An 18-year, single centre, retrospective study of long-term neurological outcomes in paediatric submersion-related cardiac arrests.

Aim: Investigate long-term outcome in paediatric submersion-related cardiac arrests (CA). Methods: Children (age one day-17 years) were included if admitted to the Erasmus MC Sophia Children's Hospital, after drowning with CA, between 2002 and 2019. Primary outcome was survival with favourable neurological outcome, defined as a Paediatric Cerebral Performance Category (PCPC) score of 1-3 at longest available follow-up. Secondary outcome were age-appropriate neuropsychological assessments at longest available follow-up. Results: Upon hospital admission, 99 children were included (median age at time of CA 3.2 years [IQR 2.0-5.9] and 65% males). Forty children died in-hospital (no return of circulation (45%) or withdrawal of life sustaining therapies (55%)) and 4 children deceased after hospital discharge due to complications following the drowning-incident. Among survivors, with a median follow-up of 2.3 years [IQR 0.2-5.5], 47 children had favourable neurological outcome (i.e. PCPC 1-3) and 8 children unfavourable (unfavourable outcome group total n = 52, i.e. PCPC 4-5 or deceased). Twenty-six (47%) children participated in a neuropsychological assessment (median follow-up 4.0 years [IQR 2.3-8.7]). Compared with normative test data, participants obtained worse general (p = 0.008) and performance (p = 0.003) intelligence scores, processing speed (p = 0.002) and visual motor integration scores (p = 0.0012). Conclusions: Although overall outcome in survivors was favourable at longest available follow-up, significant deficits in neuropsychological assessments were found. This study underlines the need for a standardized long term follow-up program as standard of care in paediatric drowning with CA.

Early brain magnetic resonance imaging findings and neurodevelopmental outcome in children with congenital heart disease: A systematic review.

AIM: To investigate the association between early brain magnetic resonance imaging (MRI) findings and neurodevelopmental outcome (NDO) in children with congenital heart disease (CHD). METHOD: A search for studies was conducted in Embase, Medline, Web of Science, Cochrane Central, PsycINFO, and Google Scholar. Observational and interventional studies were included, in which patients with CHD underwent surgery before 2 months of age, a brain MRI scan in the first year of life, and neurodevelopmental assessment beyond the age of 1 year. RESULTS: Eighteen studies were included. Thirteen found an association between either quantitative or qualitative brain metrics and NDO: 5 out of 7 studies showed decreased brain volume was significantly associated with worse NDO, as did 7 out of 10 studies on brain injury. Scanning protocols and neurodevelopmental tests varied strongly. INTERPRETATION: Reduced brain volume and brain injury in patients with CHD can be associated with impaired NDO, yet standardized scanning protocols and neurodevelopmental assessment are needed to further unravel trajectories of impaired brain development and its effects on outcome.

Withdrawal of Life-Sustaining Therapies in Children With Severe Traumatic Brain Injury.

Neuroprognostication in severe traumatic brain injury (sTBI) is challenging and occurs in critical care settings to determine withdrawal of life-sustaining therapies (WLST). However, formal pediatric sTBI neuroprognostication guidelines are lacking, brain death criteria vary, and dilemmas regarding WLST persist, which lead to institutional differences. We studied WLST practice and outcome in pediatric sTBI to provide insight into WLST-associated factors and survivor recovery trajectory ≥1 year post-sTBI. This retrospective, single center observational study included patients <18 years admitted to the pediatric intensive care unit (PICU) of Erasmus MC-Sophia (a tertiary university hospital) between 2012 and 2020 with sTBI defined as a Glasgow Coma Scale (GCS) ≤8 and requiring intracranial pressure (ICP) monitoring. Clinical, neuroimaging, and electroencephalogram data were reviewed. Multi-disciplinary follow-up included the Pediatric Cerebral Performance Category (PCPC) score, educational level, and commonly cited complaints. Seventy-eight children with sTBI were included (median age 10.5 years; interquartile range [IQR] 5.0-14.1; 56% male; 67% traffic-related accidents). Median ICP monitoring was 5 days (IQR 3-8), 19 (24%) underwent decompressive craniectomy. PICU mortality was 21% (16/78): clinical brain death (5/16), WLST due to poor neurological prognosis (WLST_neuro, 11/16). Significant differences (p < 0.001) between survivors and non-survivors: first GCS score, first pupillary reaction and first lactate, Injury Severity Score, pre-hospital cardiopulmonary resuscitation, and Rotterdam CT (computed tomography) score. WLST_neuro decision timing ranged from 0 to 31 days (median 2 days, IQR 0-5). WLST_neuro decision (n = 11) was based on neurologic examination (100%), brain imaging (100%) and refractory intracranial hypertension (5/11; 45%). WLST discussions were multi-disciplinary with 100% agreement. Immediate agreement between medical team and caregivers was 81%. The majority (42/62, 68%) of survivors were poor outcome (PCPC score 3 to 5) at PICU discharge, of which 12 (19%) in a vegetative state. One year post-injury, no patients were in a vegetative state and the median PCPC score had improved to 2 (IQR 2-3). No patients died after PICU discharge. Twenty percent of survivors could not attend school 2 years post-injury. Survivors requiring an adjusted educational level increased to 45% within this timeframe. Chronic complaints were headache, behavioral problems, and sleeping problems. In conclusion, two-thirds of sTBI PICU mortality was secondary to WLST_neuro and occurred early post-injury. Median survivor PCPC score improved from 4 to 2 with no vegetative patients 1 year post-sTBI. Our findings show the WLST decision process was multi-disciplinary and guided by specific clinical features at presentation, clinical course, and (serial) neurological diagnostic modalities, of which the testing combination was determined by case-to-case variation. This stresses the need for international guidelines to provide accurate neuroprognostication within an appropriate timeframe whereby overall survivor outcome data provides valuable context and guidance in the acute phase decision process.

Towards PErsonalised PRognosis for children with traumatic brain injury: the PEPR study protocol.

INTRODUCTION: Traumatic brain injury (TBI) in children can be associated with poor outcome in crucial functional domains, including motor, neurocognitive and behavioural functioning. However, outcome varies between patients and is mediated by complex interplay between demographic factors, premorbid functioning and (sub)acute clinical characteristics. At present, methods to understand let alone predict outcome on the basis of these variables are lacking, which contributes to unnecessary follow-up as well as undetected impairments in children. Therefore, this study aims to develop prognostic models for the individual outcome of children with TBI in a range of important developmental domains. In addition, the potential added value of advanced neuroimaging data and the use of machine learning algorithms in the development of prognostic models will be assessed. METHODS AND ANALYSIS: 210 children aged 4-18 years diagnosed with mild-to-severe TBI will be prospectively recruited from a research network of Dutch hospitals. They will be matched 2:1 to a control group of neurologically healthy children (n=105). Predictors in the model will include demographic, premorbid and clinical measures prospectively registered from the TBI hospital admission onwards as well as MRI metrics assessed at 1 month post-injury. Outcome measures of the prognostic models are (1) motor functioning, (2) intelligence, (3) behavioural functioning and (4) school performance, all assessed at 6 months post-injury. ETHICS AND DISSEMINATION: Ethics has been obtained from the Medical Ethical Board of the Amsterdam UMC (location AMC). Findings of our multicentre prospective study will enable clinicians to identify TBI children at risk and aim towards a personalised prognosis. Lastly, findings will be submitted for publication in open access, international and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL71283.018.19 and NL9051.

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.

Longitudinal two years evaluation of neuropsychological outcome in children after out of hospital cardiac arrest.

AIM: To investigate longitudinal functional and neuropsychological outcomes 3-6 and 24 months after paediatric out-of-hospital cardiac arrest (OHCA). Further, to explore the association between paediatric cerebral performance category (PCPC) and intelligence. METHODS: Prospective longitudinal single center study including children (0-17 years) with OHCA, admitted to the PICU of a tertiary care hospital between 2012 and 2017. Survivors were assessed during an outpatient multidisciplinary follow-up program 3-6 and 24 months post-OHCA. Functional and neuropsychological outcomes were assessed through interviews, neurological exam, and validated neuropsychological testing. RESULTS: The total eligible cohort consisted of 49 paediatric OHCA survivors. The most common cause of OHCA was arrhythmia (33%). Median age at time of OHCA was 48 months, 67% were males. At 3-6 and 24 months post-OHCA, respectively 74 and 73% had a good PCPC score, defined as 1-2. Compared with normative data, OHCA children obtained worse sustained attention and processing speed scores 3-6 (n = 26) and 24 (n = 27) months post-OHCA. At 24 months, they also obtained worse intelligence, selective attention and cognitive flexibility scores. In children tested at both time-points (n = 19), no significant changes in neuropsychological outcomes were found over time. Intelligence scores did not correlate with PCPC. CONCLUSION: Although paediatric OHCA survivors had a good PCPC score 3-6 and 24 months post-OHCA, they obtained worse scores on important neuropsychological domains such as intelligence and executive functioning (attention and cognitive flexibility). Follow-up should continue over a longer life span in order to fully understand the long-term impact of OHCA in childhood.

Endovascular Treatment for Acute Ischemic Stroke in Children: Experience From the MR CLEAN Registry.

BACKGROUND AND PURPOSE: Multiple trials have shown the efficacy and safety of endovascular therapy (EVT) of acute ischemic stroke in adults. Trials in children are lacking and only case reports and case series exist. However, the long-term outcome of children with acute ischemic stroke can be devastating with significant mortality and morbidity. In this study, we describe the safety and efficacy of EVT in children with anterior circulation acute ischemic stroke who were included in the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). METHODS: Patients under the age of 18 years who were treated with EVT for acute ischemic stroke between March 2014 and July 2017 were retrospectively reviewed up to 6 months after EVT. Nine children, aged 13 months to 16 years (median 14 years, interquartile range, 3-15 years), underwent EVT. Stroke cause was thromboembolism in children with end-stage heart failure on left ventricular assist device (4 of these 9 cases). Median time from onset to imaging was 133 minutes. Four children received intravenous alteplase before EVT, with median onset to needle time of 165 minutes. In all but one patient, EVT was technically successful. No major periprocedural complications occurred. RESULTS: At 24 hours after EVT, 3 children completely recovered and 4 children showed partial recovery (median National Institutes of Health Stroke Scale, 3.5), whereas 2 patients on left ventricular assist device died within the first week due to the occurrence of multiple strokes. One patient on left ventricular assist device developed a fatal massive intracranial hemorrhage and another child died due to left ventricular assist device-related complications. Among the 5 stroke survivors, all had a favorable outcome (modified Rankin Scale score, 0-2) at 6 months follow-up. CONCLUSIONS: EVT of children with acute ischemic stroke seems safe and feasible. However, these findings should be interpreted with caution as more and larger studies are needed to clarify the trade-off between risks and benefits of this treatment.

Timing and Cause of Death in Children Following Return of Circulation After Out-of-Hospital Cardiac Arrest: A Single-Center Retrospective Cohort Study.

OBJECTIVES: To determine timing and cause of death in children admitted to the PICU following return of circulation after out-of-hospital cardiac arrest. DESIGN: Retrospective observational study. SETTING: Single-center observational cohort study at the PICU of a tertiary-care hospital (Erasmus MC-Sophia, Rotterdam, The Netherlands) between 2012 and 2017. PATIENTS: Children younger than 18 years old with out-of-hospital cardiac arrest and return of circulation admitted to the PICU. MEASUREMENTS AND RESULTS: Data included general, cardiopulmonary resuscitation and postreturn of circulation characteristics. The primary outcome was defined as survival to hospital discharge. Modes of death were classified as brain death, withdrawal of life-sustaining therapies due to poor neurologic prognosis, withdrawal of life-sustaining therapies due to refractory circulatory and/or respiratory failure, and recurrent cardiac arrest without return of circulation. One hundred thirteen children with out-of-hospital cardiac arrest were admitted to the PICU following return of circulation (median age 53 months, 64% male, most common cause of out-of-hospital cardiac arrest drowning [21%]). In these 113 children, there was 44% survival to hospital discharge and 56% nonsurvival to hospital discharge (brain death 29%, withdrawal of life-sustaining therapies due to poor neurologic prognosis 67%, withdrawal of life-sustaining therapies due to refractory circulatory and/or respiratory failure 2%, and recurrent cardiac arrest 2%). Compared with nonsurvivors, more survivors had witnessed arrest (p = 0.007), initial shockable rhythm (p < 0.001), shorter cardiopulmonary resuscitation duration (p < 0.001), and more favorable clinical neurologic examination within 24 hours after admission. Basic cardiopulmonary resuscitation event and postreturn of circulation (except for the number of extracorporeal membrane oxygenation) characteristics did not significantly differ between the withdrawal of life-sustaining therapies due to poor neurologic prognosis and brain death patients. Timing of decision-making to withdrawal of life-sustaining therapies due to poor neurologic prognosis ranged from 0 to 18 days (median: 0 d; interquartile range, 0-3) after cardiopulmonary resuscitation. The decision to withdrawal of life-sustaining therapies was based on neurologic examination (100%), electroencephalography (44%), and/or brain imaging (35%). CONCLUSIONS: More than half of children who achieve return of circulation after out-of-hospital cardiac arrest died after PICU admission. Of these deaths, two thirds (67%) underwent withdrawal of life-sustaining therapies based on an expected poor neurologic prognosis and did so early after return of circulation. There is a need for international guidelines for accurate neuroprognostication in children after cardiac arrest.

Atypical neuroimaging characteristics of hemophagocytic lymphohistiocytosis in infants: a case series of hemorrhagic brain lesions in the deep grey matter.

Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem condition associated with uncontrolled overproduction and infiltration of lymphocytes and histiocytes predominantly in liver, lymph nodes, spleen, and central nervous system. Neuroimaging findings on MRI are fairly nonspecific and classically include periventricular white matter signal abnormalities and diffuse atrophy. Focal parenchymal lesions may demonstrate post contrast ring or nodular enhancement and calcification. However, the MR imaging characteristics can be highly variable. Here, we present two cases of HLH in infants with multiple hemorrhagic lesions mostly depicted in both thalami and basal ganglia regions. Thalamic, basal ganglia, and brain stem involvement with hemorrhagic changes in HLH are rarely described in literature. Early diagnosis of HLH may be lifesaving. Awareness of the disease is necessary to investigate its characteristic findings and avoiding a delay in diagnosis.

The current practice regarding neuro-prognostication for comatose children after cardiac arrest differs between and within European PICUs: A survey.

PURPOSE: To describe current practices in European Paediatric Intensive Care Units (PICUs) regarding neuro-prognostication in comatose children after cardiac arrest (CA). METHODS: An anonymous online survey was conducted among members of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) and the European Paediatric Neurology Society (EPNS) throughout January and February 2019. The survey consisted of 49 questions divided into 4 sections: general information, cardiac arrest, neuro-prognostication and follow-up. RESULTS: The survey was sent to 1310 EPNS and 611 ESPNIC members. Of the 108 respondents, 71 (66%) (23 countries, 45 PICUs) completed the "neuro-prognostication" section. Eight PICUs (20%) had a local neuro-prognostication guideline. The 3 methods considered as most useful were neurological examination (92%), magnetic resonance imaging (MRI) (82%) and continuous electroencephalography (cEEG) (45%). In 50% a Pediatric Cerebral Performance Category (PCPC) score ≥ 4 was considered as poor neurological outcome. In 63% timing of determining neurological prognosis was based on the individual patient. Once decided that neurological prognosis was futile, 55% indicated that withdrawing life-sustaining therapy (WLST) was (one of) the options, whereas 44% continued PICU treatment (with or without restrictions). In 28 PICUs (68%) CA-survivors were scheduled for follow-up visits. CONCLUSION: Local guidelines for neuro-prognostication in comatose children after CA are uncommon. Methods to assess neurological outcome were mainly neurological examination, MRI and cEEG. Consequences of poor outcome differed between respondents. Inaccuracies in neuro-prognostication can result in premature WLST, thereby biasing outcome research and creating a self-fulfilling cycle. Further research is needed to develop scientifically based international guidelines for neuro-prognostication in comatose children after CA.

A Systematic Review of Neuromonitoring Modalities in Children Beyond Neonatal Period After Cardiac Arrest.

OBJECTIVES: Postresuscitation care in children focuses on preventing secondary neurologic injury and attempts to provide (precise) prognostication for both caregivers and the medical team. This systematic review provides an overview of neuromonitoring modalities and their potential role in neuroprognostication in postcardiac arrest children. DATA RESOURCES: Databases EMBASE, Web of Science, Cochrane, MEDLINE Ovid, Google Scholar, and PsycINFO Ovid were searched in February 2019. STUDY SELECTION: Enrollment of children after in- and out-of-hospital cardiac arrest between 1 month and 18 years and presence of a neuromonitoring method obtained within the first 2 weeks post cardiac arrest. Two reviewers independently selected appropriate studies based on the citations. DATA EXTRACTION: Data collected included study characteristics and methodologic quality, populations enrolled, neuromonitoring modalities, outcome, and limitations. Evidence tables per neuromonitoring method were constructed using a standardized data extraction form. Each included study was graded according to the Oxford Evidence-Based Medicine scoring system. DATA SYNTHESIS: Of 1,195 citations, 27 studies met the inclusion criteria. There were 16 retrospective studies, nine observational prospective studies, one observational exploratory study, and one pilot randomized controlled trial. Neuromonitoring methods included neurologic examination, routine electroencephalography and continuous electroencephalography, transcranial Doppler, MRI, head CT, plasma biomarkers, somatosensory evoked potentials, and brainstem auditory evoked potential. All evidence was graded 2B-2C. CONCLUSIONS: The appropriate application and precise interpretation of available modalities still need to be determined in relation to the individual patient. International collaboration in standardized data collection during the (acute) clinical course together with detailed long-term outcome measurements (including functional outcome, neuropsychologic assessment, and health-related quality of life) are the first steps toward more precise, patient-specific neuroprognostication after pediatric cardiac arrest.

Towards integrative neuromonitoring of the surgical newborn: A systematic review.

BACKGROUND: The altered neurodevelopment of children operated on during the neonatal period might be due to peri-operative changes in the homeostasis of brain perfusion. Monitoring of vital signs is a standard of care, but it does not usually include monitoring of the brain. OBJECTIVES: To evaluate methods of monitoring the brain that might be of value. We also wanted to clarify if there are specific risk factors that result in peri-operative changes and how this might be evaluated. DESIGN: Systematic review. DATA SOURCES: A structured literature search was performed in MEDLINE in Ovid, Embase, Cochrane CENTRAL, Web of Science and Google Scholar. ELIGIBILITY CRITERIA: Studies in neonates who received peri-operative neuromonitoring were eligible for inclusion; studies on neurosurgical procedures or cardiac surgery with cardiopulmonary bypass and/or deep hypothermia cardiac arrest were excluded. RESULTS: Nineteen of the 24 included studies, totalling 374 infants, reported the use of near-infrared spectroscopy. Baseline values of cerebral oxygenation greatly varied (mean 53 to 91%) and consequently, no coherent results were found. Two studies found a correlation between cerebral oxygenation and mean arterial blood pressure. Five studies, with in total 388 infants, used (amplitude-integrated) electro-encephalography to study peri-operative brain activity. Overall, the brain activity decreased during anaesthesia and epileptic activity was more frequent in the peri-operative phase. The association between intra-operative cerebral saturation or activity and neuro-imaging abnormalities and/or neurodevelopmental outcome was investigated in six studies, but no association was found. CONCLUSION: Neuromonitoring with the techniques currently used will neither help our understanding of the altered neonatal pathophysiology, nor enable early detection of deviation from the norm. The modalities lack specificity and are not related to clinical (long-term) outcome or prognosis. Accordingly, we were unable to draw up a monitoring guideline.

Analgesics and Sedatives in Critically Ill Newborns and Infants: The Impact on Long-Term Neurodevelopment.

Inadequate pain and/or stress management in preterm- and term-born infants has been associated with increased morbidity and even mortality. However, exposure to analgosedatives during early infancy may also be one of the risk factors for subsequent neurodevelopmental impairment, at least in animal studies. Because infants admitted to neonatal or pediatric intensive care units may receive high amounts of these drugs for prolonged periods of time and the majority of these infants nowadays survive to discharge, this is of major concern. A balanced approach that incorporates the assessment and quantification of both wanted effects as well as unwanted side effects is therefore needed. In this article, the optimal dose determination of commonly used analgosedative drugs as well as their potential long-term effects on the developing human brain and neuropsychological functioning are reviewed.

Improving Long-Term Outcomes After Extracorporeal Membrane Oxygenation: From Observational Follow-Up Programs Toward Risk Stratification.

Since the introduction of extracorporeal membrane oxygenation (ECMO), more neonates and children with cardiorespiratory failure survive. Interest has therefore shifted from reduction of mortality toward evaluation of long-term outcomes and prevention of morbidity. This review addresses the changes in ECMO population and the ECMO-treatment that may affect long-term outcomes, the diagnostic modalities to evaluate neurological morbidities and their contributions to prognostication of long-term outcomes. Most follow-up data have only become available from observational follow-up programs in neonatal ECMO-survivors. The main topics are discussed in this review. Recommendations for long-term follow up depend on the presence of neurological comorbidity, the nature and extent of the underlying disease, and the indication for ECMO. Follow up should preferably be offered as standard of care, and in an interdisciplinary, structured and standardized way. This permits evaluation of outcome data and effect of interventions. We propose a standardized approach and recommend that multiple domains should be evaluated during long-term follow up of neonates and children who needed extracorporeal life support.

Fatal Subarachnoid Hemorrhage from an Aneurysm of a Persistent Primitive Hypoglossal Artery: Case Series and Literature Overview.

BACKGROUND: Persistent carotid-basilar connections have a prevalence of 0.14%. Recognizing such persistent fetal anastomoses between the carotid and the vertebrobasilar circulation is of great importance because they are reportedly associated with an increased prevalence of intracranial aneurysms. METHODS: We report the case of a 15-year-old female patient who presented with a World Federation of Neurosurgical Societies grade 5 subarachnoid hemorrhage from an aneurysm at the junction of a persistent primitive hypoglossal artery and the posterior inferior cerebellar artery origin. Supratentorially, unfortunately, there was no parenchymal blush or cortical venous return. Eventually, a multidisciplinary decision was made to withdraw care. RESULTS: Fifty-seven cases were reported in the literature to date of persistent hypoglossal arteries, 16 of which presented with an associated aneurysm, 5 with an arteriovenous malformation, and 6 with a subarachnoid hemorrhage. Our case is the youngest patient reported so far. Hypoplasia or aplasia of the vertebral artery often were encountered (36 and 13 cases, respectively), as well as carotid artery stenosis (15 cases). CONCLUSIONS: Although uncommon, it is important to recognize persistent carotid-basilar connections, since they have a considerable hemodynamic impact on the posterior cerebral circulation via the carotid system. A critical reduction in the carotid blood flow will, therefore, have ischemic consequences in the posterior cerebral territories. In addition, such connections might be associated with anomalies of the vessel wall and be predisposed to aneurysm formation. The endovascular neurointerventionalist, as well as the vascular and skull base neurosurgeon, need to be aware of their anatomy and variations.