anae12020

Review

A meta-analysis of magnesium for tetanus

C. Rodrigo,1 L. Samarakoon,2 S. D. Fernando3 and S. Rajapakse4

1 Lecturer in Medicine, 4 Professor in Medicine, Department of Clinical Medicine, 3 Professor in Parasitology, Departmentof Parasitology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka2 Senior House Officer, National Hospital, Colombo, Sri Lanka

SummaryUncontrolled studies suggest that magnesium sulphate controls spasms in patients with established tetanus. We

performed a meta-analysis of controlled trials that compared magnesium sulphate with placebo or diazepam for the

treatment of patients with tetanus. We searched PubMed, Scopus, Embase and the Cochrane clinical trials registry.

Three studies met the inclusion criteria, containing 275 participants (199 male patients, 72.4%). Magnesium sulphate did

not reduce mortality, relative risk (95% CI): vs placebo, 0.80 (0.41–1.58); vs diazepam, 1.11 (0.70–1.75). The data on

duration of total intensive care unit stay, total hospital stay and the need for ventilatory support were conflicting and

pooling of results could not be done due to methodological differences of individual trials. More controlled trials are

needed to assess the effect of magnesium sulphate on reducing autonomic instability, spasms, duration of intensive care

and hospital stays and the need for mechanical ventilation.................................................................................................................................................................

Correspondence to: S. Rajapakse

Email: [email protected]

Accepted: 29 August 2012

Effective vaccination has reduced the annual worldwide

incidence of tetanus from approximately 110 000 cases in

1980 to around 9600 in 2010 [1]. Nonetheless, established

tetanus has a high mortality and morbidity [2].

Tetanus is caused by the obligatory anaerobic gram

positive bacillus Clostridium tetani. It produces spores

that survive in animal excreta, soil, adverse environ-

mental conditions and in normal human tissue. The

spores germinate and produce two toxins; tetanospas-

min and tetanolysin [3]. The bacterium is not invasive,

but tetanospasmin is distributed in the body via blood

and lymphatics, becoming internalised at neuromuscu-

lar junctions followed by retrograde transportation to

the cytosol of motor neurons. It disrupts the function of

the inhibitory neurons that synapse with these motor

neurons, causing tetanic contraction of both agonist and

antagonist muscles in response to sensory stimuli.

Antitoxin is ineffective against established tetanus.

New synapses and new nerve terminals have to form

and take over the function of the diseased ones for the

clinical features to reverse. The clinical course of

established tetanus can be prolonged.

Treatment of established tetanus involves: sedation

and paralysis to control spasms, autonomic dysfunction

and to avoid exhaustion; surgical debridement of the

source of infection and antibiotic treatment; neutralisa-

tion of the circulating toxin; and observation and

supportive therapy.

Four meta-analyses of the treatment of tetanus have

been published. Two are of intramuscular vs intrathecal

Anaesthesia 2012, 67, 1370–1374 doi:10.1111/anae.12020

1370 Anaesthesia ª 2012 The Association of Anaesthetists of Great Britain and Ireland

anti-tetanus immunoglobulin [4, 5], one is of vitamin C

[6] and the other is of diazepam [7].

Magnesium sulphate has been used to control

muscle spasms in tetanus since the beginning of the

last century [8]. Its use became popular with reports of

better control of muscle spasms and autonomic symp-

toms in several case series [9, 10]. Magnesium antago-

nises calcium, causing vasodilatation, presynaptic

neuromuscular blockade and prevention of catechol-

amine release [11]. It also has anticonvulsant properties.

Sedation with benzodiazepines may delay ventilatory

weaning and promote ventilator-associated pneumonia.

Some authors suggest that magnesium sulphate almost

eliminates the need for artificial ventilation [10], as

it controls spasms well, whereas others question this

[12].

This study systematically reviews evidence from

randomised controlled trials, in patients with tetanus, of

the effects of intravenous magnesium sulphate on:

mortality; the durations of spasms, ventilation, intensive

care and hospital stays; and autonomic stability.

MethodsOur intention was to include randomised or non-

randomised controlled trials. We searched PubMed,

Embase, Scopus and the Cochrane clinical trial registry

for relevant articles. We searched PubMed for ‘tetanus’

in the abstract and ‘magnesium sulphate’ in any field,

without language or time restrictions. We made appro-

priate adjustments to this search strategy for the other

databases.

We read all abstracts independently, identifying key

articles by consensus. Depending on the abstracts, the

articles were classified as ‘yes’ (meets inclusion criteria),

‘no’ (does not meet inclusion criteria) and ‘doubtful’.

Authors read the full articles in the ‘doubtful’ category

and contacted original authors when the article was in a

language other than English and when no translation

was available.

We analysed the data with Review Manager 5.1 [13].

We reported dichotomous data as relative risk, RR (95%

CI) and continuous data as mean differences. We used a

random-effects model for mortality and a fixed-effect

model for other outcomes. We defined statistical

significance as a p value < 0.05, using the two-tailed

chi-squared test. We assessed heterogeneity using the I2

statistic [14]. We interpreted a I2 value greater than 70%

as a high level of heterogeneity.

ResultsFigure 1 shows the PRISMA diagram leading to the

three studies we included [15–17]. One study was

conducted in Vietnam, one in Nigeria and one in

Pakistan. Table 1 lists study details. The study by

Thwaites et al. compared magnesium sulphate vs pla-

cebo [16]. Patients in both groups received benzodiaze-

pines and neuromuscular blockers as required. In the

other two studies, the treatment arm received magne-

sium sulphate, whereas the control arm received intra-

venous diazepam [15, 17]. We therefore analysed the

two types of studies separately. We excluded four

uncontrolled case series [9, 10, 12, 18]. The three

included studies recruited 275 participants, 199 male

patients (72.4%). All were adults or older children. Two

studies recruited participants older than 15 years and

one recruited participants older than 10 years.

# of recordsidentified through

databasesearching: 179

# of additionalrecords identified

through othersources: 8

# of records after duplicatesremoved: 79

# of recordsscreened: 79

# of recordsexcluded: 72

# of full-textarticles assessed

for eligibility: 7

# of full-textarticles excludedwith reasons: 4

# of studiesincluded in qualitativesynthesis: 3

# of studiesincluded in

quantitativesynthesis

(meta-analysis): 3

Figure 1 PRISMA flow diagram on selection of studiesfor the review.

Rodrigo et al. | A meta-analysis of magnesium for tetanus Anaesthesia 2012, 67, 1370–1374

Anaesthesia ª 2012 The Association of Anaesthetists of Great Britain and Ireland 1371

The study by Thwaites et al. was a well-conducted

study with a low risk of bias. The study allocated

patients to either treatment or placebo arms randomly,

with adequate allocation concealment. It was a double-

blinded study. Osalusi et al. also had a low risk of bias,

as the allocation was random and blinding was main-

tained to analysis [15]. The study by Ali et al. was at

high risk of bias as allocation was random, but there was

no blinding [17]. Figure 2 summarises the risks of bias.

Magnesium did not reduce mortality (Fig. 3). There

was no difference in results when calculated with fixed-

effect or random-effects models. All studies reported on

length of stay, either in ICU, hospital, or both, but we

were unable to pool these data. Thwaites et al. found

that compared with placebo magnesium did not alter

ICU or hospital lengths of stay, with mean difference

(95% CI): 0.5 days (2.1 to )3.1) and 2.0 days (1.1 to

)5.1), respectively. Compared with diazepam, Ali et al.

reported that magnesium shortened ICU stay by

16.4 days (13.3–19.5). Osalusi et al. reported that mag-

nesium reduced hospital stay in survivors by 3.2 days

(0.2–6.2) compared with diazepam.

Table 1 Summary of the included studies of the review.

Ali et al. 2011 [17]

Methods Randomised controlled trial (blinding not mentioned).Participants 38 participants (28 male) randomly allocated to magnesium or diazepam.Interventions Magnesium group; 4 g iv magnesium sulphate over 20 min in 100 ml dextrose-saline, followed by

infusion of 2 g.h)1. The rate of infusion was increased by 0.25–0.5 g.h)1, 8 hourly, until spasms werecontrolled, as long as a patellar reflex was elicited.

Control group; iv diazepam (doses not mentioned).Al patients were given: anti-tetanus toxin; tetanus toxoid; iv benzyl penicillin and metronidazole;debridement of wound as needed; tracheostomy within 48 h of admission to intensive care.

Osalusi et al. 2008 [15]Methods Randomised, double-blind, controlled study.Participants 42 participants (31 male) randomly allocated to magnesium or diazepam.Interventions Magnesium group; 5 g iv magnesium sulphate in 20 ml, followed by infusion of 2 g.h)1.

Control group; 20 mg iv diazepam in 20 ml, followed by infusion 10 mg.h)1.All patients were given: metronidazole and anti-tetanus serum with active immunisation on discharge.

Thwaites et al. 2006 [16]Methods Randomised, double-blind, placebo controlled study.Participants 195 participants (140 male) randomly allocated to magnesium or placebo.Interventions Magnesium group; 40 mg.kg)1 iv magnesium sulphate over 30 min, followed by infusion of 2 g.h)1

if > 45 kg and 1.5 g.h)1 if £ 45 kg.Placebo group; glucose anhydrous 5% in water (infusion rates as above).All patients received treatments outlined in the other two studies, but also received iv diazepamand pipecuronium to control muscle spasms as required. When the dose of diazepam exceeded100 mg.day)1, iv midazolam was used.

Figure 2 Risk of bias summary: review authors’ judg-ments about each risk of bias item for each includedstudy [(+) low risk, ()) high risk, (?) unclear risk].

Anaesthesia 2012, 67, 1370–1374 Rodrigo et al. | A meta-analysis of magnesium for tetanus


Compared with placebo, magnesium did not change

the rate of ventilation: relative risk 0.92 (0.79–1.06),

p = 0.29 [13]. Ventilation was less likely for patients

treated with magnesium, compared with diazepam:

relative risk 0.33 (0.13–0.84), p = 0.001.

We could not pool data for autonomic instability

and muscle spasms, as different authors had used

different ways to assess them. Thwaites et al. reported

surrogate measures of spasm control that were difficult

to interpret, particularly as some favoured placebo

(lower creatine kinase concentrations) and some

favoured magnesium (lower midazolam and pipecuro-

nium use). Some markers for autonomic instability

showed an improvement with magnesium (heart rate),

whereas others did not (mean arterial blood pressure

and temperature). Serum calcium levels were signifi-

cantly lower in the magnesium group, but its relevance

cannot be interpreted with regard to autonomic insta-

bility as magnesium itself lowers serum calcium. We

could not interpret the frequency of spasms in Osalusi

et al.’s study, because they did not report overall rates in

the magnesium and diazepam groups, instead reporting

the rates of spasm in different time periods (for most of

which there was no difference). Osalusi et al. did not

find a significant difference for duration of spasms. Ali

et al. reported no difference in cessation of spasm, but

did not define what this meant, whereas they incorrectly

calculated as significant, a non-significant difference in

the rate of uncontrollable spasm (6 ⁄ 18 vs 4 ⁄ 18).

DiscussionThis meta-analysis shows that there is no evidence that

magnesium sulphate changes mortality in patients with

tetanus. Whether it changes the duration of total ICU

stay or hospital stay is unknown as the results from

different studies conflict.

Tetanus has become a very rare illness and therefore

it is difficult to conduct sufficiently large trials to

demonstrate the efficacy of treatment strategies. There-

fore, meta-analysis of data from smaller trials provides

useful information on the effects of different treatment

strategies. However, the variations across study designs

affect the validity of meta-analytic conclusions.

Magnesium sulphate in overdose can cause hypo-

tension, arrhythmias and paralysis with respiratory

depression. During therapy, serum magnesium sulphate

levels have to be monitored and maintained at a level of

2–4 mmol.l)1 [19]. Clinical evidence of magnesium

overdose is assessed by the loss of patellar reflex,

respiratory depression, hypotension and hypocalcaemia

[20]. The controlled trials and uncontrolled trials have

shown that magnesium sulphate is a safe drug to use in

established tetanus within its therapeutic window if

these precautions are observed.

Overall mortality was lower in the trial by Thwaites

et al. than that of Ali et al. and Osalusi et al.: 14.9% vs

52.8% and 45.2%, respectively. Tetanus appeared less

severe in the study by Thwaites et al., with a severity

score 3 ⁄ 46, whereas tetanus in nearly half the patients in

Figure 3 Forest plot of comparison of magnesium sulphate vs non-magnesium sulphate groups, with death as theoutcome (horizontal bars indicate 95% CI).

Rodrigo et al. | A meta-analysis of magnesium for tetanus Anaesthesia 2012, 67, 1370–1374

Anaesthesia ª 2012 The Association of Anaesthetists of Great Britain and Ireland 1373

Osalusi et al.’s study was classified as severe, according

to the Ablett scoring system. Ali et al. did not report

tetanus severity.

Thwaites et al. titrated magnesium to serum con-

centration, but not according to clinical response. In

uncontrolled trials, the magnesium sulphate infusion

was titrated according to the clinical response [10, 12,

18]. The effect of magnesium may be different when

titrated to different targets.

Research should determine whether magnesium

sulphate changes: the rate of artificial ventilation; the

lengths of ICU and hospital stays; the rate and severity

of autonomic instability; and the frequency and intensity

of spasms. We suggest that such trials should compare

three groups: magnesium sulphate; placebo; and diaze-

pam. The severity of tetanus should be assessed, using

standardised measures, on recruitment so that the

association between severity and effect of treatment

can be explored. Studies should be designed to allow

dose titration against both serum concentration and

symptoms.

AcknowledgementsThe authors acknowledge Ms. Chamindri Witharana

and Dr Dulika Sumathipala for their assistance with

literature searches.

Competing interestsNo external funding and no competing interests

declared.

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