Early metabolic derangements and unfavorable outcomes in pediatric traumatic brain injury: a retrospective multi-center cohort study.

Background: To study the association in moderate and severe pediatric traumatic brain injury (TBI) between hyperglycemia, hyperlactatemia, acidosis and unfavorable outcome, as assessed by Pediatric Cerebral Performance Category (PCPC) on discharge from the pediatric intensive care unit (PICU). Methods: Children <16 years old with TBI and Glasgow Coma Scale (GCS) ≤13 in an Asian multi-center PICU TBI cohort from January 2014 to October 2017 were included in this study. We defined unfavorable outcome as PCPC ≥3-moderate disability, severe disability, vegetative state, and death. We performed logistic regression to investigate the association between metabolic changes with unfavorable outcome. We divided hyperglycemia (glucose >11.1 mmol/L) during PICU admission into early-onset (within 24 h), late-onset (beyond 48 h) and persistent (throughout first 72 h). Results: Among the 305 children analyzed, 136 (44.6%) had unfavorable outcome. Children with unfavorable outcome were more likely to have early hyperglycemia (75/136, 55.1% vs. 33/169, 19.5%; P<0.001), high lactate levels >2.0 mmol/L (74/136, 54.4% vs. 56/169, 32.5%; P<0.001) and initial acidosis (85/136, 62.5% vs. 78/169, 56.1%; P=0.003) compared to those with favorable outcome. After adjusting for gender, GCS ≤8 and presence of polytrauma, early hyperglycemia [adjusted odds ratio (aOR) =3.68, 95% CI: 2.12-6.39, P<0.001] and late hyperglycemia (aOR =13.30, 95% CI: 1.64-107.8, P=0.015] were independently associated with unfavorable outcome. All children with persistent hyperglycemia died. Conclusions: We described unfavorable outcome in pediatric TBI especially with persistent hyperglycemia. Future trials should investigate the causal relationship between glycemic trends, early intervention and outcome in this cohort.

Early posttraumatic seizures in pediatric traumatic brain injury: a multicenter analysis.

OBJECTIVE: Early posttraumatic seizures (EPTSs) in children after traumatic brain injury (TBI) increase metabolic stress on the injured brain. The authors sought to study the demographic and radiographic predictors for EPTS, and to investigate the association between EPTS and death, and between EPTS and poor functional outcomes among children with moderate to severe TBI in Asia. METHODS: A secondary analysis of a retrospective TBI cohort among participating centers of the Pediatric Acute & Critical Care Medicine Asian Network was performed. Children < 16 years of age with a Glasgow Coma Scale (GCS) score ≤ 13 who were admitted to pediatric intensive care units between January 2014 and October 2017 were included. Logistic regression analysis was performed to study risk factors for EPTS and to investigate the association between EPTS and death, and between EPTS and poor functional outcomes. Poor functional outcomes were defined as moderate disability, severe disability, and coma as defined by the Pediatric Cerebral Performance Category scale. RESULTS: Overall, 313 children were analyzed, with a median age of 4.3 years (IQR 1.8-8.9 years); 162 children (51.8%) had severe TBI (GCS score < 8), and 76 children (24.3%) had EPTS. After adjusting for age, sex, and the presence of nonaccidental trauma (NAT), only younger age was significantly associated with EPTS (adjusted odds ratio [aOR] 0.85, 95% CI 0.78-0.92; p < 0.001). Forty-nine children (15.6%) in the cohort died, and 87 (32.9%) of the 264 surviving patients had poor functional outcomes. EPTS did not increase the risk of death. After adjusting for age, sex, TBI due to NAT, multiple traumas, and a GCS score < 8, the presence of EPTS was associated with poor functional outcomes (aOR 2.08, 95% CI 1.05-4.10; p = 0.036). CONCLUSIONS: EPTSs were common among children with moderate to severe TBI in Asia and were associated with poor functional outcomes among children who survived TBI.

Traumatic Brain Injury Outcomes in 10 Asian Pediatric ICUs: A Pediatric Acute and Critical Care Medicine Asian Network Retrospective Study.

OBJECTIVES: Traumatic brain injury remains an important cause of death and disability. We aim to report the epidemiology and management of moderate to severe traumatic brain injury in Asian PICUs and identify risk factors for mortality and poor functional outcomes. DESIGN: A retrospective study of the Pediatric Acute and Critical Care Medicine Asian Network moderate to severe traumatic brain injury dataset collected between 2014 and 2017. SETTING: Patients were from the participating PICUs of Pediatric Acute and Critical Care Medicine Asian Network. PATIENTS: We included children less than 16 years old with a Glasgow Coma Scale less than or equal to 13. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We obtained data on patient demographics, injury circumstances, and PICU management. We performed a multivariate logistic regression predicting for mortality and poor functional outcomes. We analyzed 380 children with moderate to severe traumatic brain injury. Most injuries were a result of road traffic injuries (174 [45.8%]) and falls (160 [42.1%]). There were important differences in temperature control, use of antiepileptic drugs, and hyperosmolar agents between the sites. Fifty-six children died (14.7%), and 104 of 324 survivors (32.1%) had poor functional outcomes. Poor functional outcomes were associated with non-high-income sites (adjusted odds ratio, 1.90; 95% CI, 1.11-3.29), Glasgow Coma Scale less than 8 (adjusted odds ratio, 4.24; 95% CI, 2.44-7.63), involvement in a road traffic collision (adjusted odds ratio, 1.83; 95% CI, 1.04-3.26), and presence of child abuse (adjusted odds ratio, 2.75; 95% CI, 1.01-7.46). CONCLUSIONS: Poor functional outcomes are prevalent after pediatric traumatic brain injury in Asia. There is an urgent need for further research in these high-risk groups.

Outcome of status asthmaticus at a pediatric intensive care unit in Hong Kong.

OBJECTIVES: To characterize the clinical course and outcome of children with status asthmaticus (SA) admitted to a pediatric intensive care unit (PICU) METHODS: All patients with SA who were admitted to a PICU from January 2003 to December 2018 were reviewed. Polymerase chain reaction (PCR) studies on nasopharyngeal aspirate for respiratory pathogens were performed from 2014 to 2018. RESULTS: Sixty-seven SA admissions constituted 2.4% of total PICU admissions (n = 2788). Fifteen (22.4%) children required noninvasive ventilation (NIV), while 7 children (10%) required invasive mechanical ventilation. Nonadherence to prior asthma therapy was common. PCR was positive for enterorvirus/rhinovirus in 84% (16 out of 19) and for any virus in 95% of nasopharyngeal aspirate (NPA) samples of patients between 2014 and 2018. Over the 16-year period, increased utilization of ipratropium bromide, magnesium sulfate and NIV was noted (P < .05). Patients who required invasive mechanical ventilation had significantly higher heart rate, lower pH and longer PICU length of stay (LOS) when compared to nonintubated children (P < .05). There was no mortality, gender difference, or seasonal characteristics in these SA admissions. Median LOS in PICU was 2 days (interquartile range 1-3 days). CONCLUSIONS: SA accounts for a small proportion of PICU admissions. LOS was short and prognosis generally good. Nonadherence to prior asthma therapy was common. The most common trigger is enterovirus/rhinovirus for children with severe asthma requiring PICU admission. A trend of increase in usage of ipratropium, magnesium sulfate and NIV was observed. Primary prevention and early treatment of exacerbation are the most important step in managing children with asthma. Regular follow-up to ensure compliance together with annual vaccination could possibly avoid PICU admissions.

Change in Pneumococcus Serotypes but not Mortality or Morbidity in Pre- and Post-13-Valent Polysaccharide Conjugate Vaccine Era: Epidemiology in a Pediatric Intensive Care Unit over 10 Years.

Aim: Pneumococcus is a common commensal and an important pathogen among children for which immunization is available. Some serotypes occasionally cause severe pneumococcal disease with high mortality and morbidity. We reviewed all pneumococcal serotypes and mortality/morbidity in a pediatric intensive care unit (PICU) following universal pneumococcal conjugate vaccine (PCV) immunization. Methods: A 13-valent PCV was introduced in the universal immunization program in late 2011 in Hong Kong. We retrospectively reviewed all pneumococcal serotypes in the pre-(2007-11) and post-(2012-16) 13-valent PCV era. Results: There were 29 (1.9%) PICU patients with pneumococcal isolation, of which 6 died (20% motality). Serogroups 6 and 19 predominated before and Serogroup 3 after 2012. In the post-13-valent PCV era, the prevalence of pneumococcus isolation in PICU was increased from 1 to 2% (p = 0.04); Serogroup 3 was the major serotype of morbidity, despite supposedly under vaccine coverage. The majority of pneumococcus were penicillin-sensitive (94%) in the post 13-valent PCV era. All pneumococcus specimens were sensitive to cefotaxime and vancomycin. Binary logistic regression showed that there were reductions in Serogroup 6 (odds ratio [OR], 0.050; 95% confidence interval [CI], 0.004-0.574; p = 0.016) and Serogroup 19 (odds ratio [OR], 0.105; 95% confidence interval [CI], 0.014-0.786; p = 0.028) but not mortality or morbidity for patients admitted after 2012. Conclusions: SPD is associated with significant morbidity and mortality, despite treatment with systemic antibiotics and ICU support. The expanded coverage of 13-valent PCV results in the reduction of Serotypes 6 and 19 but not mortality/morbidity associated with SPD in the setting of a PICU.

MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex.

Rett syndrome (RTT; OMIM 312750), a progressive neurological disorder, is caused by mutations in methyl-CpG-binding protein 2 (MECP2; OMIM 300005), a ubiquitously expressed factor. A genetic suppressor screen designed to identify therapeutic targets surprisingly revealed that downregulation of the cholesterol biosynthesis pathway improves neurological phenotypes in Mecp2 mutant mice. Here, we show that MeCP2 plays a direct role in regulating lipid metabolism. Mecp2 deletion in mice results in a host of severe metabolic defects caused by lipid accumulation, including insulin resistance, fatty liver, perturbed energy utilization, and adipose inflammation by macrophage infiltration. We show that MeCP2 regulates lipid homeostasis by anchoring the repressor complex containing NCoR1 and HDAC3 to its lipogenesis targets in hepatocytes. Consistently, we find that liver targeted deletion of Mecp2 causes fatty liver disease and dyslipidemia similar to HDAC3 liver-specific deletion. These findings position MeCP2 as a novel component in metabolic homeostasis. Rett syndrome patients also show signs of peripheral dyslipidemia; thus, together these data suggest that RTT should be classified as a neurological disorder with systemic metabolic components. We previously showed that treatment of Mecp2 mice with statin drugs alleviated motor symptoms and improved health and longevity. Lipid metabolism is a highly treatable target; therefore, our results shed light on new metabolic pathways for treatment of Rett syndrome.

Outcome of Encephalitis in Pediatric Intensive Care Unit.

OBJECTIVE: To review pathogens, morbidity and mortality in pediatric intensive care unit (PICU) patients with viral and infectious encephalitis. METHODS: Retrospective chart review of all patients with encephalitis admitted to the PICU between 2002 and 2014 was done. RESULTS: Encephalitis (n = 46) accounted for 2.7 % of PICU admissions, but 11.8 % PICU mortality over a 12-y period. A microorganism (primarily virus) was identified in 59 % of encephalitis patients in the PICU. Enteroviruses and herpes viruses were isolated from the cerebrospinal fluid (CSF). Respiratory viruses [such as respiratory syncytial virus (RSV) and influenza viruses] and enteric viruses (such as rotavirus and norovirus) were obtained in the nasopharyngeal aspirate and stool respectively, but undetectable from the CSF. More than one-fourth patients with encephalitis died in the PICU. Boys accounted for 85 % of nonsurvivors and 52 % survivors (p = 0.038). Mechanical ventilation, inotrope, intravenous immunoglobulin (IVIG) and corticosteroid usage were significantly higher among non-survivors (p 0.001-0.044). Binomial logistic regression showed that patients who received corticosteroid had a lower chance of survival than those who did not after adjusting for gender, IVIG and mechanical ventilation (adjusted odd ratio = 0.071, 95 % CI 0.006-0.881; p 0.039). Eighteen (55 %) of the survivors had moderate-to-severe neurodevelopmental impairments. CONCLUSIONS: Encephalitis is associated with significant mortality despite intensive care. Over 25 % case died and 55 % of survivors had moderate-to-severe neurodevelopmental impairments. There appeared to be no emerging outbreaks of encephalitis during the 15-y study period.

A community-based cross-sectional immunisation survey in parents of primary school students.

Immunisation is a very important aspect of child health. Invasive pneumococcal and influenza diseases have been major vaccine-available communicable diseases. We surveyed demographics and attitudes of parents of primary school students who received pneumococcal conjugate vaccination (PCV) and compared them with those who did not receive pneumococcal vaccination. The survey was carried out in randomly selected primary schools in Hong Kong. Questionnaires were sent to nine primary schools between June and September 2014. Parents of 3,485 children were surveyed, and 3,479 (1,452 PCV immunised, 2,027 un-immunised) valid questionnaires were obtained. Demographic data were generally different between the two groups. PCV-immunised children were more likely to be female (57.0 vs. 52.2%, P=0.005), born in Hong Kong (94.2 vs. 92.3%, P=0.031), have a parent with tertiary education (49.2 vs. 31.8, P<0.0005), from the higher-income group (P=0.005), have suffered upper respiratory infections, pneumonia, otitis media or sinusitis (P=0.019), and have doctor visits in preceding 12 months (P=0.009). They were more likely to have received additional immunisations outside the Hong Kong Childhood Immunization Programme (64.0 vs. 30.6%, P<0.0005) at private practitioner clinics (91.1 vs. 83.5%, P<0.0005). Un-immunised children were more likely to live with senior relatives who had not received PCV. Their parents were less likely to be aware of public education programme on PCV and influenza immunisation, and children were less likely to have received influenza vaccination. The major reasons for PCV immunisations were parent awareness that pneumococcal disease could be severe and vaccines were efficacious in prevention. The major reasons for children not being immunised with PCV were concerns about vaccine side effects, cost, vaccine not efficacious or no recommendation by family doctor or government. In conclusion, PCV unimmunized children were prevalent during the study period. Reportedly, they were generally less likely to have received influenza and other childhood vaccines, and more likely to live with senior relatives who had not received PCV and influenza. These observations provide important demographic data for public health policy in childhood immunisation programme.

Enhanced atheroprotection and lesion remodelling by targeting the foam cell and increasing plasma cholesterol acceptors.

AIMS: Atherosclerosis development can be ameliorated by promoting reverse cholesterol transport (RCT) from arteries. The process involves cholesterol efflux from foam cells to extracellular acceptors such as apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL) that mediate transport to the liver. Perilipin-2 (PLIN2) is a lipid droplet (LD)-associated protein that in macrophages facilitates cholesterol storage and prevents efflux. We hypothesized that atheroprotection would be enhanced by concurrently targeting PLIN2 to increase the efflux capacity of foam cells and increasing plasma apoA-I and HDL. METHODS AND RESULTS: PLIN2-knockout and wild-type mice lacking apolipoprotein E (PLIN2(-/-)/apoE(-/-) and PLIN2(+/+)/apoE(-/-)) were treated with a helper-dependent adenoviral vector encoding human apoA-I (HDAd-AI) or with control empty vector. Treatment with HDAd-AI increased hepatic apoA-I production, plasma apoA-I and HDL-cholesterol (HDL-C), and apoA-I deposition in lesions to a similar extent in PLIN2(-/-)/apoE(-/-) and PLIN2(+/+)/apoE(-/-) mice. However, atherosclerosis development at the aortic sinus was considerably lower in HDAd-AI-treated PLIN2(-/-)/apoE(-/-) mice. A more stable lesion phenotype, with increased collagen content, was primarily associated to treatment with HDAd-AI, but was enhanced under PLIN2 deficiency. PLIN2 deficiency and apoA-I cumulatively reduced LDs and cholesterol ester content in cultured macrophages. Neutral lipid in atheroma was significantly reduced in HDAd-AI-treated PLIN2(-/-)/apoE(-/-) mice, and RCT from macrophages to feces was enhanced in PLIN2(-/-) macrophages. CONCLUSION: These studies demonstrate a mutually beneficial relationship between PLIN2 deficiency and elevated apoA-I/HDL-C in preventing atherosclerosis development. The data support that targeting foam cell components to mobilize cholesterol may be a promising strategy to enhance the atheroprotection of plasma cholesterol acceptors.

End-of-life decision-making for newborns: a 12-year experience in Hong Kong.

SETTING: Neonatal end-of-life decisions could be influenced by cultural and ethnic backgrounds. These practices have been well described in the West but have not been systematically studied in an Asian population. OBJECTIVES: To determine: (1) different modes of neonatal death and changes over the past 12 years and (2) factors influencing end-of-life decision-making in Hong Kong. DESIGN: A retrospective study was conducted to review all death cases from 2002 to 2013 in the busiest neonatal unit in Hong Kong. Modes of death, demographical data, diagnoses, counselling and circumstances around the time of death, were collected and compared between groups. RESULTS: Of the 166 deaths, 46% occurred despite active resuscitation (group 1); 35% resulted from treatment withdrawal (group 2) and 19% occurred from withholding treatment (group 3). A rising trend towards treatment withdrawal was observed, from 20% to 47% over the 12-year period. Similar number of parents chose extubation (n=44, 27%) compared with other modalities of treatment limitation (n=45, 27%). Significantly more parents chose to withdraw rather than to withhold treatment if clinical conditions were 'stable' (p=0.03), whereas more parents chose withholding therapy if treatment was considered futile (p=0.03). CONCLUSION: In Hong Kong, a larger proportion of neonatal deaths occurred despite active resuscitation compared with Western data. Treatment withdrawal is, however, becoming increasingly more common. Unlike Western practice, similar percentages of parents chose other modalities of treatment limitation compared with direct extubation. Cultural variance could be a reason for the different end-of-life practice adopted in Hong Kong.