No new studies were identified in searches to June 2004.
Giving diazepam alone, or supplementing conventional anticonvulsants (phenobarbitone and chlorpromazine) with diazepam, was reported in one study to be associated with a statistically significantly milder clinical course and shorter duration of hospitalization.
Tetanus is transmitted by tetanus spores, which are inoculated into the body following major or minor injuries. In newborn infants, the main route of infection is through the umbilical cord, either because of cutting the cord at birth using contaminated instruments, or through unhygienic cord care practices such as the application of animal dung dressing on the umbilical cord. Acute wounds (including minor splinter punctures), burns, multiple ear piercing, tattooing and circumcision (especially female genital mutilation) may expose non-immunized individuals to tetanus infection. In 20 to 30% of cases the portal of entry is either obscure or trivial. Following inoculation, the tetanus spores germinate and produce two toxins known as tetanospasmin, which produces the characteristic features and complications of tetanus (i.e. muscle spasms and autonomic dysfunction) and tetanolysin, which causes hemolysis but otherwise plays no major role in the disease (Edsall 1976, Willis 1983, Bleck 1987, Bleck 1991).
The diagnosis of tetanus rests primarily on clinical features. These include sudden onset of muscle stiffness (rigidity) and muscle spasms (involuntary contractions) of the neck and jaw, leading to lockjaw, feeding and speech difficulties and a characteristic facial expression, the sardonic smile (risus sardonicus). Tetanus spasms, also referred to as seizures (fits), may be either localized or generalized. Tonic spasms of muscles of the neck, back, trunk, limbs and abdomen may be associated with rigid arching of the back (opisthotonus). Glottal and laryngeal spasms may develop and these are potentially life-threatening, as they may lead to aspiration or asphyxiation. Apart from deep sedation that may be associated with use of drugs in tetanus, consciousness level is usually preserved in uncomplicated tetanus. Laboratory tests may be required to exclude other medical conditions that may mimic or complicate tetanus (Bleck 1995, Osinusi 1986, Weinstein 1998). The average duration of the illness is six weeks, comprising a two-week progression period and another four weeks for recovery, which is usually complete unless complications supervene. Complications of tetanus may be due to the disease or therapeutic interventions, and include respiratory depression, autonomic dysfunction and aspiration pneumonia. Long-term neurological sequelae have been reported after tetanus disease (Luisto 1989).
Generalized tetanus is the most common and most severe form of the disease. Localized tetanus is usually a mild, self-limiting illness except when it involves the head and neck (cephalic tetanus). The severity of tetanus is determined by the frequency of spasms, and the presence of opisthotonus and autonomic dysfunction. Various prognostic scoring systems exist (Patel 1959). For example, a scoring index to determine prognosis, at the time of admission and subsequently, was described by Hendrickse (Hendrickse 1981).
Several aspects are involved in the management of tetanus including drug treatment for the muscle spasms and rigidity, the use of antibiotics to kill the bacteria, the administration of tetanus immune globulin to remove free toxins, supportive nursing care, nutritional support, physiotherapy and active immunization with tetanus toxoid. The treatment of tetanus muscle spasms and rigidity is one of the most important aspects as it is crucial to the outcome. This poses a major challenge to physicians in low and middle-income and even developed countries, as there is no standardized, universally accepted drug regimen for treating tetanus muscle spasms and rigidity. Drugs that have been used for treating tetanus muscle spasms and rigidity include: diazepam, phenobarbitone, chlorpromazine, magnesium sulphate, vecuronium, pancuronium, and less commonly pyridoxine, morphine, baclofen, dantrolene and meprobamate. Wide variations in practice exist. Some tertiary health institutions in countries such as Nigeria use a cocktail of two or more therapeutic agents that include phenobarbitone and chlorpromazine (Kaine 1975, Adedoyin 1982, Oruamabo 1986, Osinusi 1986, Antia-Obong 1991), while others use diazepam alone (Tompkins 1958, Blankson 1977, Grange 1991, Okuonghae 1992).
The choice of therapeutic agents used in the treatment of tetanus spasms and rigidity should be based on best evidence of potential benefits and harm, but at best the efficacies of the various agents can be described as controversial. Comparisons of treatment outcomes between published studies have been difficult due to differences in study population and treatment protocols (Patel 1959, Gupta 1979). Many of the reports on beneficial therapeutic effects in tetanus are experiential in nature, based on comparisons between the outcomes of current patients with those of historical controls treated with other drugs. Many of the studies claiming therapeutic benefits are not randomized, controlled trials, which are adjudged the gold standard for best therapeutic evidence. Thus, the question of the benefits and harms of diazepam compared with other pharmacologic treatments such as phenobarbitone and chlorpromazine has remained unresolved.
Although tetanus predominantly affects neonates in the most vulnerable countries, randomized controlled trials based exclusively on neonates may be lacking. Existing studies may include neonates, older children and adults, and this formed the justification for not limiting this review to neonates. Furthermore, studies in which treatments involve total paralysis and mechanical ventilation will be excluded in this review because this mode of treatment is rarely available in resource poor countries most affected by tetanus disease. A separate review on the efficacy of this method of treatment is considered more appropriate.
There is a continuing search for an optimal treatment regime, which is safe, effective, available and affordable, and which controls muscle spasms and rigidity associated with tetanus without requiring any need for artificial ventilation. The aim of this review is to evaluate the existing evidence from controlled clinical trials concerning the benefits and harms of diazepam in the treatment of muscle spasms and rigidity in tetanus.
An additional comparison was included post facto, that is diazepam alone versus any other drug plus or minus diazepam
Primary outcomes:
See: Collaborative Review Group Search Strategy
We attempted to identify all relevant studies regardless of language
or publication status (published, unpublished, in press, and in progress).
We searched all trial registers and databases using the search terms:
tetanus and diazepam. Search terms included synonyms and trade names of diazepam
such as valium, stesolid, seduxen, faustan, diazemuls, and cercin. Chemical
names were not be included in the search terms.
We searched the Cochrane Neonatal Group, Cochrane Wounds Group and Cochrane
Infectious Diseases Group specialized trials registers for relevant trials
up to the month of June 2004.
We searched The Cochrane Central Register of Controlled Trials (CENTRAL,
The Cochrane Library, Issue 2, 2004). This contains mainly reference information
to randomized controlled trials and controlled clinical trials in health
care.
We searched the following electronic databases using the topic search
terms in combination with search strategy for identifying trials developed
by The Cochrane Collaboration and detailed in the Cochrane Reviewers' Handbook
(Clarke 2003a):
1) MEDLINE (1966 to June 2004)
2) EMBASE (1980 to June 2004)
3) LILACS (La Literatura Latin americana y del Caribe de information en Ciencias de Salud) 1982 to June 2004.
We contacted organizations and individuals who have worked on related
research and these included: World Health Organization (Infectious Diseases
and Technical Report Groups); University Departments of Paediatrics in areas
currently most affected by tetanus (Africa, Asia and India); Medical Research
Council, The Gambia; Kenya Medical Research Institute, Clinical Research
Centre Kilifi, Kenya; National Institute of Medical Research, Ifakara Centre,
Tanzania; Nigeria Institute of Medical Research.
We searched conference proceedings and symposia manually for reports
of trials and contacted major pharmaceutical companies that formulate diazepam
such as Roche.
The reviewers consulted existing reviews on the topic, and identified relevant citations.
The review protocol panel, internal and external editors, checked the completeness of the search strategy.
Additional comparisons and analyses were added post facto because the two eligible studies included these groups. These were:
1) Diazepam alone versus phenobarbitone and chlorpromazine and diazepam
2) Diazepam alone versus phenobarbitone and chlorpromazine with or without diazepam
In Hendrickse 1965, a total of eight
children (five neonates, three older children) were randomly allocated to
diazepam alone group, while nine children each (seven neonates, two older
children) were allocated the control groups A and B respectively.
In Tjoen 1970, 33 children excluding neonates
were allocated to the diazepam alone group, while 38 and 37 children were
allocated to control groups A and B respectively. The reason for excluding
all neonates from the experimental intervention was described as due to 'bad
experience' with diazepam in the older children. The numbers of neonates
allocated to control groups A and B were not stated.
The experimental and control drugs were administered by the oral route
in both trials. Overall, the doses of both the experimental and control interventions
were higher in Tjoen 1970, compared to Hendrickse 1965. As much as 4-9 mg/kg diazepam was used in Tjoen 1970 compared with 0.44 to 1.1mg/kg in Hendrickse 1965.
Participants in both studies received other standard treatments for tetanus, which included intramuscular phenobarbitone and chlorpromazine given on admission to all the participants in Tjoen 1970, to control spasms and convulsions. Intramuscular paraldehyde was used for the same purpose in Hendrickse 1965. Neither of the studies reported on the role of nursing care in the standard management of tetanus.
Three comparison groups were analysed, including:
1) Diazepam alone versus phenobarbitone and chlorpromazine
2) Diazepam alone versus phenobarbitone and chlorpromazine and diazepam
3) Diazepam alone versus phenobarbitone and chlorpromazine with or without diazepam
Comparisons 2 and 3 were added post facto, because the two eligible studies, Hendrickse 1965 and Tjoen 1970, included diazepam in one of their control groups.
Diazepam alone versus phenobarbitone and chlorpromazine
There was a total of 5/41 deaths in the experimental groups and 16/47
deaths in the control groups. This effect on mortality was consistent in
both studies and was statistically significant in the meta-analysis (Relative
Risk 0.36, 95% confidence interval 0.15 to 0.86; Risk Difference -0.22, 95%
CI -0.38 to -0.06).
Diazepam alone versus phenobarbitone and chlorpromazine and diazepam
In the two studies, addition of diazepam to the control interventions
was associated with a total of 5/41 deaths in the diazepam alone groups compared
with 10/46 mortalities in the control groups, but this effect was not statistically
significant (Relative Risk 0.56; 95% confidence interval 0.22 to 1.45; Risk
Difference -0.10; 95% confidence interval -0.24 to 0.05). This effect was
similar across the two included trials.
Diazepam alone versus phenobarbitone and chlorpromazine with or without diazepam
In the two studies, the total for deaths in the experimental groups
were 5/41 compared with 26/93 in the control groups, and this effect was
of borderline statistical significance (Relative Risk 0.44, 95% confidence
interval 0.18 to 1.02; Risk Difference -0.16, 95% CI -0.29, -0.03). This
effect was similar across the two studies.
Hendrickse 1965 noted that the two
deaths in the diazepam alone group were following the addition of phenobarbitone
and chlorpromazine to one patient, and measles infection in the other patient).
We did not detect any statistically significant heterogeneity of treatment effect in any of the comparisons, suggesting that overall, the two included trials were similar in terms of populations, interventions, outcomes, quality and the direction and magnitude of treatment effects.
There were insufficient data in both trials to do sub-group analyses to estimate the role of age of participants, pattern of tetanus (localized or generalized), severity of tetanus at study entry, dose or route of administration of interventions.
2) Duration of trismus
Mean duration for this outcome was 5.3 days, 6.0 days and 9.9 days in
diazepam alone group and control groups B and A respectively.
3) Duration of tonic convulsion
Average duration for this outcome was 2.0 days, 1.5 days and 3.5 days
in the diazepam alone group and control groups B and A respectively.
4) Time to regain motor function
Mean time for sitting up was 1.0, 0.5 and 3.2 days; for standing up 1.5,
1.2, and 4.9 days; and for walking 2.6, 1.5, and 6.0 days in the diazepam
alone group and control groups B and A respectively.
5) Length of hospital stay
Mean duration of hospitalization was 7.0, 8.1, and 13.0 days in the diazepam
group and control groups and control groups B and A respectively.
The authors did not provide other data (standard deviation of means) to permit statistical analysis in this review. The authors noted that supplementing conventional anticonvulsants (phenobarbitone and chlorpromazine) with diazepam, or giving diazepam alone, was associated with statistically significant milder clinical course and shorter duration of hospitalization. However, since they did not report standard deviations, we could not perform statistical analyses in this review.
Data provided on time to death in the two trials were insufficient for any statistical analysis.
We did not find data on other adverse events (eg need for tracheostomy or ventilation support) pre-specified in the protocol.
This review aimed to determine from reliable research the efficacy and safety of diazepam compared to other treatment options used in tetanus. The two included studies were small and the logistics of randomization, in particular generation of allocation sequence and concealment of allocation, were not clear. Blinding of intervention to the caregivers or to the investigators and outcome assessors was not stated. These methodological issues potentially increased the risk of bias, and cast doubt on the internal validity of the trial results. However, while we recognize the difficulties earlier trialists in medical research may have faced in general, it is noteworthy that there are no recent trials of adequate methodological quality based on the eligibility criteria for inclusion, particularly from regions that bear the burden of tetanus. Furthermore, the inclusion of diazepam in one of the two control groups in each of the two included trials "contaminated" those control groups, so that any true effect of diazepam on death and other outcomes may have been diluted by this experimental design.
Noteworthy concerns in this review include the comparability of the study groups that included largely neonates and fewer older children and adults, the bioavailability of oral medications in sick neonates, and the huge difference in the dose of diazepam used in the two studies, which varied by as much as nine fold. Rather than any differences in biological constitution, pathogenesis and pathophysiology of tetanus between neonates, older children and adults, it is the low passive immunity due to inadequate maternal immunization, unhygienic cord care practices, and principal portal of entry by the umbilicus that are the major risk factors unique to neonates. These factors account for their greater predisposition to tetanus compared with other groups. Nevertheless, the effect of a predominantly neonatal age group in the trials may be more evident and possibly change the findings once we diaggregate the two groups, but doing this may further dilute and weaken the power of the studies and findings. Doubts about the bioavailability of medications administered orally in sick neonates will be justified where the sickness involves and/or affects the gastrointestinal tract, in which case there will be clinical pointers supporting same such as abdominal distension, vomiting and/or diarrhoea. In such situations, absorption of gastrointestinal contents including medications may be impaired. Usually, unless tetanus is complicated by septicaemia with gastrointestinal involvement, medications and feeds are usually given via nasogastric tube in the settings where the disease burden is high.
Although there is a consistent beneficial effect in both Hendrickse 1965 and Tjoen 1970 suggesting that diazepam given alone that diazepam alone is more efficacious in treating tetanus compared with other conventional treatment, and that combination therapy may be harmful, this observation is methodologically and statistically limited, and insufficient to support or justify a change in current practice. Also, there were no data on safety of the interventions used in both trials.
Giving diazepam alone or supplementing conventional anticonvulsants (phenobarbitone and chlorpromazine) with diazepam, was reported to be associated with statistically significant milder clinical course and shorter duration of hospitalization in one study.
Applicability:
Location
Data included in this review are from studies conducted in areas
that still bear the burden of tetanus and these include Nigeria in sub-Saharan
Africa and Indonesia in South East Asia. These resource poor countries still
grapple with the burden of tetanus, cannot afford treatments requiring total
paralysis and ventilation support as is the case in developed countries,
and therefore still depend on the interventions under review. They have the
greatest need for evidence of effects of drugs used in treating tetanus.
Populations
The two trials enrolled neonates (who are the most affected by tetanus)
as well as post-neonatal children, but not adults. However, the studies failed
to stratify randomisation or report outcome data according to age; but we
recognize that the smallness of sample size in the trials, particularly in
Hendrickse 1965, could have precluded stratification into subgroups.
Benefits and risks
Both trials show that diazepam alone is associated with fewer deaths
and that additional drugs or combination treatment are not beneficial and
may cause harm in tetanus. However, these studies are dated and are insufficient
methodologically and statistically for any definite conclusion on benefits.
Also, both trials did not provide data of safety of the interventions.
This review clearly demonstrates the paucity of recent randomized trials of adequate methodological quality on the benefits and harms of major therapeutic interventions used for treating tetanus, and reinforce the need for further investigations in this area. While a large prospective multi-center trial may be warranted, it is hoped that in the light of clear evidence about the preventive efficacy of tetanus toxoid immunization, concerted efforts should be reinforced towards preventive interventions and ultimate eradication of tetanus such that there will not be enough case materials for a trial of this nature. However, in the event that a trial becomes absolutely necessary, the flaws of existing trials should be prevented in any future trial and adequate attention should be paid to randomization, blinding and the types of experimental and control interventions given. Also, future trialists should endeavour to state the study objectives and inclusion criteria explicitly; categorize participants by severity of disease; use other clinically pragmatic outcomes; record adverse events. Trial reports should conform to the CONSORT (Consolidated Standards of Reporting Trials) statement to permit the reader to clearly understand the trial design, conduct, analysis, interpretation and report (Moher 2003).
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Hendrickse 1965 | Randomized controlled trial Blinding of allocation (No) Blinding of intervention (No) Blinding of outcome (No) Complete follow up (Unclear) | Sample size: 26 Neonates: 19 Older children: 7 Age range: 1 month to 10 years | Experimental: Diazepam only Dose: (0.44 to 1.1mg/kg) 6 hourly Route: Oral No. allocated: 8 Controls: (2) Group B | Deaths (1) In-hospital, directly related to tetanus: Diazepam: 1 Control group A: 7 Control group B: 5 (2) In-hospital, related to other causes Total deaths: 14/26 | Study location: Ibadan, Nigeria. | B |
| Tjoen 1970 | Quasi- randomized controlled trial. Blinding of allocation (No) Blinding of intervention (No) Blinding of outcome (No) Complete follow up (Unclear) | Sample size: 108 Neonates: 33 Older children: 75 Age range: 3 days to 12 years | Experimental: Diazepam only Dose: (1.5 to 9.0 mg /kg) per day No. allocated: 33 (excluded neonates) Controls (2) Group B Route: Oral | Deaths (1) In-hospital, directly related to tetanus: Diazepam: 3 Control group A: 8 Control group B: 2 (2) In-hospital, related to other causes Total deaths: 17/108 | Study location: Jakarta, Indonesia. | C |
| Study | Reason for exclusion |
| Bhandari 1980 | Not randomized controlled trial and no diazepam alone treatment group. |
| Daud 1981 | Randomized controlled trial but no diazepam alone treatment group. |
| Femi-Pearse 1966 | Not randomized controlled trial. |
| Hendrickse 1966 | Part of continuation of a preliminary randomized study conducted in 1965, but diazepam only group was excluded. |
| Husada 1976 | Not randomized and no diazepam alone group. Diazepam was given to all treatment groups. |
| Joseph 1978 | Not randomized controlled trial. |
| Keswan 1983 | Not ramdomized controlled trial. |
| Norredam 1970 | Not randomized controlled trial. |
| Sugitha 1983 | Not randomized controlled trial. |
| Vassa 1974 | Not randomized and no diazepam alone treatment group. |
Hendrickse RG, Sherman PM. Tetanus in childhood: report of a therapeutic trial of diazepam. British Medical Journal 1966;2:860-2.
Tjoen 1970 {published data only}
Tjoen LW, Darmawan S, Ismael S, Sudigbia I, Suradi R, Munthe BG. The effect of diazepam on tetanus. Paediatrica Indonesiana 1970;10:248-58.
Bhandari NR, Shrivastava V. A study of tetanus neonatorum: different regimens of treatment. Indian Paediatrics 1980;17:803-8.
Daud 1981 {published data only}
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Femi-Pearse 1966 {published data only}
Femi-Pearse D. Experience with diazepam in tetanus. British Medical Journal 1966;2:862-5.
Hendrickse 1966 {published data only}
Hendrickse RG, Sherman PM. Tetanus in childhood: report of a therapeutic trial of diazepam. British Medical Journal 1966;2:860-2.
Husada 1976 {published data only}
Husada T, Rampengan TH, Harjanto IG, Arif IG, Munir M. Neonatal tetanus. Evaluation of treatment and a proposal for classification of severity. Paediatrica Indonesia 1976;16:345-54.
Joseph 1978 {published data only}
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Keswan 1983 {published data only}
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Norredam 1970 {published data only}
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Sugitha 1983 {published data only}
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Vassa 1974 {published data only}
Vassa NT, Doshi HV, Yajnik VH, Shah SS, Joshi KR, Patel SH. Comparative clinical trial of diazepam with other conventional drugs in tetanus. Postgraduate Medical Journal 1974;50:755-8.
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01.01 Deaths (in-hospital, all-cause)
02 Diazepam alone versus phenobarbitone and chlorpromazine and diazepam
02.01 Deaths (in-hospital, all-cause)
03 Diazepam alone versus phenobarbitone and chlorpromazine with or without diazepam
03.01 Deaths (in-hospital, all-cause)
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Diazepam alone versus phenobarbitone and chlorpromazine | ||||
| 01 Deaths (in-hospital, all-cause) | 2 | 88 | RR (fixed), 95% CI | 0.36 [0.15, 0.86] |
| 02 Diazepam alone versus phenobarbitone and chlorpromazine and diazepam | ||||
| 01 Deaths (in-hospital, all-cause) | 2 | 87 | RR (fixed), 95% CI | 0.56 [0.22, 1.45] |
| 03 Diazepam alone versus phenobarbitone and chlorpromazine with or without diazepam | ||||
| 01 Deaths (in-hospital, all-cause) | 2 | 134 | RR (fixed), 95% CI | 0.44 [0.18, 1.02] |
| Clinical course | Control Group A | Control Group B | Diazepam |
| Spasm of abdominal wall | 6.3 | 2.8 | 2.6 |
| Trismus | 9.9 | 6.0 | 5.3 |
| Tonic convulsion | 3.5 | 1.5 | 2.0 |
| Time to regain motor function | |||
| Sitting up | 3.2 | 0.5 | 1.0 |
| Standing up | 4.9 | 1.2 | 1.5 |
| Walking | 6.0 | 1.5 | 2.6 |
| Hospital stay | 13.0 | 8.1 | 7.0 |
| This review is published as a Cochrane review in The
Cochrane Library, Issue 4, 2004 (see http://www.thecochranelibrary.com/ for information).
Cochrane reviews are regularly updated as new evidence emerges and in response
to comments and criticisms, and The Cochrane Library should be consulted
for the most recent version of the Review. |
