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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.

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.

Supplemental Digital Content is available in the text., OBJECTIVES: To 1) analyze the short-term biochemical improvements and clinical outcomes following treatment of children with post-severe acute respiratory syndrome coronavirus-2 inflammatory syndrome (multisystem inflammatory syndrome in children/pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2) admitted to U.K. PICUs and 2) collate current treatment guidance from U.K. PICUs. DESIGN: Multicenter observational study. SETTING: Twenty-one U.K. PICUs. PATIENTS: Children (< 18 yr) admitted to U.K. PICUs between April 1, 2020, and May 10, 2020, fulfilling the U.K. case definition of pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Routinely collected, deidentified data were analyzed. Propensity score and linear mixed effects models were used to analyze the effect of steroids, IV immunoglobulin, and biologic agents on changes in C-reactive protein, platelet counts, and lymphocyte counts over the course of PICU stay. Treatment recommendations from U.K. clinical guidelines were analyzed. Over the 6-week study period, 59 of 78 children (76%) received IV immunoglobulin, 57 of 78 (73%) steroids, and 18 of 78 (24%) a biologic agent. We found no evidence of a difference in response in clinical markers of inflammation between patients with multisystem inflammatory syndrome in children/pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 who were treated with IV immunoglobulin, steroids, or biologics, compared with those who were not. By the end of the study period, most patients had received immunomodulation. The 12 patients who did not receive any immunomodulators had similar decrease in inflammatory markers as those treated. Of the 14 guidelines analyzed, the use of IV immunoglobulin, steroids, and biologics was universally recommended. CONCLUSIONS: We were unable to identify any short-term benefit from any of the treatments, or treatment combinations, administered. Despite a lack of evidence, treatment guidelines for multisystem inflammatory syndrome in children/pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 have become very similar in advising step-wise treatments. Retaining clinical equipoise regarding treatment will allow clinicians to enroll children in robust clinical trials to determine the optimal treatment for this novel important condition.

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.

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.

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.

OBJECTIVES: Reports from China relating to coronavirus disease (COVID-19) in children indicate a milder disease course compared with adults. Although a few pediatric COVID-19 reports from other parts of the world exist, there are none from the United Kingdom. We describe the clinical characteristics of children with COVID-19 admitted to a specialist children’s hospital in United Kingdom. METHODS: Retrospective case-series of inpatients with a positive polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2, during a 6-week period from March 14 to April 24, 2020. RESULTS: Forty-five children tested positive for severe acute respiratory syndrome coronavirus 2 during the study period. Median (interquartile range) age was 3.5 (0.7–12) years, and 31 (69%) were male. Children with comorbidities constituted 64% (29 of 45) of the study population, including 44% (20 of 45) who were considered “extremely vulnerable.” Fever (67%) and cough (55%) were the most common symptoms. High C-reactive protein (>10 mg/L) was observed in 68% (19 of 28). Lymphopenia ( CONCLUSIONS: COVID-19 had a relatively mild course of illness in majority of the hospitalized children that included a subgroup of vulnerable children with significant comorbidities. Confirmation of this in larger nationwide studies of children is required.

Summary Background In April, 2020, clinicians in the UK observed a cluster of children with unexplained inflammation requiring admission to paediatric intensive care units (PICUs). We aimed to describe the clinical characteristics, course, management, and outcomes of patients admitted to PICUs with this condition, which is now known as paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Methods We did a multicentre observational study of children (aged

Objectives To describe implementation and early evaluation of using quantitative electroencephalography for electrographic seizure detection by PICU clinician staff. Design Prospective observational study of electrographic seizure detection by PICU clinicians in patients monitored with quantitative electroencephalography. Quantitative electroencephalography program implementation included a continuous education and training package. Continuous quantitative electroencephalography monitoring consisted of two-channel amplitude-integrated electroencephalography, color density spectral array, and raw-electroencephalography. Setting PICU. Patients Children less than 18 years old admitted to the PICU during the 14-month study period and deemed at risk of electrographic seizure. Interventions None. Measurements and main results Real time electrographic seizure detection by a PICU team was analyzed for diagnostic accuracy and promptness, against electrographic seizure identification by a trained neurophysiologist, retrospectively reading the same quantitative electroencephalography and blinded to patient details. One-hundred one of 1,510 consecutive admissions (6.7%) during the study period underwent quantitative electroencephalography monitoring. Status epilepticus (35%) and suspected hypoxic-ischemic injury (32%) were the most common indications for quantitative electroencephalography. Electrographic seizure was diagnosed by the neurophysiologist in 12% (n = 12) of the cohort. PICU clinicians correctly diagnosed all 12 patients (100% sensitivity and negative predictive value). An additional eleven patients had a false-positive diagnosis of electrographic seizure (false-positive rate = 52% [31-73%]) leading to a specificity of 88% (79-94%). Median time to detect seizures was 25 minutes (5-218 min). Delayed recognition of electrographic seizure (> 1 hr from onset) occurred in five patients (5/12, 42%). Conclusions Early evaluation of quantitative electroencephalography program to detect electrographic seizure by PICU clinicians suggested good sensitivity for electrographic seizure detection. However, the high false-positive rate is a challenge. Ongoing work is needed to reduce the false positive diagnoses and avoid electrographic seizure detection delays. A comprehensive training program and regular refresher updates for clinical staff are key components of the program.

Children were relatively spared during COVID-19 pandemic. However, the recently reported hyperinflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome-"Paediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2" (PIMS-TS) has caused concern. We describe cardiac findings and short-term outcomes in children with PIMS-TS at a tertiary children's hospital. Single-center observational study of children with PIMS-TS from 10th April to 9th May 2020. Data on ECG and echocardiogram were retrospectively analyzed along with demographics, clinical features and blood parameters. Fifteen children with median age of 8.8 (IQR 6.4-11.2) years were included, all were from African/Afro-Caribbean, South Asian, Mixed or other minority ethnic groups. All showed raised inflammatory/cardiac markers (CRP, ferritin, Troponin I, CK and pro-BNP). Transient valve regurgitation was present in 10 patients (67%). Left Ventricular ejection fraction was reduced in 12 (80%), fractional shortening in 8 (53%) with resolution in all but 2. Fourteen (93%) had coronary artery abnormalities, with normalization in 6. ECG abnormalities were present in 9 (60%) which normalized in 6 by discharge. Ten (67%) needed inotropes and/or vasopressors. None needed extracorporeal life support. Improvement in cardiac biochemical markers was closely followed by improvement in ECG/echocardiogram. All patients were discharged alive and twelve (80%) have been reviewed since. Our entire cohort with PIMS-TS had cardiac involvement and this degree of involvement is significantly more than other published series and emphasizes the need for specialist cardiac review. We believe that our multi-disciplinary team approach was crucial for the good short-term outcomes.

Introduction: There is a need for a universal risk-adjustment model that may be used regardless of the indication and nature of neonatal or paediatric extracorporeal membrane oxygenation support. The ‘paediatric extracorporeal membrane oxygenation prediction’ model appeared to be a promising candidate but required external validation. Methods: We performed a validation study using institutional database of extracorporeal membrane oxygenation patients (2008-2019). We used the published paediatric extracorporeal membrane oxygenation prediction score calculator to derive estimated mortality based on the model in this cohort of patients in our institutional database. We used standardized mortality ratio, area under the receiver operating characteristic curve and Hosmer-Lemeshow goodness-of-fit test in 10 deciles to assess model performance. Results: We analysed 154 extracorporeal membrane oxygenation episodes in 150 patients. About 53% of the patients were full term (age ⩽30 days and gestation at birth ⩾37 weeks) neonates. The commonest category of extracorporeal membrane oxygenation support was cardiac (42%). The overall in-paediatric intensive care unit mortality was 37% (57/154) and the in-hospital mortality was 42% (64/154). Distribution of estimated mortality risk was similar to the derivation study. The calculated standardized mortality ratio was 0.81 based on the paediatric extracorporeal membrane oxygenation prediction model of risk-adjustment. The area under the receiver operating characteristic curve was 0.55 (0.45-0.64) and Hosmer-Lemeshow-test p value Conclusion: This small single-centre study with a small number of events was unable to validate the paediatric extracorporeal membrane oxygenation prediction-model of risk-adjustment. Although this remains the most promising of all the available models, further validation in larger data sets and/or refinement may be required before widespread use.

Background Pupillary light reflex (PLR) has traditionally been assessed using a pen torch (light). Although the terms "brisk" or "sluggish" are often used, it is unclear what characteristics of the PLR result in this description. More recently, automated infrared pupillometry has enabled us to quantify the different components of a PLR. Methods We conducted a 2-part questionnaire survey of pediatric intensive care unit (PICU) nurses. In part 1, nurses were requested to describe the key characteristics that they associate with a brisk or sluggish PLR in free-text responses. In part 2, after an introduction to pupillometry and the different components of a PLR, nurses were asked to rank the relative importance of latency (time taken for pupil to start reacting to light), percentage change (in pupil size after light stimulus), and constriction velocity (rate of constriction after light stimulus) in relation to a pupil being described as "brisk" and "sluggish. Results Fifty nurses responded. In part 1, "Quick" was the commonest term used (36% of respondents) to describe a brisk PLR, and 72% used "slow" for a sluggish PLR. Most descriptions most closely mapped to features of latency and/or constriction velocity. In part 2, latency was ranked the most important component on pupillometry for describing brisk (32%) and sluggish (34%) PLRs. Constriction velocity was ranked as the most important by 18% (brisk) and 20% (sluggish), whereas 44% (brisk) and 46% (sluggish) ranked percentage change behind the other 2 characteristics. Conclusion Latency, followed by the constriction velocity, was felt by PICU nurses to be the most important characteristic of the PLR that results in terms "brisk" or "sluggish" being used at the bedside to describe a PLR. We plan to compare these subjective opinions with objective findings from pupillometry.

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 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.

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., Graphical abstract, Genomics; Immune response; Immune system disorder; Immunology

OBJECTIVES: To determine if transfusing ABO compatible platelets has a greater effect on incremental change in platelet count as compared to ABO incompatible platelets in critically ill children.DESIGN: Secondary analysis of a prospective, observational study. Transfusions were classified as either ABO compatible, major incompatibility, or minor incompatibility. The primary outcome was the incremental change in platelet count. Transfusion reactions were analyzed as a secondary outcome.SETTING: Eighty-two PICUs in 16 countries.PATIENTS: Children (3 d to 16 yr old) were enrolled if they received a platelet transfusion during one of the predefined screening weeks.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: Five-hundred three children were enrolled and had complete ABO information for both donor and recipient, as well as laboratory data. Three-hundred forty-two (68%) received ABO-identical platelets, 133 (26%) received platelets with major incompatibility, and 28 (6%) received platelets with minor incompatibility. Age, weight, proportion with mechanical ventilation or underlying oncologic diagnosis did not differ between the groups. After adjustment for transfusion dose, there was no difference in the incremental change in platelet count between the groups; the median (interquartile range) change for ABO-identical transfusions was 28 × 10 cells/L (8-68 × 10 cells/L), for transfusions with major incompatibility 26 × 10 cells/L (7-74 × 10 cells/L), and for transfusions with minor incompatibility 54 × 10 cells/L (14-81 × 10 cells/L) (p = 0.37). No differences in count increment between the groups were noted for bleeding (p = 0.92) and nonbleeding patients (p = 0.29). There were also no differences observed between the groups for any transfusion reaction (p = 0.07).CONCLUSIONS: No differences were seen in the incremental change in platelet count nor in transfusion reactions when comparing major ABO incompatible platelet transfusions with ABO compatible transfusions in a large study of critically ill children. Studies in larger, prospectively enrolled cohorts should be performed to validate whether ABO matching for platelet transfusions in critically ill children is necessary.

Paediatric multisystem inflammatory syndrome: temporally associated with SARS-COV-2 (PIMS-TS) is a well described rare but severe COVID-19 related syndrome. PIMS-TS have been reported in children from geographical areas of high COVID-19 infection. Most children with PIMS-TS require management in an intensive care unit with variable respiratory involvement. Adults recovering from COVID-19 infection have been reported to suffer from respiratory morbidity but such outcomes are unknown in children. We present the first report of normal short term respiratory outcomes as measured by spirometry in children with SARS-COV-2 antibody positive, PIMS-TS syndrome managed at a specialist children’s hospital in the UK.

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; increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken when symptoms were resolving, identified recovery-associated immune features including CD163+ monocytes, emergence of a new population of immature neutrophils and, in some patients, a transient increase in arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL6 may be preferable to IL1 or TNF-a. We identified potential new 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. Funding Information: Birmingham Women’s and Children’s Hospital Charity funded the single cell RNA sequencing analysis. No other external funding was received. Declaration of Interests: None declared. Ethics Approval Statement: Reviewed and approved by South of Birmingham Research Ethics Committee (REC: 17/WM/0453, IRAS: 233593).

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.

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.

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.

BackgroundDuring the COVID-19 outbreak, reports have surfaced of children who present with features of a multisystem inflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome – Paediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2 pandemic (PIMS-TS). Initial reports find that many of the children are PCR-negative for SARS-CoV-2, so it is difficult to confirm whether this syndrome is a late complication of viral infection in an age group largely spared the worst consequences of this infection, or if this syndrome reflects enhanced surveillance.MethodsChildren hospitalised for symptoms consistent with PIMS-TS between 28 April and 8 May 2020, and who were PCR-negative for SARS-CoV-2, were tested for antibodies to viral spike glycoprotein using an ELISA test.ResultsEight patients (age range 7–14 years, 63% male) fulfilled case-definition for PIMS-TS during the study period. Six of the eight patients required admission to intensive care. All patients exhibited significant IgG and IgA responses to viral spike glycoprotein. Further assessment showed that the IgG isotypes detected in children with PIMS-TS were of the IgGl and lgG3 subclasses, a distribution similar to that observed in samples from hospitalised adult COVID-19 patients. In contrast, lgG2 and lgG4 were not detected in children or adults. IgM was not detected in children, which contrasts with adult hospitalised adult COVID-19 patients of whom all had positive IgM responses.ConclusionsStrong IgG antibody responses can be detected in PCR-negative children with PIMS-TS. The low detection rate of IgM in these patients is consistent with infection having occurred weeks previously and that the syndrome onset occurs well after the control of SARS-CoV-2 viral load. This implies that the disease is largely immune-mediated. Lastly, this indicates that serology can be an appropriate diagnostic tool in select patient groups.

Pupillary light reflex (PLR) has traditionally been assessed using a pen torch (light). Although the terms "brisk" or "sluggish" are often used, it is unclear what characteristics of the PLR result in this description. More recently, automated infrared pupillometry has enabled us to quantify the different components of a PLR.We conducted a 2-part questionnaire survey of pediatric intensive care unit (PICU) nurses. In part 1, nurses were requested to describe the key characteristics that they associate with a brisk or sluggish PLR in free-text responses. In part 2, after an introduction to pupillometry and the different components of a PLR, nurses were asked to rank the relative importance of latency (time taken for pupil to start reacting to light), percentage change (in pupil size after light stimulus), and constriction velocity (rate of constriction after light stimulus) in relation to a pupil being described as "brisk" and "sluggish.Fifty nurses responded. In part 1, "Quick" was the commonest term used (36% of respondents) to describe a brisk PLR, and 72% used "slow" for a sluggish PLR. Most descriptions most closely mapped to features of latency and/or constriction velocity. In part 2, latency was ranked the most important component on pupillometry for describing brisk (32%) and sluggish (34%) PLRs. Constriction velocity was ranked as the most important by 18% (brisk) and 20% (sluggish), whereas 44% (brisk) and 46% (sluggish) ranked percentage change behind the other 2 characteristics.Latency, followed by the constriction velocity, was felt by PICU nurses to be the most important characteristic of the PLR that results in terms "brisk" or "sluggish" being used at the bedside to describe a PLR. We plan to compare these subjective opinions with objective findings from pupillometry.

Background: Clinicians observed a cluster of children with unexplained inflammation requiring admission to United Kingdom (UK) paediatric intensive care units (PICUs) in April 2020. Despite multiple guidelines, which treatments are effective in Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS) is unknown. Methods: Multicentre observational study of children (

This study examines 1-year outcomes of critical care patients in the UK after COVID-19 multisystem inflammatory syndrome in children.

Objectives To describe the indications and thresholds for plasma and platelet transfusions for pediatric extracorporeal membrane oxygenation, to compare responses to these transfusions and to describe institutional protocols directing their administration. Design Subgroup analysis of two prospective, observational studies paired with survey of sites who enrolled subjects into this cohort. Setting Fifty-one PICUs in 13 countries. Patients Children (3 d to 16 yr old) were enrolled if they received a plasma or platelet transfusion while on extracorporeal membrane oxygenation during one of the predefined screening weeks. Interventions None. Measurements and main results Forty-eight children on extracorporeal membrane oxygenation received plasma transfusions and 90 received platelet transfusions. Sixty percent of plasma transfusions (29/48) and 79% of the platelet transfusions (71/90) were given for prophylaxis of bleeding. The median (interquartile range) international normalized ratio prior to transfusion, known in 75% of the patients (36/48), was 1.45 (1.20-1.85). The median (interquartile range) total platelet count prior to transfusion, known in all of the patients, was 70 × 10/L (52-90 × 10/L). The international normalized ratio and total platelet count values prior to transfusion did not vary based on bleeding versus nonbleeding indications. The median (interquartile range) reduction in international normalized ratio for mild coagulopathies (international normalized ratio ≤ 2.0) was 0.1 (0.4-0), median (interquartile range) increase in fibrinogen was 0.2 g/L (0.1-0.4 g/L) and median increase in total platelet count was 34 × 10/L (10-74 × 10/L). Through the course of their admission, children supported by extracorporeal membrane oxygenation received a total median (interquartile range) dose of 75 mL/kg (36-159 mL/kg) of plasma transfusions and 92 mL/kg (42-239 mL/kg) of platelet transfusions. Institutional protocols varied but provided guidance for platelet transfusions more commonly. Conclusions Children supported by extracorporeal membrane oxygenation receive large volumes of plasma and platelet transfusions with some institutional guidance in the form of protocols, but significant variation in practice. Interventional studies are necessary to provide evidence to direct the transfusion of hemostatic products in children supported by extracorporeal membrane oxygenation.

ObjectiveProlonged admission to a paediatric intensive care unit (PICU) consumes significant healthcare resource. An increase in the number of long-stay admissions and bed utilisation has been reported elsewhere in the world but not in the UK. If an increasing trend of long-stay admissions is evident, this may have significant implications for provision of paediatric intensive care in the future.Design/setting/patientsWe retrospectively analysed prospectively collected data from Birmingham Children’s Hospital, UK, over a 20-year period from 1998 to 2017. PICU admissions, bed-days, length of stay and mortality trends were analysed and reported over four different epochs (1998–2002, 2003–2007, 2008–2012 and 2013–2017) for long-stay admissions (PICU length of stay ≥28 days) and others. Differences in patient demographics, diagnostic categorisation and hospital utilisation were also analysed.ResultsIn total, 24 203 admissions accounted for 131 553 bed-days over the 20-year period. 705 (2.9%) long-stay admissions accounted for 42 312 (32%) bed-days. Proportion of long-stay admissions and corresponding bed-days increased from 1.6% and 20.5% in 1998–2002 to 4.5% and 42.6%, respectively, in 2013–2017 (pConclusionsA significant increase in the proportion of prolonged PICU admissions with disproportionately high resource utilisation and mortality is evident over two decades.

OBJECTIVES: Little is known about platelet transfusions in pediatric critical illness. We sought to describe the epidemiology, indications, and outcomes of platelet transfusions among critically ill children.DESIGN: Prospective cohort study.SETTING: Multicenter (82 PICUs), international (16 countries) from September 2016 to April 2017.PATIENTS: Children ages 3 days to 16 years prescribed a platelet transfusion in the ICU during screening days.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: Over 6 weeks, 16,934 patients were eligible, and 559 received at least one platelet transfusion (prevalence, 3.3%). The indications for transfusion included prophylaxis (67%), minor bleeding (21%), and major bleeding (12%). Thirty-four percent of prophylactic platelet transfusions were prescribed when the platelet count was greater than or equal to 50 × 10 cells/L. The median (interquartile range) change in platelet count post transfusion was 48 × 10 cells/L (17-82 × 10 cells/L) for major bleeding, 42 × 10 cells/L (16-80 × 10 cells/L) for prophylactic transfusions to meet a defined threshold, 38 × 10 cells/L (17-72 × 10 cells/L) for minor bleeding, and 25 × 10 cells/L (10-47 × 10 cells/L) for prophylaxis in patients at risk of bleeding from a device. Overall ICU mortality was 25% but varied from 18% to 35% based on indication for transfusion. Upon adjusted analysis, total administered platelet dose was independently associated with increased ICU mortality (odds ratio for each additional 1 mL/kg platelets transfused, 1.002; 95% CI, 1.001-1.003; p = 0.005).CONCLUSIONS: The majority of platelet transfusions are given as prophylaxis to nonbleeding children, and significant variation in platelet thresholds exists. Studies are needed to clarify appropriate indications, with focus on prophylactic transfusions.

OBJECTIVE Factors influencing the development of hyperglycemia and pattern of insulin requirement in children undergoing cardiac surgery are poorly understood. This study investigated the impact of age on the pattern of hyperglycemia and insulin requirement in children after cardiac surgery. DESIGN Cohort study, based on a prospectively collected dataset for patients enrolled into the Control of Hyperglycemia in Pediatric Intensive Care trial. SETTING A 24-bedded multidisciplinary PICU. PATIENTS Children randomized to the tight glycemic control arm (target blood glucose, 4-7 mmol/L [72-126 mg/dL]) of the Control of Hyperglycemia in Pediatric Intensive Care trial following cardiac surgery. Children were categorized into four age groups (neonate, 1-30 d; infant, 31-365 d; young child, 1-5 yr; older child, 5-16 yr) for analyses of patterns of hyperglycemia and insulin requirement over the 12-hour period following initiation of insulin. INTERVENTIONS Insulin titration was performed based on blood glucose value and rate of change of blood glucose using an algorithm developed for the Control of Hyperglycemia in Pediatric Intensive Care trial. MEASUREMENTS AND MAIN RESULTS Of 92 children, 72 children (78%) randomized to the tight glycemic control group developed hyperglycemia (blood glucose, > 7 mmol/L [126 mg/dL]) and received insulin. Older age was associated with higher blood glucose and a higher insulin dose per kilogram over the first 3 hours of the study period (p ≤ 0.02). Cumulative insulin dose was significantly higher in older children (median, 1.3 U/kg [range, 0.2-5.75]) compared with other age groups (neonate, 0.37 [0.05-2.2]; infant, 0.45 [0.05-2.2]; young child, 0.35 [0.05-0.81]) (p = 0.004). Age group, rather than body mass index, carbohydrate intake, or cardiac surgery variables, was the only variable (coefficient: 1.14 ± 0.3; p < 0.001) associated with cumulative insulin dose on multivariate analysis. CONCLUSIONS When tight glycemic control is targeted in children who have undergone cardiac surgery, children in the older child age group (5-16 yr) require insulin at significantly higher doses. Further study is needed to understand the mechanisms involved.

Unplanned extubation (UE) is an important paediatric intensive care unit (PICU) quality indicator. Studies on UE have been modest in size, with accurate UE rate calculation potentially hampered by ventilation episodes recorded in calendar days. We wished to document UE rates, outcomes, associated factors and quantify error when calendar days rather than exact timings are used. We recorded prospectively all UE episodes and potential associated factors in our 20-bed PICU for 12,533 admissions (2000–2013). Ventilation episodes were recorded to the minute, with non-invasive and tracheostomy ventilation excluded. Analysis utilised multilevel mixed-effects Poisson regression, adjusting for multiple ventilation episodes in the same patient. Overall, 243 UEs occurred within 14,141 ventilation episodes (31,564 intubated days), giving a UE rate of 0.77 (95 % CI 0.67–0.87) episodes per 100 intubated days. If calendar ventilation days were used, the yearly UE rate was underestimated by 27–35 %. UE rates decreased with time, by approximately 0.05/100 intubated days each year. Associations with UE incidence rate included patient age, source of admission, disease severity and diagnostic category, with nasal tubes decreasing the risk. Although UE versus planned extubation was associated with a higher re-intubation rate (43 versus 8 %) and longer median PICU stay (4.6 versus 2.6 days, p