Sedation Research in Critically Ill Pediatric Patients: Proposals for Future Study Design From the Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research IV Workshop.

OBJECTIVES: Sedation and analgesia for infants and children requiring mechanical ventilation in the PICU is uniquely challenging due to the wide spectrum of ages, developmental stages, and pathophysiological processes encountered. Studies evaluating the safety and efficacy of sedative and analgesic management in pediatric patients have used heterogeneous methodologies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) IV hosted a series of multidisciplinary meetings to establish consensus statements for future clinical study design and implementation as a guide for investigators studying PICU sedation and analgesia. DESIGN: Twenty-five key elements framed as consensus statements were developed in five domains: study design, enrollment, protocol, outcomes and measurement instruments, and future directions. SETTING: A virtual meeting was held on March 2-3, 2022, followed by an in-person meeting in Washington, DC, on June 15-16, 2022. Subsequent iterative online meetings were held to achieve consensus. SUBJECTS: Fifty-one multidisciplinary, international participants from academia, industry, the U.S. Food and Drug Administration, and family members of PICU patients attended the virtual and in-person meetings. Participants were invited based on their background and experience. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Common themes throughout the SCEPTER IV consensus statements included using coordinated multidisciplinary and interprofessional teams to ensure culturally appropriate study design and diverse patient enrollment, obtaining input from PICU survivors and their families, engaging community members, and using developmentally appropriate and validated instruments for assessments of sedation, pain, iatrogenic withdrawal, and ICU delirium. CONCLUSIONS: These SCEPTER IV consensus statements are comprehensive and may assist investigators in the design, enrollment, implementation, and dissemination of studies involving sedation and analgesia of PICU patients requiring mechanical ventilation. Implementation may strengthen the rigor and reproducibility of research studies on PICU sedation and analgesia and facilitate the synthesis of evidence across studies to improve the safety and quality of care for PICU patients.

Pediatric Intensive Care Unit Patients: Sedation, Monitoring, and Neurodevelopmental Outcomes.

The design and conduct of pediatric sedation studies in critically ill patients have historically been challenging due to the complexity of the pediatric intensive care unit (PICU) environment and the difficulty of establishing equipoise. Clinical trials, for instance, represent 1 important means of advancing our knowledge in this field, but there is a paucity of such studies in the literature. Accounting for ground-level factors in planning for each trial phase (eg, enrollment, intervention, assessment, and follow-up) and the presence of broader system limitations is of key importance. In addition, there is a need for early planning, coordination, and obtaining buy-in from individual study sites and staff to ensure success, particularly for multicenter studies. This review synthesizes the current state of pediatric sedation research and the myriad of challenges in designing and conducting successful trials in this particular area. The review poses consideration for future research directions, including novel study designs, and discusses electroencephalography monitoring and neurodevelopmental outcomes of PICU survivors.

Changes in Distribution of Severe Neurologic Involvement in US Pediatric Inpatients With COVID-19 or Multisystem Inflammatory Syndrome in Children in 2021 vs 2020.

Importance: In 2020 during the COVID-19 pandemic, neurologic involvement was common in children and adolescents hospitalized in the United States for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related complications. Objective: To provide an update on the spectrum of SARS-CoV-2-related neurologic involvement among children and adolescents in 2021. Design, Setting, and Participants: Case series investigation of patients reported to public health surveillance hospitalized with SARS-CoV-2-related illness between December 15, 2020, and December 31, 2021, in 55 US hospitals in 31 states with follow-up at hospital discharge. A total of 2253 patients were enrolled during the investigation period. Patients suspected of having multisystem inflammatory syndrome in children (MIS-C) who did not meet criteria (n = 85) were excluded. Patients (<21 years) with positive SARS-CoV-2 test results (reverse transcriptase-polymerase chain reaction and/or antibody) meeting criteria for MIS-C or acute COVID-19 were included in the analysis. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening neurologic involvement was adjudicated by experts based on clinical and/or neuroradiological features. Type and severity of neurologic involvement, laboratory and imaging data, vaccination status, and hospital discharge outcomes (death or survival with new neurologic deficits). Results: Of 2168 patients included (58% male; median age, 10.3 years), 1435 (66%) met criteria for MIS-C, and 476 (22%) had documented neurologic involvement. Patients with neurologic involvement vs without were older (median age, 12 vs 10 years) and more frequently had underlying neurologic disorders (107 of 476 [22%] vs 240 of 1692 [14%]). Among those with neurologic involvement, 42 (9%) developed acute SARS-CoV-2-related life-threatening conditions, including central nervous system infection/demyelination (n = 23; 15 with possible/confirmed encephalitis, 6 meningitis, 1 transverse myelitis, 1 nonhemorrhagic leukoencephalopathy), stroke (n = 11), severe encephalopathy (n = 5), acute fulminant cerebral edema (n = 2), and Guillain-Barré syndrome (n = 1). Ten of 42 (24%) survived with new neurologic deficits at discharge and 8 (19%) died. Among patients with life-threatening neurologic conditions, 15 of 16 vaccine-eligible patients (94%) were unvaccinated. Conclusions and Relevance: SARS-CoV-2-related neurologic involvement persisted in US children and adolescents hospitalized for COVID-19 or MIS-C in 2021 and was again mostly transient. Central nervous system infection/demyelination accounted for a higher proportion of life-threatening conditions, and most vaccine-eligible patients were unvaccinated. COVID-19 vaccination may prevent some SARS-CoV-2-related neurologic complications and merits further study.

Scoping Review: Neurocognitive Outcome Assessments After Critical Illness in Children.

OBJECTIVES: To map the literature regarding assessment of neurocognitive outcomes in PICU survivors. Secondary objectives were to identify literature gaps and to provide data for development of a Core Outcome Measures Set in the domain. METHODS: Planned, a priori analysis was performed of data from an over-all scoping review of Post-Intensive Care Syndrome-pediatrics (PICS-p) functional outcomes. English-language databases and registries from 1970 to 2017 were searched by a medical librarian to identify manuscripts reporting on Post Intensive Care Syndrome-pediatrics (PICS-p). Further, detailed data extraction for neurocognitive outcomes was performed focusing on study characteristics, instruments used, and populations. RESULTS: 114 instruments evaluated neurocognitive function in 183 manuscripts. 83% of manuscripts were published after 2000. Median of 3 (IQR 2-5) neurocognitive instruments per manuscript were reported. Wechsler Scales (45%), clinical neurologic evaluations (21%), Pediatric Cerebral Performance Category (20%), Bayley Scales of Infant Development (16%), and Vineland Adaptive Behavior Scales (11%) were the most commonly used instruments. Median sample size was 65 (IQR 32-129) subjects. Most (63%) assessments were conducted in-person and parents/guardians (40%) provided the information. Patients with congenital heart disease and traumatic brain injury were most commonly evaluated (31% and 24% of manuscripts, respectively). Adolescents were the most commonly studied age group (34%). Baseline function was infrequently assessed (11% of manuscripts); most studies assessed patients at only one time point after PICU discharge. Within studies, neurocognitive assessments were often combined with others - especially social (18%) and physical (8%). CONCLUSIONS: 183 manuscripts studied the neurocognitive domain of PICS-p. Studies were quantitative and tended to focus on populations with anticipated cognitive impairment. Considerable variability exists among the chosen 114 instruments used; however, 4 instruments were frequently chosen with focus on intelligence, cerebral functioning, and developmental and adaptive behavior. The literature is marked by lack of agreement on methodologies but reflects the burgeoning interest in studying PICS-p neurocognitive outcomes.

Intubation practice and outcomes among pediatric emergency departments: A report from National Emergency Airway Registry for Children (NEAR4KIDS).

BACKGROUND: Tracheal intubation (TI) practice across pediatric emergency departments (EDs) has not been comprehensively reported. We aim to describe TI practice and outcomes in pediatric EDs in contrast to those in intensive are units (ICUs) and use the data to identify quality improvement targets. METHODS: Consecutive TI encounters from pediatric EDs and ICUs in the National Emergency Airway Registry for Children (NEAR4KIDS) database from 2015 to 2018 were analyzed for patient, provider, and practice characteristics and outcomes: adverse TI-associated events (TIAEs), oxygen desaturation (SpO2 < 80%), and procedural success. A multivariable model identified factors associated with TIAEs in the ED. RESULTS: A total of 756 TIs in 13 pediatric EDs and 12,512 TIs in 51 pediatric/cardiac ICUs were reported. Median (interquartile range [IQR]) patient age for ED TIs was higher (32 [7-108] months) than that for ICU TIs (15 [3-91] months; p < 0.001). Proportion of TIs for respiratory decompensation (52% of ED vs. 64% ICU), shock (26% vs. 14%), and neurologic deterioration (30% vs. 11%) also differed by location. Limited neck mobility was reported more often in the ED (16% vs. 6%). TIs in the ED were performed more often via video laryngoscopy (64% vs. 29%). Adverse TIAE rates (15.6% ED, 14% ICU; absolute difference = 1.6%, 95% confidence interval [CI] = -1.1 to 4.2; p = 0.23) and severe TIAE rates (5.4% ED, 5.8% ICU; absolute difference = -0.3%, 95% CI = -2.0 to 1.3; p = 0.68) were not different. Oxygen desaturation was less commonly reported in ED TIs (13.6%) than ICU TIs (17%, absolute difference = -3.4%, 95% CI = -5.9 to -0.8; p = 0.016). Among ED TIs, shock as an indication (adjusted odds ratio [aOR] = 2.15, 95% CI = 1.26 to 3.65) and limited mouth opening (aOR = 1.74, 95% CI = 1.04 to 2.93) were independently associated with TIAEs. CONCLUSIONS: While TI characteristics vary between pediatric EDs and ICUs, outcomes are similar. Shock and limited mouth opening were independently associated with adverse TI events in the ED.

Design and reporting characteristics of clinical trials investigating sedation practices in the paediatric intensive care unit: a scoping review by SCEPTER (Sedation Consortium on Endpoints and Procedures for Treatment, Education and Research).

OBJECTIVES: To conduct a scoping review of sedation clinical trials in the paediatric intensive care setting and summarise key methodological elements. DESIGN: Scoping review. DATA SOURCES: PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature and grey references including ClinicalTrials.gov from database inception to 3 August 2021. STUDY SELECTION: All human trials in the English language related to sedation in paediatric critically ill patients were included. After title and abstract screening, full-text review was performed. 29 trials were eligible for final analysis. DATA EXTRACTION: A coding manual was developed and pretested. Trial characteristics were double extracted. RESULTS: The majority of trials were single centre (22/29, 75.9%), parallel group superiority (17/29, 58.6%), double-blinded (18/29, 62.1%) and conducted in an academic setting (29/29, 100.0%). Trial enrolment (≥90% planned sample size) was achieved in 65.5% of trials (19/29), and retention (≥90% enrolled subjects) in 72.4% of trials (21/29). Protocol violations were reported in nine trials (31.0%). The most commonly studied cohorts were mechanically ventilated patients (28/29, 96.6%) and postsurgical patients (11/29, 37.9%) with inclusion criteria for age ranging from 0±0.5 to 15.0±7.3 years (median±IQR). The median age of enrolled patients was 1.7 years (IQR=4.4 years). Patients excluded from trials were those with neurological impairment (21/29, 72.4%), complex disease (20/29, 69.0%) or receipt of neuromuscular blockade (10/29, 34.5%). Trials evaluated drugs/protocols for sedation management (20/29, 69.0%), weaning (3/29, 10.3%), daily interruption (3/29, 10.3%) or protocolisation (3/29, 10.3%). Primary outcome measures were heterogeneous, as were assessment instruments and follow-up durations. CONCLUSIONS: There is substantial heterogeneity in methodological approach in clinical trials evaluating sedation in critically ill paediatric patients. These results provide a basis for the design of future clinical trials to improve the quality of trial data and aid in the development of sedation-related clinical guidelines.

Diabetes Insipidus Complicating Management in a Child with COVID-19 and Multiorgan System Failure: A Novel Use for Furosemide.

Judicious balance of fluids is needed for optimal management of acute respiratory distress syndrome (ARDS). Achieving optimal fluid balance is difficult in patients with disorders of fluid homeostasis such as diabetes insipidus (DI). There is little data on the use of Furosemide to aid in balancing fluid and electrolytes in patients with DI. Here, we present a critically ill 11-year-old female with developmental delay, septo-optic dysplasia, central DI, and respiratory failure secondary to COVID-19 ARDS. She required careful titration of a Vasopressin infusion in addition to IV Furosemide for successful management of fluid and electrolyte derangements. On admission, she demonstrated high-volume urine output with mild hypernatremia (serum sodium 156 mmol/L). Despite her maximum Vasopressin infusion rate of 8 mU/kg/hr, by day two of admission, she voided a total of 4 L resulting in severe hypernatremia (serum sodium 171 mmol/L). With continually high Vasopressin infusion rates, her overall fluid balance became increasingly net positive, although her hypernatremia persisted. Her ARDS continued to worsen. After 48 hours of the addition of intermittent Furosemide, successful diuresis along with resolution of hypernatremia was achieved. The combination of IV Furosemide with Vasopressin infusion resulted in tailored diuresis and more controlled titration of serum sodium levels than adjustment in Vasopressin and fluids alone. These results are in contradistinction to the published literature, which focuses on the use of thiazide diuretics in managing DI. This experience highlights the potential for loop diuretics to aid in establishing a desired fluid and electrolyte status in managing patients with both DI and ARDS.

Long-Term Neurobehavioral and Quality of Life Outcomes of Critically Ill Children after Glycemic Control.

OBJECTIVES: To investigate adaptive skills, behavior, and quality health-related quality of life in children from 32 centers enrolling in the Heart And Lung Failure-Pediatric INsulin Titration randomized controlled trial. STUDY DESIGN: This prospective longitudinal cohort study compared the effect of 2 tight glycemic control ranges (lower target, 80-100 mg/dL vs higher target, 150-180 mg/dL) 1-year neurobehavioral and health-related quality of life outcomes. Subjects had confirmed hyperglycemia and cardiac and/or respiratory failure. Patients aged 2-16 years old enrolled between April 2012 and September 2016 were studied at 1 year after intensive care discharge. The primary outcome, adaptive skills, was assessed using the Vineland Adaptive Behavior Scale. Behavior and health-related quality of life outcomes were assessed as secondary outcomes using the Pediatric Quality of Life and Child Behavior Checklist at baseline and 1-year follow-up. Group differences were evaluated using regression models adjusting for age category, baseline overall performance, and risk of mortality. RESULTS: Of 369 eligible children, 358 survived after hospital discharge and 214 (60%) completed follow-up. One-year Vineland Adaptive Behavior Scale-II composite scores were not different (mean ± SD, 79.9 ± 25.5 vs 79.4 ± 26.9, lower vs higher target; P = .20). Improvement in Pediatric Quality of Life total health from baseline was greater in the higher target group (adjusted mean difference, 8.2; 95% CI, 1.1-15.3; P = .02). CONCLUSIONS: One-year adaptive behavior in critically ill children with lower vs higher target glycemic control did not differ. The higher target group demonstrated improvement from baseline in overall health. This study affirms the lack of benefit of lower glucose targeting. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01565941.

Short-Term Adverse Outcomes Associated With Hypoglycemia in Critically Ill Children.

OBJECTIVES: Previous studies report worse short-term outcomes with hypoglycemia in critically ill children. These studies relied on intermittent blood glucose measurements, which may have introduced detection bias. We analyzed data from the Heart And Lung Failure-Pediatric INsulin Titration trial to determine the association of hypoglycemia with adverse short-term outcomes in critically ill children. DESIGN: Nested case-control study. SETTING: Thirty-five PICUs. A computerized algorithm that guided the timing of blood glucose measurements and titration of insulin infusion, continuous glucose monitors, and standardized glucose infusion rates were used to minimize hypoglycemia. PATIENTS: Nondiabetic children with cardiovascular and/or respiratory failure and hyperglycemia. Cases were children with any hypoglycemia (blood glucose < 60 mg/dL), whereas controls were children without hypoglycemia. Each case was matched with up to four unique controls according to age group, study day, and severity of illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 112 (16.0%) of 698 children who received the Heart And Lung Failure-Pediatric INsulin Titration protocol developed hypoglycemia, including 25 (3.6%) who developed severe hypoglycemia (blood glucose < 40 mg/dL). Of these, 110 cases were matched to 427 controls. Hypoglycemia was associated with fewer ICU-free days (median, 15.3 vs 20.2 d; p = 0.04) and fewer hospital-free days (0 vs 7 d; p = 0.01) through day 28. Ventilator-free days through day 28 and mortality at 28 and 90 days did not differ between groups. More children with insulin-induced versus noninsulin-induced hypoglycemia had zero ICU-free days (35.8% vs 20.9%; p = 0.008). Outcomes did not differ between children with severe versus nonsevere hypoglycemia or those with recurrent versus isolated hypoglycemia. CONCLUSIONS: When a computerized algorithm, continuous glucose monitors and standardized glucose infusion rates were used to manage hyperglycemia in critically ill children with cardiovascular and/or respiratory failure, severe hypoglycemia (blood glucose < 40 mg/dL) was uncommon, but any hypoglycemia (blood glucose < 60 mg/dL) remained common and was associated with worse short-term outcomes.

Delirium in the Pediatric Cardiac Extracorporeal Membrane Oxygenation Patient Population: A Case Series.

OBJECTIVE: To determine the prevalence of delirium in children who require extracorporeal membrane oxygenation. DESIGN: Prospective observational longitudinal cohort study. SETTING: Urban academic cardiothoracic ICU. PATIENTS: All consecutive admissions to the cardiothoracic ICU who required venoarterial extracorporeal membrane oxygenation support. INTERVENTIONS: Daily delirium screening with the Cornell Assessment for Pediatric Delirium. MEASUREMENTS AND MAIN RESULTS: Eight children required extracorporeal membrane oxygenation during the study period, with a median extracorporeal membrane oxygenation duration of 202 hours (interquartile range, 99-302). All eight children developed delirium during their cardiothoracic ICU stay. Seventy-two days on extracorporeal membrane oxygenation were included in the analysis. A majority of patient days on extracorporeal membrane oxygenation were spent in coma (65%). Delirium was diagnosed during 21% of extracorporeal membrane oxygenation days. Only 13% of extracorporeal membrane oxygenation days were categorized as delirium free and coma free. Delirium screening was successfully completed on 70/72 days on extracorporeal membrane oxygenation (97%). CONCLUSIONS: In this cohort, delirium occurred in all children who required venoarterial extracorporeal membrane oxygenation. It is likely that this patient population has an extremely high risk for delirium and will benefit from routine screening in order to detect and treat delirium sooner. This has potential to improve both short- and long-term outcomes.

Delirium in Children After Cardiac Bypass Surgery.

OBJECTIVES: To describe the incidence of delirium in pediatric patients after cardiac bypass surgery and explore associated risk factors and effect of delirium on in-hospital outcomes. DESIGN: Prospective observational single-center study. SETTING: Fourteen-bed pediatric cardiothoracic ICU. PATIENTS: One hundred ninety-four consecutive admissions following cardiac bypass surgery, 1 day to 21 years old. INTERVENTIONS: Subjects were screened for delirium daily using the Cornell Assessment of Pediatric Delirium. MEASUREMENTS AND MAIN RESULTS: Incidence of delirium in this sample was 49%. Delirium most often lasted 1-2 days and developed within the first 1-3 days after surgery. Age less than 2 years, developmental delay, higher Risk Adjustment for Congenital Heart Surgery 1 score, cyanotic disease, and albumin less than three were all independently associated with development of delirium in a multivariable model (all p < 0.03). Delirium was an independent predictor of prolonged ICU length of stay, with patients who were ever delirious having a 60% increase in ICU days compared with patients who were never delirious (p < 0.01). CONCLUSIONS: In our institution, delirium is a frequent problem in children after cardiac bypass surgery, with identifiable risk factors. Our study suggests that cardiac bypass surgery significantly increases children's susceptibility to delirium. This highlights the need for heightened, targeted delirium screening in all pediatric cardiothoracic ICUs to potentially improve outcomes in this vulnerable patient population.

Health care-associated infections in children after cardiac surgery.

Few recent studies have assessed the epidemiology of health care-associated infections (HAIs) in the pediatric population after cardiac surgery. A retrospective cohort study was performed to assess the epidemiology of several types of HAIs in children 18 years of age or younger undergoing cardiac surgery from July 2010 to June 2012. Potential pre-, intra-, and postoperative risk factors, including adherence to the perioperative antibiotic prophylaxis regimen at the authors' hospital, were assessed by multivariable analysis using Poisson regression models. Microorganisms associated with HAIs and their susceptibility patterns were described. Overall, 634 surgeries were performed, 38 (6 %) of which were complicated by an HAI occurring within 90 days after surgery. The HAIs included 7 central line-associated bloodstream infections (CLABSIs), 12 non-CLABSI bacteremias, 6 episodes of early postoperative infective endocarditis (IE), 9 surgical-site infections (SSIs), and 4 ventilator-associated pneumonias (VAPs). Mechanical ventilation (rate ratio [RR] 1.07 per day; 95 % confidence interval [CI] 1.03-1.11; p = 0.0002), postoperative transfusion of blood products (RR 3.12; 95 %, CI 1.38-7.06; p = 0.0062), postoperative steroid use (RR 3.32; 95 % CI 1.56-7.02; p = 0.0018), and continuation of antibiotic prophylaxis longer than 48 h after surgery (RR 2.56; 95 % CI 1.31-5.03; p = 0.0062) were associated with HAIs. Overall, 66.7 % of the pathogens associated with SSIs were susceptible to cefazolin, the perioperative antibiotic prophylaxis used by the authors' hospital. In conclusion, HAIs occurred after 6 % of cardiac surgeries. Bacteremia and CLABSI were the most common. This study identified several potentially modifiable risk factors that suggest interventions. Further studies should assess the role of improving adherence to perioperative antibiotic prophylaxis, the age of transfused red blood cells, and evidence-based guidelines for postoperative steroids.

A randomized clinical trial evaluating nasal continuous positive airway pressure for acute respiratory distress in a developing country.

OBJECTIVE: Invasive mechanical ventilation is often not an option for children with acute respiratory infections in developing countries. An alternative is continuous positive airway pressure (CPAP). The authors evaluated the effectiveness of CPAP in children presenting with acute respiratory distress in a developing country. STUDY DESIGN: A randomized, controlled trial was conducted in 4 rural hospitals in Ghana. Children, 3 months to 5 years of age, presenting with tachypnea and intercostal or subcostal retractions or nasal flaring were randomly assigned to receive CPAP immediately or 1 hour after presentation. CPAP was applied by locally trained nurses. The primary outcome measure was change in respiratory rate at 1 hour. RESULTS: The study was stopped after the enrollment of 70 subjects because of a predetermined stop value of P < .001. Mean respiratory rate of children who received immediate CPAP fell by 16 breaths/min (95% CI 10-21) in the first hour compared with no change in children who had CPAP delayed by 1 hour (95% CI -2 to +5). Thirty-five of the patients had a positive malaria blood smear. There were 3 deaths as a result of severe malaria. No major complications of CPAP use were noted. CONCLUSIONS: CPAP decreases respiratory rate in children with respiratory distress compared with children not receiving CPAP. The technology was successfully used by local nurses. No complications were associated with its use. CPAP is a relatively low-cost, low-technology that is a safe method to decrease respiratory rate in children with nonspecific respiratory distress.

Sh3rf2/POSHER protein promotes cell survival by ring-mediated proteasomal degradation of the c-Jun N-terminal kinase scaffold POSH (Plenty of SH3s) protein.

We report that Sh3rf2, a homologue of the pro-apoptotic scaffold POSH (Plenty of SH3s), acts as an anti-apoptotic regulator for the c-Jun N-terminal kinase (JNK) pathway. siRNA-mediated knockdown of Sh3rf2 promotes apoptosis of neuronal PC12 cells, cultured cortical neurons, and C6 glioma cells. This death appears to result from activation of JNK signaling. Loss of Sh3rf2 triggers activation of JNK and its target c-Jun. Also, apoptosis promoted by Sh3rf2 knockdown is inhibited by dominant-negative c-Jun as well as by a JNK inhibitor. Investigation of the mechanism by which Sh3rf2 regulates cell survival implicates POSH, a scaffold required for activation of pro-apoptotic JNK/c-Jun signaling. In cells lacking POSH, Sh3rf2 knockdown is unable to activate JNK. We further find that Sh3rf2 binds POSH to reduce its levels by a mechanism that requires the RING domains of both proteins and that appears to involve proteasomal POSH degradation. Conversely, knockdown of Sh3rf2 promotes the stabilization of POSH protein and activation of JNK signaling. Finally, we show that endogenous Sh3rf2 protein rapidly decreases following several different apoptotic stimuli and that knockdown of Sh3rf2 activates the pro-apoptotic JNK pathway in neuronal cells. These findings support a model in which Sh3rf2 promotes proteasomal degradation of pro-apoptotic POSH in healthy cells and in which apoptotic stimuli lead to rapid loss of Sh3rf2 expression, and consequently to stabilization of POSH and JNK activation and cell death. On the basis of these observations, we propose the alternative name POSHER (POSH-eliminating RING protein) for the Sh3rf2 protein.

The association of age, illness severity, and glycemic status in a pediatric intensive care unit.

OBJECTIVE: Tight glycemic control in critically ill children is controversial. The benefits of controlling hyperglycemia may be offset by the risk of hypoglycemia on the immature brain. Both age and severity of illness may influence the risks and benefits of tight glycemic control. We hypothesize that rates of hypoglycemia (blood glucose <60 mg/dL) and hyperglycemia (blood glucose >150 mg/dL) in children will correlate with age and illness severity. DESIGN: Retrospective chart review. SETTING: Thirty-two-bed university-affiliated pediatric intensive care unit. PATIENTS: Children <19 yrs old admitted between January and September 2006. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We recorded all blood glucose measurements for up to 10 days of each pediatric intensive care unit visit and assessed rates of hypoglycemia and hyperglycemia based on age, medical vs. surgical therapy, length of stay, therapeutic intervention (Therapeutic Intervention Scoring System), and illness severity (Pediatric Risk of Mortality III). A total of 8853 blood glucose values in 616 patients were recorded. Spontaneous hypoglycemia was noted in 18.8% of patients <1 yr compared with 5.1% to 11.3% of patients in older age groups. Hyperglycemia occurred in 47% of patients <1 yr, which increased to 58.9% in patients 13-18 yrs. Rates of hypoglycemia were not affected by medical/surgical status. Surgical patients had an increased risk of hyperglycemia. Rates of hypo- and hyperglycemia increased with higher Pediatric Risk of Mortality III, Therapeutic Intervention Scoring System, length of stay, and days of mechanical ventilation. Increased rates of hypo-/hyperglycemia were observed in patients who died. CONCLUSIONS: The youngest patients are at higher risk for spontaneous hypoglycemia, whereas hyperglycemia occurs more often in the older ages. Higher rates of hypo-/hyperglycemia were noted in sicker patients and in those requiring more therapeutic interventions. Our results suggest that special consideration should be given to the safety of the youngest patients given their higher risk of hypoglycemia if an investigation of tight glycemic control is performed.