Ketamine exposure during embryogenesis inhibits cellular proliferation in rat fetal cortical neurogenic regions.

BACKGROUND: Developmental neurotoxicity of ketamine, an N-methyl-D-aspartate receptor antagonist, must be considered due to its widespread uses for sedation/analgesia/anesthesia in pediatric and obstetric settings. Dose-dependent effects of ketamine on cellular proliferation in the neurogenic regions of rat fetal cortex [ventricular zone (VZ) and subventricular zone (SVZ)] were investigated in this in vivo study. METHODS: Timed-pregnant Sprague-Dawley rats at embryonic day 17 (E17) were given with different doses of ketamine intraperitoneally (0, 1, 2, 10, 20, 40, and 100 mg/kg). Proliferating cells in the rat fetal brains were labeled by injecting 100 mg/kg of 5-bromo-2'-deoxyuridine (BrdU) intraperitoneally. BrdU-labeled cells were detected by immunostaining methods. The numbers of BrdU-positive cells in VZ and SVZ of rat fetal cortex were employed to quantify proliferation in the developing rat cortex. RESULTS: Ketamine dose-dependently reduced the number of BrdU-positive cells in VZ (P < 0.001) and SVZ (P < 0.001) of the rat fetal cortex. SVZ showed greater susceptibility to ketamine-induced reduction of proliferation in rat fetal cortex, occurring even at clinically relevant doses (2 mg/kg). CONCLUSION: These data suggest that exposure to ketamine during embryogenesis can dose-dependently inhibit the cellular proliferation in neurogenic regions of the rat fetal cortex.

Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants.

AIM: The therapeutic options available to treat neonatal pain are limited, and one alternative for nonopioid systemic treatment is paracetamol. However, pharmacokinetic data from prolonged administration of intravenous paracetamol in neonates are limited. The aim of this study was to present pharmacokinetics after multiple dose of intravenous paracetamol in very preterm infants of <32 weeks' gestation. METHODS: Fifteen very preterm infants received five, six-hourly doses of intravenous paracetamol (7.5 mg/kg). Blood samples were taken to measure paracetamol, glutathione and hepatic function, together with urine samples for paracetamol metabolites. RESULTS: A two-compartment pharmacokinetic model gave the best fit for all individual patients and resulted in a predictable pharmacokinetic profile. The estimated pharmacokinetic population parameters were volume of distribution 0.764 ± 0.225 L/kg, elimination rate constant (ke ) 0.117 ± 0.091/h and intercompartment rate constants k12 0.607 ± 0.734/h and k21 1.105 ± 0.762/h. CONCLUSION: Our study found that multiple doses of intravenous paracetamol resulted in a predictable pharmacokinetic profile in very preterm infants. Increases in postmenstrual age and weight were associated with increased clearance. No evidence of hepatotoxicity was found.

Baseline serum concentrations of zinc, selenium, and prolactin in critically ill children.

OBJECTIVES: To describe serum concentrations of zinc, selenium, and prolactin in critically ill children within 72 hours of PICU admission, and to investigate relationships between these immunomodulators and lymphopenia. DESIGN: An analysis of baseline data collected as part of the multicenter Critical Illness Stress Induced Immune Suppression (CRISIS) Prevention Trial. SETTING: PICUs affiliated with the Collaborative Pediatric Critical Care Research Network. PATIENTS: All children enrolled in the CRISIS Prevention Trial that had baseline serum samples available for analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 293 critically ill children enrolled in the CRISIS Prevention Trial, 284 had baseline serum samples analyzed for prolactin concentration, 280 for zinc concentration, and 278 for selenium concentration within 72 hours of PICU admission. Lymphocyte counts were available for 235 children. Zinc levels ranged from nondetectable (< 0.1 µg/mL) to 2.87 µg/mL (mean 0.46 µg/mL and median 0.44 µg/mL) and were below the normal reference range for 235 (83.9%) children. Selenium levels ranged from 26 to 145 ng/mL (mean 75.4 ng/mL and median 74.5 ng/mL) and were below the normal range for 156 (56.1%) children. Prolactin levels ranged from nondetectable (< 1 ng/mL) to 88 ng/mL (mean 12.2 ng/mL and median 10 ng/mL). Hypoprolactinemia was present in 68 (23.9%) children. Lymphopenia was more likely in children with zinc levels below normal than those with zinc levels within or above the normal range (82 of 193 [42.5%] vs. 10 of 39 [25.6%], p = 0.0498). Neither selenium nor prolactin concentrations were associated with lymphopenia (p = 1.0 and p = 0.72, respectively). CONCLUSIONS: Serum concentrations of zinc, selenium, and prolactin are often low in critically ill children early after PICU admission. Low serum zinc levels are associated with lymphopenia, whereas low selenium and prolactin levels are not. The implications of these findings and the mechanisms by which they occur merit further study.

The role of the Data and Safety Monitoring Board in a clinical trial: the CRISIS study.

OBJECTIVES: Randomized clinical trials are commonly overseen by a Data and Safety Monitoring Board comprised of experts in medicine, ethics, and biostatistics. Data and Safety Monitoring Board responsibilities include protocol approval, interim review of study enrollment, protocol compliance, safety, and efficacy data. Data and Safety Monitoring Board decisions can affect study design and conduct, as well as reported findings. Researchers must incorporate Data and Safety Monitoring Board oversight into the design, monitoring, and reporting of randomized trials. DESIGN: Case study, narrative review. METHODS: The Data and Safety Monitoring Board's role during the comparative pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial is described. FINDINGS: The National Institutes of Health-appointed CRISIS Data and Safety Monitoring Board was charged with monitoring sample size adequacy and feasibility, safety with respect to adverse events and 28-day mortality, and efficacy with respect to the primary nosocomial infection/sepsis outcome. The Federal Drug Administration also requested Data and Safety Monitoring Board interim review before opening CRISIS to children below 1 yr of age. The first interim analysis found higher 28-day mortality in one treatment arm. The Data and Safety Monitoring Board maintained trial closure to younger children and requested a second interim data review 6 months later. At this second meeting, mortality was no longer of concern, whereas a weak efficacy trend of lower infection/sepsis rates in one study arm emerged. As over 40% of total patients had been enrolled, the Data and Safety Monitoring Board elected to examine conditional power and unmask treatment arm identities. On finding somewhat greater efficacy in the placebo arm, the Data and Safety Monitoring Board recommended stopping CRISIS due to futility. CONCLUSIONS: The design and operating procedures of a multicenter randomized trial must consider a pivotal Data and Safety Monitoring Board role. Maximum study design flexibility must be allowed, and investigators must be prepared for protocol modifications due to interim findings. The Data and Safety Monitoring Board must have sufficient clinical and statistical expertise to assess potential importance of interim treatment differences in the setting of multiple looks at accumulating data with numerous outcomes and subgroups.

Physicians' conceptualization of "closure" as a benefit of physician-parent follow-up meetings after a child's death in the pediatric intensive care unit.

We examined physicians' conceptualization of closure as a benefit of follow-up meetings with bereaved parents. The frequency of use and the meaning of the word "closure" were analyzed in transcripts of interviews with 67 critical care physicians affiliated with the Collaborative Pediatric Critical Care Research Network. In all, 38 physicians (57 percent) used the word "closure" at least once (median: 2; range: 1 to 7), for a total of 86 times. Physicians indicated that closure is a process or trajectory rather than an achievable goal. They also indicated that parents and physicians can move toward closure by gaining a better understanding of the causes and circumstances of the death and by reconnecting with, or resolving relationships between, parents and health professionals. Physicians suggested that a primary reason to conduct follow-up meetings is that such meetings offer parents and physicians an opportunity to move toward closure. Future research should attempt to determine whether followup meetings reduce the negative effects of bereavement for parents and physicians.

Ketamine alters the neurogenesis of rat cortical neural stem progenitor cells.

OBJECTIVE: High doses or prolonged exposure to ketamine increase neuronal apoptosis in the developing brain, although effects on neural stem progenitor cells remain unexplored. This study investigated dose- and time-dependent responses to ketamine on cell death and neurogenesis in cultured rat fetal cortical neural stem progenitor cells. DESIGN: Laboratory-based study. SETTING: University research laboratory. SUBJECT: Sprague-Dawley rats. INTERVENTIONS: Neural stem progenitor cells were isolated from the cortex of Sprague-Dawley rat fetuses on embryonic day 17. In dose-response experiments, cultured neural stem progenitor cells were exposed to different concentrations of ketamine (0-100 µM) for 24 hrs. In time-course experiments, neural stem progenitor cells cultures were exposed to 10 µM ketamine for different durations (0-48 hrs). MEASUREMENTS AND MAIN RESULTS: Apoptosis and necrosis in neural stem progenitor cells were assessed using activated caspase-3 immunostaining and lactate dehydrogenase assays, respectively. Proliferative changes in neural stem progenitor cells were detected using bromo-deoxyuridine incorporation and Ki67 immunostaining. Neuronal differentiation was assessed using Tuj-1 immunostaining. Cultured neural stem progenitor cells were resistant to apoptosis and necrosis following all concentrations and durations of ketamine exposure tested. Ketamine inhibited proliferation with decreased numbers of bromo-deoxyuridine-positive cells following ketamine exposure to 100 µM for 24 hrs (p<.005) or 10 µM for 48 hrs (p< .01), and reduced numbers of Ki67-positive cells following exposure to ketamine concentration>10 µM for 24 hrs (p<.001) or at 10 µM for 48 hrs (p<.01). Ketamine enhanced neuronal differentiation, with all ketamine concentrations increasing Tuj-1-positive neurons (p<.001) after 24-hrs of exposure. This also occurred with all exposures to 10 µM ketamine for >8 hrs (p<.001). CONCLUSIONS: Clinically relevant concentrations of ketamine do not induce cell death in neural stem progenitor cells via apoptosis or necrosis. Ketamine alters the proliferation and increases the neuronal differentiation of neural stem progenitor cells isolated from the rat neocortex. These studies imply that ketamine exposure during fetal or neonatal life may alter neurogenesis and subsequent brain development.

The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial.

OBJECTIVES: Nosocomial infection/sepsis occurs in up to 40% of children requiring long-term intensive care. Zinc, selenium, glutamine, metoclopramide (a prolactin secretalogue), and/or whey protein supplementation have been effective in reducing infection and sepsis in other populations. We evaluated whether daily nutriceutical supplementation with zinc, selenium, glutamine, and metoclopramide, compared to whey protein, would reduce the occurrence of nosocomial infection/sepsis in this at-risk population. DESIGN: Randomized, double-blinded, comparative effectiveness trial. SETTING: Eight pediatric intensive care units in the National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. PATIENTS: Two hundred ninety-three long-term intensive care patients (age 1-17 yrs) expected to require >72 hrs of invasive care. INTERVENTIONS: Patients were stratified according to immunocompromised status and center and then were randomly assigned to receive daily enteral zinc, selenium, glutamine, and intravenous metoclopramide (n = 149), or daily enteral whey protein (n = 144) and intravenous saline for up to 28 days of intensive care unit stay. The primary end point was time to development of nosocomial sepsis/infection. The analysis was intention to treat. MEASUREMENTS AND MAIN RESULTS: There were no differences by assigned treatment in the overall population with respect to time until the first episode of nosocomial infection/sepsis (median whey protein 13.2 days vs. zinc, selenium, glutamine, and intravenous metoclopramide 12.1 days; p = .29 by log-rank test) or the rate of nosocomial infection/sepsis (4.83/100 days whey protein vs. 4.99/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .81). Only 9% of the 293 subjects were immunocompromised and there was a reduction in rate of nosocomial infection/sepsis with zinc, selenium, glutamine, and intravenous metoclopramide in this immunocompromised group (6.09/100 days whey protein vs. 1.57/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .011). CONCLUSION: Compared with whey protein supplementation, zinc, selenium, glutamine, and intravenous metoclopramide conferred no advantage in the immune-competent population. Further evaluation of zinc, selenium, glutamine, and intravenous metoclopramide supplementation is warranted in the immunocompromised long-term pediatric intensive care unit patient.

Physicians' experiences and perspectives regarding follow-up meetings with parents after a child's death in the pediatric intensive care unit.

OBJECTIVE: To investigate critical care physicians' experiences and perspectives regarding follow-up meetings with parents after a child's death in the pediatric intensive care unit. Parents of children who die in the pediatric intensive care unit often desire a follow-up meeting with the physicians who cared for their child. DESIGN: Semistructured, audio-recorded telephone interviews. SETTING: Six clinical centers affiliated with the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. PARTICIPANTS: Seventy critical care physicians (i.e., attendings and fellows) practicing or training at a Child Health and Human Development Collaborative Pediatric Critical Care Research Network clinical center between February 1, 2008 and June 30, 2008. MEASUREMENTS AND MAIN RESULTS: Twenty-three (33%) physicians reported never participating in a follow-up meeting with bereaved parents; 22 (31%) participated in one to five meetings; and 25 (36%) participated in more than five meetings. Of those with prior experience, 44 (94%) met with parents at the hospital and 40 (85%) met within 3 months of the death. Meeting content included discussing autopsy, parent questions, hospital course, cause of death, genetic risk, bereavement services, and legal or administrative issues; providing emotional support; and receiving parent feedback. Forty (85%) physicians perceived the meetings to be beneficial to families, and 35 (74%) to physicians. Barriers included time and scheduling, family and physician unwillingness, distance and transportation, language and cultural issues, parent anger, and lack of a system for meeting initiation and planning. CONCLUSIONS: Critical care physicians have a wide range of experience conducting follow-up meetings with bereaved parents. Although physicians perceive benefits to follow-up meetings, barriers exist that interfere with their implementation in clinical practice.

The Collaborative Pediatric Critical Care Research Network Critical Pertussis Study: collaborative research in pediatric critical care medicine.

OBJECTIVE: To provide an updated overview of critical pertussis to the pediatric critical care community and describe a study of critical pertussis recently undertaken. SETTING: The six sites, seven hospitals of the Collaborative Pediatric Critical Care Research Network, and 17 outside sites at academic medical centers with pediatric intensive care units. RESULTS: Despite high coverage for childhood vaccination, pertussis causes substantial morbidity and mortality in US children, especially among infants. In pediatric intensive care units, Bordetella pertussis is a community-acquired pathogen associated with critical illness and death. The incidence of medical and developmental sequelae in critical pertussis survivors remains unknown, and the appropriate strategies for treatment and support remain unclear. The Collaborative Pediatric Critical Care Research Network Critical Pertussis Study has begun to evaluate critical pertussis in a prospective cohort. CONCLUSION: Research is urgently needed to provide an evidence base that might optimize management for critical pertussis, a serious, disabling, and too often fatal illness for U.S. children and those in the developing world.

The effect of tai chi on cognition in elders with cognitive impairment.

This one-arm pilot study investigated the effect of tai chi on cognition in elders with cognitive impairment. Although no significant difference existed between pre- and post-test performance on all cognition measures, a dose-response relationship was demonstrated between attendance and some cognition measures.

Rationale and design of the pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial.

Despite implementation of CDC recommendations and bundled interventions for preventing catheter-associated blood stream infection, ventilator-associated pneumonia, or urinary catheter-associated infections, nosocomial infections and sepsis remain a significant cause of morbidity and mortality in critically ill children. Recent studies suggest that acquired critical illness stress-induced immune suppression (CRISIS) plays a role in the development of nosocomial infection and sepsis. This condition can be related to inadequate zinc, selenium, and glutamine levels, as well as hypoprolactinemia, leading to stress-induced lymphopenia, a predominant T(H)2 monocyte/macrophage state, and subsequent immune suppression. Prolonged immune dysfunction increases the likelihood of nosocomial infections associated with invasive devices. Although strategies to prevent common complications of critical illness are routinely employed (eg, prophylaxis for gastrointestinal bleeding, thrombophlebitis), no prophylactic strategy is used to prevent stress-induced immune suppression. This is the authors' rationale for the pediatric CRISIS prevention trial (NCT00395161), designed as a randomized, double-blind, controlled clinical investigation to determine if daily enteral supplementation with zinc, selenium, and glutamine as well as parenteral metoclopramide (a dopamine 2 receptor antagonist that reverses hypoprolactinemia) prolongs the time until onset of nosocomial infection or sepsis in critically ill children compared to enteral supplementation with whey protein. If effective, this combined nutritional and pharmacologic approach may lessen the excess morbidity and mortality as well as resource utilization associated with nosocomial infections and sepsis in this population. The authors present the design and analytic plan for the CRISIS prevention trial.

The effect of tai chi on knee osteoarthritis pain in cognitively impaired elders: pilot study.

This article reports a pilot study of the effect of tai chi (TC), a pharmacological adjunct and mild aerobic exercise, on osteoarthritic knee pain in elders with cognitive impairment (CI). The TC program included a warm-up, 12-form Sun-style TC, and a cool-down period, for a total of 20-40 minutes per session, twice a week for 15 weeks. The results showed no significant differences in knee pain after the TC intervention in 7 elders with CI. However, more minutes of TC attendance were related to improved pain scores (Spearman's rho=.78, P < .05). Greater accuracy in TC performance was also correlated with improvements in pain scores (Spearman's rho = .70, P=.08). Of 4 elders who participated in TC practice regularly (more than 20 sessions), 3 showed clinically important improvements, but 3 elders who participated in no sessions or only a few sessions showed no improvement.

Long-term deficits of preterm birth: evidence for arousal and attentional disturbances.

OBJECTIVE: Quantitative measures of pre-attentional, attentional and frontal lobe processes were compared to evaluate quantitative measures of these deficits in Ex-Preterm vs. Ex-Term adolescents. METHODS: We compared 43 Ex-Preterm with 26 Ex-Term adolescents using the P50 auditory potential, the Psychomotor Vigilance Task (PVT), a reaction time (RT) test, and Near Infrared Spectroscopy (NIRS). RESULTS: The mean amplitude (+/-SE) of the P50 amplitude was similar in the Ex-Preterm (1.8+/-1.4 microV) vs. Ex-Term adolescents (1.8+/-0.6 microV, df = 68, F = 0.05, p = 0.8), but the Ex-Preterm group showed a trimodal distribution in amplitude (High, 3.3+/-0.4 microV, df=42.25, F=19.2, p < 0.01; Medium, 1.7+/-0.1 microV, df = 39, F = 0.41, p = 0.53; Low, 0.7+/-0.1 microV, df = 40, F = 49.5, p < 0.01) suggested by statistically significant variance between populations (Kolmogorov-Kuiper test, df = 42.25, F = 5.4, p < 0.01). Mean RT was longer in Ex-Preterm (250+/-8 ms) vs. Ex-Term subjects (200+/-5 ms, df = 68, F = 18.8, p < 0.001). PVT lapses were increased in Ex-Preterm subjects, and varied inversely with P50 amplitude (Overall Mean 17+/-5 lapses, df = 67, F = 5.34, p < 0.05; Low P50 amplitude, 25+/-10, df = 40, F = 8.8, p < 0.01; Medium, 21+/-11, df = 38, F = 5.37, p < 0.05; High, 6+/-2, df = 39, F = 6.78, p < 0.01) vs. Ex-Term subjects (2+/-0.4 lapses, p < 0.01). NIRS levels did not differ statistically, but tended to correlate with P50 amplitude in the Ex-Preterm group. CONCLUSIONS: These findings suggest differential pre-attentional, attentional and frontal lobe dysfunction in Ex-Preterm adolescents. SIGNIFICANCE: These measures could provide a means to objectively assess differential dysregulation of arousal and attention in Ex-Preterm adolescents, allowing optimization of therapeutic designs.

Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial.

BACKGROUND: Relationships between plasma morphine concentrations and neonatal responses to endotracheal tube (ETT) suctioning are unknown in preterm neonates. METHODS: Ventilated preterm neonates (n=898) from 16 centres were randomly assigned to placebo (n=449) or morphine (n=449). After an i.v. loading dose (100 microg kg(-1)), morphine infusions [23-26 weeks postmenstrual age (PMA) 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); and 30-32 weeks 30 microg kg(-1) h(-1)] were established for a maximum of 14 days. Open-label morphine (20-100 microg kg(-1)) was given for pain or agitation. Morphine assay and neonatal response to ETT suctioning was measured at 20-28 and 70-76 h after starting the drug infusion and at 10-14 h after discontinuation of the study drug. The concentration-effect response was investigated using non-linear mixed effects models. RESULTS: A total of 5119 data points (1598 measured morphine concentrations and 3521 effect measures) were available from 875 neonates for analysis. Clearance was 50% that of the mature value at 54.2 weeks PMA (CLmat(50)) and increased from 2.05 litre h(-1) 70 kg(-1) at 24 weeks PMA to 6.04 litre h(-1) 70 kg(-1) at 32 weeks PMA. The volume of distribution in preterm neonates was 190 litre 70 kg(-1) (CV 51%) and did not change with age. There was no relationship between morphine concentrations (range 0-440 microg litre(-1)) and heart rate changes associated with ETT suctioning or with the Premature Infant Pain Profile. CONCLUSIONS: A sigmoid curve describing maturation of morphine clearance is moved to the right in preterm neonates and volume of distribution is increased compared with term neonates. Morphine does not alter the neonatal response to ETT suctioning.

Redefining the golden hour in pediatric transport.

OBJECTIVE: To emphasize the urgent need for research efforts and application of goal-directed therapy in the pediatric transport environment. DESIGN: Review of existing literature and commentary on current pediatric transport practices. CONCLUSIONS: Pediatric transport has evolved significantly since its inception >2 decades ago. Advancements in technology and therapeutic interventions now afford an opportunity to extend intensive care into the transport environment. However, misapplication of the concept of the golden hour has led to a focus on speed of transfer to tertiary care facilities, often delaying early, goal-directed therapeutic interventions. If we are to further improve outcomes for critically ill children, we must extend early institution of goal-directed therapy into the pretertiary hospital setting and bring expertise to the child.

Parents' perspectives on physician-parent communication near the time of a child's death in the pediatric intensive care unit.

OBJECTIVE: Communicating bad news about a child's illness is a difficult task commonly faced by intensive care physicians. Greater understanding of parents' scope of experiences with bad news during their child's hospitalization will help physicians communicate more effectively. Our objective is to describe parents' perceptions of their conversations with physicians regarding their child's terminal illness and death in the pediatric intensive care unit (PICU). DESIGN: A secondary analysis of a qualitative interview study. SETTING: Six children's hospitals in the National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. PARTICIPANTS: Fifty-six parents of 48 children who died in the PICU 3-12 months before the study. INTERVENTIONS: Parents participated in audio recorded semistructured telephone interviews. Interviews were analyzed using established qualitative methods. MEASUREMENTS AND MAIN RESULTS: Of the 56 parents interviewed, 40 (71%) wanted to provide feedback on the way information about their child's terminal illness and death was communicated by PICU physicians. The most common communication issue identified by parents was the physicians' availability and attentiveness to their informational needs. Other communication issues included honesty and comprehensiveness of information, affect with which information was provided, withholding of information, provision of false hope, complexity of vocabulary, pace of providing information, contradictory information, and physicians' body language. CONCLUSIONS: The way bad news is discussed by physicians is extremely important to most parents. Parents want physicians to be accessible and to provide honest and complete information with a caring affect, using lay language, and at a pace in accordance with their ability to comprehend. Withholding prognostic information from parents often leads to false hopes and feelings of anger, betrayal, and distrust. Future research is needed to investigate whether the way bad news is discussed influences psychological adjustment and family functioning among bereaved parents.

Ethical and logistical considerations of multicenter parental bereavement research.

BACKGROUND: Multicenter research has the potential to recruit participants with diverse racial, ethnic, and geographic backgrounds and is essential for understanding heterogeneity in bereavement. The National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) is a multicenter network charged with conducting research on the pathophysiology and management of critical illness in childhood. Among its research activities, the CPCCRN has undertaken research in parental bereavement because most childhood deaths in the United States occur in hospitals, primarily in critical care units. OBJECTIVE: The purpose of this paper is to discuss ethical and logistical issues found by the CPCCRN to be problematic to multicenter research with bereaved parents and to explore research strategies that may be practicably implemented. RESULTS: Ethical and logistical challenges encountered by the CPCCRN included issues of privacy; confidentiality; voluntariness; minimizing risks; working with multiple institutional review boards; researcher qualifications, training and support; and methods of data collection. Strategies to address these challenges included local recruitment of participants; flexibility in consent methods across sites; participant options for methods of data collection; involvement of local bereavement support services; central training of researchers with systematic monitoring and opportunities for support; and use of a secure Web-based collaborative workspace. CONCLUSIONS: Multicenter parental bereavement research has distinct ethical issues that must be addressed by the logistics of the research plan. Greater attention to the issues identified may facilitate research to reduce adverse mental and physical health outcomes in a diverse population of bereaved individuals.

Epidemiology and treatment of painful procedures in neonates in intensive care units.

CONTEXT: Effective strategies to improve pain management in neonates require a clear understanding of the epidemiology and management of procedural pain. OBJECTIVE: To report epidemiological data on neonatal pain collected from a geographically defined region, based on direct bedside observation of neonates. DESIGN, SETTING, AND PATIENTS: Between September 2005 and January 2006, data on all painful and stressful procedures and corresponding analgesic therapy from the first 14 days of admission were prospectively collected within a 6-week period from 430 neonates admitted to tertiary care centers in the Paris region of France (11.3 millions inhabitants) for the Epidemiology of Procedural Pain in Neonates (EPIPPAIN) study. MAIN OUTCOME MEASURE: Number of procedures considered painful or stressful by health personnel and corresponding analgesic therapy. RESULTS: The mean (SD) gestational age and intensive care unit stay were 33.0 (4.6) weeks and 8.4 (4.6) calendar days, respectively. Neonates experienced 60,969 first-attempt procedures, with 42,413 (69.6%) painful and 18,556 (30.4%) stressful procedures; 11,546 supplemental attempts were performed during procedures including 10,366 (89.8%) for painful and 1180 (10.2%) for stressful procedures. Each neonate experienced a median of 115 (range, 4-613) procedures during the study period and 16 (range, 0-62) procedures per day of hospitalization. Of these, each neonate experienced a median of 75 (range, 3-364) painful procedures during the study period and 10 (range, 0-51) painful procedures per day of hospitalization. Of the 42,413 painful procedures, 2.1% were performed with pharmacological-only therapy; 18.2% with nonpharmacological-only interventions, 20.8% with pharmacological, nonpharmacological, or both types of therapy; and 79.2% without specific analgesia, and 34.2% were performed while the neonate was receiving concurrent analgesic or anesthetic infusions for other reasons. Prematurity, category of procedure, parental presence, surgery, daytime, and day of procedure after the first day of admission were associated with greater use of specific preprocedural analgesia, whereas mechanical ventilation, noninvasive ventilation and administration of nonspecific concurrent analgesia were associated with lower use of specific preprocedural analgesia. CONCLUSION: During neonatal intensive care in the Paris region, large numbers of painful and stressful procedures were performed, the majority of which were not accompanied by analgesia.

Web-based method for translating neurodevelopment from laboratory species to humans.

Biomedical researchers and medical professionals are regularly required to compare a vast quantity of neurodevelopmental literature obtained from an assortment of mammals whose brains grow at diverse rates, including fast developing experimental rodent species and slower developing humans. In this article, we introduce a database-driven website, which was created to address this problem using statistical-based algorithms to integrate hundreds of empirically derived developing neural events in 10 mammalian species (http://translatingtime.net/). The site, based on a statistical model that has evolved over the past decade, currently incorporates 102 different neurodevelopmental events obtained from 10 species: hamsters, mice, rats, rabbits, spiny mice, guinea pigs, ferrets, cats, rhesus monkeys, and humans. Data are arranged in a Structured Query Language database, which allows comparative brain development measured in postconception days to be converted and accessed in real time, using Hypertext Preprocessor language. Algorithms applied to the database also allow predictions for dates of specific neurodevelopmental events where empirical data are not available, including for the human embryo and fetus. By designing a web-based portal, we seek to make these comparative data readily available to all those who need to efficiently estimate the timing of neurodevelopmental events in the human fetus, laboratory species, or across several different species. In an effort to further refine and expand the applicability of this database, we include a mechanism to submit additional data.

Parents' perspectives regarding a physician-parent conference after their child's death in the pediatric intensive care unit.

OBJECTIVE: To investigate parents' perspectives on the desirability, content, and conditions of a physician-parent conference after their child's death in the pediatric intensive care unit (PICU). STUDY DESIGN: Audio-recorded telephone interviews were conducted with 56 parents of 48 children. All children died in the PICU of one of six children's hospitals in the National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) 3 to 12 months before the study. RESULTS: Only seven (13%) parents had a scheduled meeting with any physician to discuss their child's death; 33 (59%) wanted to meet with their child's intensive care physician. Of these, 27 (82%) were willing to return to the hospital to meet. Topics that parents wanted to discuss included the chronology of events leading to PICU admission and death, cause of death, treatment, autopsy, genetic risk, medical documents, withdrawal of life support, ways to help others, bereavement support, and what to tell family. Parents sought reassurance and the opportunity to voice complaints and express gratitude. CONCLUSIONS: Many bereaved parents want to meet with the intensive care physician after their child's death. Parents seek to gain information and emotional support, and to give feedback about their PICU experience.