Clinical research resource support for off-site research coordinators in intensive and specialty care units.

Clinical Research Coordinators (CRCs) are vital collaborators in a clinical research project. They often are the primary liaisons between investigators and human participants in studies and are involved in every aspect of many protocols, including participant recruitment, care (both usual medical care and specific study-related monitoring and procedures), data collection, specimen processing, and follow-up. The Clinical Translational Science Award program, which was created by the National Institutes of Health in 2006, has significantly expanded the venues in which Clinical Research Resource (CRR) - based CRCs are embedded. CRCs functioning in these areas, outside of the research-focused in-patient environment of the CRR, are designated as "off-site" CRCs. Many of these locations, such as intensive care units and emergency departments, require that CRCs interact regularly with healthcare providers whose primary functions are focused on providing optimal patient care rather than research and often involving very complex patients. These off-site CRCs require additional training and support outside of the usual research-oriented environment of the CRR. They are required to function within the context of the patient-care team while fostering implementation of collaborative research. This is a description of such a program specifically geared to off-site CRCs with the goal of enhancing the quality of research and experiences of CRCs.

The interaction between diet and neurobehavior in very low birth weight infants.

BACKGROUND: Modulation of behavior and physiology by dietary perturbations early in life can provide clues to the pathogenesis of adult diseases. We tested the hypothesis that a period of early protein supplementation modulates sympathetic nervous system activity demonstrated indirectly by an increase in active sleep state distribution in very low birth weight (VLBW) infants. METHODS: VLBW infants (n = 71) were randomized to a total parenteral nutritional regimen providing 18% of the energy intake as amino acids (AA) or a conventional regimen providing 12.5% to achieve targeted AA intakes of 4 g/kg/day (0.004 kcal/kg/day) and 3 g/kg/day (0.003 kcal/kg/day), respectively. Both groups were weaned to enteral feeding and advanced to provide similar AA intake of 4 g/kg/day (0.004 kcal/kg/day). Six-hour daytime, behavioral sleep studies were performed when the infants reached full enteral intake (165 ml/kg/day). RESULTS: Infants in the high protein group spent more time in active sleep (77.2 ± 10.5% vs. 70.7 ± 11.8%), p < 0.01 and less time in quiet sleep (12.9 ± 3.4% vs. 17.7 ± 7.0%, p < 0.01) as compared to the conventional group. No group differences were observed for indeterminate sleep, awake, or crying states. CONCLUSIONS: These results suggest that dietary intake may indirectly influence sympathetic nervous system activity. IMPACT: Infants randomized to an early, high protein nutritional regimen spent an increased percentage of time in active sleep, supporting the hypothesis that nutrition and behavior are interactive. Furthermore, sleep states are an indirect measure of sympathetic nervous system activity, suggesting that dietary intake may influence sympathetic nervous system activity. This study highlights the importance of considering the impact of nutrition during critical periods of development in order to further understand and improve the long-term outcomes of very low birth weight infants.

The role of absolute monocyte counts in predicting severity of necrotizing enterocolitis.

OBJECTIVE: Necrotizing enterocolitis (NEC) is an inflammatory bowel disease of preterm infants marked by an absolute monocyte count (AMC) drop in peripheral blood. Our objective was to determine whether the degree of AMC drop at illness onset correlates with eventual severity of disease. STUDY DESIGN: The percentage change in AMC was retrospectively calculated for each of 29 rule-out NEC and 76 NEC cases from baseline to illness onset, and then compared across stages. RESULTS: Median AMC changes of +0.5% (p = 0.56) were found in rule-out NEC, compared with -44.5% (p < 0.0001) in Stage 2 and -81.9% (p < 0.0001) in Stage 3. An AMC change cutoff of -75% distinguishes Stages 2 and 3. CONCLUSIONS: The severity of NEC correlated with the extent of AMC change in a dose-response fashion. Percent AMC change may be a useful marker for identifying NEC at onset and prognosticating disease severity.

Effect of red blood cell storage time on markers of hemolysis and inflammation in transfused very low birth weight infants.

BackgroundProlonged storage of transfused red blood cells (RBCs) is associated with hemolysis in healthy adults and inflammation in animal models. We aimed to determine whether storage duration affects markers of hemolysis (e.g., serum bilirubin, iron, and non-transferrin-bound iron (NTBI)) and inflammation (e.g., interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1) in transfused very low birth weight (VLBW) infants.MethodsBlood samples from 23 independent transfusion events were collected by heel stick before and 2-6 h after transfusion.ResultsSerum iron, total bilirubin, NTBI, and MCP-1 levels were significantly increased after transfusion of RBCs (P<0.05 for each comparison). The storage age of transfused RBCs positively correlated with increases in NTBI following transfusion (P<0.001; R2=0.44). No associations between storage duration and changes in the other analytes were observed.ConclusionTransfusion of RBCs into VLBW infants is associated with increased markers of hemolysis and the inflammatory chemokine MCP-1. RBC-storage duration only correlated with increases in NTBI levels following transfusion. NTBI was only observed in healthy adults following 35 days of storage; however, this study suggests that VLBW infants are potentially more susceptible to produce this pathological form of iron, with increased levels observed after transfusion of only 20-day-old RBCs.

Feed and Wrap MRI Technique in Infants.

The feed and wrap technique refers to the use of feeding and swaddling to induce natural sleep in infants. It can be used prior to an magnetic resonance imaging (MRI) scan, avoiding sedation or anesthesia. We performed a retrospective review of feed and wrap MRI scans in infants 3 months or younger over a 2-year period at our center (279 scans) to evaluate the efficacy of this technique. Of scan results reviewed, 79% addressed the clinical question, 20% partially addressed the clinical question, and 1% were technically inadequate. History of preterm birth (odds ratio [OR] = 2.368; P = .032) and spine MRI (OR = 2.821; P = .001) were associated with a less-successful scan outcome. The feed and wrap technique can be used successfully in infants undergoing MRI; however, it may be less successful in preterm infants and those requiring spinal MRI. A standardized technique performed by experienced personnel may avoid anesthesia and sedation in infants who require MRI.

Comparison of Feeding Strategies for Infants With Hypoplastic Left Heart Syndrome: A Randomized Controlled Trial.

INTRODUCTION: Infants with hypoplastic left heart syndrome are at risk for growth failure, particularly after stage 1 procedures. The effect of continuous enteral feedings on weight gain has not been previously investigated. METHODS: A randomized controlled trial was performed in infants with hypoplastic left heart syndrome and single ventricle variants after stage 1 procedures. Eligible infants were randomized to a continuous and intermittent feeding regimen or an exclusive intermittent feeding regimen after stage 1 procedures and continued until hospital discharge. Anthropometric measures and markers of nutritional status were assessed throughout hospitalization. RESULTS: Twenty-six infants completed the study. There were no significant differences in weight gain, growth, or nutritional status. Weight gain on full enteral feedings was 24.3 versus 23.6 g/d (P = .88) for the combination (continuous and intermittent) versus intermittent feeding groups. Weight-for-age Z scores at discharge were -1.37 versus -1.2 (P = .59) for the combination versus intermittent groups. CONCLUSIONS: No significant differences in weight gain, growth, or nutritional status were observed at hospital discharge between the two feeding strategies. Despite both groups achieving target daily weight gain after attaining full feeds, growth failure continued to be a problem after stage 1 procedures. Further strategies to improve growth during initial hospitalization are needed.

Nutritional needs of the micropreterm infant.

We have used an expansive definition of a micropreterm infant as <30 weeks' gestation to provide a global perspective to a "high risk" group of preterm infants for which there are little published data to guide nutritional management. Consensus nutritional guidelines for preterm infants have been developed for infants >1000 g birth weight and >28 weeks' gestational age. Micropreterm infants have greater nutritional deficits at birth than more mature preterm infants and accumulate greater postnatal deficits. Nutritional guidelines based on the needs of preterm infants born >28 weeks' gestation are unlikely, on a theoretical basis, to meet nutritional requirements of micropreterm infants. Unfortunately, very few good quality studies have addressed the nutritional requirements of this group specifically; this makes it difficult to formulate solid, evidence-based nutritional recommendations for these neonates. Nutritional management of micropreterm infants is based on recommendations established for preterm infants, which are adjusted after considering an infant's gestational age, birth weight, and clinical status. Minimal enteral feeding should commence on the first or second day of life, with incremental advancement and fortification of human milk when 100 mL/kg is tolerated. Early use of parenteral nutrition is recommended, ideally initiated within the first hours of life and enteral feeds are being established; this will help prevent the accumulation of nutritional deficits and incidence of growth failure. Fortified human milk should be given in order to meet nutritional requirements. When human milk is not available in sufficient quantity, a preterm formula should be given.

Mapping clinical phenotype data elements to standardized metadata repositories and controlled terminologies: the eMERGE Network experience.

BACKGROUND: Systematic study of clinical phenotypes is important for a better understanding of the genetic basis of human diseases and more effective gene-based disease management. A key aspect in facilitating such studies requires standardized representation of the phenotype data using common data elements (CDEs) and controlled biomedical vocabularies. In this study, the authors analyzed how a limited subset of phenotypic data is amenable to common definition and standardized collection, as well as how their adoption in large-scale epidemiological and genome-wide studies can significantly facilitate cross-study analysis. METHODS: The authors mapped phenotype data dictionaries from five different eMERGE (Electronic Medical Records and Genomics) Network sites studying multiple diseases such as peripheral arterial disease and type 2 diabetes. For mapping, standardized terminological and metadata repository resources, such as the caDSR (Cancer Data Standards Registry and Repository) and SNOMED CT (Systematized Nomenclature of Medicine), were used. The mapping process comprised both lexical (via searching for relevant pre-coordinated concepts and data elements) and semantic (via post-coordination) techniques. Where feasible, new data elements were curated to enhance the coverage during mapping. A web-based application was also developed to uniformly represent and query the mapped data elements from different eMERGE studies. RESULTS: Approximately 60% of the target data elements (95 out of 157) could be mapped using simple lexical analysis techniques on pre-coordinated terms and concepts before any additional curation of terminology and metadata resources was initiated by eMERGE investigators. After curation of 54 new caDSR CDEs and nine new NCI thesaurus concepts and using post-coordination, the authors were able to map the remaining 40% of data elements to caDSR and SNOMED CT. A web-based tool was also implemented to assist in semi-automatic mapping of data elements. CONCLUSION: This study emphasizes the requirement for standardized representation of clinical research data using existing metadata and terminology resources and provides simple techniques and software for data element mapping using experiences from the eMERGE Network.

Evaluating Phenotypic Data Elements for Genetics and Epidemiological Research: Experiences from the eMERGE and PhenX Network Projects.

Combining genome-wide association studies (GWAS) data with clinical information from the electronic medical record (EMR) provide unprecedented opportunities to identify genetic variants that influence susceptibility to common, complex diseases. While mining the vastness of EMR greatly expands the potential for conducting GWAS, non-standardized representation and wide variability of clinical data and phenotypes pose a major challenge to data integration and analysis. To address this requirement, we present experiences and methods developed to map phenotypic data elements from eMERGE (Electronic Medical Record and Genomics) to PhenX (Consensus Measures for Phenotypes and Exposures) and NCI's Cancer Data Standards Registry and Repository (caDSR). Our results suggest that adopting multiple standards and biomedical terminologies will expose studies to a broader user community and enhance interoperability with a wider range of studies, in turn promoting cross-study pooling of data to detect both more subtle and more complex genotype-phenotype associations.

Effects of body position on thermal, cardiorespiratory and metabolic activity in low birth weight infants.

BACKGROUND: Low birth weight (LBW) infants sleeping prone are known to exhibit many physiological differences from those sleeping supine, including lower energy expenditure (heat production) and higher surface temperature. This apparent increase in heat storage suggests that heat loss may be inhibited in the prone position which, in turn, might influence cardiorespiratory activity. AIMS: To determine the effects of body position (prone vs. supine) on absolute surface temperature profile (heat storage), central-peripheral (C-P) thermal gradients (vasomotor response), cardiorespiratory activity and metabolic gas exchange in growing LBW infants. METHODS: Six-hour continuous recordings of absolute surface temperature profiles, cardiorespiratory activity and O2 and CO2 exchange, along with minute-to-minute assessment of behavioral sleep states were performed in 32 healthy growing LBW infants (birth weight 805-1590 g, gestational age 26-35 weeks and postconceptional age at study 33-38 weeks). Each infant was randomly assigned to the prone or supine position for the first 3 h of the study and then reversed for the second 3 h. Surface temperatures were recorded from 4 sites (forehead, flank, forearm and leg) and averaged each minute. Central (forehead and flank)-to-peripheral (forearm and leg) and forehead-to-environment (H-E) thermal gradients were calculated from the surface temperatures. Corresponding sleep states were aligned with minute averages obtained from the temperature and cardiorespiratory measurements. Data were then sorted for prone and supine positions during quiet (QS) and active sleep (AS) and compared using paired t-tests. RESULTS: In the prone position during both AS and QS, infants had higher forehead, flank, forearm and leg surface temperatures, narrower C-P gradients, higher heart rates and respiratory frequency, and lower heart rate and respiratory variability. Despite similar environmental temperatures, the H-E gradient was higher in the prone position. In the prone position infants demonstrated lower O2 consumption and CO2 production and a higher respiratory quotient. CONCLUSIONS: Despite thermoregulatory adjustments in cardiorespiratory function, infants sleeping prone have relatively higher body temperature. The cardiorespiratory responses to this modest increase in temperature indicate that thermal and metabolic control of cardiac and respiratory pumps seem to work in opposition. The consequences of any attendant changes in blood gas activity (e.g. hypocapnia and/or increased mixed venous oxygen concentration) due to this override of metabolic control remains speculative.

Is the early and aggressive administration of protein to very low birth weight infants safe and efficacious?

PURPOSE OF REVIEW: Most conventionally managed very low birth weight infants experience postnatal growth restriction. There is some evidence that this postnatal growth restriction may have long-lasting effects, and contribute to short stature and poor neurodevelopmental outcomes. There is also evidence suggesting that early protein intake may improve growth in these very low birth weight infants. Therefore, to optimize protein intake early in the infant's neonatal course seems a logical goal. RECENT FINDINGS: Randomized controlled trials provide evidence of short-term safety and efficacy for starting amino acid infusion as soon as possible after birth at 2.5-3.0 g/kg/day in very low birth weight infants; however, there are no long-term data to support the safety or efficacy of this practice. There is some evidence from recent studies of improved growth by providing 4.0 g/kg/day of amino acid early in the neonatal period while keeping the nitrogen to energy ratio above 1:100 and continuing with this protein intake during the infants stay in the hospital. At the present time long-term safety of this strategy is also not known. SUMMARY: Appropriately designed large-scale randomized controlled trials are needed to determine the long-term safety and efficacy of early and aggressive administration of protein to very low birth weight infants.

Enteral intake for very low birth weight infants: what should the composition be?

Providing optimal nutrition to satisfy the growth needs of very low birth weight infants is critical. The available preterm formulas and fortified human milk diets provide protein intakes of approximately 3.5 to 3.6 g/kg/d when volumes sufficient to provide 120 kcal/kg/d are fed to these infants. These intakes support growth and protein accretion at about or slightly greater than intrauterine rate and lead to relatively increased fat deposition. However, most very low birth infants fed these diets remain below the 10th percentile of the intrauterine growth standards at discharge. There is clear evidence that, with respect to growth, very low birth infants are likely to benefit from a higher protein intake; however, there is no clear evidence that energy intakes greater than 120 kcal/kg/d are needed. Although the upper limit of protein intake and the ideal protein:energy ratio remain controversial, there is enough evidence to support the beneficial and safe use of formulas providing protein:energy ratio of 3.2 to 3.3 g/100 kcal.

Interactions between sleeping position and feeding on cardiorespiratory activity in preterm infants.

Infants sleeping in the prone position are at greater risk for sudden infant death syndrome (SIDS). Sleep position-dependent changes in cardiorespiratory activity may contribute to this increased risk. Cardiorespiratory activity is also affected by feeding. Twenty prematurely-born infants were studied at 31-36 weeks postconceptional age while sleeping in the prone and supine positions. Heart rate, respiratory rate, and patterns of variability were recorded during interfeed intervals, and effects of position and time after feeding were analyzed by repeated measures analyses of variance. There were significant effects of both sleeping position and time after feeding. Heart rate is higher and heart period variability is lower in the prone position, and the effects of sleeping position on cardiac functioning are more pronounced during the middle of the intrafeed interval. In preterm infants, autonomic responses to nutrient processing modulate the cardiorespiratory effects of sleeping position. Prone sleeping risk may vary with time after feeding.

Quality of diet, body position, and time after feeding influence behavioral states in low birth weight infants.

The effects of variations in carbohydrate and fat intake and body position on behavioral activity states were evaluated in 64 healthy, growing low birth weight infants (birth weight, 750-1600 g). The infants, enrolled in a prospective, randomized, double-blind, controlled study of effects of quality of dietary energy, were fed one of the five formulas. These formulas contained fixed intakes of protein (4 g/kg per day) but different intakes of carbohydrate (9.1 to 20.4 g/kg per day) and fat (4.3 to 9.5 g/kg per day). Six-hour daytime sleep studies were performed at 2-wk intervals from time of full enteral intake until discharge (mean postconceptional age at first study, 33.2 +/- 1.8 wk). Infants were randomly assigned to the prone or supine position for the first 3-h postprandial period; the position was reversed during the second 3 h. Behavioral activity state, i.e. quiet sleep (QS), active sleep, indeterminate sleep, awake, or crying was coded each minute throughout the postprandial period. The overall incidence of QS was almost double in the prone position versus the supine (p < 0.0001). In contrast, the probability of being in either of the two wakeful states (awake and crying) was increased when infants were placed in supine position (p < 0.0001). Increased likelihood of being in QS while prone was found only during the 30 min after and before feeding in a 150-min prandial cycle. In contrast, increased amounts of awake and crying in supine position were observed throughout the feeding interval. As carbohydrate intake increased, time spent in QS in supine position increased (from 8.6% to 12.5%, p < 0.02), and a trend in the same direction was noted for the prone position (p = 0.06). However, during postprandial minutes 10-100, when QS is likely to be entrained by the nutrient intake, enhancement of QS was found in the prone position only (p < 0.02). Carbohydrate intake influences the total time spent and the distribution of behavioral activity states within the postprandial period in low birth weight infants. The effect of nutrient intake on sleep profile is dependent on body position and time after feed. Mechanistic hypotheses relating sudden infant death syndrome to sleeping position may need to take these observations into account.