Abstract
Background
Clinical management of the muscle spasms and rigidity of tetanus poses a difficult therapeutic problem to physicians everywhere, especially in resource poor countries. There are wide variations in therapeutic regimens commonly used in clinical practice due to uncertainties about effectiveness of conventional drugs. Diazepam compared to other drugs (eg phenobarbitone and chlorpromazine) may have advantages because of combined anticonvulsant, muscle relaxant, sedative and anxiolytic effects.
Objectives
To compare diazepam to other drugs in treating the muscle spasms and rigidity of tetanus in children and adults.
Search methods
We searched the Cochrane Neonatal Group trials register (June 2004), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2004), MEDLINE (1966 to June 2004), EMBASE (1980 to June 2004), LILACS (2004), CINAHL (June 2004), Science Citation Index, African Index Medicus, conference abstracts and reference lists of articles. We contacted researchers, experts and organizations working in the field and used personal communication.
Selection criteria
Randomized and quasi-randomized controlled trials.
Data collection and analysis
We independently identified eligible trials, assessed trial methodological quality and extracted data.
Main results
Two studies met the inclusion criteria. Method of generation of allocation sequence, concealment of allocation and blinding were unclear in both studies. A total of 134 children were allocated to three treatment groups comprising diazepam alone, phenobarbitone and chlorpromazine, or phenobarbitone and chlorpromazine and diazepam.
Meta-analysis of in-hospital deaths indicates that children treated with diazepam alone had a better chance of survival than those treated with combination of phenobarbitone and chlorpromazine (Relative Risk for death 0.36; 95% confidence interval 0.15 to 0.86; Risk Difference -0.22; 95% CI -0.38 to -0.06).
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.
Authors’ conclusions
Although this review suggests that diazepam alone compared with combination of phenobarbitone and chlorpromazine may be more effective in treating tetanus, the small size, methodological limitations and lack of data on drug safety from available trials preclude definite conclusions to support change in current clinical practice. The application of this observation should be moderated by local needs and circumstances, pending the availability of better evidence. We recommend a reinforcement of preventive measures against tetanus infection and it is hoped that in the light of clear evidence about the preventive efficacy of tetanus toxoid immunization, concerted efforts should be made towards preventive interventions and ultimate eradication such that there will not be enough case materials for a trial. In the event of a need for a trial, a large prospective, multicenter, randomized controlled trial, which compares diazepam alone with combinations of other drugs (excluding diazepam) will be ideal.
Plain language summary
Diazepam for treating tetanus
Tetanus is a disease caused by bacteria (Clostridium tetani) found in soil and faeces. It can be immunised against but continues to kill children and adults. Newborn infants are the most vulnerable, particularly in Bangladesh, India, Indonesia, Nigeria and Pakistan, mainly because of unhygienic umbilical cord practices. Puncture wounds, burns, multiple ear piercing, tattooing and circumcision (male and female) can also cause tetanus infection. The symptoms include a sudden onset of muscle stiffness and spasms (involuntary contractions) in the neck, jaw and back, sufficient to cause rigid arching of the back. Glottal and laryngeal spasms may result in fluid being sucked into the breathing passages (aspiration) or inability to breathe (asphyxiation). These spasms progress over two weeks and recovery then takes some four weeks. Complications of the disease or its treatment include depressed breathing, extrapyramidal signs that mimic the tetanus spasms and rigidity, body (autonomic) dysfunction and pneumonia. Supportive nursing, nutritional support and physiotherapy are important. Mechanical ventilation is rarely available in resource poor countries to treat total paralysis. Drugs are needed to reducing the muscle spasms and rigidity, antibiotics to kill the bacteria and tetanus immunoglobulin to remove the toxins in the body. Diazepam has anticonvulsant, muscle relaxant, sedative and anxiety reducing effects. Diazepam treatment was associated with fewer deaths than was treatment with a combination of phenobarbitone and chlorpromazine. Combination treatments with diazepam did not give any further benefit (and may cause harm). The review authors searched the medical literature and identified two randomised controlled trials with a total of 134 hospitalized neonates and older children who had tetanus from Nigeria (19 neonates, seven children aged between one month and 10 years of age) and Indonesia (74 neonates, 34 children aged between three days and 12 years). All drugs were given orally as medications and feeds are usually given via nasogastric tube in the settings where the disease burden is high. Neither study provided information on the safety of the interventions or followed up survivors beyond discharge from hospital.
