Ashima Madan

Serial Serum C-Reactive Protein Levels in the Diagnosis of Neonatal Infection

Objective. To evaluate serial serum C-reactive protein (CRP) levels for diagnosis of neonatal infection. Setting. A regional intensive care nursery and two community intensive care nurseries. Methods. All neonates treated for suspected bacterial infection were prospectively evaluated using a standardized clinical pathway. Infants were categorized as having proven sepsis (bacteria isolated from blood, cerebrospinal fluid, or urine culture), probable sepsis (clinical and laboratory findings consistent with bacterial infection without a positive culture), or no sepsis (findings not consistent with sepsis), without consideration of CRP levels. Infants whose blood cultures yielded skin flora but who demonstrated no other signs of bacterial infection were not considered to have sepsis. CRP levels were determined at the initial evaluation and on each of the next two mornings. Sensitivity, specificity, predictive values, and likelihood ratios were calculated for the first (CRP #1), second (CRP #2), higher of the second and third (CRP #2 and #3), or highest of all three CRP levels (CRP × 3). Results. Sepsis was suspected within the first 3 days after birth in 1002 infants (early-onset) and on 184 occasions in 134 older infants (late-onset). There were 20 early-onset and 53 late-onset episodes of proven sepsis, and 74 early-onset and 12 late-onset episodes of probable sepsis. CRP #1 had sensitivities of 39.4% and 64.6% for proven or probable sepsis and 35.0% and 61.5% for proven sepsis in early-onset and late-onset episodes, respectively. CRP levels on the morning after the initial evaluation (CRP #2) had higher sensitivities (92.9% and 85.0% for proven or probable sepsis and 78.9% and 84.4% for proven sepsis in early-onset and late-onset episodes, respectively), and normal results were associated with lower likelihoods of infection (likelihood ratios for normal results of 0.10 and 0.19 for proven or probable sepsis and 0.27 and 0.21 for proven sepsis, in early-onset and late-onset episodes, respectively). Three serial serum CRP levels had sensitivities of 97.8% and 98.1% for proven or probable sepsis and 88.9% and 97.5% for proven sepsis in early-onset and late-onset episodes, respectively. The negative predictive values for CRP × 3 were 99.7% and 98.7% for both proven or probable sepsis and for proven sepsis in early-onset and late-onset episodes, respectively. A CRP level obtained at the time of the initial evaluation can be omitted without significant loss of sensitivity or negative predictive value: the sensitivities of CRP #2 and #3 were 97.6% and 94.4% for proven or probable sepsis and 88.9% and 96.4% for proven sepsis in early-onset and late-onset episodes, respectively; negative predictive values were 99.7% both for proven and for proven or probable early-onset sepsis, 97.6% for proven or probable late-onset infection, and 98.8% for proven late-onset infection. Serial normal CRP levels were associated with a markedly reduced likelihood of infection as compared with that in the entire population before testing, with likelihood ratios ranging from 0.03 to 0.16 for the various subgroups. Maximum CRP levels >3 mg/dL had positive predictive values >20% for proven or probable early-onset infections and for proven or probable and proven late-onset infections, but only those >6 mg/dL had such a high positive predictive value for proven early-onset sepsis. Conclusions. Serial CRP levels are useful in the diagnostic evaluation of neonates with suspected infection. Two CRP levels <1 mg/dL obtained 24 hours apart, 8 to 48 hours after presentation, indicate that bacterial infection is unlikely. The sensitivity of a normal CRP at the initial evaluation is not sufficient to justify withholding antibiotic therapy. The positive predictive value of elevated CRP levels is low, especially for culture-proven early-onset infections.

Retinopathy of Prematurity and Pulse Oximetry: A National Survey of Recent Practices

OBJECTIVE: To determine if practices related to the use of pulse oximetry in the first 2 weeks following birth and after 2 weeks of age have a relationship to the rate of retinopathy of prematurity (ROP) and retinal ablation surgery in infants ≤1500 g.STUDY DESIGN: A questionnaire was mailed in July 2001 to 318 neonatal intensive care units (NICUs) in the United States and information was collected regarding SpO2 guidelines and the rate of both severe ROP and retinal ablation surgery.RESULTS: A total of 142 surveys were returned (45%). In all, 87% of the NICUs had SpO2 guidelines, and 60% of these centers maintained a different range of SpO2 for infants ≤ or >2 weeks of age. The range of SpO2 was 82 to 100% with an average minimum (min) and maximum (max) of 89 and 95%, respectively. In the NICUs with an SpO2 max of >98% in the first 2 weeks following birth, the rate of retinal ablation surgery was 5.5 vs 3% in those units with a max SpO2 >98% (p<0.05). After 2 weeks of age, the rate of retinal ablation surgery was 3.3% when max SpO2 was >92 vs 1.3% when the max SpO2 was ≤92% (p<0.00001). The rate of ≥stage 3 ROP after 2 weeks of age was 5.5% when max SpO2 was >92 vs 2.4% when max SpO2 was ≤92% (p<0.0005).CONCLUSION: NICUs in the US today have a wide range of SpO2 guidelines. The results of this survey show a “gradient of risk” towards less retinal ablation surgery when the max SpO2 is <98% in the first 2 weeks following birth (p<0.05). There was a statistically significant lower rate of ≥stage 3 ROP and retinal ablation surgery when the max SpO2 was ≤92% after the first 2 weeks of age. A randomized, controlled trial is needed to establish a safe upper limit of SpO2 in the premature infant at risk for developing ROP.

Reduction in Red Blood Cell Transfusions Among Preterm Infants: Results of a Randomized Trial With an In-Line Blood Gas and Chemistry Monitor

Background. Critically ill, extremely premature infants develop anemia because of intensive laboratory blood testing and undergo multiple red blood cell (RBC) transfusions in the early weeks of life. To date, researchers have had only limited success in finding ways to reduce transfusions significantly in this patient population. Objective. To reduce RBC transfusions for these infants by using a point-of-care bedside monitor that returns analyzed blood to the patient. Design, Setting, and Patients. This was a prospective, 2-center, randomized, open, controlled, clinical trial with a 1:1 assignment of extremely low birth weight infants (weighing 500–1000 g at birth) to control or monitor groups and analysis with the intention-to-treat approach. Predefined RBC transfusion criteria were applied uniformly in the 2 groups. Interventions. Clinical treatment of study subjects with an in-line, ex vivo, bedside monitor that withdraws blood through an umbilical artery catheter, analyzes blood gases and sodium, potassium, and hematocrit levels, and returns the sample to the patient. Main Outcome Measures. The total volume and number of RBC transfusions during the first 2 weeks of life and the total volume of blood removed for laboratory testing. Results. The trial was terminated prematurely when one centers NICU changed its standard method of laboratory testing. In the first 2 weeks of life, there was a nonsignificant 17% lower cumulative RBC transfusion volume in the monitor group (n = 46), compared with the control group (n = 47). However, data from the first week only (the period of greater catheter use) demonstrated a significant 33% lower cumulative RBC transfusion volume in the monitor group. Cumulative phlebotomy loss was ∼25% less in the monitor group throughout the 2-week study period. There was no difference between groups in neonatal mortality, morbidity, and neurodevelopmental outcome rates at 18 to 24 months. This is the first randomized trial documenting that RBC transfusions administered to neonates can by reduced by decreasing laboratory phlebotomy loss. Conclusions. As long as an umbilical artery catheter is available for blood sampling with an in-line blood gas and chemistry monitor, significant reductions in neonatal RBC transfusions can be achieved. The patients most likely to benefit from monitor use are the smallest, most critically ill newborns.

Perinatal Systemic Inflammatory Response Syndrome and Retinopathy of Prematurity

Fetal and neonatal inflammation is associated with several morbidities of prematurity. Its relationship to retinopathy of prematurity (ROP) has not been investigated. Our objective was to determine the relationship between cytokine levels and ROP in the first 3 postnatal wks. Data for this study were derived from the NICHD Cytokine Study. Dried blood spots (DBS) were obtained from infants <1000 g on days 0–1, 3 ± 1, 7 ± 2, 14 ± 3, and 21 ± 3. Infants were classified into three groups—no, mild, and severe ROP. Multiplex Luminex assay was used to quantify 20 cytokines. Temporal profiles of cytokines were evaluated using mixed-effects models after controlling for covariates. Of 1074 infants enrolled, 890 were examined for ROP and 877 included in the analysis. ROP was associated with several clinical characteristics on unadjusted analyses. Eight cytokines remained significantly different across ROP groups in adjusted analyses. IL-6 and IL-17 showed significant effects in early time periods (D0–3); TGF-β, brain-derived neurotrophic factor (BDNF), and regulated on activation, normal T cell expressed and secreted (RANTES) in later time periods (D7–21) and IL-18, C-reactive protein (CRP), and neurotrophin-4 (NT-4) in both early and later time periods. We conclude that perinatal inflammation may be involved in the pathogenesis of ROP.

Reduction in Red Blood Cell Transfusions Using a Bedside Analyzer in Extremely Low Birth Weight Infants

BACKGROUND:Preterm infants typically experience heavy phlebotomy losses from frequent laboratory testing in the first few weeks of life. This results in anemia, requiring red blood cell (RBC) transfusions. We recently introduced a bedside point-of-care (POC) blood gas analyzer (iSTAT, Princeton, NJ) that requires a smaller volume of blood to replace conventional Radiometer blood gas and electrolyte analysis used by our neonatal intensive care unit (NICU). The smaller volume of blood required for sampling (100 vs 300–500 μl), provided an opportunity to assess if a decrease in phlebotomy loss occurred and, if so, to determine if this resulted in decreased transfusions administered to extremely low birth weight (ELBW) infants.OBJECTIVE:We hypothesized that the use of the POC iSTAT analyzer that measures pH, PCO2, PO2, hemoglobin, hematocrit, serum sodium, serum potassium and ionized calcium would result in a significant decrease in the number and volume of RBC transfusions in the first 2 weeks of life.DESIGN/METHODS:A retrospective chart review was conducted of all inborn premature infants with birth weights less than 1000 g admitted to the NICU that survived for 2 weeks of age during two separate 1-year periods. Blood gas analysis was performed by conventional laboratory methods during the first period (designated Pre-POC testing) and by the iSTAT POC device during the second period (designated post-POC testing). Data collected for individual infants included the number of RBC transfusions, volume of RBCs transfused, and the number and kind of blood testing done. There was no effort to change either the RBC transfusion criteria applied or blood testing practices.RESULTS:The mean (±SD) number of RBC transfusions administered in the first 2 weeks after birth was 5.7±3.74 (n=46) in the pre-POC testing period to 3.1±2.07 (n=34) in the post-POC testing period (p<0.001), a 46% reduction. The mean volume of RBC transfusions decreased by 43% with use of the POC analyzer, that is, from 78.4±51.6 ml/kg in the pre-POC testing group to 44.4±32.9 ml/kg in the Post-POC testing group (p<0.002). There was no difference between the two periods in the total number of laboratory blood tests done.CONCLUSIONS:Use of a bedside blood gas analyzer is associated with clinically important reductions in RBC transfusions in the ELBW infant during the first two weeks of life.

Racial Differences in Birth Weight of Term Infants in a Northern California Population

BACKGROUND: Census data show that an increasing proportion of the population of the United States is of Asian or Hispanic origin. Reference curves used to characterize fetal growth relative to gestational age are predominantly based on data for White infants. The goal of this study was to compare the birth weight distributions for term Asian or Hispanic infants with that for White infants, and to determine whether the prevalence of small (SGA) or large size(LGA) for gestational age differs between Asian or Hispanic and White infants.SETTING: A community hospital in Northern California.STUDY DESIGN: Data was collected prospectively from May 1 to September 13, 2000 on all singleton term infants born at this hospital. Gestational age was assessed by the best obstetrical estimate and ethnicity was determined by parental report. Infants were categorized as White, Hispanic, Chinese, Asian Indian, Other Asian, and Other. Birth weights, length, and head circumferences were compared using ANOVA and the Student–Newman–Keuls test. Differences in rates of diagnosis of SGA or LGA were assessed by chi square.RESULTS: 1539 infants were included in the study sample; 30% were White, 21% Asian Indian, 15% Chinese, 9% Hispanic, 7% other Asian, and 18% Other. Asian (Chinese, Asian Indian, or Other Asian), Hispanic, and Other babies had lower mean birth weights, shorter mean lengths, and smaller mean head circumferences than White babies. Asian, Hispanic, and Other male babies were lighter, shorter, and had smaller heads than white male babies. Asian females, but not Hispanic or Other ones, were lighter and had smaller head circumferences than White females; Asian Indian, Other Asian, and Other females had shorter lengths than White female infants. Indian and Other Asian, but not Chinese, babies were more likely than White babies to be SGA; babies in all three Asian groups were less likely than White babies to be LGA.CONCLUSION: Failure to account for ethnic differences in intrauterine growth may lead to inaccurate diagnosis of fetal growth abnormalities in infants of Asian ancestry.

Visual Development in Very Low Birth Weight Infants

Extremely preterm infants are at risk for neurodevelopmental problems and the visual system is particularly vulnerable. However, development of visual function in preterm infants with little or no retinal or neurologic injury has not been well defined. This study compared development of visual function in preterm infants without severe retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL) to that of term infants at 5–7 mo corrected age. Twenty-one very low birth weight (VLBW) preterm infants (24–32 wk gestational age, weighing < 1500 g), and 22 healthy term infants were tested at 5–7 mo corrected age. Infants with any IVH/PVL and > Stage II ROP or Plus disease were excluded. Contrast sensitivity, grating acuity, and vernier acuity were measured using swept-parameter visual evoked potentials. Thresholds and maximum amplitudes were compared between groups. VLBW and term infants showed no differences in sensitivity for contrast (67.5 versus 63.8), grating resolution (12.4 versus 12.5 cpd) or vernier acuity (1.2 versus 1.0 arcmin). However, the amplitudes for swept contrast (p < 0.03) and swept vernier offset (p < 0.04) stimuli were higher in VLBW infants. Visual thresholds in VLBW infants without serious retinal or neurologic abnormalities were not significantly different from those of term infants, suggesting that increased visual experience does not influence visual sensitivity. The higher amplitudes in VLBW infants, suggests that visual experience may affect responses to suprathreshold stimuli.

Bioluminescence for biological sensing in living mammals.

Noninvasive in vivo assays are required for the study of biological processes that are dynamic involving intact organ systems and complex physiologic changes, such as tissue oxygenation. Optical methods that use external light sources in the near infrared (nir) have been developed for oxygenation determinations and have widespread application in medicine and biomedical research (Jobsis, 1977; Benaron et al., 1997). Further refinements in these methods are providing powerful tools for research; however, access to in vivo information relating to some physiologic changes can not be assessed using nir monitoring and imaging. To address this unmet need for additional real-time bioassays, we have developed an in vivo method utilizing bioluminescent reporters, or photoproteins, as indicators of biological functions (Contag et al., 1995). In contrast to other optical methods which use external sources of light, the photoproteins provide an internal source of light that can be monitored externally as an indicator of biological processes such as infection and gene expression (Contag et al., 1995, 1996, 1997).

Visual development in preterm infants

Preterm birth can affect many neurological functions and is known to affect vision when damage to the visual cortex or optic radiations occurs. However, it is not known whether extreme preterm birth affects visual development, either favorably or unfavorably. Additional time in an extrauterine environment could conceivably allow the acceleration of visual abilities as a result of additional experience. Although recent studies suggest that even apparently healthy preterm infants may suffer some degree of loss of neurological function. In this paper we describe what is known about visual development in preterm infants, and we make the case that additional studies are needed to clarify the impact of preterm birth on vision. Because the visual system now lends itself to quantitative studies of function, it could offer researchers and clinicians a method of detecting subtle effects of preterm birth on neurological development and function. Cortical and retinal injuries in infants occur against the background of a developing visual system. However, we know very little about visual development in preterm infants who have not experienced a cerebral or retinal insult, let alone those who have. Studies using technologies that are sensitive enough to discern subtle variations in acuity outcomes in preverbal infants are needed. Investigations to ascertain normal preterm infant acuity development are necessary to identify negative or positive effects of preterm birth on vision. In this paper we describe anatomical and physiological forces that make the preterm brain likely to experience alterations in visual development, and stress the importance of early detection of visual impairment in these infants. We also review our current knowledge of visual development in preterm infants. Studies of blindness in children will have the greatest impact and likelihood of success if they concentrate on the first months after birth. The leading causes of blindness in children in western countries are cerebral or cortical visual impairment, retinopathy of prematurity (ROP), optic nerve hypoplasia, and congenital retinal disease. All these conditions are congenital, with acquired blindness in children (i.e. blindness developing after the neonatal period) being uncommon. Data from several blindness registries show an important trend: low-birthweight children are more likely to be affected by bilateral visual impairment than are term children. This finding undoubtedly reflects the fact that cortical visual impairment and ROP are the first and second leading causes of pediatric blindness, and both are associated with preterm birth. Results from the Cryotherapy for ROP study show at least two important trends. First, children with successful retinal ablation and favorable retinal outcome may still suffer impaired acuity. This is largely due to cerebral factors, although the incidence of cortical visual impairment in a cohort of verylow-birthweight infants without ROP is unknown. Second, a spectrum of acuity outcomes in infants with favorable retinal outcomes can be discerned in the Cryotherapy for ROP study, indicating that cortical and cerebral factors affect acuity in a continuous fashion. Vision is a complex process with many different components, such as grating acuity (the ability to detect the thinnest possible line), vernier acuity (the ability to detect line offsets), and contrast sensitivity. These components are also referred to as functions. So far, large-scale trials of preterm infants have focused on grating acuity as an outcome measure, but there are many different types of acuity and each has its own developmental course. Logically, each function probably has particular vulnerabilities to injury, depending on the nature and timing of the insult. Studies on preterm infant vision should, therefore, consider other visual functions, e.g. contrast sensitivity, vernier acuity, and midand high-level visual processing, in an effort to discern effects of preterm birth and injury on vision development. More subtle disorders of higher visual processing also occur as a result of either extreme preterm birth itself or damage from preterm birth. Cortical visual dysfunction is linked to preterm birth; it is defined as disorders of higher visual function. Given the extraordinary rate of cortical/cognitive

A Pulmonary Score for Assessing the Severity of Neonatal Chronic Lung Disease

Background. Limited data are available to describe the spectrum of severity of neonatal chronic lung disease. In the multicenter Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity trial, all infants had some degree of pulmonary dysfunction, because eligibility required a median oxygen saturation of ≤94% with room air. Infants randomized to the supplemental oxygen group (oxygen saturation target of 96–99%) had more pulmonary morbidity than did those in the conventional group (oxygen saturation target of 88–94%). This prompted the retrospective development of a pulmonary severity score to compare the baseline status of the 2 groups. Objectives. To describe a pulmonary score that reflects the severity of neonatal lung disease and to evaluate the association of the score and its components with subsequent pulmonary morbidity through 3 months of corrected age. Design and Methods. A pulmonary score was developed empirically by a consensus panel of 3 neonatologists and was defined as the fraction of inspired oxygen (Fio2) × (support) + (medications), where Fio2 is the actual or “effective” (for nasal cannula) Fio2; support is 2.5 for a ventilator, 1.5 for nasal continuous positive airway pressure, or 1.0 for nasal cannula or hood oxygen; and medications is 0.20 for systemic steroids for bronchopulmonary dysplasia, 0.10 each for regular diuretics or inhaled steroids, and 0.05 each for methylxanthines or intermittent diuretics. The scores could range from 0.21 to 2.95. Pulmonary morbidity was defined as any of the following occurring from randomization at a mean of 35.4 weeks’ postmenstrual age through 3 months of corrected age: death or rehospitalization with a pulmonary cause; an episode of pneumonia/sepsis/exacerbation of chronic lung disease; or continued hospitalization, supplemental oxygen therapy, diuretic treatment, or systemic steroid therapy at 3 months. Between-group differences were tested with the Kruskal-Wallis or χ2 test. Results. Data through death or the 3-month corrected age examination were available for 588 infants. Enrolled infants represented a wide spectrum of severity of chronic lung disease, with baseline pulmonary scores at randomization ranging from 0.21 to 2.6. The median pulmonary score at enrollment did not differ between the conventional and supplemental groups (0.42 and 0.45, respectively). However, higher baseline pulmonary scores were observed for infants who did versus did not develop subsequent pulmonary morbidity (0.48 vs 0.38). The pulmonary score was associated with subsequent pulmonary morbidity. Regression analyses adjusting for Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity group assignment, gestational age at birth, race, gender, and postmenstrual age at randomization revealed that the score was a significant independent predictor of subsequent pulmonary morbidity (odds ratio: 7.2; 95% confidence interval: 3.6-14.4). Conclusions. The pulmonary score, calculated near term, reflects a wide spectrum of bronchopulmonary dysplasia severity and is associated with subsequent pulmonary morbidity through corrected age of 3 months. This simple score could prove useful in clinical and research settings. Validation of the score requires additional study.