The most serious complication of childhood acute immune thrombocytopenic purpura (ITP), intracranial haemorrhage, occurs in about 1% of children with platelet counts below 20 x 10(9)/L. We conducted a randomised study to explore three treatment options in this high-risk group. 146 children (> 6 months and < 18 years old) with typical acute ITP and platelet counts of 20 x 10(9)/L or lower were randomised to receive high-dose intravenous immunoglobulin G (IVIgG) 1 g/kg on 2 consecutive days (n = 34), 0.8 g/kg once (n = 35), intravenous anti-D 25 micrograms/kg on 2 consecutive days (n = 38), or oral prednisone 4 mg/kg per day with tapering and discontinuation of prednisone by day 21 (n = 39). The rate of response as reflected by the number of days with platelet counts at 20 x 10(9)/L or lower and the time taken to achieve a platelet count 50 x 10(9)/L or more was significantly faster for both IVIgG groups than for the anti-D group (p < 0.05); the difference between prednisone and IVIgG was significant (p < 0.05) only for the IVIgG 0.8 g/kg group, and responses to the two IgG groups were similar. These differences in response rates were reflected in the percentages of children with platelet counts of 20 x 10(9)/L or lower at 72 hours following the start of treatment: 3% (IVIgG 0.8 g/kg x 1), 6% (IVIgG 1 g/kg x 2), 18% (anti-D), and 21% (oral prednisone 4 mg/kg/day). Treatment-associated toxicities included a fall in haemoglobin with anti-D (to less than 100 g/L in 24% of cases); weight gain with oral prednisone; and fever, nausea, vomiting, and headache with IVIgG. On the basis of these results, intravenous anti-D cannot be recommended as initial therapy for children with acute ITP and platelet counts of 20 x 10(9)/L or lower. A single dose of 0.8 g/kg IVIgG offers the fastest recovery for the least treatment; additional IgG or oral prednisone can be reserved for the one-third of children who continue to have platelet counts of 20 x 10(9)/L or less at 48-72 hours after the start of treatment.

Although midazolam is used for sedation of mechanically ventilated newborn babies, this treatment has not been evaluated in a randomised trial. We have done a prospective placebo-controlled study of the effects of midazolam on haemodynamic variables and sedation as judged by a five-item behaviour score. 46 newborn babies on mechanical ventilation for respiratory distress syndrome were randomly assigned to receive midazolam (n = 24) or placebo (n = 22) as a continuous infusion. Doses of midazolam were calculated to obtain plasma concentrations between 200 and 1000 ng/mL within 24 h of starting treatment and to maintain these values throughout the study. Haemodynamic and ventilatory variables were noted every hour, as were complications and possible side-effects of treatment. Mean (SD) duration of inclusion was 78.7 (30.9) h. 1 patient in the treatment group and 7 in the placebo group were withdrawn because of inadequate sedation (p < 0.05). Midazolam gave a significantly better sedative effect than placebo, as estimated by the behaviour score (p < 0.05). Heart rate and blood pressure were reduced by treatment but remained within the normal range for gestational age and there was no effect on ventilatory indices. The incidence of complications was similar in the two groups. No midazolam-related side-effects were noted. Continuous infusion of midazolam at doses adapted to gestational age induces effective sedation in newborn babies on mechanical ventilation, with positive effects on haemodynamic variables. The course of the respiratory distress syndrome was not influenced by this treatment. Midazolam was given over only a few days and the limited effects on heart rate and blood pressure that we report should not encourage long-term administration.

It has yet to be established whether substantial reduction of plasma lipids will lead to retardation, and to what extent and how quickly, of diffuse and focal coronary atheroma. The Multicentre Anti-Atheroma Study (MAAS) is a randomised double-blind clinical trial of 381 patients with coronary heart disease assigned to treatment with diet and either simvastatin 20 mg daily or placebo for 4 years. Patients on simvastatin had a 23% reduction in serum cholesterol, a 31% reduction in low-density lipoprotein cholesterol, and a 9% increase in high-density lipoprotein cholesterol compared with placebo over 4 years. Quantitative coronary angiography was done at baseline, and after 2 and 4 years. 167 patients (89%) on placebo and 178 (92%) on simvastatin had baseline and follow-up angiograms. In the placebo group there were reductions in mean lumen diameter (-0.08 mm) and in minimum lumen diameter (-0.13 mm). Treatment effects were +0.06 (95% CI 0.02 to 0.10) and +0.08 mm (0.03 to 0.14) for mean and minimum lumen diameter, respectively (combined p = 0.006). Patients on placebo had an increase in mean diameter stenosis of 3.6% and the treatment effect of simvastatin was -2.6% (-4.4 to -0.8). Treatment effects were observed regardless of diameter stenosis at baseline. On a per-patient basis, angiographic progression occurred less often in the simvastatin group, 41 versus 54 patients; and regression was more frequent, 33 versus 20 patients (combined p = 0.02). Significantly more new lesions and new total occlusions developed in the placebo group, 48 versus 28, and 18 versus 8, respectively. There was no difference in clinical outcome. The numbers of patients who died or had a myocardial infarction were 16 and 14 in the placebo and simvastatin groups, respectively. In the placebo group more patients underwent coronary angioplasty or re-vascularisation, 34 versus 23 on simvastatin. The trial showed that 20 mg simvastatin daily over 4 years reduces hyperlipidaemia and slows progression of diffuse and focal coronary atherosclerosis.

Biliary stents are liable to clog. We investigated whether a choleretic plus an antibiotic could delay clogging. 20 consecutive patients with a malignant biliary stricture were randomised after endoscopic insertion of a polyethylene stent to receive ursodeoxycholic acid plus norfloxacin (13-15 mg/kg and 400 mg, daily) or conservative treatment. The drug combination was associated with: a longer median patency of first (49 vs 6 weeks) and all stents (38 vs 7 weeks); a prolonged median survival (67 vs 18 weeks); and a shorter mean hospital stay (0.2 vs 1.0 days per week of survival). Thus ursodeoxycholic acid plus norfloxacin may prevent stent clogging.

In retrospective studies, perioperative blood transfusions were associated with poor prognosis after surgery for cancer and were a major independent risk factor for postoperative bacterial infection. Leucocyte-depleted, in contrast to buffy-coat-depleted, blood has no immunosuppressive effects in transplantation and so might lack detrimental effects on cancer prognosis and postoperative infections. We studied this hypothesis in a controlled trial by randomly allocating patients to receive either leucocyte-depleted red cells or packed cells without buffy coat when blood was needed. Between 1987 and 1990, 871 eligible patients with colorectal cancer, including 697 patients operated upon with curative intent, were randomised in the 16 participating hospitals. Neither the eligible group nor the curative group showed significant differences between the two trial transfusions in survival, disease-free survival, cancer recurrence rates, or overall infection rates after an average follow-up of 36 months. Patients who had a curative resection and who received blood of any sort had a lower 3-year survival than non-transfused patients (69% vs 81%, p = 0.001) and a higher infection rate (39% vs 24%, p < 0.001). Colorectal cancer recurrence rates, however, were not influenced by blood transfusion (30% vs 26%, p = 0.22). These combined observations confirm the association between blood transfusion and poor patient survival but indicate that the relation is not due to promotion of cancer.

The mortality of critically ill patients with acute renal failure has been halved through intervention by haemodialysis. However, several reports suggest that the course of the disorder may be prolonged by this procedure. Our prospective randomised study was done to see whether the generation of inflammatory mediators by bio-compatible membranes has an adverse effect on the outcome of acute renal failure. 52 patients, similar in age, severity of acute renal failure, general disease status (APACHE II), and management of acute renal failure or its related conditions, were divided into two groups. Haemodialysis was done with cuprophane or polyacrylonitrile membranes. Cuprophane membranes induced intense activation of the complement system (as judged by measurement of C3a) and lipooxygenase pathway (leukotriene B4) resulting in alterations of neutrophil kinetics and function. The cuprophane group had a lower survival rate (38 vs 65%), a higher proportion of patients dying from sepsis (71 vs 40%), required more haemodialysis sessions (12 vs 9), and demonstrated delayed resolution and recovery from acute renal failure than the polyacrylonitrile group. The difference in mortality regarding lethal sepsis as cause of death was statistically significant. Our observations indicate that the outcome of critically ill patients with acute renal failure may be influenced by bio-incompatibility reactions to the dialysis membrane. These results have direct implications for such patients on haemodialysis.

Preterm, low-birthweight (LBW) newborn infants are at high risk of neonatal mortality and morbidity and need early referral for special paediatric care. In developing countries, birthweight and gestational age often cannot be measured and a practical screening tool based on surrogate neonatal body measurements to identify high-risk infants would be very useful. We studied a consecutive series of 843 singleton infants born at a referral hospital in Addis Ababa, Ethiopia. Gestational age, birthweight, and four body measurements (chest, head, and mid-arm circumferences and length) were accurately recorded. We randomly divided the series into equal-sized training and validation groups. In the training group, we used a recursive partitioning technique to develop a simple predictive algorithm--infants were classified as high risk if head circumference was 31 cm or less or if chest circumference was 30 cm or less, and were classified as low risk otherwise. When tested in the validation group, this algorithm had sensitivity, specificity, and negative predictive value for prediction of preterm and LBW births above 90%. Thus, neonatal body measurements can be combined into a pragmatic, accurate screening tool suitable for clinical use in developing countries.

In severe heart failure many deaths are sudden and are presumed to be due to ventricular arrhythmias. The GESICA trial evaluated the effect of low-dose amiodarone on two-year mortality in patients with severe heart failure. Our prospective multicentre trial included 516 patients on optimal standard treatment for heart failure. Patients were randomised to 300 mg/day amiodarone (260) or to standard treatment (256). Intention-to-treat analysis showed 87 deaths in the amiodarone group (33.5%) compared with 106 in the control group (41.4%) (risk reduction 28%; 95% CI 4%-45%; log rank test p = 0.024). There were reductions in both sudden death (risk reduction 27%; p = 0.16) and death due to progressive heart failure (risk reduction 23%; p = 0.16). Fewer patients in the amiodarone group died or were admitted to hospital due to worsening heart failure (119 versus 149 in the control group; risk reduction 31%; 95% CI 13-46%; p = 0.0024). The decrease in mortality and hospital admission was present in all subgroups examined and independent of the presence of non-sustained ventricular tachycardia. Side-effects were reported in 17 patients (6.1%); amiodarone was withdrawn in 12. Low-dose amiodarone proved to be an effective and reliable treatment, reducing mortality and hospital admission in patients with severe heart failure independently of the presence of complex ventricular arrhythmias.

We did a prospective study of women with singleton viable pregnancies at 10-13 weeks' gestation who requested first-trimester fetal karyotyping because of advanced maternal age, parental anxiety, or family history of chromosomal abnormality. Women were counselled as to the available options of non-invasive screening or invasive testing by mid-trimester amniocentesis, early amniocentesis (EA), or chorionic villus sampling (CVS), or randomisation to EA or CVS at 10-13 weeks. EA was done in 731 patients (493 by choice and 238 by randomisation) and CVS in 570 (320 by choice and 250 by randomisation). Both procedures were done by transabdominal ultrasound-guided insertion of a 20-gauge needle. The rate of successful sampling was the same for both procedures (97.5%). Spontaneous loss (intrauterine or neonatal death) was significantly higher after EA (total group mean = 5.3%, 95% CI 3.8-7.2; randomised subgroup mean = 5.9%, 3.3-9.7) than after CVS (total group: mean = 2.3%, 1.2-3.9; randomised subgroup: mean = 1.2%, 0.3-3.5). The gestation at delivery and birthweight of the infants after EA and CVS were similar. In the EA group the incidence of talipes equinovarus (1.63%), was higher than in the CVS group (0.56%), but this difference was not significant.

Studies in the USA and Japan have shown that tacrolimus (FK506) is a potent immunosuppressant. To compare the efficacy and safety of tacrolimus-based and conventional cyclosporin-based immunosuppressive regimens we recruited 545 liver transplant recipients from eight European centres into a randomised open trial. Analysis of the data at 12 months post-transplant showed that tacrolimus was associated with a significant reduction in acute, refractory acute, and chronic rejection episodes. The rates were, for acute rejection, tacrolimus 40.5% vs 49.8% cyclosporin (p = 0.040; absolute difference 9.3% [95% CI 0.9-17.8%]). For refractory acute and chronic rejections the comparisons were 0.8% vs 5.3% (p = 0.005) and 1.5% vs 5.3% (p = 0.032). There results were seen despite significantly lower corticosteroid usage. The incidence of infection was also lower in patients receiving tacrolimus. Patient and graft survival rates were not significantly different (tacrolimus 82.9% and 77.5%; cyclosporin 77.5% and 72.6%). Safety data were comparable--the most serious events being renal impairment, disturbances of glucose metabolism, and neurological complications--but these events were more common in the tacrolimus group. In this trial tacrolimus had advantages over cyclosporin in respect of lower rejection rates, even though less concurrent immunosuppression was administered.

The risk of blood-borne diseases has substantially increased the use of autologous blood transfusion. Many autologous donors, however, still need homologous transfusions. To find out whether recombinant erythropoietin (rhEPO) reduces requirements for homologous blood transfusion, we carried out a randomised, controlled trial, in which patients were stratified according to blood volume. We studied 95 autologous blood donors undergoing elective hip surgery. 50 patients were randomly assigned 500 U/kg rhEPO subcutaneously twice a week for 3 weeks, and 45 patients received no treatment (control group). The patients each donated two units of blood before surgery. Only 5 (10%) rhEPO-treated patients received homologous transfusions compared with 16 (36%) controls (p < 0.01). rhEPO was most useful in patients with a blood volume below 4 L and an estimated blood loss below 2 L or with a blood volume of 4-5 L and blood loss of 1-2 L. Continued administration of rhEPO caused no further increase in reticulocyte counts after the fourth injection, which was accompanied by a pronounced depletion of storage iron. rhEPO treatment had no effect on renal function, platelet count, or blood pressure. Subcutaneous rhEPO is an effective and safe way to reduce exposure to homologous blood in autologous donors. Its use can be restricted to a subpopulation of autologous blood donors, which improves the cost-effectiveness of this expensive approach.

In developing countries, the age at which breastfed infants are first given complementary foods is of public health importance because of the risk of diarrhoeal disease from contaminated weaning foods, and the potential risk of growth faltering if foods are inappropriately delayed. To evaluate whether there are any advantage of complementary feeding prior to 6 months, low-income primiparous mothers who had exclusively breastfed for 4 months were randomly assigned to one of 3 groups: continued exclusive breastfeeding to 6 months (EBF) (n = 50); introduction of complementary foods at 4 months with ad libitum nursing from 4-6 months (SF) (n = 47); and introduction of complementary foods at 4 months, with maintenance of baseline nursing frequency from 4-6 months (SF-M) (n = 44). Baby foods in jars were provided to the SF and SF-M groups from 4 to 6 months. Subjects were visited weekly and provided with lactation guidance; at 4, 5, and 6 months measurements were made of infant intake and breast milk composition. At 4 months, breast milk intake averaged 797 (139) g per day (no difference among groups). Between 4 and 6 months, breast milk intake was unchanged in EBF infants (+6) but decreased in the SF (-103), and SF-M (-62) groups (p < 0.001). Change in total energy intake (including solid foods) and infant weight and length gain did not differ significantly between groups. Weight and length gain from 4-6 months were comparable to those of breastfed infants in an affluent USA population. The results indicate that breastfed infants self-regulate their total energy intake when other foods are introduced. As a result, there is no advantage in introducing complementary foods before 6 months in this population, whereas there may be disadvantages if there is increased exposure to contaminated weaning foods.

A beneficial effect of periodic vitamin A supplementation on childhood mortality has been demonstrated, but the effect on morbidity is less clear. We investigated the effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections (ALRI) in children from northeastern Brazil in a randomised, double-blind, placebo-controlled community trial. 1240 children aged 6-48 months were assigned vitamin A or placebo every 4 months for 1 year. They were followed up at home three times a week, and data about the occurrence and severity of diarrhoea and ALRI were collected. Any child with cough and respiratory rate above 40 breaths per min was visited by a paediatrician. The overall incidence of diarrhoea episodes was significantly lower in the vitamin-A-supplemented group than in the placebo group (18.42 vs 19.58 x 10(-3) child-days; rate ratio 0.94 [95% Cl 0.90-0.98]). The benefit of supplementation was greater as regards severe episodes of diarrhoea; the incidence was 20% lower in the vitamin A group than in the placebo group (rate ratio 0.80 [0.65-0.98]). With the standard definition of diarrhoea (> or = 3 liquid or semi-liquid stools in 24 h) the effect of vitamin A on mean daily prevalence did not reach significance, but as the definition of diarrhoea was made more stringent (increasing number of stools per day), a significant benefit became apparent, reaching for diarrhoea with 6 or more liquid or semi-liquid stools in 24 h a 23% lower prevalence. We found no effect of vitamin A supplementation on the incidence of ALRI. The reduction in severity of diarrhoea may be the most important factor in the lowering of mortality by vitamin A supplementation.

Guidelines on asthma management recommend that in patients who still have symptoms on treatment with low-dose inhaled corticosteroids the first step should be an increase in inhaled corticosteroid dose. The addition of long-acting inhaled beta 2-adrenoceptor agonists is another option. We have compared these two strategies in a randomised, double-blind, parallel-group trial. We studied 429 adult asthmatic patients who still had symptoms despite maintenance treatment with 200 micrograms twice daily inhaled beclomethasone dipropionate (BDP). 3 did not provide verifiable data. Of the others, 220 were assigned salmeterol xinafoate (50 micrograms twice daily) plus BDP and 206 were assigned higher-dose BDP (500 micrograms twice daily) for 6 months. The mean morning peak expiratory flow increased from baseline in both groups, but the increase was greater in the salmeterol/BDP group than in the higher-dose BDP group at all time points (differences 16-21 L/min, p < 0.05). Mean evening PEF also increased with salmeterol/BDP but not with higher-dose BDP. There were significant differences in favour of salmeterol/BDP in diurnal variation of PEF (all time points) and in use of rescue bronchodilator (salbutamol) and daytime and night-time symptoms (some time points). There was no significant difference between the groups in adverse effects or exacerbations of asthma, indicating that in this group of patients regular beta 2-agonist therapy was not associated with any risk of deteriorating asthma control over 6 months. This study suggests a need for a flexible approach to asthma management.

The effect of oral aspirin on the healing rate of chronic venous leg ulcers was compared with that of placebo in a double-blind randomised trial. 20 subjects with chronic venous leg ulcers were randomised to daily enteric-coated aspirin 300 mg or placebo, and standardised compression bandaging. 4 months of treatment achieved ulcer healing in 38% of the patients receiving aspirin compared with 0% of those receiving placebo (p < 0.007). 52% of the aspirin-treated group showed significant reduction in ulcer size compared with 26% of placebo recipients (p < 0.007). Reduction in ulcer surface area was significantly better in the aspirin-treated group at 2 (p < 0.01) and 4 months (p < 0.002) compared with that in the placebo group.

The safety and immunogenicity of a new virosome influenza vaccine was compared to commercial whole-virus vaccine and subunit vaccine in elderly people. The virosome vaccine was made by extracting the haemagglutinin from influenza virus and incorporating it into the membrane of liposomes composed of phosphatidylcholine (PC) and phosphatidylethanolamine (PE). 126 residents of a nursing home, aged 63-102, were randomised to receive one of the vaccines. All three were well tolerated and caused a significant rise in the geometric mean anti-haemagglutinin inhibiting (HAI) antibody titre to the 3 vaccine components (H1N1 Singapore, H3N2 Beijing, and B/Yamagata). The virosome formulation caused the highest geometric mean titres in addition to significantly (p = 0.039-0.0016) higher rates of more than four-fold or more titre rises to all 3 vaccine components. The percentage of those immunised who achieved protective levels of antibody (HAI > or = 40) was significantly (p = 0.035-0.0017) higher for the H1N1 and B/Yamagata strains following immunisation with virosome formulation. Participants with non-protective baseline titres to the H1N1 or B/Yamagata strains were more likely (p = 0.0049-0.006) to achieve protective levels of antibodies after immunisation with the virosome vaccine. Immunisation with the virosome formulation did not result in a significant rise in anti-PC or anti-PE antibodies.