Publication Recommendations to Report Laboratory Data of Neonates - a Modified Delphi Approach.

BACKGROUND: Clinical and analytical information on laboratory data of neonates in scientific publications is sparse and incomplete. Furthermore, interpreting neonatal laboratory data can be complex due to their time-dependent and developmental physiology, and paucity of well-established age-appropriate reference ranges for neonates. This study aims to develop publication recommendations to report laboratory data of neonates to enhance the quality of these data in research and clinical care. METHODS: A modified Delphi approach was used to develop recommendations in cooperation with the International Neonatal Consortium. A Core Group, including different stakeholders, was responsible for developing the recommendations, in collaboration with a Reflection Group, responsible for providing additional input. RESULTS: The recommendations were classified into three categories: 'Clinical Characteristics', 'Bio-analytical Information' and 'Data-analytical Information'. These were each divided into 'Core Data' (always to be reported) and 'Supplemental Considerations' (to be reported when considered relevant to the study). CONCLUSION: Our recommendations provide guidance on standardization of neonatal laboratory data in publications. This will enhance the comparison, replication, and application of study results in research initiatives and clinical practice. Furthermore, these recommendations also serve as foundational work to develop reference ranges for neonatal laboratory values by standardizing the quality of information needed for such efforts. IMPACT: Standardized reporting of neonatal laboratory data in scientific publications will enhance the comparison, replication, and application of study results in research initiatives and clinical practice, as well as improve reporting to regulatory agencies. To integrate multistakeholder perspectives, a modified Delphi approach was used to develop publication recommendations which strengthens the applicability of the recommendations. Implementation of standardization will likely improve the overall quality of neonatal clinical research and neonatal healthcare. In addition, these recommendations are foundational to develop reference ranges for neonatal laboratory values by standardizing the quality of information needed for such efforts.

Nurses' Knowledge, Communication Needs, and Future Directions in Neonatal Research: Results of an International Survey.

BACKGROUND: Preterm birth is a significant contributor to neonatal morbidity and mortality. Despite legislative efforts to increase pediatric drug development, neonatal clinical trials continue to be infrequent. The International Neonatal Consortium (INC) includes nurses as key stakeholders in their mission to accelerate safe and effective therapies for neonates. PURPOSE: INC developed a survey for nurses, physicians, and parents to explore communication practices and stakeholders' perceptions and knowledge regarding clinical trials in neonatal intensive care units (NICUs). METHODS: A stepwise consensus approach was used to solicit responses to an online survey. The convenience sample was drawn from INC organizations representing the stakeholder groups. Representatives from the National Association of Neonatal Nurses and the Council of International Neonatal Nurses, Inc, participated in all stages of the survey development process, results analysis, and publication of results. RESULTS: Participants included 188 nurses or nurse practitioners, mainly from the United States, Canada, the European Union, and Japan; 68% indicated some level of research involvement. Nurses expressed a lack of effective education to prepare them for participation in research. Results indicated a lack of a central information source for staff and systematic approaches to inform families of studies. The majority of nurses indicated they were not asked to provide input into clinical trials. Nurses were uncertain about research consent and result disclosure processes. IMPLICATIONS FOR PRACTICE AND RESEARCH: This study indicates the need to educate nurses in research, improve NICU research communication through standardized, systematic pathways, and leverage nurse involvement to enhance research communication.

The neonatal adverse event severity scale: current status, a stakeholders' assessment, and future perspectives.

To support informed decisions on drug registration and prescription, clinical trials need tools to assess the efficacy and safety signals related to a given therapeutic intervention. Standardized assessment facilitates reproducibility of results. Furthermore, it enables weighted comparison between different interventions, instrumental to facilitate shared decisions. When focused on adverse events in clinical trials, tools are needed to assess seriousness, causality and severity. As part of such a toolbox, the international Neonatal Consortium (INC) developed a first version of the neonatal adverse event severity scale (NAESS). This version underwent subsequent validation in retro-and prospective trials to assess its applicability and impact on the inter-observer variability. Regulators, sponsors and academic researchers also reported on the use of the NAESS in regulatory documents, trial protocols and study reports. In this paper, we aim to report on the trajectory, current status and impact of the NAESS score, on how stakeholders within INC assess its relevance, and on perspectives to further develop this tool.

Response biomarkers in neonatal intervention studies.

BackgroundUp to 90% of all drugs used in neonatal intensive care units (NICUs) have not been clinically tested for safety and efficacy. To promote drug development for neonates, the pharmaceutical industry is moving toward rigorous testing, necessitating the need to development, and validating biomarkers in neonates to predict their response. The objective of this review is to evaluate the quality of the response biomarker reporting in neonatal clinical trials.MethodsA validated literature search strategy was applied. Prospective neonatal intervention studies reporting response biomarkers published in 2014 were included. The data were extracted independently and in duplicate using a data-extraction form.ResultsFollowing the full-text review, 167 published prospective neonatal trials were included; 35% (59/167) reported the use of response biomarkers. In these 59 trials, we identified 275 biomarkers used to measure the response (pharmacodynamics and safety) reported as primary or secondary outcomes. Heart rate and oxygen saturation were the most commonly reported. Measurement and instrumentation data were often not provided.ConclusionWe identified a huge variability in the selection, measurement, and reporting of neonatal response biomarkers in prospective intervention studies. Reporting initiatives are needed to reduce research waste and improve the reproducibility of biomarker use in neonatal intervention studies.

Children's risk and resilience following a natural disaster: genetic vulnerability, posttraumatic stress, and depression.

OBJECTIVE: We examined children's risk and resilience following a natural disaster, evaluating the role of stress, social support, and two genetic markers: the short allele of the serotonin transporter gene (5-HTTLPR), and the met allele of the Brain-Derived Neurotrophic Factor (BDNF).Under high levels of hurricane exposure or hurricane-related stressors, we expected children displaying the markers would report greater symptoms of posttraumatic stress disorder (PTSD) and depression than children without these markers. Social support was explored as an additional moderating variable. METHOD: Eight months after Hurricane Ike, 116 children (M age=8.85 years, SD=.89; 54% girls) residing in Galveston, Texas, provided saliva samples and completed measures of hurricane exposure and stress, and symptoms of PTSD and depression; 80 also completed a social support measure. RESULTS: For BDNF, analyses revealed several Gene by Environment interactions; greater stress was related to more symptoms of PTSD and depression, and this effect was stronger for children with the met allele. No findings emerged for 5-HTTLPR. Stressors and social support also were associated with children's PTSD and depressive symptoms. LIMITATIONS: Findings should be tempered by the relatively small sample, especially for analysis that included social support. CONCLUSIONS: The met allele (BDNF) may play a role in children's disaster reactions. Further research should consider the complex interplay between genes, stressors, support, and psychological outcomes over time.

Transfusion outcomes in patients undergoing coronary artery bypass grafting treated with prasugrel or clopidogrel: TRITON-TIMI 38 retrospective data analysis.

OBJECTIVE: Coronary artery bypass grafting-related bleeding and associated transfusion is a concern with dual antiplatelet therapy in patients with acute coronary syndromes. The objective of the present study was to characterize a potential risk-adjusted difference in transfusion requirements between prasugrel and clopidogrel cohorts. METHODS: The data from 422 patients undergoing isolated coronary artery bypass grafting from the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 were analyzed retrospectively. RESULTS: We found no difference in baseline transfusion risk scores between cohorts. As predicted, the number of units of red blood cells transfused perioperatively correlated with the transfusion risk score (P < .0001). Overall, the 12-hour chest tube drainage volumes and platelet transfusion rates in the prasugrel cohort were significantly greater. However, no statistically significant differences were found in the number of red blood cell transfusions, total hemostatic components transfused, or total blood donor exposure. A significantly greater number of platelet units were transfused postoperatively in the prasugrel patients who underwent surgery within 5 days or less after withdrawal of drug. In an analysis adjusted for the predicted risk of mortality, total donor exposure was not associated with increased mortality. CONCLUSIONS: The use of prasugrel compared with clopidogrel was associated with greater 12-hour chest tube drainage volumes and platelet transfusion rates but without any significant differences in red blood cell transfusions, total hemostatic components transfused, or total blood donor exposure.

Biomarker response to drotrecogin alfa (activated) in children with severe sepsis: results from the RESOLVE clinical trial*.

OBJECTIVE: REsearching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE), a phase III trial of drotrecogin alfa (activated) in pediatric severe sepsis, examined biomarker changes in inflammation and coagulation. This report describes biomarker profiles in early severe sepsis and the pharmacodynamic assessment of drotrecogin alfa (activated) in RESOLVE. DESIGN: Serial measurements of interleukin-1ß, interleukin-6, interleukin-8, interleukin-10, tissue necrosis factor-α, procalcitonin, D-dimer, and thrombin-antithrombin complex were performed at baseline and daily over the first five study days. Protein C levels were performed at baseline and at the end of the 96-hr study drug infusion. Analysis of variance-based log-transformed data compared the treatment groups for each measured variable. SETTING: : One hundred four pediatric intensive care units in 18 countries. PATIENTS: Four hundred seventy-seven children between 38 wks corrected gestational age and 17 yrs with sepsis-induced cardiovascular and respiratory dysfunction. INTERVENTIONS: Drotrecogin alfa (activated). MEASUREMENTS AND MAIN RESULTS: Pharmacodynamic activity of drotrecogin alfa (activated) compared with placebo was observed with reduction of D-dimer on day 1 (p < .01) and thrombin-antithrombin complex on days 1-4 (p < .05). There were no significant changes by treatment in multiple cytokines or procalcitonin. In the overall population, a median protein C difference was not observed (p > .05) with drotrecogin alfa (activated) administration compared with placebo, although a difference (median percentage change from baseline) in favor of drotrecogin alfa (activated) was observed in patients >1 yr old (p = .0449). CONCLUSIONS: While children in the RESOLVE trial were similar to adults in that they showed a relationship between severity of coagulation and inflammation abnormalities and mortality, their pharmacodynamic response to drotrecogin alfa (activated) differed with respect to changes in protein C activity and systemic inflammation.

Mortality benefit with prasugrel in the TRITON-TIMI 38 coronary artery bypass grafting cohort: risk-adjusted retrospective data analysis.

OBJECTIVES: The objective of this study was to characterize the bleeding, transfusion, and other outcomes of patients related to the timing of prasugrel or clopidogrel withdrawal before coronary artery bypass grafting (CABG). BACKGROUND: There is little evidence to guide clinical decision making regarding the use of prasugrel in patients who may need urgent or emergency CABG. Experience with performing CABG in the presence of clopidogrel has raised concern about perioperative bleeding complications that are unresolved. METHODS: A subset of the TRITON-TIMI 38 study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38), in which patients with acute coronary syndrome were randomized to treatment with aspirin and either clopidogrel or prasugrel, underwent isolated CABG (N = 346). A supplemental case report form was designed and administered, and the data combined with the existing TRITON-TIMI 38 database. Baseline imbalances were corrected for using elements of the European System for Cardiac Operative Risk Evaluation and The Society of Thoracic Surgeons predictive algorithm. RESULTS: A significantly higher mean 12-h chest tube blood loss (655 ± 580 ml vs. 503 ± 378 ml; p = 0.050) was observed with prasugrel compared with clopidogrel, without significant differences in red blood cell transfusion (2.1 U vs. 1.7 U; p = 0.442) or the total donor exposure (4.4 U vs. 3.0 U; p = 0.463). All-cause mortality was significantly reduced with prasugrel (2.31%) compared with 8.67% with clopidogrel (adjusted odds ratio: 0.26; p = 0.025). CONCLUSIONS: Despite an increase in observed bleeding, platelet transfusion, and surgical re-exploration for bleeding, prasugrel was associated with a lower rate of death after CABG compared with clopidogrel.

Protein C in critical illness.

PURPOSE: The role of protein C in critical illness is assessed. SUMMARY: Conversion of protein C to activated protein C (APC) requires thrombin and thrombomodulin. When thrombin is not bound to thrombomodulin, it can convert fibrinogen to fibrin, factor V to factor Va, and factor VIII to factor VIIIa but will not convert protein C to APC. When thrombin is bound to thrombomodulin, it can convert protein C to APC but cannot convert fibrinogen, factor V, or factor VIII. Activation of protein C is accelerated by the presence of endothelial protein C receptors. In conjunction with protein S, APC limits coagulation by inactivating factors Va and VIIIa, which decreases thrombin-mediated inflammation. By inhibiting the formation of thrombin and the release of proinflammatory cytokines, APC reduces the inflammatory response to infection. By inducing cell signaling, APC directly modulates the cellular response to infection, resulting in antiinflammatory, cytoprotective, and barrier-protective activities. APC is metabolized by protease inhibitors and other proteins in the plasma. Conversion of protein C to APC is impaired in severe sepsis. During severe sepsis, endogenous levels of the inactive precursor protein C are reduced because of decreased production by the liver and degradation by enzymes. More than 85% of patients with severe sepsis have low levels of protein C. Absolute levels of protein C correlate with morbidity and mortality outcomes of the sepsis population, regardless of age, infecting microorganism, presence of shock, disseminated intravascular coagulation, degree of hypercoagulation, or severity of illness. CONCLUSION: The protein C pathway is a natural homeostatic regulator with multiple mechanisms of action. Blood protein C concentration is inversely correlated with morbidity and mortality in sepsis and other critical illness.

From bench to bedside: a review of the clinical trial development plan of drotrecogin alfa (activated).

OBJECTIVE: To provide a comprehensive overview of the various clinical trials of drotrecogin alfa (activated) (DrotAA) completed by Eli Lilly and Company over the past 10 years. METHODS: Eli Lilly and Company data from phase 1 through phase 4 trials, observational studies, and compassionate-use studies of DrotAA were reviewed. Safety, efficacy, and pharmacokinetic data were included. The review excluded pediatric studies and studies recently concluded where the manuscript was in press. All studies included in the review were approved by the ethical review boards at the participating institutions. RESULTS: Over 9000 adults with severe sepsis have been enrolled in DrotAA clinical trials through December 2005 and the results of the clinical evaluation of DrotAA have been widely disseminated in publications. Analyses of the data indicate that the pharmacokinetics of DrotAA are both linear and dose-proportional. The phase 2 and phase 3 studies of administration of DrotAA to patients with severe sepsis demonstrated a significant reduction in mortality and were associated with a favorable benefit/risk profile. Three of these trials (a phase 2 and two phase 3, PROWESS and ENHANCE) evaluated the effect of DrotAA in adult patients with sepsis associated with acute organ dysfunction (severe sepsis) while another phase 3 trial (ADDRESS) was conducted in the non-indicated population of adult patients with severe sepsis associated with a lower risk of death. A phase 4 trial demonstrated no significant difference in steady-state plasma concentrations or elimination half-life of DrotAA between patients < or =135 kg and >135 kg, indicating that DrotAA should be dosed by actual body weight. DISCUSSION: The challenges and limitations of the clinical development plan for DrotAA are discussed. CONCLUSION: DrotAA is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death. DrotAA is not indicated in adult patients with severe sepsis and low risk of death. The clinical plan for DrotAA continues with a focus on tailored therapy and identifying the most appropriate patients for DrotAA treatment.

Linking the sepsis triad of inflammation, coagulation, and suppressed fibrinolysis to infants.

Sepsis continues to be a significant cause of morbidity and mortality in hospitalized newborns and premature infants. The pathophysiology and disease state of sepsis appear to be similar between adults and children. Both groups display symptoms that indicate a systemic inflammatory response leading to coagulopathy, hypotension, inadequate perfusion of peripheral tissues and organs, and, ultimately, organ failure and death. By presenting a comparison of adult and neonatal pathophysiology, as well as a supporting literature review and clinical evidence, this article links the pathways of inflammation, activation of coagulation, and impaired fibrinolysis, known as the sepsis cascade, to neonatal sepsis. Knowledge of the pathophysiology has important clinical and research implications. Unlike traditional antimicrobial therapy, new potential therapies, currently under investigation for the treatment of sepsis, target the cellular response rather than the invading organism. A more complete understanding of the pathophysiology of sepsis may also lead to diagnostic tools with improved sensitivity and specificity for early recognition and treatment.

Guide to a systematic physical assessment in the infant with suspected infection and/or sepsis.

This article provides the resources for the bedside caregiver to conduct a focused physical assessment of the infant with suspected sepsis. The importance of obtaining a complete history to identify associated obstetric and neonatal risk factors is emphasized. Further evaluation of the infant's clinical presentation for signs and symptoms suggestive of a systemic inflammatory response to infection is discussed, along with a step-by-step guide to a systematic physical assessment. Strategies to evaluate physical findings in context with the available diagnostic data to develop a differential diagnosis are provided. The international consensus definitions for the sepsis continuum are presented and are compared and contrasted to the definitions more commonly used in the neonatal population. The article provides tables that can serve as checklists to structure a thorough obstetric and neonatal history and to further evaluate the infant's systemic inflammatory response to infection.