Christoph P. Hornik

PI3K/Akt and apoptosis: Size matters

Recent research has examined Akt and Akt-related serine–threonine kinases in signaling cascades that regulate cell survival and are important in the pathogenesis of degenerative diseases and in cancer. We seek to recapitulate the research that has helped to define the current understanding of the role of the Akt pathway under normal and pathologic conditions, also in view of genetic models of Akt function. In particular, we will evaluate the mechanisms of Akt regulation and the role of Akt substrates in Akt-dependent biologic responses in the decisions of cell death and cell survival. Here, we hope to establish the mechanisms of apoptosis suppression by Akt kinase as a framework for a more general understanding of growth factor-dependent regulation of cell survival.

Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units.

BACKGROUND Very-low-birth-weight (VLBW, <1500 g birth weight) infants are at high risk for both early- and late-onset sepsis. Prior studies have observed a predominance of Gram-negative organisms as a cause of early-onset sepsis and Gram-positive organisms as a cause of late-onset sepsis. These reports are limited to large, academic neonatal intensive care units (NICUs) and may not reflect findings in other units. The purpose of this study was to determine the risk factors for sepsis, the causative organisms, and mortality following infection in a large and diverse sample of NICUs. METHODS We analysed the results of all cultures obtained from VLBW infants admitted to 313 NICUs from 1997 to 2010. RESULTS Over 108,000 VLBW infants were admitted during the study period. Early-onset sepsis occurred in 1032 infants, and late-onset sepsis occurred in 12,204 infants. Gram-negative organisms were the most commonly isolated pathogens in early-onset sepsis, and Gram-positive organisms were most commonly isolated in late-onset sepsis. Early- and late-onset sepsis were associated with increased risk of death controlling for other confounders (odds ratio 1.45 [95% confidence interval [CI] 1.21,1.73], and OR 1.30 [95%CI 1.21, 1.40], respectively). CONCLUSIONS This is the largest report of sepsis in VLBW infants to date. Incidence for early-onset sepsis and late-onset sepsis has changed little over this 14-year period, and overall mortality in VLBW infants with early- and late-onset sepsis is higher than in infants with negative cultures.

Medication Use in the Neonatal Intensive Care Unit

OBJECTIVE The aim of the article is to provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time. STUDY DESIGN We performed a retrospective review (2005-2010) of a large prospectively collected administrative database. RESULT Medications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56-681 exposures per 1,000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram. CONCLUSION Medication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are Food and Drug Administration -approved in infants.

Cumulative Radiation Exposure and Cancer Risk Estimation in Children With Heart Disease

Background— Children with heart disease are frequently exposed to imaging examinations that use ionizing radiation. Although radiation exposure is potentially carcinogenic, there are limited data on cumulative exposure and the associated cancer risk. We evaluated the cumulative effective dose of radiation from all radiation examinations to estimate the lifetime attributable risk of cancer in children with heart disease. Methods and Results— Children ⩽6 years of age who had previously undergone 1 of 7 primary surgical procedures for heart disease at a single institution between 2005 and 2010 were eligible for the study. Exposure to radiation-producing examinations was tabulated, and cumulative effective dose was calculated in millisieverts. These data were used to estimate lifetime attributable risk of cancer above baseline using the approach of the Committee on Biological Effects of Ionizing Radiation VII. The cohort included 337 children exposed to 13 932 radiation examinations. Conventional radiographs represented 92% of examinations, whereas cardiac catheterization and computed tomography accounted for 81% of cumulative exposure. Overall median cumulative effective dose was 2.7 mSv (range, 0.1–76.9 mSv), and the associated lifetime attributable risk of cancer was 0.07% (range, 0.001%–6.5%). Median lifetime attributable risk of cancer ranged widely depending on surgical complexity (0.006%–1.6% for the 7 surgical cohorts) and was twice as high in females per unit exposure (0.04% versus 0.02% per 1-mSv effective dose for females versus males, respectively; P<0.001). Conclusions— Overall radiation exposures in children with heart disease are relatively low; however, select cohorts receive significant exposure. Cancer risk estimation highlights the need to limit radiation dose, particularly for high-exposure modalities.

Use of the complete blood cell count in early-onset neonatal sepsis.

Background: Early-onset sepsis (EOS) is an important cause of morbidity and mortality in neonates, and its diagnosis remains challenging. The complete blood cell count and differential have been previously evaluated as diagnostic tools for EOS in small, single-center reports. We evaluated the diagnostic accuracy of the complete blood cell count and differential in EOS in a large, multicenter population of neonates admitted to the neonatal intensive care unit. Methods: Using a cohort of 166,092 neonates with suspected EOS with cultures admitted to 293 neonatal intensive care units, we calculated odds ratios and receiver operating characteristic curves for complete blood cell count indices and prediction of a positive culture. We determined sensitivity, specificity and likelihood ratios for various commonly used cutoff values from the complete blood cell count. Results: Low white blood cell counts, low absolute neutrophil counts and high immature-to-total neutrophil ratios were associated with increasing odds of infection (highest odds ratios: 5.38, 6.84 and 7.97, respectively). Specificity and negative predictive values were high (73.7%–99.9% and >99.8%). However, sensitivities were low (0.3%–54.5%) for all complete blood cell count indices analyzed. Conclusion: Low white blood cell count, absolute neutrophil count and high immature-to-total neutrophil ratio were associated with increasing odds of infection, but no complete blood cell count-derived index possesses the sensitivity to rule out reliably EOS in neonates.

Fluconazole Loading Dose Pharmacokinetics and Safety in Infants

Background: Invasive candidiasis is a leading cause of morbidity and mortality in critically ill infants. Prompt administration of fluconazole and achievement of the therapeutic target (area under the curve 0 to 24 hours >400 mg*h/L) improve outcomes in candidemic patients. A loading dose of fluconazole is advised for older patients but has not been evaluated in infants. We sought to determine the pharmacokinetics and safety of a fluconazole loading dose in infants at risk for invasive fungal infection. Methods: We enrolled 10 hospitalized infants <60 days old with suspected systemic fungal infection in this open-label study; 9 received a 25-mg/kg fluconazole loading dose followed by a maintenance dose of 12 mg/kg every 24 hours for 4 additional days. Plasma samples were obtained following the loading and steady-state doses (doses 3–5). We used a 1-compartment model to fit the data to estimate pharmacokinetic indices. Results: Data from 57 drug concentrations obtained from 8 infants (median postnatal age, 16 days [interquartile range, 13–32] and median gestational age, 37 weeks [35–38]) showed that the median fluconazole area under the curve 0 to 24 hours (mg*h/L) in this population was 479 (347–496). Of the 8 infants who received the loading dose, 5 (63%) achieved the therapeutic target on the first day of dosing, and all infants achieved a fluconazole 24-hour trough concentration >8 &mgr;g/mL. No adverse events were thought to be related to fluconazole therapy. Conclusions: A loading dose of fluconazole (25 mg/kg) was safe in this small cohort of young infants and achieved the therapeutic target more rapidly than traditional dosing.

Severe Acute Malnutrition in Childhood: Hormonal and Metabolic Status at Presentation, Response to Treatment, and Predictors of Mortality

OBJECTIVE Malnutrition is a major cause of childhood morbidity and mortality. To identify and target those at highest risk, there is a critical need to characterize biomarkers that predict complications prior to and during treatment. METHODS We used targeted and nontargeted metabolomic analysis to characterize changes in a broad array of hormones, cytokines, growth factors, and metabolites during treatment of severe childhood malnutrition. Children aged 6 months to 5 years were studied at presentation to Mulago Hospital and during inpatient therapy with milk-based formulas and outpatient supplementation with ready-to-use food. We assessed the relationship between baseline hormone and metabolite levels and subsequent mortality. RESULTS Seventy-seven patients were enrolled in the study; a subset was followed up from inpatient treatment to the outpatient clinic. Inpatient and outpatient therapies increased weight/height z scores and induced striking changes in the levels of fatty acids, amino acids, acylcarnitines, inflammatory cytokines, and various hormones including leptin, insulin, GH, ghrelin, cortisol, IGF-I, glucagon-like peptide-1, and peptide YY. A total of 12.2% of the patients died during hospitalization; the major biochemical factor predicting mortality was a low level of leptin (P = .0002), a marker of adipose tissue reserve and a critical modulator of immune function. CONCLUSIONS We have used metabolomic analysis to provide a comprehensive hormonal and metabolic profile of severely malnourished children at presentation and during nutritional rehabilitation. Our findings suggest that fatty acid metabolism plays a central role in the adaptation to acute malnutrition and that low levels of the adipose tissue hormone leptin associate with, and may predict, mortality prior to and during treatment.

The complex relationship between center volume and outcome in patients undergoing the norwood operation

BACKGROUND Norwood outcomes vary across centers, and a relationship between center volume and outcome has been previously described. It is unclear whether this volume-outcome relationship exists across all levels of patient risk or holds true for all centers. We evaluated the impact of patient risk status on the relationship between center volume and outcome, and the extent to which differences in center volume account for between-center variation in outcome. METHODS Infants in The Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing the Norwood operation (2000 to 2009) were included. Mortality associated with annual Norwood volume overall and across patient preoperative risk tertiles was evaluated in multivariable analysis. We also estimated the proportion of between-center variation in mortality explained by center volume. RESULTS The cohort included 2,557 infants from 53 centers: 34 centers with 0 to 10 Norwood cases per year; 13 centers with 11 to 20 cases per year; and 6 centers with more than 20 cases per year. Unadjusted in-hospital mortality was 22%. In multivariable analysis, lower center volume was associated with higher mortality (odds ratio in low-volume versus high-volume centers 1.54, 95% confidence interval: 1.02 to 2.32, p=0.04). The volume-outcome relationship did not differ across preoperative risk tertiles (p=0.7). Norwood volume explained an estimated 14% of the between-center variation in mortality observed, and significant between-center variation in mortality remained after adjusting for volume (p<0.001). CONCLUSIONS Center volume is modestly associated with outcome after the Norwood operation independent of patient risk status. However, this relationship explains only a portion of the between-center variation in mortality in this cohort.

Relative Impact of Surgeon and Center Volume on Early Mortality After the Norwood Operation

BACKGROUND Previous studies suggest center volume is associated with outcome after the Norwood operation; however, the impact of surgeon volume is less clear. We evaluated the relative impact of surgeon and center volume on mortality in a large Norwood cohort. METHODS Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing the Norwood operation (2000 to 2009) were included. Using multivariable logistic regression, we evaluated the relationship between in-hospital mortality and annual center and surgeon volume, adjusting for patient factors. RESULTS A total of 2,555 patients were operated on at 53 centers by 111 surgeons. Overall unadjusted mortality was 22.1%. When analyzed individually, both lower center and surgeon volume were associated with higher mortality (odds ratio for centers with 0 to 10 vs >20 cases per year 1.56 [95% confidence interval 1.05 to 2.31]; odds ratio for surgeons with 0 to 5 vs >10 cases per year 1.60 [95% confidence interval 1.12 to 2.27]). When analyzed together, the addition of surgeon volume to the center volume models attenuated but did not completely mitigate the association of center volume with outcome (relative attenuation of odds ratio=34%). Adjusted mortality rates in low, medium, and high volume centers were 25.6%, 22.3%, and 17.7%, respectively. Across all center volume strata, lower volume surgeons had higher adjusted mortality rates. CONCLUSIONS Both center and surgeon volumes appear to influence Norwood outcomes. These data suggest outcomes may potentially be improved through strategies that take advantage of the positive influence of both of these variables. This could include further investigation into the feasibility of regional collaborations, and the development of quality improvement initiatives within and across centers.

Drug Labeling and Exposure in Neonates

IMPORTANCE Federal legislation has led to a notable increase in pediatric studies submitted to the Food and Drug Administration (FDA), resulting in new pediatric information in product labeling. However, approximately 50% of drug labels still have insufficient information on safety, efficacy, or dosing in children. Neonatal information in labeling is even scarcer because neonates comprise a vulnerable subpopulation for which end-point development is lagging and studies are more challenging. OBJECTIVE To quantify progress made in neonatal studies and neonatal information in product labeling as a result of recent legislation. DESIGN, SETTING, AND PARTICIPANTS We identified a cohort of drug studies between 1997 and 2010 that included neonates as a result of pediatric legislation using information available on the FDA website. We determined what studies were published in the medical literature, the legislation responsible for the studies, and the resulting neonatal labeling changes. We then examined the use of these drugs in a cohort of neonates admitted to 290 neonatal intensive care units (NICUs) (the Pediatrix Data Warehouse) in the United States from 2005 to 2010. EXPOSURE Infants exposed to a drug studied in neonates as identified by the FDA website. MAIN OUTCOMES AND MEASURES Number of drug studies with neonates and rate of exposure per 1000 admissions among infants admitted to an NICU. RESULTS In a review of the FDA databases, we identified 28 drugs studied in neonates and 24 related labeling changes. Forty-one studies encompassed the 28 drugs, and 31 (76%) of these were published. Eleven (46%) of the 24 neonatal labeling changes established safety and effectiveness. In a review of a cohort of 446,335 hospitalized infants, we identified 399 drugs used and 1,525,739 drug exposures in the first 28 postnatal days. Thirteen (46%) of the 28 drugs studied in neonates were not used in NICUs; 8 (29%) were used in fewer than 60 neonates. Of the drugs studied, ranitidine was used most often (15,627 neonates, 35 exposures per 1000 admissions). CONCLUSIONS AND RELEVANCE Few drug labeling changes made under pediatric legislation include neonates. Most drugs studied are either not used or rarely used in US NICUs. Strategies to increase the study of safe and effective drugs for neonates are needed.