Physicians declining patient enrollment in a critical care trial: a case study in thromboprophylaxis.

PURPOSE: To analyze the frequency, rationale and determinants of attending physicians requesting that their eligible patients not be approached for participation in a thromboprophylaxis trial. METHODS: Research personnel in 67 centers prospectively documented eligible non-randomized patients due to physicians declining to allow their patients to be approached. RESULTS: In 67 centers, 3,764 patients were enrolled, but 1,460 eligible patients had no consent encounter. For 218 (14.9 %) of these, attending physicians requested that their patients not be approached. The most common reasons included a high risk of bleeding (31.2 %) related to fear of heparin bioaccumulation in renal failure, the presence of an epidural catheter, peri-operative status or other factors; specific preferences for thromboprophylaxis (12.4 %); morbid obesity (9.6 %); uncertain prognosis (6.4 %); general discomfort with research (3.7 %) and unclear reasons (17.0 %). Physicians were more likely to decline when approached by less experienced research personnel; considering those with[10 years of experience as the reference category, the odds ratios (OR) for physician refusals to personnel without trial experience was 10.47 [95 % confidence interval (CI) 2.19-50.02] and those with less than 10 years experience was 1.72 (95 % CI 0.61-4.84). Physicians in open rather than closed units were more likely to decline (OR 4.26; 95 % CI 1.27-14.34). Refusals decreased each year of enrollment compared to the pilot phase. CONCLUSIONS: Tracking, analyzing, interpreting and reporting the rates and reasons for physicians declining to allow their patients to be approached for enrollment provides insights into clinicians' concerns and attitudes to trials. This information can encourage physician communication and education, and potentially enhance efficient recruitment.

A pilot prospective study of the vascular repair response following red cell transfusion in critically ill patients.

BACKGROUND: Red blood cell transfusion has been associated with adverse outcomes including infection, delayed recovery and increased mortality in some patient populations. Circulating cells that yield endothelial-like vascular progenitor cell (VPC) clusters are correlated with vascular repair and recovery after ischaemic injury. The impact of red cell transfusion on VPC clusters and vascular repair remains uncertain. STUDY DESIGN: We prospectively enrolled patients admitted to intensive care requiring red cell transfusion and subjects at low likelihood of requiring red cell transfusion. Levels of VPC clusters and plasma levels of angiogenic cytokines were compared. A total of 17 patients were recruited and had blood samples collected at time of enrolment and at 24-48 h, 48-72 h and 1 week following transfusion. RESULTS: We could not discern differences in the number of VPC clusters between transfused patients (n = 6) and non-transfused subjects (n = 11) at baseline or throughout the study period. VPC cluster levels demonstrated wide variance and were highest at 24-h post-enrolment in the entire cohort. Furthermore, levels of all 16 cytokines analysed were not significantly different between transfused and non-transfused patients and we did not observe a correlation between cytokine concentrations and levels of circulating VPC-cluster forming cells in the overall study population. CONCLUSIONS: Our data suggest that assessment of vascular repair responses after red blood cell transfusion in critically ill patients is challenging. Although our study did not allow us to discern an influence of red cell transfusion on VPC cluster levels or angiogenic cytokines, new methods evaluating vascular repair mechanisms may be required.

Very early onset seasonal affective disorder: a case study.

A four year old boy was referred from Scotland, with a seasonal pattern of depressive symptoms dating back to infancy and meeting criteria for Major Depressive Disorder with Seasonal Pattern by the age of three years. There was consistency in reports between informants and across contexts and significant improvement with light therapy.

Neonatal mortality in a rural area of The Gambia.

Childhood mortality in Upper River Division, The Gambia is high, 99 per 1000 mid-year population, and 27% of deaths occur is the neonatal period. The aims of the present study were to describe patterns of neonatal death and to identify risk factors. Cause of death was investigated using a neonatal post-mortem questionnaire, and a population-based, matched case-control study was conducted to identify potential risk factors. The neonatal mortality rate in Upper River Division was 39 per 1000 live births (95% CI 36.8-41.2). The rates in the early and late neonatal periods were 21.0 (19.4-22.6) and 18.0 (16.5-19.5), respectively. Infection accounted for 57% of all deaths. In the early neonatal period, 30% of deaths were due to prematurity. Only 55% of babies who died presented for treatment and 84% died at home. Risk factors for neonatal death were primiparity (OR 2.18), previous stillbirth (OR 3.19), prolonged labour (OR 2.80) and pre-lacteal feeding (OR 3.38). A protective effect was seen in association with delivery by a trained traditional birth attendant (OR 0.34) and the application of shea nut butter, a traditional medicine, to the cord stump (OR 0.07). This study has identified the need to understand the reasons underlying the widespread use of pre-lacteal feeds and the barriers to health service use in this community in order to plan effective interventions.

Nasopharyngeal carriage of pneumococci in Gambian children and in their families.

BACKGROUND: Nasopharyngeal carriage of pneumococci is prevalent among children in developing countries but little is known about the relationship of nasopharyngeal carriage to invasive disease or about the way in which pneumococci spread within households. OBJECTIVES: To determine the prevalence of nasopharyngeal carriage in healthy and sick Gambian children and to investigate transmission within households. METHODS: Nasopharyngeal swabs were obtained by the per nasal route and cultured for pneumococci on selective media. Pneumococci were serotyped with the use of latex particles coated with type-specific antisera. RESULTS: Pneumococci were isolated from the nasopharynx of 73 (90.1%) of 81 children with invasive pneumococcal disease, 86 (76.1%) of 113 healthy, age-matched control children and 911 (85.1%) of 1071 sick children. Pneumococci belonging to serotypes 1, 14 and 12 were isolated significantly more frequently from cases than from matched controls. In 43 (76.8%) of 56 children with invasive disease, pneumococci isolated from the nasopharynx and from the blood or other sterile site belonged to the same serotype. Pneumococci of the same serotype as the bacterium responsible for invasive disease in a child were obtained from 72 (8.5%) of 843 family members, most frequently from young siblings of the case patients. CONCLUSION: Nasopharyngeal carriage of pneumococci is more prevalent among young Gambian children than among adults and invasive infections are probably acquired more frequently from siblings than from parents. However, further studies are needed to confirm this hypothesis with more discriminating markers than polysaccharide serotyping.

A study of risk factors for pneumococcal disease among children in a rural area of west Africa.

BACKGROUND: Pneumoccal infection is one of the leading causes of pneumonia, meningitis and septicaemia in developing countries. We have investigated possible risk factors for pneumococcal disease among children living in a rural area of The Gambia. METHODS: A prospective case-control study was conducted in which children with pneumococcal infection were identified from among children attending out-patient and under-fives clinics and matched according to age with healthy children selected randomly from the local community. A questionnaire was used to investigate possible nutritional, medical, socioeconomic and environmental risk factors for pneumococcal disease. RESULTS: An increased risk of pneumococcal disease was associated with poor weight gain, a history of serious illness in the previous 6 months, exposure to cigarette smoke or being carried on mother's back while cooking. The risk of pneumococcal disease was reduced among children whose mothers had a personal source of income. CONCLUSIONS: The incidence of pneumococcal disease could be reduced by improving nutrition and taking steps to identify and rehabilitate those children whose weight is faltering or falling. Encouraging mothers to develop greater financial independence may also be beneficial. Reduced exposure to smoke should be promoted by improving ventilation in kitchens, introducing more efficient and less polluting stoves, keeping children away from smoky environments and discouraging parental smoking.

PIP: Pneumococcal infection is a leading cause of pneumonia, meningitis, and septicemia in developing countries. The authors investigated possible risk factors for pneumococcal disease during 1989-91 among children living in the rural Upper River Division of The Gambia. A prospective case-control study approach was used in which 80 children with pneumococcal infection were matched according to age with 159 healthy children randomly selected from the local community. The subjects were of mean age 14.0-14.2 months. A questionnaire was used to identify possible nutritional, medical, socioeconomic, and environmental risk factors for pneumococcal disease. The study found an increased risk of pneumococcal disease to be associated with poor weight gain, a history of serious illness during the previous 6 months, exposure to cigarette smoke, or being carried upon a mother's back while she cooks. The risk of pneumococcal disease was reduced among children whose mothers had a personal source of income. The authors suggest reducing the incidence of pneumococcal disease by improving nutrition and growth monitoring, encouraging mothers to develop greater financial independence, and reducing children's exposure to smoke.

Immunization with a pneumococcal capsular polysaccharide vaccine during pregnancy.

The feasibility of preventing invasive pneumococcal infections during the first few months of life by immunization during pregnancy has been investigated. One hundred and fifty Gambian women were immunized with either a 23-valent pneumococcal polysaccharide vaccine or a meningococcal polysaccharide vaccine during the last trimester of pregnancy. Pregnant women showed a good antibody response to five of the six pneumococcal polysaccharides tested (types 1, 3, 5, 6, 14 and 19) but not to type 6 polysaccharide. Mean cord blood/maternal blood IgG antibody ratios varied from 24% (type 1) to 49% (type 3) and differed substantially between individual mother/infant pairs. Pneumococcal antibody levels were higher at birth in infants of women immunized with pneumococcal polysaccharide vaccine than in control infants. However, these antibodies disappeared rapidly during the first few months of life and it is uncertain how much clinical protection against pneumococcal infection maternal immunization would have provided.

Pneumococcal disease among children in a rural area of west Africa.

BACKGROUND: The pneumococcus is a frequent cause of pneumonia and other serious infections among young children in developing countries. Defining the pattern of pneumococcal infection in these countries is important so that, with the advent of pneumococcal conjugate vaccines, rational vaccination policies can be developed. METHODS: Children younger than 5 years of age who attended clinics in a rural area of The Gambia, West Africa, were screened by assistants during a 2-year period. Children with predefined features suggestive of a diagnosis of pneumonia, meningitis or septicemia were referred to the Medical Research Council Field Station at Basse for investigation. RESULTS: Of 2898 children investigated 103 cases of invasive pneumococcal disease (70 definite and 33 probable) were identified, suggesting that the incidence of this infection in the study community is at least 554/100,000/year in children younger than 1 year of age and 240/100,000/year in those younger than 5 years, rates many times higher than those found in industrialized societies. The mean age of presentation was 15 months; more boys than girls were affected. Cases of pneumonia were encountered 8 times more frequently than those of meningitis. Antibiotic resistance was rarely found and cases of pneumonia, but not meningitis, responded well to treatment. Case-fatality rates in children with pneumonia and meningitis were 1 and 55%, respectively. The most prevalent pneumococcal serotypes were types 6, 14, 19, 1 and 5. CONCLUSION: About 60% of invasive pneumococcal infection in children in this community could potentially be prevented by a nine-valent pneumococcal conjugate vaccine (types 1, 4, 5, 6B, 9, 14, 18, 19F and 23) given at the ages of 2, 3 and 4 months.

Predictors for a positive blood culture in African children with pneumonia.

BACKGROUND: Blood culture isolation rates for children with pneumonia are generally low. Therefore it would be helpful if epidemiologic studies could identify children who have a higher than average chance of yielding a positive culture. METHODS: Simple clinical and laboratory predictors of a positive blood culture were investigated in 1222 children younger than 5 years of age with pneumonia who presented at rural dispensaries in The Gambia, West Africa. RESULTS: A high temperature (chi square for linear trend, 24.1; P < 0.0001), a rapid respiratory rate (chi square for linear trend, 6.33; P = 0.010), dehydration (odds ratio, 2.33; P < 0.001), nasal flaring (odds ratio, 2.06; P = 0.001), grunting (odds ratio, 4.01; P < 0.001), dullness to percussion (odds ratio, 2.31; P < 0.001), bronchial breathing (odds ratio, 2.61; P < 0.001) and diminished breath sounds (odds ratio, 2.07; P < 0.001) were positive predictors for a positive blood culture. Wheezing (odds ratio, 0.16; P < 0.001) and malaria parasitemia (odds ratio, 0.26; P = 0.008) were negative predictors. A combination of these findings were used to assess how the number of cultures taken might be reduced without substantially reducing the yield of positive cultures. For example it was found that exclusion of children with a temperature of < 38.0 degrees C and/or a respiratory rate of < 50/min and/or wheezing would have reduced the number of cultures taken by 55.6% but would have led to a loss of only 31.3% of positive cultures. CONCLUSION: Careful selection of children investigated by blood culture could help to reduce the work required during the preparations for and conduct of pneumococcal vaccine trials.

Meningococcal antibody titres in infants of women immunised with meningococcal polysaccharide vaccine during pregnancy.

Seventy five Gambian women were immunised with a single dose of a group A+group C meningococcal polysaccharide vaccine during the last trimester of pregnancy. IgG antibody titres were measured in mothers and in their infants by an enzyme-linked immunosorbent assay (ELISA). All women had a good response to vaccination and maternal antibodies were high at the time of delivery (23.2 micrograms/ml for group A antibodies and 14.3 micrograms/ml for group C antibodies). However, only a proportion of this antibody crossed the placenta; cord blood:maternal antibody ratios were 30% for group A antibody and 44% for group C antibody, respectively. Considerable variability in cord blood:maternal blood ratios was seen between individuals. This could not be related to age, parity, or ethnic group. Mean group A and group C cord blood:maternal blood ratios were lower in women with serological evidence of syphilis than in seronegative women, and diminished transfer of group A antibody was noted in women with active malarial infection of the placenta. Antibody titres declined rapidly in infants and by the age of 3-4 months these had reached control values. Maternal immunisation may give infants some protection against group A and group C meningococcal disease but only during the first few months of life.

Importance of enteric bacteria as a cause of pneumonia, meningitis and septicemia among children in a rural community in The Gambia, West Africa.

Two thousand eight hundred ninety-eight children younger than 5 years old were investigated during a 2-year period in a rural area of The Gambia for possible pneumonia, meningitis or septicemia. After clinical examination and appropriate investigations, 1014 children were diagnosed as having pneumonia, 31 as having meningitis and 100 as having septicemia. Nine hundred seven children had a final diagnosis of malaria including 702 who satisfied the World Health Organization criteria for a diagnosis of pneumonia. A bacterial etiology was established in 115 (11%) patients with a final diagnosis of pneumonia, in 25 (81%) with meningitis and in 29 (29%) with suspected septicemia. Overall the pneumococcus was the leading pathogen identified among children with pneumonia and meningitis and ranked third among those with septicemia. However, during the wet season, when malaria transmission was highest, 50% of blood culture isolates obtained from children satisfying the World Health Organization criteria for a diagnosis of pneumonia were Salmonella or coliform species, and the pneumococcus and Haemophilus influenzae type b accounted for only 43% of isolates. Thus enteric bacteria may be as important as those bacteria more usually associated with respiratory disease among children presenting with a clinical picture of pneumonia during the wet season. This finding has important implications for case management and surveillance for antibiotic resistance.

Overlap in the clinical features of pneumonia and malaria in African children.

Pneumonia and malaria are common causes of childhood morbidity and mortality in many developing countries and simple guidelines have been proposed to facilitate their diagnosis by relatively unskilled health workers. We have studied children in The Gambia attending out-patient and under-five clinics with clinically suspected pneumonia (cough or difficulty in breathing and a raised respiratory rate) during periods of high or low malaria transmission. During a period of high malaria transmission, 33% of these children had radiological evidence of pneumonia (with or without malaria parasitaemia) compared to 38% who had malaria parasitaemia, no radiological evidence of pneumonia and no other obvious cause of fever. Corresponding figures during a period of low malaria transmission were 48% and 6% respectively. The clinical overlap between pneumonia and malaria has important implications for case management strategies and evaluation of disease-specific interventions in regions in which both pneumonia and malaria are prevalent.

The effect of temperature reduction on respiratory rate in febrile illnesses.

A raised respiratory rate is a useful sign in the diagnosis of pneumonia in children. It was observed that children with malaria and other febrile illnesses may also present with a raised respiratory rate. To determine the extent to which increased body temperature contributes to the raised respiratory rate observed in these children the effect of change in body temperature on respiratory rate was measured in 186 sick Gambian children with a raised respiratory rate, including those with pneumonia or malaria. A temperature dependent effect on respiratory rate of 3.7 breaths per minute per degree centigrade was demonstrated for the whole study cohort, with no significant difference between children with pneumonia or malaria. Twenty three per cent of children with pneumonia whose temperature fell had a final respiratory rate below that currently recommended by the World Health Organisation for the diagnosis of pneumonia. It is concluded that respiratory rate is to some extent dependent on body temperature in children with febrile illnesses such as pneumonia and malaria, but that this does not alone account for the raised respiratory rate seen in these children. The effect of reduction in body temperature on respiratory rate does not help to distinguish children with pneumonia from those with malaria. A history of recent use of an antipyretic or other measures to control fever is important when evaluating children for possible pneumonia.

Sensitivity of Plasmodium falciparum in The Gambia to co-trimoxazole.

In The Gambia co-trimoxazole is used widely to treat children with an acute respiratory infection (ARI). Because malaria may sometimes be mistaken for ARI, some children with malaria are treated with co-trimoxazole. Therefore, we investigated the sensitivity of Gambian isolates of Plasmodium falciparum to this drug. Six days after the start of treatment with co-trimoxazole 3.3% of blood films of 65 asymptomatic subjects were positive, and 7.7% were positive after 21 d. One of 10 patients with ARI and malaria treated with co-trimoxazole had a positive blood film 3 d after the start of treatment but was negative thereafter. All 10 patients recovered satisfactorily. Thirty 'wild' isolates of P. falciparum were tested in vitro against co-trimoxazole at a ration of 5 parts sulphamethoxazole (SMZ) to 1 part trimethoprim (TMP). The mean EC50s, using a 36 h assay, were 1.2 x 10(-7) and 2.5 x 10(-8) M for SMZ and TMP respectively. When a [3H]hypoxanthine incorporation assay was employed, values of 5.7 x 10(-7) M for SMZ and 1.2 x 10(-7) M for TMP were obtained. These values are well below the peak plasma concentration. Our findings suggest that co-trimoxazole is effective against falciparum malaria in The Gambia. However, if it were to be used widely, the parasite would be likely to develop resistance to this and other dihydrofolate reductase inhibitor antimalarials.

Factors affecting the duration of breast feeding: 2. Early feeding practices and social class.

Breast milk intake by babies on the third and the sixth postpartum day was measured by a test-weigh procedure in a group of 47 mothers and babies. Women who gave the largest amount of breast milk to their babies on the third postpartum day continued to breast feed for longer than women who gave smaller amounts. These mothers also suckled most frequently, gave least additional fluid to their babies, and their infants regained their birth weight most rapidly. However, an increased early milk intake and duration of breast feeding were both associated with higher social class. These results suggest that, although practices in the initiation of breast feeding are relevant, factors in the background and environment of the mother are also of fundamental importance. Thus recent emphasis on the importance of breast-feeding practices in the immediate puerperium should not divert attention from the equally important task of establishing the optimum conditions for breast feeding in the home environment of mothers.

How long should a breast feed last?

Patterns of milk flow were studied in 50 mothers who were breast-feeding normal birth-weight babies on days 5-7 of the puerperium by progressive test weighing at 5-min intervals during two consecutive feeds. Compared with a regime in which mothers attempted to feed for 10 X 10 min on alternate breasts, a regime of 5 X 5 X 5 X 5 min increased the amount of milk taken in the first 10 min did not influence the final milk intake of the suckling-induced prolactin release. The wide variation of breast-feeding patterns between mothers was demonstrated in respect of the duration of the feed (mean 17.3 min; S.D. +/- 3.1; range 7-30 min), the initial rate of milk flow (mean 6 g/min; S.D. +/- 4.2, range 1-14 g/min) and the final milk intake (mean 70.9 g; S.D. +/- 20.5, range 42-125 g). The advice to breast-feed for 20 min was in appropriate for the majority of mothers because the nutritive feeding time was 15 min or less in 75% of the feeding episodes. The milk intake correlated with the initial rate of milk flow but not with the duration of the feed, the infant's birth weight, or the time since the last feed. It is suggested that the duration of a breast feed should be determined by the infant's response and not by an arbitrary time schedule.

The relationship between suckling-induced prolactin response and lactogenesis.

The PRL response to suckling was studied during the first week of the puerperium. Mean basal levels of PRL showed no significant changing during the first week of the puerperium, but there were progressive rises in both the maximum suckling-induced response and the total area under the response curve, which reached peak values on the fourth day after delivery. Despite large variations between individuals in basal PRL levels (range, 0.3-7.0 U/liter), peak suckling-induced response (range, 0.1-9.9 U/liter), and total response (range, 0.6-63.0 arbitrary units), there was much less variability within individuals between consecutive feeds. Using an electronic balance, 20 patients on days 5 and 6 were classified either as good feeders (greater than 60 g milk/feed) or poor feeders (less than or equal to 60 g milk/feed) on the basis of 2 consecutive test weights. The mean PRL response to suckling in 11 good feeders was no different from that in 9 poor feeders, and there was no significant correlation between milk yield and PRL response. Six patients whose infants were in the special care nursery had lactation initiated and maintained by breast pump for an average of 5.6 days. Although the PRL response to the breast pump was very small, these patients also had satisfactory milk yields (mean, 86 g). Although the presence of PRL is essential for lactation, the data in this paper suggest that there is no close temporal correlation between PRL concentrations and milk yield.