Respiratory

1. RSV-positive infants were significantly less likely to have an SBI than those who tested negative (7% vs. 12.5%, RR 0.6, p < .05) and at reduced risk for SBI (OR 0.58).

2. Infants <28 days old were significantly more likely to have an SBI than older infants (10.1% vs. 5.5%).

Original Date of Publication: June 2004

Study Rundown: Serious bacterial infections (SBIs) such as meningitis and bacteremia, are sources of significant morbidity and mortality in febrile infants under two months of age. While many studies had investigated the risk factors for SBIs, at the time of this study, no researchers had investigated the potential interaction of viral infection in febrile infants on simultaneous SBI. This study investigated the risk of SBI in febrile infants diagnosed with respiratory syncytial virus (RSV) infections. RSV was associated with a reduced risk of concurrent SBI; however, many RSV-positive infants had simultaneous urinary tract infections and younger infants (<28 days old) were found to have statistically similar SBI rates regardless of RSV positivity. Potential clinical implications of this study include limiting testing for infants >1 month of age with RSV to urinalysis only, while continuing a full workup for younger infants regardless of their viral status.

1. Respiratory distress syndrome (RDS) and perinatal mortality were significantly less common among preterm infants whose mothers received betamethasone prior to delivery.

Original Date of Publication: Oct 1972

Study Rundown: Respiratory complications of preterm birth are an important and common cause of preterm morbidity and mortality. Prior to 34 weeks estimated gestational age, fetal lungs are considered immature due to the lack of surfactant present in pulmonary alveoli. As the fetal lungs develop, they begin to produce greater quantities of surfactant and specifically increase the amount of lecithin production, thus increasing the lecithin to sphingomyelin ratio (L/S ratio), which is a marker of fetal lung maturity. An L/S ratio >2 in fetal amniotic fluid has been shown to be associated with fetal lung maturity and decreased risk of respiratory distress syndrome (RDS) while an L/S ratio <1.5 is associated with an increased risk of RDS.

As of the late 1969s, there were no interventions to reduce the respiratory morbidity associated with preterm birth. In the late 1960s, animal studies in lambs and rabbits demonstrated that fetal lung maturity was accelerated in animal fetuses whose mothers received glucocorticoids prior to preterm delivery. These studies stimulated obstetricians and scientists to test whether fetal lung maturity might be similarly improved in humans. Unlike some other animals (e.g. cows), the human placenta is relatively permeable to glucocorticoids, suggesting that maternal administration of steroids would allow transfer of these medicines to the preterm fetus. In the present work, authors randomized women at risk of preterm delivery to receive antenatal steroids or placebo and compared the incidence of RDS between groups.

This landmark study demonstrated a decreased incidence of RDS among fetuses born to women who received antenatal steroids. Strengths included randomized, double-blinded design and standardization of the primary outcome of RDS via the Silverman score (respiratory rate, grunting, chest retractions). Limitations included a small sample size of women who delivered at the same institution in New Zealand.

1. Among 10 infants treated for respiratory distress syndrome with artificial surfactant in this landmark trial, significant improvements in blood pressure, acid-base status, arterial oxygenation, and radiologic findings were observed.

2. Infants also required significantly less oxygen therapy and ventilator pressure following surfactant administration.

Original Date of Publication: January 1980

Study Rundown: Hyaline membrane disease (HMD), now known as infant respiratory distress syndrome (RDS), is a pulmonary disease of young infants most often linked to fetal immaturity. After the landmark 1959 discovery by Avery et al. connecting insufficient surfactant with RDS, methods of treating the disease were investigated. As surfactant was known to reduce lung surface tension, making it easier to maintain patent alveoli, this study built upon work in animals as the first trial of artificial surfactant treatment for RDS in human infants. Using a mixture of natural and synthetic lipids including dipalmitoyl lethicin (the primary component of surfactant) and phosphatidyl glycerol, researchers administered artificial surfactant to 10 infants diagnosed with RDS and examined their laboratory, clinical examination, and radiologic changes. Significant reductions in systolic blood pressure (SBP), along with improvements in arterial oxygenation, arterial-alveolar oxygen concentration differences, acid-base balance, and radiologic findings were seen. Infants also required significantly less inspired oxygen and ventilator pressure after surfactant administration. This study was limited by a lack of randomization, comparison to control infants, and its small sample size. Despite these limitations, this study led to future, large, randomized, clinical trials that further solidified the benefits of artificial surfactant use among infants with RDS. Antenatal corticosteroids coupled with post-delivery surfactant and ventilation are now commonplace treatments for infants in neonatal intensive care and have been proven to significantly improve clinical outcomes among infants suffering from poor lung development.

1. Among infants randomized to undergo either newborn screen with cystic fibrosis (CF) testing included or undergo normal pediatric surveillance, those who underwent newborn screen were diagnosed significantly earlier.

2. Infants diagnosed based on surveillance were significantly more likely to be severely malnourished compared to those diagnosed by newborn screen.

Original Date of Publication: January 2001

Study Rundown: Cystic fibrosis (CF) is an autosomal recessive disease responsible for multi-system organ involvement most commonly secondary to impaired chloride channel transport. Patients with CF often experience pulmonary, sinus, endocrine, and nutrition complications. At the time of this study’s publication, many patients were diagnosed through sweat testing following recognition of signs/symptoms linked to the disease. In 1996, the average age of diagnosis was 5 years and this delay in diagnosis was associated with worse nutritional status and lung disease. In order to provide support for a recommendation for CF diagnosis via newborn screening, this clinical trial investigated the potential benefits of neonatal screening on nutrition outcomes. Infants were diagnosed using testing for elevated immunoreactive trypsinogen (IRT), which was later modified to include both IRT and DNA testing. A total incidence rate of 1:3938 was seen in the cohort, with those who underwent newborn screening diagnosed significantly earlier than those diagnosed by surveillance. In addition, those who were diagnosed on newborn screening were at significantly lower risk of being severely malnourished (having height and weight values below the 10th percentile) when compared to those diagnosed by surveillance. The randomized and blinded nature of this study strengthened the value of its results; however, it was limited in the change of diagnostic technique partway through the study resulting in a potential decrease in the number of cases identified on newborn screen. This study aided in establishing the value of early diagnosis and early intervention in the care of children with CF. Since the introduction of newborn screening, every state in the United States has adopted use of either IRT or combined IRT-DNA testing. Now, nearly 60% of cases of CF are diagnosed by newborn screen, up from under 10% in 2001, with the average age of diagnosis under 2 years.

1. Children recruited for weight and cardiovascular risk assessment were found to have higher frequencies of cardiac risks factors as their BMIs increased.

2. Among the cardiovascular risk factors assessed, overweight youth had the highest odds of having elevated insulin levels.

Original Date of Publication: June 1999

Study Rundown: The Bogalusa Heart Study was initiated in 1972 in Bogalusa, Louisiana and stands as the longest running biracial study of children, focused on identifying early contributors to coronary artery disease and hypertension. Although being overweight was an established risk factor for multiple adverse health outcomes including insulin abnormalities and blood pressure changes at the time of the investigation, this 1999 study added insight into the connection between early weight risk and cardiovascular health and was one of the first studies to factor sex, race/ethnicity, and age into analysis.

Eleven percent of the 9167 children included in the study were overweight. Cardiac risk factors increased in prevalence as body mass index (BMI, referred to as Quetlet index levels in the paper) went beyond the 85th percentile with considerable risk elevations as BMI increased from the 95th to 97th percentile and beyond. Among the risk factors, overweight youth were found to have the highest odds of having elevated insulin levels. Being overweight was considered an effective screening tool for cardiovascular risk with over 50% of overweight participants having at least 1 risk factor (positive predictive value [PPV] > 50%). Differences between African Americans and whites were noted when examining diastolic blood pressure (DBP) and insulin levels. Low density lipoprotein cholesterol (LDLC), DBP, and systolic blood pressure (SBP) differed significantly between age groups. Tricep skinfold thickness as a surrogate for weight elevation was found to add little to the connection to risk factors when BMI was known. While BMI is a useful surrogate for assessing weight status, it has limited accuracy among certain populations including those with very high or low levels of muscle mass. Despite this limitation, this study produced results agreeing with previous findings and strengthened the evidence to support prevention and early intervention for overweight youth.

1. Among children exposed to lead early in life, serum lead levels at 24 months of age were significantly associated with decreased cognitive performance on measures of intelligence and educational achievement at 10 years old.

2. Each 0.48 μmol/L (10 μg/dL) increase in serum lead at 24 months of age was associated with a 5.8 point decline in a measure of intelligence quotient and an 8.9 point decline in educational achievement score during cognitive testing at 10 years of age.

Original Date of Publication: December 1992

Study Rundown: At the time of this publication, prior studies investigating early, low-level lead exposure and cognition later in life had mixed findings. Previous reports assessed the potential connection between lead levels and cognitive performance into preschool years. This was the first study to investigate the effects of early low-level lead exposure on cognitive performance into school age. One hundred forty-eight children were assessed from birth to 10 years of age for serum lead levels and cognitive development through intelligence quotient (IQ) testing via the Wechsler Intelligence Scale for Children-Revised (WISC-R) and the Kaufman Test of Educational Achievement Brief Form (K-TEA). Findings indicated that serum lead levels at 24 months of age were significantly associated with IQ and neuropsychiatric performance at 10 years old, a finding which was upheld after controlling for covariates. There is no known reason as to why children are most vulnerable to lead toxicity in this specific time frame. This study was limited by the potential role of bias towards children available for follow-up as multiple participants were lost from 5 years of age to 10 years old. In addition, this cohort was of higher socioeconomic status (SES) and intelligence than the average citizen, which may have allowed for an enhanced view of the cognitive effects of lead, but makes the findings less generalizable compared to previous study cohorts of lower SES who were more likely to be exposed to environmental lead. This study indicated that even at low levels, early lead exposure is linked to poor cognitive development through school age. Combined with previous work, these findings encouraged the Centers for Disease Control to lower the benchmark for toxic lead levels to the current 0.24 μmol/L or 5 μg/dL.

1. In a study population of girls 3-12 years of age, it was found that African-American females developed secondary sexual characteristics at a significantly earlier age than white girls.

2. African-American females had earlier menarche at 12.16 years of age, compared to 12.88 years of age among white females.

Original Date of Publication: April 1997

Study Rundown: The onset of female pubertal changes varies greatly by race/ethnicity and setting. As the start of secondary characteristics marks a significant physiologic and psychological change in an individual’s life, being able to anticipate onset is essential to providing proper medical care. Prior to the initiation of this work, no nationally representative, racially diverse data was available to assess female pubertal status in the United States. This cross-sectional study stood as the first to investigate secondary sexual characteristics and menses onset among girls 3-12 years of age that could provide evidence representative of national norms. Researchers found that African-American girls developed secondary sexual characteristics including breast development, axillary hair, and pubic hair significantly earlier than white females, with all girls starting puberty six months to a year earlier than reported in prior studies. The average age of menarche in African-American females was 12.16 years of age compared to 12.88 years in white females. This study is limited by potential selection bias with non-random sample selection, the lack of hormone testing to provide a potential endocrinologic etiology for these developmental differences, and participants being heavier and taller, on average, than girls in the nationally-representative height and weight values provided by the Health and Nutrition Examination Surveys. Findings from this study indicated that the initiation of sex education and physician counseling should be tailored accordingly to earlier pubertal changes among girls.

Follow-up work to this initial paper was completed and published as documented below to dispel confusion regarding studies investigating this subject matter after 1997. One commentary further emphasized girls maturing earlier than previously documented with significant differences between race/ethnic groups persisting. In addition, the contribution of weight and other health characteristics to early pubertal onset is highlighted. Another, more recent publication supported these findings, indicating that thelarche onset differed by race/ethnicity and started earlier in those with higher BMI.

1. Preterm infants randomized to delayed cord clamping for 30 seconds after birth required less cardiorespiratory intervention, less supplemental oxygen and fewer blood transfusions compared to controls.

Original Date of Publication: January 1993

Study Rundown: Prematurity is a major contributor to neonatal morbidity, mortality and healthcare costs in the United States. As of 2015, Over 11% of all births in the United States are preterm. Preterm infants are most notably at increased risk for respiratory complications as a result of lack of surfactant production related to delivery prior to completion of fetal lung maturation. Due to concerns for respiratory compromise or even failure following preterm birth, preterm infants have traditionally been handed off to awaiting neonatal intensive care unit staff as soon as possible following delivery. This urgency has translated to immediate cord clamping following delivery. Additionally, there has historically been a greater abundance of teachings detailing adverse neonatal events associated with delayed cord clamping (e.g. volume overload, polycythemia, hyperbilirubinemia) compared to adverse events associated with immediate cord clamping (e.g. hypovolemia). Despite this traditional dictum, there have been numerous and repeated claims that delayed cord clamping is particularly beneficial among preterm infants. In the present study, authors conduct the first randomized investigation to determine whether holding the preterm infant in a position to facilitate placental transfusion for 30 seconds after delivery prior to cord clamping is associated with fetal benefit.

This landmark study demonstrated that delayed umbilical cord clamping was associated with numerous benefits to the preterm neonate and stimulated additional investigations further characterizing these benefits. Strengths included randomized design and numerous markers of respiratory, cardiac and hematologic function. Weaknesses included a single-site investigation and small sample size of 36 infants.

1. Absence of six established predictors was found to have close to 100% negative predictive value for clinically-important traumatic brain injury (ciTBI) when applied to head trauma patients under 18 years of age.

2. An algorithm was proposed, applying these predictors, in order to prevent physicians from using unnecessary computed tomography (CT) in pediatric patients at low risk for ciTBI.

Original Date of Publication: September 15, 2009

Study Rundown: TBI continues to be one of the leading causes of morbidity and mortality among the pediatric population. At the time of this study, CT was the standard imaging technique for identifying TBI patients requiring intervention after head trauma. However, the known increase in malignancy risk associated with CT scans led to this study, identifying patients at low risk for ciTBI in order to reduce unnecessary CT scans. Through the use of a large study cohort from various emergency departments, researchers analyzed the negative predictive values (NPV) and sensitivities associated with a proposed “prediction rule” defined as having none of the identified ciTBI predictors versus having any cTBI predictors. The NPV and sensitivity of this prediction rule was then analyzed with researchers finding an NPV of >98% and sensitivity >94% in the prediction of ciTBI and TBI-negative CT scans in participants of all ages. Despite the fact that researchers did not CT scan all participants and sensitivities were not found to be 100%, this large, adequately powered study found similar results among both derivation and validation participant groups. With their findings, researchers were able to construct algorithms guiding physicians on appropriate CT scans use in head-injured patients. Altered mental status (AMS) and signs of skull fracture were established as branching points for patients at highest risk for ciTBI.

1. Among 100 children presenting to one children’s hospital for prolonged febrile illnesses, the majority of cases were of an infectious etiology (52 cases).

2. Significantly more febrile illnesses in younger children were due to infectious causes, while those due to inflammatory conditions were significantly more likely to occur in older children.

Original Date of Publication: April 1975

Study Rundown: The issue of prolonged febrile illness in children presents a diagnostic challenge to pediatric practitioners. At the time of this study’s publication, there were no guidelines for diagnosis and management of children with fevers of unknown origin (FUO), a term still without a clear definition even today. It is often defined as temperature > 38.3˚C for at least 8 days without any obvious cause following initial outpatient or hospital evaluation. This study investigated prolonged fever in 100 children in order to better define guidelines for the care of those with FUO, defined in this study as a temperature > 38.5˚C, > 5 times during a two-week period. Of the 100 records included, the most common fever etiology was infection (52 cases). Findings indicated that significantly more young children had fevers of infectious etiologies, while significantly more older children had collagen-inflammatory fever etiologies. Based on the findings that 62% of children had stories and presentations consistent with etiology, researchers recognized the importance of a thorough history and physical in diagnosis. With 80% of children receiving antibiotics prior to official diagnosis and no resolution in their symptoms, the use of antibiotic therapy prior to hospitalization was discouraged and use of diagnostic cultures encouraged. In addition, erythrocyte sedimentation rate (ESR) testing and protein analysis were deemed more useful than complete blood count (CBC) and urinalysis (UA). Other procedures and imaging techniques were helpful when indicated by the history and physical.

This study was limited by its small sample size, lack of patient racial/ethnic diversity, and use of only one institution as a source of patient reports. Decades and multiple studies and reports on FUO later, many of the conclusions drawn from this landmark study still stand. Infection remains the most common cause of prolonged febrile illness. The importance of history and physical in diagnosing children with FUO continues to be emphasized; however specific recommendations for initial testing include CBC, ESR, C-reactive protein, blood cultures, UA and culture, chest radiograph, tuberculosis testing, electrolytes, and blood urea nitrogen, creatinine, liver panel, and HIV serology. Further workup including radiography is recommended based off of history and physical.

1. A Bacterial Meningitis Score of 0 accurately identified all children with aseptic meningitis in the study’s validation group.

2. The negative predictive value of a BMS score of 0 was 100% with a specificity of 73% in predicting bacterial meningitis. A BMS score of >2 was found to have a sensitivity and positive predictive value of 87% in predicting bacterial meningitis.

Original Date of Publication: October 4, 2002

Study Rundown: Bacterial meningitis is associated with significant morbidity and mortality. At the time of this study, many children found to have CSF pleocytosis were admitted for intravenous antibiotic therapy and blood culture monitoring while distinguishing bacterial from aseptic meningitis. As individuals diagnosed with viral meningitis can be managed as outpatients, this study sought to create and validate a clinical prediction rule to aid in identifying patients at low risk for bacterial meningitis. This was the first study to create and validate a multivariate scoring system to identify those pediatric patients at low risk for bacterial meningitis in the post-Hib era. Researchers were able to create a scoring system that accurately stratified patients at low and high risk for bacterial meningitis diagnosis. This study was limited in both its design and potential referral bias as evidenced by the high percentage of patient participants with bacterial meningitis (18%). Through use of this prediction rule, clinicians may be able to better identify patients who could be cared for outside of the hospital setting. Of note, this scoring system was further validated in a follow-up analysis published in JAMA in 2007.