 5 patients required ventilator support.

In this study it had been observed that tetanus patients treated with intravenous magnesium sulfate in combination with diazepam had better outcomes in respect to both morbidity and mortality than those patients treated with only diazepam in the previous years. The average duration of reflex spasm, a major determinant of tetanus outcomes was 19 days vs. 14 days in previous years and the study year respectively and this was statistically significant (P = <0.001). Autonomic manifestations were observed in 24% vs. 10% but serious ANS involvement were noted 12% vs. 8% patients in previous years and the study year respectively and both these observations were also statistically significant (P = 0.028). Respiratory depression occurred in 12% vs. 2% cases in previous years and the study year respectively (P = 0.017) and this was due to less requirement of total dose of diazepam in the combination therapy with magnesium sulfate. Aspiration pneumonia, mainly occurred in severe and very severe group of tetanus patients in 10% cases in previous years but seen in only 5% cases in the study year though the reduction of this complication was not statistically significant (P = 0.149). Myocarditis, a very rare but serious complication of tetanus, was observed in 2.3 % vs. 1% patients in previous years and study year respectively (P = 0.560). The average duration of hospital stay was 27 days in the previous years whereas this was 22 days in the study year (P = < 0.001). Complete recovery was observed in 48% cases in previous years but this was observed in 69% cases in study year (P = 0.018). It had also been observed that there was less requirements of ventilator support in these patients treated with magnesium sulphate and diazepam though one randomized controlled trial showed that magnesium sulfate did not decrease the requirement of ventilator support, and thus more studies are needed to establish this fact. ^[11] The overall mortality observed was 10.46% in previous years whereas this was only 4.65% in the study year (P = <0.02). This significant decrease in mortality in the study group was probably due to shorter duration of reflex spasm, less respiratory depression and fewer serious ANS involvement. The major limitations of this study was that it was an observational study and their might be some observation bias during the selection of patients from previous year.

So, with the use of magnesium sulfate in combination with diazepam in the treatment of moderate to very severe tetanus cases it had been observed that there were decrease in duration of reflex spasm, ANS involvement, respiratory depression, duration of hospital stay and overall mortality in respect to previous year and all these were statistically significant. This was probably due to the effects of magnesium sulfate, particularly its action on autonomic nervous system besides its antispasmodic property. But there were no significant decrease in occurrence of myocarditis, aspiration pneumonia and cardiac arrhythmia which was probably due to parasympathetic instability, in which magnesium sulfate had no role. In the developing countries like India where tetanus case prevalence is very high but with limited ICU facility, magnesium sulfate would be particularly helpful in decreasing both morbidity and mortality of this serious disease. Moreover magnesium sulfate is very cheap, easy to administer and its therapeutic effect can easily be monitored clinically (by knee jerk). Thus , magnesium sulphate in a dosage titrated to the preservation of the knee jerk could be used in combination with diazepam to control both the spasms and autonomic instability because of it’s morbidity and mortality benefits particularly with limited ICU facility.

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1755-6783.127799

[Figure 1], [Figure 2], [Figure 3]

[Table 1]