Elsevier

The Lancet

Volume 368, Issue 9545, 21–27 October 2006, Pages 1436-1443
The Lancet

Articles
Magnesium sulphate for treatment of severe tetanus: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(06)69444-0Get rights and content

Summary

Background

The most common cause of death in individuals with severe tetanus in the absence of mechanical ventilation is spasm-related respiratory failure, whereas in ventilated patients it is tetanus-associated autonomic dysfunction. Our aim was to determine whether continuous magnesium sulphate infusion reduces the need for mechanical ventilation and improves control of muscle spasms and autonomic instability.

Methods

We did a randomised, double blind, placebo controlled trial in 256 Vietnamese patients over age 15 years with severe tetanus admitted to the Hospital for Tropical Medicine, Ho Chi Minh City, Vietnam. Participants were randomly assigned magnesium sulphate (n=97) or placebo solution (n=98) intravenously for 7 days. The primary outcomes were requirement of assisted ventilation and of drugs to control muscle spasms and cardiovascular instability within the 7-day study period. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN74651862.

Findings

No patients were lost to follow-up. There was no difference in requirement for mechanical ventilation between individuals treated with magnesium and those receiving placebo (odds ratio 0·71, 95% CI 0·36–1·40; p=0·324); survival was also much the same in the two groups. However, compared with the placebo group, patients receiving magnesium required significantly less midazolam (7·1 mg/kg per day [0·1–47·9] vs 1·4 mg/kg per day [0·0–17·3]; p=0·026) and pipecuronium (2·3 mg/kg per day [0·0–33·0] vs 0·0 mg/kg per day [0·0–14·8]; p=0·005) to control muscle spasms and associated tachycardia. Individuals receiving magnesium were 4·7 (1·4–15·9) times less likely to require verapamil to treat cardiovascular instability than those in the placebo group. The incidence of adverse events was not different between the groups.

Interpretation

Magnesium infusion does not reduce the need for mechanical ventilation in adults with severe tetanus but does reduce the requirement for other drugs to control muscle spasms and cardiovascular instability.

Introduction

Tetanus is an important cause of hospital admission and death in parts of the world with limited vaccination programmes. At least 1 million cases require hospital treatment worldwide every year and there are about 400 000 deaths.1, 2 The disease is caused by a neurotoxin released from wounds infected with Clostridium tetani, a bacterium transmitted as spores and present in soil throughout the world.

Tetanus is a painful and protracted disease characterised by increased muscle tone, muscle spasm, and, in severe cases, cardiovascular instability secondary to autonomic dysfunction. The toxin blocks neurotransmitter release from the inhibitory pathways of the motor and autonomic nervous systems, which can result in unrestrained neuronal activity of both pathways.3 Data from a limited number of controlled trials suggest that antitoxin and antibiotics—penicillin or metronidazole—improve outcome.4, 5 However, beyond these disease-specific therapies, the optimum management of the respiratory compromise and cardiovascular instability that characterise the severe form of the disease remains uncertain.6 Supportive management is focused on controlling muscle spasms, maintaining and protecting the upper airway and providing adequate ventilation, and limiting the consequences of autonomic dysfunction.

Benzodiazepines, often in very high doses, have been the mainstay of controlling muscle spasms, although there is little evidence to support their use over alternative sedatives such as phenobarbital and chlorpromazine.7, 8, 9 Severe spasms might necessitate the use of non-depolarising neuromuscular blocking agents,10, 11 although the use of such drugs requires ready access to mechanical ventilation. However, such facilities are often absent in settings where tetanus is common.

Autonomic dysfunction with labile blood pressure, heart rate, and temperature is difficult to treat irrespective of the setting,2, 12 and occurs in those with severe disease, usually in the second week of illness. Where there is access to mechanical ventilation, and respiratory muscle spasm can be controlled, autonomic dysfunction is the most common cause of death.13 A range of treatments have been advocated, including the use of morphine, clonidine, beta-adrenergic receptor blockade, and epidural bupivacaine, but none is supported by evidence from controlled trials.9, 10, 14, 15, 16, 17, 18

Magnesium sulphate was first used in the treatment of tetanus more than 100 years ago19 and has several attractive therapeutic properties including muscle relaxation, which could control spasms, and cardiovascular effects (eg, vasodilatation, lowering of heart rate, and a reduction of systemic catecholamine release), all of which could ameliorate the effects of autonomic dysfuntion.20, 21 Whether magnesium improves the outcome of tetanus remains uncertain. In 1985, James and Manson22 did an open label, uncontrolled study of ten patients with severe tetanus in Zimbabwe that suggested that a continuous magnesium infusion (1–3 g/h) might help control blood pressure and heart rate. In Sri Lanka, Attygalle and Rodrigo23 reported treating eight patients with severe tetanus with continuous magnesium infusion, titrating against patella reflex (serum concentrations 2–4 mmol/L), and noted that spasms were reduced within 2–3 h of starting the infusion and were abolished within 24 h. The same protocol was used to treat a further 40 patients and magnesium was seen to reduce not only the use of neuromuscular blocking agents to control severe spasms but also the requirement for mechanical ventilation when compared with historical controls.24 The authors concluded that magnesium should be used as a first-line agent for treatment of tetanus.25

However, Thwaites and Farrar26 were not so enthusiastic, and suggested that this conclusion seemed premature without any data from an adequately powered controlled study. There was concern about the potential adverse effects of magnesium. In particular, muscle weakness induced by magnesium could paradoxically increase the requirement for mechanical respiratory support, which could be dangerous in settings without access to such facilities.

To address these issues we did a randomised, double blind, placebo controlled study of magnesium sulphate in patients with severe tetanus. Our aim was to determine whether magnesium can control muscle spasm and autonomic activity and reduce the need for mechanical ventilation in such individuals.

Section snippets

Participants

The study was done in the tetanus unit at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam. The unit consists of a 14 bed intensive care ward reserved for the care of patients with tetanus, and serves the local community as well as acting as a tertiary referral centre for the whole of southern Vietnam (population about 35 million). The unit admits about 300 patients with tetanus every year, 75% of whom have severe tetanus and require mechanical ventilation.

Only patients over 15

Results

Of 256 patients initially assessed for eligibility, 195 patients with severe tetanus were randomly assigned either magnesium or placebo from May, 2002, to April, 2005 (figure 1). One patient in the magnesium group was given placebo in error. Although no patients were lost to follow-up, a number in both groups discontinued treatment early (figure 1). Primary outcome data were available from all patients entered into the study.

Baseline serum concentrations of magnesium were 0·76 mmol/L (IQR

Discussion

Our results show that magnesium infusions for the treatment of severe tetanus in adults did not affect the requirement for mechanical ventilation, either during the 7 days of infusion or for the rest of the hospital stay. However, such infusions did improve both muscle spasm control and cardiovascular stability, as shown by a significant reduction in the daily requirement of both sedation (midazolam) and neuromuscular blockade (pipecuronium). There was no effect on survival.

The primary outcome

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