Authors should describe the problem that prompted the work. The nature, scope, and severity of the problem should provide the background and a compelling rationale for the trial. The Helsinki Declaration states that biomedical research involving people should be based on a thorough knowledge of the scientific literature, that is, it is unethical to expose human subjects unnecessarily to the risks of research. Some clinical trials have been shown to be unnecessary because the question they addressed had been, or could have been, answered by a systematic review of the existing literature. A systematic review is a scientific appraisal of existing research, which is prepared using a systematic, transparent approach to minimise biases. A systematic review should be undertaken before mounting a trial.
The the need for a new trial should be justified in the background. Ideally, the background should include a reference to a systematic review of previous similar trials, or a note of the absence of such trials.
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‘The evaluation of the medical care in general and of the area
perinatology in particular, shows alarming results. It has been seen
only 15% of the health related practices are based on valid scientific
This situation is even more serious in Latin American countries, where
significant proportion of the care administered to women during the
period, delivery, and the postpartum are scientifically verified as
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Pre-eclampsia, a multisystem disorder of pregnancy usually associated with raised blood pressure and proteinuria, complicates 2-8% of pregnancies. Although outcome is often good pre-eclampsia is a major cause of morbidity and mortality for the woman and her child. It accounts for an estimated one fifth of antenatal admissions, two thirds of referrals to day care assessment units, and a quarter of obstetric admissions to intensive care units. Eclampsia is rare, affecting around 1 in 2000 deliveries in the UK for example, but is associated with a considerably higher morbidity and mortality.
Anticonvulsants may be administered to women with pre-eclampsia in the belief that these reduce the risk of a seizure, and so improve outcome. There is considerable variation in clinical practice but if an anticonvulsant is used, magnesium sulphate has recently emerged as the most rational choice. As for all prophylaxis, however, there is a particular responsibility to ensure that it does more good than harm. If magnesium sulphate does reduce the risk of eclampsia, the potential for benefit is relatively low (unless there are other beneficial effects), as most women would not have convulsed anyway. This is important as very large numbers of women and babies could be exposed to prophylactic anticonvulsants. In the US, for example, 5% of pregnant women receive magnesium sulphate before delivery. If the same usage was applied in the UK, 35,000 women would be treated each year. However, the incidence of eclampsia is only about 400 women/year without the use of magnesium sulphate. So, even if magnesium sulphate halves this risk, 200 women might be protected from fitting but 34,800 would have been exposed to the possible adverse effects.
The first question to be answered is whether magnesium sulphate reduces the risk of eclampsia. Even if it does do so, before it can safely be introduced into clinical practice more information is required about: (a) the size of the risk reduction; (b) effects on other important outcomes for the woman and child; (c) disease severity at which benefits outweigh the risks and (d) the cost consequences of different forms of care. Magnesium sulphate is cheap and relatively, easy to administer, but there could be a considerable cost for women, children and the health services if it is used routinely for pre-eclampsia without proper evaluation.
Systematic review of anticonvulsants for women with
pre-eclampsia A recent systematic review of randomised trials
that, currently, there is insufficient evidence to either support or
the use of prophylactic anticonvulsants. Twelve trials have
evaluated anticonvulsants for women with pre-eclampsia. Two small
studies were excluded from the review because either no clinical
outcomes were reported, or they were not reported separately for
pre-eclampsia and eclampsia.
Two trials have compared magnesium sulphate with no anticonvulsant (228
women, South Africa; 64 women, Taiwan) and two have compared magnesium
with placebo (822 women, South Africa; 135 women, USA). One
quasi-randomised study (59 women, Tanzania compared oral diazepam with
The remaining trials compared magnesium sulphate with diazepam (38
women, Mexico; 28 women, Malaysia) or with phenytoin (2138 women, USA;
115 women, USA; 54 women, USA).
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Aneurysmal subarachnoid haemorrhage (SAH) is a significant cause of death and continuing disability in relatively young patients with an annual incidence of between 6 and 12 per 100,000 population in most western countries. The natural history of the disease is such that over 30% of patients will die within 24 hours of the bleed and a further 25- 30% will succumb in the next four weeks without some form of surgical intervention.
The publication of the International Co-operative Study on the Timing of Aneurysm Surgery provided the most extensive data to date on the results of modern management in a large number of patients treated in experienced neurosurgical centres. Over 3,000 patients were entered in a prospective observational study from 1980 to 1983. The results showed that the overall mortality rates in the surgical patients were between 20% and 28% depending on the timing of surgery and the grade of the patient. Patients in grade 3/4 (stuporose or comatose) had mortality rates between 39% and 79%. Overall good outcomes occurred in approximately 60% of patients, leaving approximately 20% of patients with residual morbidity. Of the patients planned for surgery between 11 and 14 days, 14% rebled pre-operatively. Many of these rebleeds were either fatal or resulted in a significantly poorer outcome. More recent surgical series of selected patients from experienced centres have suggested lower rates of serious morbidity and mortality following surgery. e.g. 15% for grades 1 and 2 in posterior circulation aneurysms operated acutely, but 19% overall for all grades.
A recent multicentre prospective randomised study examining the prevention of vasospasm with cisternal rTPA, showed a 3 month mortality of 19% and a good outcome in only 50% of patients with severe SAH operated within 48 hours of the haemorrhage (some of these patients were Grade 5). Three patients rebled between 14 days and 3 months after surgery. This emphasises the still serious outcome in the condition even with modern surgical management techniques in large centers’ (ISAT Trial - go to protocol)
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