How to perform and interpret a middle cerebral artery transcranial Doppler examination in children at risk of brain injury.

Transcranial Doppler (TCD) ultrasound is a non-invasive neuromonitoring technique that falls under the umbrella of point-of-care ultrasound. In this article, we provide a primer to encourage clinicians to perform TCD examinations and to aid them with accurately interpreting the scans. We focus on the middle cerebral artery waveforms and use traumatic brain injury as a model for brain insult.

Impact of prematurity on long-stay paediatric intensive care unit admissions in England 2008-2018.

BACKGROUND: Survival following extreme preterm birth has improved, potentially increasing the number of children with ongoing morbidity requiring intensive care in childhood. Previous single-centre studies have suggested that long-stay admissions in paediatric intensive care units (PICUs) are increasing. We aimed to examine trends in long-stay admissions (≥28 days) to PICUs in England, outcomes for this group (including mortality and PICU readmission), and to determine the contribution of preterm-born children to the long-stay population, in children aged <2 years. METHODS: Data was obtained from the Paediatric Intensive Care Audit Network (PICANet) for all children <2 years admitted to National Health Service PICUs from 1/1/2008 to 31/12/2018 in England. We performed descriptive analysis of child characteristics and PICU outcomes. RESULTS: There were 99,057 admissions from 67,615 children. 2,693 children (4.0%) had 3,127 long-stays. Between 2008 and 2018 the annual number of long-stay admissions increased from 225 (2.7%) to 355 (4.0%), and the proportion of bed days in PICUs occupied by long-stay admissions increased from 24.2% to 33.2%. Of children with long-stays, 33.5% were born preterm, 53.5% were born at term, and 13.1% had missing data for gestational age. A considerable proportion of long-stay children required PICU readmission before two years of age (76.3% for preterm-born children). Observed mortality during any admission was also disproportionately greater for long-stay children (26.5% for term-born, 24.8% for preterm-born) than the overall rate (6.3%). CONCLUSIONS: Long-stays accounted for an increasing proportion of PICU activity in England between 2008 and 2018. Children born preterm were over-represented in the long-stay population compared to the national preterm birth rate (8%). These results have significant implications for future research into paediatric morbidity, and for planning future PICU service provision.

Hospital admissions linked to SARS-CoV-2 infection in children and adolescents: cohort study of 3.2 million first ascertained infections in England.

OBJECTIVE: To describe hospital admissions associated with SARS-CoV-2 infection in children and adolescents. DESIGN: Cohort study of 3.2 million first ascertained SARS-CoV-2 infections using electronic health care record data. SETTING: England, July 2020 to February 2022. PARTICIPANTS: About 12 million children and adolescents (age <18 years) who were resident in England. MAIN OUTCOME MEASURES: Ascertainment of a first SARS-CoV-2 associated hospital admissions: due to SARS-CoV-2, with SARS-CoV-2 as a contributory factor, incidental to SARS-CoV-2 infection, and hospital acquired SARS-CoV-2. RESULTS: 3 226 535 children and adolescents had a recorded first SARS-CoV-2 infection during the observation period, and 29 230 (0.9%) infections involved a SARS-CoV-2 associated hospital admission. The median length of stay was 2 (interquartile range 1-4) days) and 1710 of 29 230 (5.9%) SARS-CoV-2 associated admissions involved paediatric critical care. 70 deaths occurred in which covid-19 or paediatric inflammatory multisystem syndrome was listed as a cause, of which 55 (78.6%) were in participants with a SARS-CoV-2 associated hospital admission. SARS-CoV-2 was the cause or a contributory factor in 21 000 of 29 230 (71.8%) participants who were admitted to hospital and only 380 (1.3%) participants acquired infection as an inpatient and 7855 (26.9%) participants were admitted with incidental SARS-CoV-2 infection. Boys, younger children (<5 years), and those from ethnic minority groups or areas of high deprivation were more likely to be admitted to hospital (all P<0.001). The covid-19 vaccination programme in England has identified certain conditions as representing a higher risk of admission to hospital with SARS-CoV-2: 11 085 (37.9%) of participants admitted to hospital had evidence of such a condition, and a further 4765 (16.3%) of participants admitted to hospital had a medical or developmental health condition not included in the vaccination programme's list. CONCLUSIONS: Most SARS-CoV-2 associated hospital admissions in children and adolescents in England were due to SARS-CoV-2 or SARS-CoV-2 was a contributory factor. These results should inform future public health initiatives and research.

Examining safety and efficacy of a fixed concentration heparin dosing strategy for anticoagulation in neonatal extracorporeal membrane oxygenation.

OBJECTIVES: The paediatric intensive care unit changed heparin infusion dosing from a variable weight-based concentration to a fixed concentration strategy, when smart pump-based drug library was introduced. This change meant significantly lower rates of infusion were needed for the same dose of heparin in the neonatal population. We performed a safety and efficacy assessment of this change. METHODS: We performed a retrospective single-centre evaluation based on data from respiratory VA-extracorporeal membrane oxygenation (ECMO) patients weighing ≤5 kg, pre and post the change to fixed strength heparin infusion. Efficacy was analysed by distribution of activated clotting times (ACT) and heparin dose requirements between the groups. Safety was analysed using thrombotic and haemorrhagic event rates. Continuous variables were reported as median, interquartile ranges, and non-parametric tests were used. Generalised estimating equations (GEE) were used to analyse associations of heparin dosing strategy with ACT and heparin dose requirements in the first 24 h of ECMO. Incidence rate ratios of circuit related thrombotic and haemorrhagic events between groups were analysed using Poisson regression with offset for run hours. RESULTS: 33 infants (20 variable weight-based, 13 fixed concentration) were analysed. Distribution of ACT ranges and heparin dose requirements were similar between the two groups during the ECMO run and this was confirmed by GEE. Incidence rate ratios of thrombotic (fixed v weight-based) (1.9 [0.5-8], p = .37), and haemorrhagic events (0.9 [0.1-4.9], p = .95) did not show statistically significant differences. CONCLUSIONS: Fixed concentration dosing of heparin was at least equally effective and safe compared to a weight-based dosing.

Critical Care Course of Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 and Response to Immunomodulation.

We describe the critical care course of children with a novel hyperinflammatory syndrome associated with coronavirus disease 2019 (COVID-19) pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with focus on trajectory before and after immunomodulation. Overall, 10 patients who met the U.K. Royal College of Pediatrics and Child Health case definition during a 2-month study period were analyzed. All tested positive for SARS-CoV-2 IgG antibody. Although only 20% were ventilated, 100% required inotropic or vasopressor support. All children had significantly raised inflammatory markers with a median C-reactive protein of 248 (175-263) mg/L, ferritin of 1,561 (726-2,255) µg/L, and troponin-I of 723 (351-2,235) ng/L. Six patients had moderately impaired myocardial function and two had severe impairment. None needed extracorporeal membrane oxygenation. Despite severe illness only a brief period of critical care support of 3 to 5 days was required. Eight received at least one dose of intravenous immunoglobulin. Six received high-dose steroids. Clinical improvement including cardiovascular stability and reduction in inflammatory markers may have occurred with and without immunomodulation.

The brain in pediatric critical care: unique aspects of assessment, monitoring, investigations, and follow-up.

As survival after pediatric intensive care unit (PICU) admission has improved over recent years, a key focus now is the reduction of morbidities and optimization of quality of life for survivors. Neurologic disorders and direct brain injuries are the reason for 11-16% of admissions to PICU. In addition, many critically ill children are at heightened risk of brain injury and neurodevelopmental difficulties affecting later life, e.g., complex heart disease and premature birth. Hence, assessment, monitoring and protection of the brain, using fundamental principles of neurocritical care, are crucial to the practice of pediatric intensive care medicine. The assessment of brain function, necessary to direct appropriate care, is uniquely challenging amongst children admitted to the PICU. Challenges in assessment arise in children who are unstable, or pharmacologically sedated and muscle relaxed, or who have premorbid abnormality in development. Moreover, the heterogeneity of diseases and ages in PICU patients, means that high caliber evidence is harder to accrue than in adult practice, nonetheless, great progress has been made over recent years. In this 'state of the art' paper about critically ill children, we discuss (1) patient types at risk of brain injury, (2) new standardized clinical assessment tools for age-appropriate, clinical evaluation of brain function, (3) latest evidence related to cranial imaging, non-invasive and invasive monitoring of the brain, (4) the concept of childhood 'post intensive are syndrome' and approaches for neurodevelopmental follow-up. Better understanding of these concepts is vital for taking PICU survivorship to the next level.

Vitamin D status of children with paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS).

Coronavirus disease 2019 (COVID-19) has caused mild illness in children, until the emergence of the novel hyperinflammatory condition paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS). PIMS-TS is thought to be a post-SARS-CoV-2 immune dysregulation with excessive inflammatory cytokine release. We studied 25 hydroxyvitamin D (25OHD) concentrations in children with PIMS-TS, admitted to a tertiary paediatric hospital in the UK, due to its postulated role in cytokine regulation and immune response. Eighteen children (median (range) age 8·9 (0·3-14·6) years, male = 10) met the case definition. The majority were of Black, Asian and Minority Ethnic (BAME) origin (89 %, 16/18). Positive SARS-CoV-2 IgG antibodies were present in 94 % (17/18) and RNA by PCR in 6 % (1/18). Seventy-eight percentage of the cohort were vitamin D deficient (< 30 nmol/l). The mean 25OHD concentration was significantly lower when compared with the population mean from the 2015/16 National Diet and Nutrition Survey (children aged 4-10 years) (24 v. 54 nmol/l (95 % CI -38·6, -19·7); P < 0·001). The paediatric intensive care unit (PICU) group had lower mean 25OHD concentrations compared with the non-PICU group, but this was not statistically significant (19·5 v. 31·9 nmol/l; P = 0·11). The higher susceptibility of BAME children to PIMS-TS and also vitamin D deficiency merits contemplation. Whilst any link between vitamin D deficiency and the severity of COVID-19 and related conditions including PIMS-TS requires further evidence, public health measures to improve vitamin D status of the UK BAME population have been long overdue.

In the eye of the storm: impact of COVID-19 pandemic on admission patterns to paediatric intensive care units in the UK and Eire.

BACKGROUND: The coronavirus disease-19 (COVID-19) pandemic had a relatively minimal direct impact on critical illness in children compared to adults. However, children and paediatric intensive care units (PICUs) were affected indirectly. We analysed the impact of the pandemic on PICU admission patterns and patient characteristics in the UK and Ireland. METHODS: We performed a retrospective cohort study of all admissions to PICUs in children < 18 years during Jan-Dec 2020, using data collected from 32 PICUs via a central database (PICANet). Admission patterns, case-mix, resource use, and outcomes were compared with the four preceding years (2016-2019) based on the date of admission. RESULTS: There were 16,941 admissions in 2020 compared to an annual average of 20,643 (range 20,340-20,868) from 2016 to 2019. During 2020, there was a reduction in all PICU admissions (18%), unplanned admissions (20%), planned admissions (15%), and bed days (25%). There was a 41% reduction in respiratory admissions, and a 60% reduction in children admitted with bronchiolitis but an 84% increase in admissions for diabetic ketoacidosis during 2020 compared to the previous years. There were 420 admissions (2.4%) with either PIMS-TS or COVID-19 during 2020. Age and sex adjusted prevalence of unplanned PICU admission reduced from 79.7 (2016-2019) to 63.1 per 100,000 in 2020. Median probability of death [1.2 (0.5-3.4) vs. 1.2 (0.5-3.4) %], length of stay [2.3 (1.0-5.5) vs. 2.4 (1.0-5.7) days] and mortality rates [3.4 vs. 3.6%, (risk-adjusted OR 1.00 [0.91-1.11, p = 0.93])] were similar between 2016-2019 and 2020. There were 106 fewer in-PICU deaths in 2020 (n = 605) compared with 2016-2019 (n = 711). CONCLUSIONS: The use of a high-quality international database allowed robust comparisons between admission data prior to and during the COVID-19 pandemic. A significant reduction in prevalence of unplanned admissions, respiratory diseases, and fewer child deaths in PICU observed may be related to the targeted COVID-19 public health interventions during the pandemic. However, analysis of wider and longer-term societal impact of the pandemic and public health interventions on physical and mental health of children is required.

The immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells, with increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated immune features including increased monocyte CD163 levels, emergence of a new population of immature neutrophils and, in some patients, transiently increased plasma arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL-6 may be preferable to IL-1 or TNF-α. We identified several potential mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C suggesting complement inhibitors could be used to treat the disease.

Worldwide epidemiology of neuro-coronavirus disease in children: lessons for the next pandemic.

PURPOSE OF REVIEW: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has overwhelmed the global community, negatively impacting patient health and research efforts; associated neurological manifestations are a significant cause of morbidity. This review outlines the worldwide epidemiology of neurologic manifestations of different SARS-CoV-2 clinical pediatric phenotypes, including acute coronavirus disease 2019 (COVID-19), multisystem inflammatory syndrome in children (MIS-C) and postacute sequelae of COVID-19 (PASC). We discuss strategies to develop adaptive global research platforms for future investigation into emerging pediatric neurologic conditions. RECENT FINDINGS: Multicenter, multinational studies show that neurological manifestations of acute COVID-19, such as smell/taste disorders, headache, and stroke, are common in hospitalized adults (82%) and children (22%), associated with increased mortality in adults. Neurological manifestations of MIS-C are reported in up to 20% of children, including headache, irritability, and encephalopathy. Data on PASC are emerging and include fatigue, cognitive changes, and headache. Reports of neurological manifestations in each phenotype are limited by lack of pediatric-informed case definitions, common data elements, and resources. SUMMARY: Coordinated, well resourced, multinational investigation into SARS-CoV-2-related neurological manifestations in children is critical to rapid identification of global and region-specific risk factors, and developing treatment and mitigation strategies for the current pandemic and future health neurologic emergencies.

Characteristics of Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Comparison With Influenza in Children Admitted to U.K. PICUs.

OBJECTIVES: Severe acute respiratory syndrome coronavirus-2 affects adults disproportionately more than children. A small proportion of children with severe acute respiratory syndrome coronavirus-2 required admission to a PICU. We describe the nationwide U.K. PICU experience of severe acute respiratory syndrome coronavirus-2 infection during the first wave of the pandemic and compare this with the critical care course of the 2019 influenza cohort. DESIGN: Prospective nationwide cohort study of characteristics of severe acute respiratory syndrome coronavirus-2-positive children. Data collection utilized routine Pediatric Intensive Care Audit Network and severe acute respiratory syndrome coronavirus-2-specific data. SETTING: All U.K. PICUs. PATIENTS: Children less than 18 years old, admitted to U.K. PICUs between March 14, 2020, and June 13, 2020, and a positive severe acute respiratory syndrome coronavirus-2 polymerase chain reaction. Children admitted to U.K. PICUs in 2019 with influenza provided comparison. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 76 PICU admissions among 73 children with a positive severe acute respiratory syndrome coronavirus-2 polymerase chain reaction test. Prevalence of PICU admissions per million was 5.2 for children versus 260 for adults. Ten children (14%) were identified on routine screening. Seventeen children (23%) had pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2. Seventeen (23%) had coinfections. Invasive ventilation was required in seven of 17 children (41%) with pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 versus 38 of 56 other severe acute respiratory syndrome coronavirus-2 positive children (68%), with 77% requiring vasoactive support versus 43%, respectively. Seven children (10%) died. In comparison with influenza children, severe acute respiratory syndrome coronavirus-2 children were older (median [interquartile range]: 10 [1-13] vs 3 yr [1-8 yr]), more often Black or Asian (52% v 18%), higher weight z score (0.29 [-0.80 to 1.62] vs -0.41 [-1.37 to 0.63]), and higher deprivation index (3.3 [-1 to 6.3] vs 1.2 [-1.8 to 4.4]). Comorbidities, frequency of organ supports, and length of stay were similar. CONCLUSIONS: This nationwide study confirms that PICU admissions with severe acute respiratory syndrome coronavirus-2 infections were infrequent. We have reported similarities and differences in sociodemographic characteristics, organ support interventions, and outcomes of children affected by severe acute respiratory syndrome coronavirus-2 compared with influenza.

Pediatric Inflammatory Multisystem Syndrome: Time to Collaborate.

There is significant variability in the names and case definition of pediatric inflammatory multisystem syndrome associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Such variability leads to adverse consequences in the quest for further knowledge and management strategies. It is time to collaborate to gain consensus.

Traumatic Brain Injury Practice Guidelines: Variability in U.K. PICUs.

OBJECTIVES: Traumatic brain injury in children is a leading cause of morbidity and mortality. Lack of high-quality evidence may lead to variation in management within and between PICUs. We examined U.K. pediatric traumatic brain injury management guidelines for extent of variability. DESIGN: Analysis of U.K. PICU traumatic brain injury guidelines for areas of consistency and variation among each other and against the second edition of Brain Trauma Foundation pediatric traumatic brain injury guidelines. SETTING: Not applicable. SUBJECTS: Not applicable. INTERVENTIONS: Textual analysis of U.K. PICU guidelines. MEASUREMENTS AND MAIN RESULTS: Twelve key clinical topics in three traumatic brain injury management domains were identified. We performed textual analysis of recommendations from anonymized local guidelines and compared them against each other and the Brain Trauma Foundation pediatric traumatic brain injury guidelines. Fifteen guidelines used by 16 of the 20 U.K. PICUs that manage traumatic brain injury were analyzed. Relatively better consistency was observed for intracranial pressure treatment thresholds (10/15), avoiding prophylactic hyperventilation (15/15), cerebrospinal fluid drainage (13/15), barbiturate (14/15), and decompressive craniectomy (12/15) for intracranial hypertension. There was less consistency in indications for intracranial pressure monitoring (3/15), cerebral perfusion pressure targets (2/15), target osmolarities (7/15), and hyperventilation for intracranial hypertension (2/15). Variability in choice and hierarchy of the interventions for intracranial hypertension were observed, albeit with some points of consistency. CONCLUSIONS: Significant variability in pediatric traumatic brain injury management guidelines exists. Despite the heterogeneity, we have highlighted a few points of consistency within the key topic areas of pediatric traumatic brain injury management. We anticipate that this provides impetus for further work around standardization.

Acute Kidney Injury in Pediatric Inflammatory Multisystem Syndrome Temporally Associated With Severe Acute Respiratory Syndrome Coronavirus-2 Pandemic: Experience From PICUs Across United Kingdom.

OBJECTIVES: To study the prevalence, evolution, and clinical factors associated with acute kidney injury in children admitted to PICUs with pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2. DESIGN: Multicenter observational study. SETTING: Fifteen PICUs across the United Kingdom. PATIENTS: Patients admitted to United Kingdom PICUs with pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 between March 14, 2020, and May 20, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Deidentified data collected as part of routine clinical care were analyzed. All children were diagnosed and staged for acute kidney injury based on the level of serum creatinine above the upper limit of reference interval values according to published guidance. Severe acute kidney injury was defined as stage 2/3 acute kidney injury. Uni- and multivariable analyses were performed to study the association between demographic data, clinical features, markers of inflammation and cardiac injury, and severe acute kidney injury. Over the study period, 116 patients with pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 were admitted to 15 United Kingdom PICUs. Any-stage acute kidney injury occurred in 48 of 116 patients (41.4%) and severe acute kidney injury in 32 of 116 (27.6%) patients, which was mostly evident at admission (24/32, 75%). In univariable analysis, body mass index, hyperferritinemia, high C-reactive protein, Pediatric Index of Mortality 3 score, vasoactive medication, and invasive mechanical ventilation were associated with severe acute kidney injury. In multivariable logistic regression, hyperferritinemia was associated with severe acute kidney injury (compared with nonsevere acute kidney injury; adjusted odds ratio 1.04; 95% CI, 1.01-1.08; p = 0.04). Severe acute kidney injury was associated with longer PICU stay (median 5 days [interquartile range, 4-7 d] vs 3 days [interquartile range, 1.5-5 d]; p < 0.001) and increased duration of invasive mechanical ventilation (median 4 days [interquartile range, 2-6 d] vs 2 days [interquartile range, 1-3 d]; p = 0.04). CONCLUSIONS: Severe acute kidney injury occurred in just over a quarter of children admitted to United Kingdom PICUs with pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2. Hyperferritinemia was significantly associated with severe acute kidney injury. Severe acute kidney injury was associated with increased duration of stay and ventilation. Although short-term outcomes for acute kidney injury in pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 appear good, long-term outcomes are unknown.

NEUROlogical Prognosis After Cardiac Arrest in Kids (NEUROPACK) study: protocol for a prospective multicentre clinical prediction model derivation and validation study in children after cardiac arrest.

INTRODUCTION: Currently, we are unable to accurately predict mortality or neurological morbidity following resuscitation after paediatric out of hospital (OHCA) or in-hospital (IHCA) cardiac arrest. A clinical prediction model may improve communication with parents and families and risk stratification of patients for appropriate postcardiac arrest care. This study aims to the derive and validate a clinical prediction model to predict, within 1 hour of admission to the paediatric intensive care unit (PICU), neurodevelopmental outcome at 3 months after paediatric cardiac arrest. METHODS AND ANALYSIS: A prospective study of children (age: >24 hours and <16 years), admitted to 1 of the 24 participating PICUs in the UK and Ireland, following an OHCA or IHCA. Patients are included if requiring more than 1 min of cardiopulmonary resuscitation and mechanical ventilation at PICU admission Children who had cardiac arrests in PICU or neonatal intensive care unit will be excluded. Candidate variables will be identified from data submitted to the Paediatric Intensive Care Audit Network registry. Primary outcome is neurodevelopmental status, assessed at 3 months by telephone interview using the Vineland Adaptive Behavioural Score II questionnaire. A clinical prediction model will be derived using logistic regression with model performance and accuracy assessment. External validation will be performed using the Therapeutic Hypothermia After Paediatric Cardiac Arrest trial dataset. We aim to identify 370 patients, with successful consent and follow-up of 150 patients. Patient inclusion started 1 January 2018 and inclusion will continue over 18 months. ETHICS AND DISSEMINATION: Ethical review of this protocol was completed by 27 September 2017 at the Wales Research Ethics Committee 5, 17/WA/0306. The results of this study will be published in peer-reviewed journals and presented in conferences. TRIAL REGISTRATION NUMBER: NCT03574025.