Risk Factors of Impaired Neuropsychologic Outcome in School-Aged Survivors of Neonatal Critical Illness.

OBJECTIVE: Until now, long-term outcome studies have focused on general cognitive functioning and its risk factors following neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia. However, it is currently unknown which neuropsychological domains are most affected in these patients and which clinical variables can be used to predict specific neuropsychological problems. This study aimed to identify affected neuropsychological domains and its clinical determinants in survivors of neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia. DESIGN: Prospective follow-up study. SETTING: Tertiary university hospital. PATIENTS: Sixty-five 8-year-old survivors of neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Intelligence, attention, memory, executive functioning and visuospatial processing were evaluated using validated tests and compared with Dutch reference data. Assessed risk factors of outcome were illness severity indicators, number of anesthetic procedures in the first year of life, and growth at 1 year. Patients had average intelligence (mean intelligence quotient ± SD, 95 ± 16), but significantly poorer sustained attention (mean z score ± SD, -2.73 ± 2.57), verbal (immediate, -1.09 ± 1.27; delayed, -1.14 ± 1.86), and visuospatial memory (immediate, -1.48 ± 1.02; delayed, -1.57 ± 1.01; recognition, -1.07 ± 3.10) than the norm. Extracorporeal membrane oxygenation-treated congenital diaphragmatic hernia patients had significantly lower mean intelligence quotient (84 ± 12) than other neonatal extracorporeal membrane oxygenation patients (94 ± 10) and congenital diaphragmatic hernia patients not treated with extracorporeal membrane oxygenation (100 ± 20). Maximum vasoactive-inotropic score was negatively associated with delayed verbal (B = -0.02; 95% CI, -0.03 to -0.002; p = 0.026) and visuospatial memory (B = -0.01; 95% CI, -0.02 to -0.001; p = 0.024). CONCLUSIONS: We found memory and attention deficits in 8-year-old neonatal extracorporeal membrane oxygenation and congenital diaphragmatic hernia survivors. The maximum dose of vasoactive medication was negatively associated with verbal and visuospatial memory, which may suggest an effect of early cerebral hypoperfusion in determining these abnormalities.

Working Memory Training Following Neonatal Critical Illness: A Randomized Controlled Trial.

OBJECTIVES: To test the immediate and long-term effectiveness of Cogmed Working Memory Training following extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia. DESIGN: A nationwide randomized controlled trial assessing neuropsychologic outcome immediately and 1 year post Cogmed Working Memory Training, conducted between October 2014 and June 2017. Researchers involved in the follow-up assessments were blinded to group allocation. SETTING: Erasmus MC-Sophia Children's Hospital, Rotterdam, and Radboud University Medical Center, Nijmegen, the Netherlands. PATIENTS: Eligible participants were neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia survivors (8-12 yr) with an intelligence quotient greater than or equal to 80 and a z score less than or equal to -1.5 on at least one (working) memory test at first assessment. INTERVENTIONS: Cogmed Working Memory Training, comprising 25 45-minute training sessions for 5 consecutive weeks at home. MEASUREMENTS AND MAIN RESULTS: Participants were randomized to Cogmed Working Memory Training (n = 19) or no intervention (n = 24) (two dropped out after T0). Verbal working memory (estimated coefficient = 0.87; p = 0.002) and visuospatial working memory (estimated coefficient=0.96, p = 0.003) significantly improved at T1 post Cogmed Working Memory Training but was similar between groups at T2 (verbal, p = 0.902; visuospatial, p = 0.416). Improvements were found at T2 on long-term visuospatial memory following Cogmed Working Memory Training (estimated coefficient = 0.95; p = 0.003). Greater improvements in this domain at T2 following Cogmed Working Memory Training were associated with better self-rated school functioning (r = 0.541; p = 0.031) and parent-rated attention (r = 0.672; p = 0.006). CONCLUSIONS: Working memory improvements after Cogmed Working Memory Training disappeared 1 year post training in neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia survivors. Gains in visuospatial memory persisted 1 year post intervention. Cogmed Working Memory Training may be beneficial for survivors with visuospatial memory deficits.

Neurobiologic Correlates of Attention and Memory Deficits Following Critical Illness in Early Life.

OBJECTIVES: Survivors of critical illness in early life are at risk of long-term-memory and attention impairments. However, their neurobiologic substrates remain largely unknown. DESIGN: A prospective follow-up study. SETTING: Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands. PATIENTS: Thirty-eight school-age (8-12 yr) survivors of neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia with an intelligence quotient greater than or equal to 80 and a below average score (z score ≤ -1.5) on one or more memory tests. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Intelligence, attention, memory, executive functioning, and visuospatial processing were assessed and compared with reference data. White matter microstructure and hippocampal volume were assessed using diffusion tensor imaging and structural MRI, respectively. Global fractional anisotropy was positively associated with selective attention (ß = 0.53; p = 0.030) and sustained attention (ß = 0.48; p = 0.018). Mean diffusivity in the left parahippocampal region of the cingulum was negatively associated with visuospatial memory, both immediate (ß = -0.48; p = 0.030) and delayed recall (ß = -0.47; p = 0.030). Mean diffusivity in the parahippocampal region of the cingulum was negatively associated with verbal memory delayed recall (left: ß = -0.52, p = 0.021; right: ß = -0.52, p = 0.021). Hippocampal volume was positively associated with verbal memory delayed recall (left: ß = 0.44, p = 0.037; right: ß = 0.67, p = 0.012). Extracorporeal membrane oxygenation treatment or extracorporeal membrane oxygenation type did not influence the structure-function relationships. CONCLUSIONS: Our findings indicate specific neurobiologic correlates of attention and memory deficits in school-age survivors of neonatal extracorporeal membrane oxygenation and congenital diaphragmatic hernia. A better understanding of the neurobiology following critical illness, both in early and in adult life, may lead to earlier identification of patients at risk for impaired neuropsychological outcome with the use of neurobiologic markers.

Neonatal critical illness and development: white matter and hippocampus alterations in school-age neonatal extracorporeal membrane oxygenation survivors.

AIM: To examine the neurobiology of long-term neuropsychological deficits after neonatal extracorporeal membrane oxygenation (ECMO). METHOD: This cross-sectional study assessed white matter integrity and hippocampal volume of ECMO survivors (8-15y) and healthy children (8-17y) using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (MRI) respectively. Neuropsychological outcome was evaluated in ECMO survivors. Included clinical predictors of white matter integrity: age start ECMO, ECMO duration, highest oxygenation index before ECMO, highest mean airway pressure, and mechanical ventilation duration. RESULTS: ECMO survivors (n=23) had lower global fractional anisotropy than healthy children (n=54) (patients=0.368; comparison group=0.381; p=0.018), but similar global mean diffusivity (p=0.410). ECMO survivors had lower fractional anisotropy in the left cingulum bundle (ECMO survivors=0.345; comparison group=0.399; p<0.001) and higher mean diffusivity in a region of the left parahippocampal cingulum (patients=0.916; comparison group=0.871; p<0.001). Higher global mean diffusivity predicted worse verbal memory in ECMO survivors (n=17) (ß=-0.74, p=0.008). ECMO survivors (n=23) had smaller bilateral hippocampal volume than healthy children (n=43) (left, p<0.001; right, p<0.001) and this was related to worse verbal memory (left, ß=0.65, p=0.018; right, ß=0.71, p=0.006). INTERPRETATION: Neonatal ECMO survivors are at risk for long-term brain alterations, which may partly explain long-term neuropsychological impairments. Neuroimaging may contribute to better risk stratification of long-term impairments.

Growing Up After Critical Illness: Verbal, Visual-Spatial, and Working Memory Problems in Neonatal Extracorporeal Membrane Oxygenation Survivors.

OBJECTIVES: To assess neuropsychologic outcome in 17- and 18-year-old neonatal extracorporeal membrane oxygenation survivors. DESIGN: A prospective longitudinal follow-up study. SETTING: Follow-up program at the Erasmus MC-Sophia Children's Hospital in Rotterdam, The Netherlands. PATIENTS: Thirty adolescents 17 or 18 years old, treated between 1991 and 1997, underwent neuropsychologic assessment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Attention, memory, executive functioning, visual-spatial functions, social-emotional functioning, and behavior were assessed with validated instruments, and data were compared with reference data. Included predictors for analysis of adverse outcome were diagnosis, age at start extracorporeal membrane oxygenation, convulsions, and use of antiepileptics. Adolescents' performance (expressed as mean [SD] z score) was significantly lower than the norm on short-term and long-term verbal memory (z score = -1.40 [1.58], p = 0.016; z score = -1.54 [1.67], p = 0.010, respectively), visual-spatial memory (z score = -1.65 [1.37], p = 0.008; z score = -1.70 [1.23], p = 0.008, respectively), and working memory (32% vs 9% in the norm population). Parents reported more problems for their children regarding organization of materials (z score = -0.60 [0.90]; p = 0.03) and behavior evaluation (z score = -0.53 [0.88]; p = 0.05) on a questionnaire. Patients reported more withdrawn/depressed behavior (z score = -0.47 [0.54]; p = 0.02), somatic complaints (z score = -0.43 [0.48]; p = 0.03), and social problems (z score = -0.41 [0.46]; p = 0.04). Patients reported more positive feelings of self-esteem and an average health status. CONCLUSIONS: Adolescents treated with neonatal extracorporeal membrane oxygenation are at risk of verbal, visual-spatial, and working memory problems. Future research should focus on 1) the longitudinal outcome of specific neuropsychologic skills in adolescence and adulthood; 2) identifying risk factors of neuropsychologic dysfunction; 3) evaluating to what extent "severity of illness" is responsible for acquired brain injury; and 4) effects of timely cognitive rehabilitation.

Extracorporeal Life Support Organization (ELSO) Guidelines for Follow-up After Neonatal and Pediatric Extracorporeal Membrane Oxygenation.

Neonates and children who have survived critical illness severe enough to require extracorporeal membrane oxygenation (ECMO) are at risk for neurologic insults, neurodevelopmental delays, worsening of underlying medical conditions, and development of new medical comorbidities. Structured neurodevelopmental follow-up is recommended for early identification and prompt interventions of any neurodevelopmental delays. Even children who initially survive this critical illness without new medical or neurologic deficits remain at risk of developing new morbidities/delays at least through adolescence, highlighting the importance of structured follow-up by personnel knowledgeable in the sequelae of critical illness and ECMO. Structured follow-up should be multifaceted, beginning predischarge and continuing as a coordinated effort after discharge through adolescence. Predischarge efforts should consist of medical and neurologic evaluations, family education, and co-ordination of long-term ECMO care. After discharge, programs should recommend a compilation of pediatric care, disease-specific care for underlying or acquired conditions, structured ECMO/neurodevelopmental care including school performance, parental education, and support. Institutionally, regionally, and internationally available resources will impact the design of individual center's follow-up program. Additionally, neurodevelopmental testing will need to be culturally and lingually appropriate for centers' populations. Thus, ECMO centers should adapt follow-up program to their specific populations and resources with the predischarge and postdischarge components described here.

Neurocognitive Outcome After Treatment With(out) ECMO for Neonatal Critical Respiratory or Cardiac Failure.

Over the years, it has become clear that children growing up after neonatal critical illness are at high risk of long-term neurocognitive deficits that impact their school performance and daily life activities. Although the pathophysiological mechanisms remain largely unknown, emerging evidence seems to suggest that long-term neuropsychological deficits following neonatal critical illness are not associated with the type of treatment, such as extracorporeal membrane oxygenation (ECMO), but rather with underlying disease processes. In this review, neurocognitive outcome and brain pathology following neonatal critical respiratory and cardiac illness, either treated with or without ECMO, are described and compared in order to gain insight into potential underlying pathophysiological mechanisms. Putting these findings together, it becomes apparent that both children with complex congenital heart disease and children who survived severe respiratory failure are at risk of neurocognitive deficits later in life. Neurorehabilitation strategies, such as Cogmed working-memory training, are discussed. While prevention of neurocognitive deficits altogether should be strived for in the future, this is not realistic at this moment. It is therefore of great importance that children growing up after neonatal critical illness receive long-term care that includes psychoeducation and personalized practical tools that can be used to improve their daily life activities.

Training-induced white matter microstructure changes in survivors of neonatal critical illness: A randomized controlled trial.

In a nationwide randomized controlled trial, white matter microstructure was assessed before and immediately after Cogmed Working-Memory Training (CWMT) in school-age neonatal critical illness survivors. Eligible participants were survivors (8-12 years) with an IQ ≥ 80 and a z-score of ≤ -1.5 on (working)memory test at first assessment. Diffusion Tensor Imaging was used to assess white matter microstructure. Associations between any training-induced changes and improved neuropsychological outcome immediately and one year post-CWMT were evaluated as well. The trial was conducted between October 2014-June 2017 at Erasmus MC-Sophia, Rotterdam, Netherlands. Researchers involved were blinded to group allocation. Participants were randomized to CWMT(n = 14) or no-intervention(n = 20). All children completed the CWMT. Global fractional anisotropy(FA) increased significantly post-CWMT compared to no-intervention(estimated-coefficient = .007, p = .015). Increased FA(estimated coefficient = .009, p = .033) and decreased mean diffusivity(estimated-coefficient = -.010, p = .018) were found in the left superior longitudinal fasciculus(SFL) post-CWMT compared no-intervention. Children after CWMT who improved with >1SD on verbal working-memory had significantly higher FA in the left SLF post-CWMT(n = 6; improvement = .408 ±â€¯.01) than children without this improvement post-CWMT(n = 6; no-improvement = .384 ±â€¯.02), F(1,12) = 6.22, p = .041, ηp2 = .47. No other structure-function relationships were found post-CWMT. Our findings demonstrate that white matter microstructure and associated cognitive outcomes are malleable by CWMT in survivors of neonatal critical illness.

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.

Neuropsychological Follow-up After Neonatal ECMO.

OBJECTIVE: To assess the longitudinal development of intelligence and its relation to school performance in a nationwide cohort of neonatal extracorporeal membrane oxygenation (ECMO) survivors and evaluate predictors of outcome at 8 years of age. METHODS: Repeated measurements assessed intelligence of neonatal ECMO survivors at 2, 5, and 8 years (n = 178) with the use of validated, standardized instruments. Selective attention (n = 148) and type of education were evaluated in the 8-year-olds. RESULTS: Intelligence remained stable and average across development (mean ± SD IQ: at 2 years, 102 ± 18; at 5 years, 100 ± 17; and at 8 years, 99 ± 17 [P = .15]). Children attending regular education without the need for help (n = 101; mean z score: -1.50 ± 1.93) performed significantly better on the selective attention task compared with those children who needed extra help (n = 65; mean z score: -2.54 ± 3.18) or those attending special education (n = 13; mean z score: -4.14 ± 3.63) (P = .03). However, only children attending special education had below-average intelligence (mean IQ: 76 ± 15), compared with average intelligence for those attending regular education, both with help (mean IQ: 95 ± 15) and without help (mean IQ: 105 ± 16). Compared with children with other diagnoses, children with congenital diaphragmatic hernia (CDH) scored significantly lower on both IQ (CDH, mean IQ: 93 ± 20; meconium aspiration syndrome, mean IQ: 100 ± 15; other diagnoses, mean IQ: 100 ± 19 [P = .04]) and selective attention (CDH, mean z score: -3.48 ± 3.46; meconium aspiration syndrome, mean z score: -1.60 ± 2.13; other diagnoses, mean z score: -1.65 ± 2.39 [P = .002]). CONCLUSIONS: For the majority of neonatal ECMO survivors, intelligence testing alone did not identify those at risk for academic problems. We propose internationally standardized follow-up protocols that focus on long-term, problem-oriented neuropsychological assessment.