Joel Verter

Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial

Children with sickle cell anemia have an increased susceptibility to bacterial infections, especially to those caused by Streptococcus pneumoniae. We therefore conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial to test whether the regular, daily administration of oral penicillin would reduce the incidence of documented septicemia due to S.pneumoniae in children with sickle cell anemia who were under the age of three years at the time of entry. The children were randomly assigned to receive either 125 mg of penicillin V potassium (105 children) or placebo (110 children) twice daily. The trial was terminated 8 months early, after an average of 15 months of follow-up, when an 84 percent reduction in the incidence of infection was observed in the group treated with penicillin, as compared with the group given placebo (13 of 110 patients vs. 2 of 105; P = 0.0025), with no deaths from pneumococcal septicemia occurring in the penicillin group but three deaths from the infection occurring in the placebo group. On the basis of these results, we conclude that children should be screened in the neonatal period for sickle cell hemoglobinopathy and that those with sickle cell anemia should receive prophylactic therapy with oral penicillin by four months of age to decrease the morbidity and mortality associated with pneumococcal septicemia.

Coronary Artery Disease in 116 Kindred with Familial Type II Hyperlipoproteinemia

Analysis of cardiovascular status in adult relatives of 116 kindred affected with familial hyperbetalipoproteinemia (type II hyperlipoproteinemia) was carried out to assess coronary artery disease (CAD) risk in relatives with type II (II) compared to unaffected family members. Over 90% of the 738 living relatives were interviewed by one investigator and 12 lead electrocardiograms were obtained. In these, and in 285 deceased relatives, physician and hospital records were utilized to determine CAD events by standard criteria. This study, the largest of its kind, permitted more precise and extensive determination of the CAD risk accompanying severe hyperbetalipoproteinemia than has heretofore been possible. CAD was diagnosed in 29.5% of IIs compared with 10.5% of normal relatives (N) (P < .001). The IIs and Ns did not differ significantly with regard to age distribution, sex, hypertension, smoking habits, or body mass index. According to the Rose questionnaire, angina pectoris was diagnosed in 21.8% of IIs and 6.5% of Ns (P < .001). Documented myocardial infarction occurred in 6% of IIs versus 1% of Ns (P = .002). CAD death or myocardial infarction occurred in 10.1% of IIs compared with 1.8% of Ns (P < .001). The cumulative probability of nonfatal or fatal CAD by age 40 in male IIs was 16% (1 in 6); by age 60, the expectation of an event had risen to 52% (1 in 2). Among male Ns, the risk of nonfatal or fatal CAD by age 60 was 12.7%, lagging 20 years behind that seen in male IIs. In female IIs, the risk of nonfatal or fatal CAD by age 60 was 32.8% compared with only 9.1% in female Ns.

Persistent Pulmonary Hypertension of the Newborn in the Era Before Nitric Oxide: Practice Variation and Outcomes

Objectives. In the era before widespread use of inhaled nitric oxide, to determine the prevalence of persistent pulmonary hypertension (PPHN) in a multicenter cohort, demographic descriptors of the population, treatments used, the outcomes of those treatments, and variation in practice among centers. Study Design. A total of 385 neonates who received ≥50% inspired oxygen and/or mechanical ventilation and had documented evidence of PPHN (2D echocardiogram or preductal or postductal oxygen difference) were tracked from admission at 12 Level III neonatal intensive care units. Demographics, treatments, and outcomes were documented. Results. The prevalence of PPHN was 1.9 per 1000 live births (based on 71 558 inborns) with a wide variation observed among centers (.43–6.82 per 1000 live births). Neonates with PPHN were admitted to the Level III neonatal intensive care units at a mean of 12 hours of age (standard deviation: 19 hours). Wide variations in the use of all treatments studied were found at the centers. Hyperventilation was used in 65% overall but centers ranged from 33% to 92%, and continuous infusion of alkali was used in 75% overall, with a range of 27% to 93% of neonates. Other frequently used treatments included sedation (94%; range: 77%–100%), paralysis (73%; range: 33%–98%), and inotrope administration (84%; range: 46%–100%). Vasodilator drugs, primarily tolazoline, were used in 39% (range: 13%–81%) of neonates. Despite the wide variation in practice, there was no significant difference in mortality among centers. Mortality was 11% (range: 4%–33%). No specific therapy was clearly associated with a reduction in mortality. To determine whether the therapies were equivalent, neonates treated with hyperventilation were compared with those treated with alkali infusion. Hyperventilation reduced the risk of extracorporeal membrane oxygenation without increasing the use of oxygen at 28 days of age. In contrast, the use of alkali infusion was associated with increased use of extracorporeal membrane oxygenation (odds ratio: 5.03, compared with those treated with hyperventilation) and an increased use of oxygen at 28 days of age. Conclusions. Hyperventilation and alkali infusion are not equivalent in their outcomes in neonates with PPHN. Randomized trials are needed to evaluate the role of these common therapies.

The prognostic significance of proteinuria: The Framingham study☆

Despite considerable clinical experience with proteinuria, its prognostic meaning in the ambulatory general population is poorly documented. From a 16-year study of 5209 men and women in the Framingham cohort it is evident that proteinuria, even in casual urine specimens, carries substantial risk with the mortality rate increased threefold. Proteinuria was three times as common in hypertensive persons and also occurred to excess in diabetic patients and in persons with cardiac enlargement. In the absence of these factors, proteinuria was so uncommon that its risk could not be accurately assessed. Among persons with these associated risk factors, those with proteinuria have higher death rates than those without proteinuria. In men, overall mortality and cardiovascular mortality rates remained significantly increased even when other contributors to risk were taken into account. Proteinuria in the ambulatory general population is not a benign condition and carries a serious prognosis. It appears to reflect widespread vascular damage.

Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants

BACKGROUND Septicemia is a major antecedent of morbidity and mortality in very low birth weight (501- to 1500-g) infants. Our purpose was to determine prospectively the incidence, clinical presentation, laboratory features, risk factors, morbidity and mortality associated with late onset septicemia in infants 501 to 1500 g. METHODS Clinical data were prospectively collected for 2416 infants enrolled in a multicenter trial to determine the efficacy of intravenous immunoglobulin in preventing nosocomial infections. Septicemia was confirmed by positive blood culture in 395 symptomatic infants. Multivariate analyses of factors associated with septicemia were performed. RESULTS Sixteen percent of VLBW infants developed septicemia at a median age of 17 days. Factors associated with septicemia by logistic regression included male gender, lower gestational age and birth weight and decreased baseline serum IgG concentrations. Increasing apnea (55%), feeding intolerance, abdominal distension or guaiac-positive stools (43%), increased respiratory support (29%), lethargy and hypotonia (23%) were the dominant presenting features of septicemia. An abnormal white blood cell count (46%), unexplained metabolic acidosis (11%) and hyperglycemia (10%) were the most common laboratory indicators. Septicemic infants, compared with nonsepticemic infants, had significantly increased mortality (21% vs. 9%), longer hospital stay (98 vs. 58 days) and more serious morbidity, including severe intraventricular hemorrhage, bronchopulmonary dysplasia and increased ventilator days (P < 0.001). CONCLUSIONS Late onset septicemia is common in very low birth weight infants, and the rate is inversely proportional to gestational age and birth weight. Septicemia is more common in males and those with low initial serum IgG values. A set of clinical signs (apnea, bradycardia, etc.) and laboratory values (leukocytosis, immature white blood cells and neutropenia) increase the probability of late onset sepsis, but they have poor positive predictive value.

Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage

OBJECTIVE To determine the differences in short term outcome of very low birthweight infants attributable to sex. METHODS Boys and girls weighing 501–1500 g admitted to the 12 centres of the National Institute of Child Health and Human Development Neonatal Research Network were compared. Maternal information and perinatal data were collected from hospital records. Infant outcome was recorded at discharge, at 120 days of age if the infant was still in hospital, or at death. Best obstetric estimate based on the last menstrual period, standard obstetric factors, and ultrasound were used to assign gestational age in completed weeks. Data were collected on a cohort that included 3356 boys and 3382 girls, representing all inborn births from 1 May 1991 to 31 December 1993. RESULTS Mortality for boys was 22% and that for girls 15%. The prenatal and perinatal data indicate few differences between the sex groups, except that boys were less likely to have been exposed to antenatal steroids (odds ratio (OR) = 0.80) and were less stable after birth, as reflected in a higher percentage with lower Apgar scores at one and five minutes and the need for physical and pharmacological assistance. In particular, boys were more likely to have been intubated (OR = 1.16) and to have received resuscitation medication (OR = 1.40). Boys had a higher risk (OR > 1.00) for most adverse neonatal outcomes. Although pulmonary morbidity predominated, intracranial haemorrhage and urinary tract infection were also more common. CONCLUSIONS Relative differences in short term morbidity and mortality persist between the sexes.

Estimation of the multivariate logistic risk function: a comparison of the discriminant function and maximum likelihood approaches.

Abstract We have considered the case in which the multivariate logistic model holds for risk of disease. That is, we assume the probability that a person with independent variable values X 1 ,… , x k develops the disease is given by P(X 1 ,…X k )=[1+e −a− ∑ i=1 k β i x i ] −1 for some constants α and β i . Truett, Cornfield and Kannel [1] have proposed the use of the linear discriminant function in estimating the coefficients α and β i . Their method is theoretically correct if the distribution of ( x 1 ,…, x k ) is multivariate normal both for the well and for the diseased populations, with equal variance-covariance matrices in the two populations, or if the linear compound α + Σβ i x i is univariate normal for the two populations, again with equal variance-covariance matrices, where the β i are now the population values of the linear discriminant coefficients. Walker and Duncan [3] suggest an iterative procedure which gives maximum likelihood estimates for the coefficients. On theoretical grounds the maximum likelihood method is preferable, since it does not assume any particular distribution for ( x 1 ,…, x k ) and it gives results which asymptotically converge to the proper values if the logistic model holds [5]. On the other hand, the discriminant function approach is computationally simpler and may be more convenient to apply for very large amounts or data or when computer facilities are limited. We have compared the two methods theoretically, for the case when all independent variables are of the attribute type, and empirically, using Framingham 12-yr incidence data for (1) coronary heart disease and (2) CHD death or myocardial infarction. Our results suggest the following if the logistic model holds but the normality assumptions on the independent variables are violated: 1. (a) β i which are zero will tend to be estimated as zero for large samples by the method of maximum likelihood, but not necessarily by the discrimination function method; 2. (b) if any β i are non-zero they will tend to be estimated as non-zero by either method, but the discriminant function approach will give asymptotically biased estimates for those β i and for α; 3. (c) empirically, the assessment of significance for a variable, as measured by the ratio of the estimated coefficient to its estimated standard error, is apt to be about the same whichever method is used; 4. (d) empirically, the maximum likelihood method usually gives slightly better fits to the model, as evaluated from observed and expected numbers of cases per decile of risk; 5. (e) there is a theoretical basis for the possibility that the discriminant function will give a very poor fit, even if the model holds. Of course we are not able to show that conclusion (c) will hold generally, even though it holds for our examples. Moreover, conclusion (a) warns that use of the discriminant function technique can give misleading results regarding significance. Hence, it would seem that use of the maximum likelihood method would be preferable, whenever practical, in situations where the normality assumptions are violated, especially when many of the independent variables are qualitative.

Classification of deaths after myocardial infarction as arrhythmic or nonarrhythmic (The Cardiac Arrhythmia Pilot Study)

The Cardiac Arrhythmia Pilot Study (CAPS) was a randomized, double-blind trial of antiarrhythmic drugs (encainide, flecainide, moricizine, imipramine and placebo) in 502 patients with at least 10 ventricular premature complexes/hour, 6 to 60 days after acute myocardial infarction. CAPS tested the feasibility of performing a larger study to determine if suppression of ventricular ectopic activity after acute myocardial infarction could improve survival. Patients in CAPS were followed for 1 year. All death or cardiac arrest events were evaluated by at least 2 investigators using a classification scheme that characterized the underlying mechanism as cardiac arrhythmic, cardiac nonarrhythmic or noncardiac. Forty-five patients (9%) died or had cardiac arrest during the 1-year follow-up, 29 (64%) within 1 hour from the onset of symptoms and 16 greater than 1 hour from the onset of symptoms. Twenty-three deaths (51%) were classified as arrhythmic, 19 (42%) as nonarrhythmic and 3 (7%) as noncardiac. Acute myocardial ischemia or infarction was associated with the death/cardiac arrest event in 16 patients (36%), 8 in the arrhythmic death group. Discrepancies in classification among reviewers were particularly common in patients with long-standing symptoms of congestive heart failure, in whom it was frequently difficult to identify the precise moment of the onset of symptoms in the death/cardiac arrest event. Using only the temporal relation of symptoms to categorize deaths or cardiac arrests, the mechanism of 12 (27%) of the 45 patients was in disagreement with the classification based on the Events Committee review. Classification of death as sudden or nonsudden is not equivalent to the classification of death as arrhythmic or nonarrhythmic.

Bacteremia in sickle hemoglobinopathies

We analyzed 178 episodes of bacteremia that occurred during 13,771 patient-years of follow-up of 3451 patients with sickle hemoglobinopathies. Age-specific incidence rates of bacteremia were calculated for patients with sickle cell anemia (SS) and sickle cell-hemoglobin C (SC) disease. The incidence rate was highest among children with SS and SC younger than age 2 years. Children with SC showed an abrupt decrease after age 2 years, whereas children with SS had a gradual decline in rate from 2 to 6 years of age. The predominant pathogen in patients younger than 6 years was Streptococcus pneumoniae (66%); gram-negative organisms were responsible for 50% of bacteremias in patients 6 years and older. Urinary tract infection was present during 73% of Escherichia coli bacteremias, and 77% of Salmonella bacteremias were associated with osteomyelitis. In contrast, no focus of infection was present in 52% of pneumococcal bacteremias. The incidence of pneumococcal bacteremia in children with SS younger than age 3 years was 6.1 events/100 patient-years; the case fatality rate for pneumococcal sepsis in this age group was 24%. No hematologic or demographic variables were associated with occurrence of pneumococcal bacteremia in young children. Retrospective analysis of pneumococcal bacteremia suggests that the prophylactic use of penicillin may decrease the incidence in children younger than 3 years of age.

Discontinuing penicillin prophylaxis in children with sickle cell anemia

OBJECTIVE To evaluate the consequences of discontinuing penicillin prophylaxis at 5 years of age in children with sickle cell anemia who had received prophylactic penicillin for much of their lives. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING Eighteen teaching hospitals throughout the United States. PATIENTS Children with sickle cell anemia (hemoglobin SS or hemoglobin S beta 0-thalassemia) who had received prophylactic penicillin therapy for at least 2 years immediately before their fifth birthday and had received the 23-valent pneumococcal vaccine between 2 and 3 years of age and again at the time of randomization. Of 599 potential candidates, 400 were randomly selected and followed for an average of 3.2 years. INTERVENTIONS After randomization, patients received the study medication twice daily--either penicillin V potassium, 250 mg, or an identical placebo tablet. Patients were either seen in the clinic or contacted every 3 months thereafter for an interval history and dispensing of the study drug. A physical examination was scheduled every 6 months. MAIN OUTCOME MEASURES The primary end point was a comparison of the incidence of bacteremia or meningitis caused by Streptococcus pneumoniae in children continuing penicillin prophylaxis versus those receiving the placebo. RESULTS Six children had a systemic infection caused by S. pneumoniae, four in the placebo group (2.0%; 95% confidence interval 0.5%, 5.0%) and two in the continued penicillin prophylaxis group (1.0%; 95% confidence interval 0.1%, 3.6%) with a relative risk of 0.5 (95% confidence interval 0.1, 2.7). All invasive isolates were either serotype 6(A or B) or serotype 23F. Four of the isolates were penicillin susceptible, and two (one from each treatment group) were penicillin and multiply antibiotic resistant. Adverse effects of the study drug were reported for three patients (nausea, vomiting, or both), one of whom was in the placebo group. CONCLUSION Children with sickle cell anemia who have not had a prior severe pneumococcal infection or a splenectomy and are receiving comprehensive care may safely stop prophylactic penicillin therapy at 5 years of age. Parents must be aggressively counseled to seek medical attention for all febrile events in children with sickle cell anemia.