Saskia J. Gischler

Acute kidney injury is a frequent complication in critically ill neonates receiving extracorporeal membrane oxygenation: a 14-year cohort study

IntroductionNewborns in need of extracorporeal membrane oxygenation (ECMO) support are at high risk of developing acute kidney injury (AKI). AKI may occur as part of multiple organ failure and can be aggravated by exposure to components of the extracorporeal circuit. AKI necessitates adjustment of dosage of renally eliminated drugs and avoidance of nephrotoxic drugs. We aimed to define systematically the incidence and clinical course of AKI in critically ill neonates receiving ECMO support.MethodsThis study reviewed prospectively collected clinical data (including age, diagnosis, ECMO course, and serum creatinine (SCr)) of all ECMO-treated neonates within our institution spanning a 14-year period. AKI was defined by using the Risk, Injury, Failure, Loss of renal function, and End-stage renal disease (RIFLE) classification. SCr data were reviewed per ECMO day and compared with age-specific SCr reference values. Accordingly, patients were assigned to RIFLE categories (Risk, Injury, or Failure as 150%, 200%, or 300% of median SCr reference values). Data are presented as median and interquartile range (IQR) or number and percentage.ResultsOf 242 patients included, 179 (74%) survived. Median age at the start of ECMO was 39 hours (IQR, 26 to 63); median ECMO duration was 5.8 days (IQR, 3.9 to 9.4). In total, 153 (64%) patients had evidence of AKI, with 72 (30%) qualifying as Risk, 55 (23%) as Injury, and 26 (11%) as Failure. At the end of the study period, only 71 (46%) patients of all 153 AKI patients improved by at least one RIFLE category. With regression analysis, it was found that nitric oxide ventilation (P = 0.04) and younger age at the start of ECMO (P = 0.004) were significant predictors of AKI. Survival until intensive care unit discharge was significantly lower for patients in the Failure category (35%) as compared with the Non-AKI (78%), Risk (82%), and Injury category (76%), with all P < 0.001, whereas no significant differences were found between the three latter RIFLE categories.ConclusionsTwo thirds of neonates receiving ECMO had AKI, with a significantly increased mortality risk for patients in the Failure category. As AKI during childhood may predispose to chronic kidney disease in adulthood, long-term monitoring of kidney function after ECMO is warranted.

Follow-up of newborns treated with extracorporeal membrane oxygenation: a nationwide evaluation at 5 years of age

IntroductionExtracorporeal membrane oxygenation (ECMO) is a supportive cardiopulmonary bypass technique for babies with acute reversible cardiorespiratory failure. We assessed morbidity in ECMO survivors at the age of five years, when they start primary school and major decisions for their school careers must be made.MethodsFive-year-old neonatal venoarterial-ECMO survivors from the two designated ECMO centres in The Netherlands (Erasmus MC – Sophia Childrens Hospital in Rotterdam, and University Medical Center Nijmegen) were assessed within the framework of an extensive follow-up programme. The protocol included medical assessment, neuromotor assessment, and psychological assessment by means of parent and teacher questionnaires.ResultsSeventeen of the 98 children included in the analysis (17%) were found to have neurological deficits. Six of those 17 (6% of the total) showed major disability. Two of those six children had a chromosomal abnormality. Three were mentally retarded and profoundly impaired. The sixth child had a right-sided hemiplegia. These six children did not undergo neuromotor assessment. Twenty-four of the remaining 92 children (26%) showed motor difficulties: 15% actually had a motor problem and 11% were at risk for this. Cognitive delay was identified in 11 children (14%). The mean IQ score was within the normal range (IQ = 100.5).ConclusionNeonatal ECMO in The Netherlands was found to be associated with considerable morbidity at five years of age. It appeared feasible to have as many as 87% of survivors participate in follow-up assessment, due to cooperation between two centres and small travelling distances. Objective evaluation of the long-term morbidity associated with the application of this highly invasive technology in the immediate neonatal period requires an interdisciplinary follow-up programme with nationwide consensus on timing and actual testing protocol.

Motor performance in five-year-old extracorporeal membrane oxygenation survivors: A population-based study

IntroductionVeno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a cardio-pulmonary bypass technique to provide life support in acute reversible cardio-respiratory failure when conventional management is not successful. Most neonates receiving ECMO suffer from meconium aspiration syndrome (MAS), congenital diaphragmatic hernia (CDH), sepsis or persistent pulmonary hypertension (PPH). In five-year-old children who underwent VA-ECMO therapy as neonates, we assessed motor performance related to growth, intelligence and behaviour, and the association with the primary diagnosis.MethodsIn a prospective population-based study (n = 224) 174 five-year-old survivors born between 1993 and 2000 and treated in the two designated ECMO centres in the Netherlands (Radboud University Medical Centre Nijmegen and Sophia Childrens Hospital, Erasmus MC – University Medical Center Rotterdam) were invited to undergo follow-up assessment including a paediatric assessment, the movement assessment battery for children (MABC), the revised Amsterdam intelligence test (RAKIT) and the child behaviour checklist (CBCL).ResultsTwenty-two percent of the children died before the age of five, 86% (n = 149) of the survivors were assessed. Normal development in all domains was found in 49% of children. Severe disabilities were present in 13%, and another 9% had impaired motor development combined with cognitive and/or behavioural problems. Chi-squared tests showed adverse outcome in MABC scores (P < 0.001) compared with the reference population in children with CDH, sepsis and PPH, but not in children with MAS. Compared with the Dutch population height, body mass index (BMI) and weight for height were lower in the CDH group (P < 0.001). RAKIT and CBCL scores did not differ from the reference population. Total MABC scores, socio-economic status, growth and CBCL scores were not related to each other, but negative motor outcome was related to lower intelligence quotient (IQ) scores (r = 0.48, P < 0.001).ConclusionsThe ECMO population is highly at risk for developmental problems, most prominently in the motor domain. Adverse outcome differs between the primary diagnosis groups. Objective evaluation of long-term developmental problems associated with this highly invasive technology is necessary to determine best evidence-based practice. The ideal follow-up programme requires an interdisciplinary team, the use of normal-referenced tests and an international consensus on timing and actual outcome measurements.

Congenital diaphragmatic hernia with(out) ECMO: impaired development at 8 years.

Objective To evaluate developmental and social-emotional outcomes at 8 years of age for children with congenital diaphragmatic hernia (CDH), treated with or without neonatal extracorporeal membrane oxygenation (ECMO) between January 1999 and December 2003. Design Cohort study with structural prospective follow-up. Setting Level III University Hospital. Patients 35 children (ECMO: n=16; non-ECMO: n=19) were assessed at 8 years of age. Interventions None. Main outcome measures Intelligence and motor function. Concentration, behaviour, school performance, competence and health status were also analysed. Results Mean (SD) intelligence for the ECMO group was 91.7 (19.5) versus 111.6 (20.9) for the non-ECMO group (p=0.015). Motor problems were apparent in 16% of all participants and differed significantly from the norm (p=0.015) without differences between treatment groups. For all participants, problems with concentration (68%, p<0.001) and with behavioural attention (33%, p=0.021) occurred more frequently than in reference groups, with no difference between treatment groups. School performance and competence were not affected. Conclusions Children with CDH—whether or not treated with neonatal ECMO—are at risk for long-term morbidity especially in the areas of motor function and concentration. Despite their impairment, children with CDH have a well-developed feeling of self-competence.

Neonatal extracorporeal membrane oxygenation: impaired health at 5 years of age.

Objective: Children treated with neonatal extracorporeal membrane oxygenation may show physical and mental morbidity at a later age. We compared the health-related quality of life of these children with normative data. Design: Prospective longitudinal follow-up study. Setting: Outpatient clinic of a level III university hospital. Patients: Ninety-five 5-yr-old children who had received neonatal extracorporeal membrane oxygenation support between January 1999 and December 2005. Interventions: None. Measurements and Main Results: The pediatric quality of life inventory was administered at 5 yrs of age. The mothers (n = 74) as proxy-reporters assigned significantly lower health-related quality of life scores for their children than did the parents in the healthy reference group for the total functioning scale of the pediatric quality of life inventory (mean difference: 8.1; p < 0.001). Mothers’ scores for 31 children (42%) were indicative of impaired health-related quality of life (≥−1 SD below the reference norm). The children (n = 78) themselves scored significantly lower than did their healthy peers on total functioning (mean difference: 11.0; p < 0.001). Thirty-two children (41%) indicated an impaired health-related quality of life themselves. For the mother proxy- reports, the duration of extracorporeal membrane oxygenation support (R2 = 0.009; p = 0.010) and the presence of chronic lung disease (R2 = 0.133; p = 0.002) were negatively related to total functioning. Children with a disabled health status for neuromotor functioning, maximum exercise capacity, behavior, and cognitive functioning at 5 yrs of age had a higher odds ratio of also having a lower health-related quality of life. Health status had no influence on reported emotional functioning. Conclusions: Overall, children treated with extracorporeal membrane oxygenation in the neonatal period reported low health-related quality of life at 5 yrs of age. Because only emotional health-related quality of life was not associated with health status, the pediatric quality of life inventory might be a measure of health status rather than of health-related quality of life. In contrast with conclusions from others, we found that 5-yr-old children might be too young to rate their own health-related quality of life.

Prospective longitudinal evaluation of lung function during the first year of life after repair of congenital diaphragmatic hernia.

Objective: To evaluate lung function and respiratory morbidity prospectively during the first year of life in patients with congenital diaphragmatic hernia and to study the effect of extracorporeal membrane oxygenation therapy. Design: Prospective longitudinal cohort study. Setting: Outpatient clinic of a tertiary-level pediatric hospital. Patients: The cohort of 43 infants included 12 patients treated with extracorporeal membrane oxygenation. Evaluation was at 6 and 12 months; 33 infants were evaluated at both time points. Interventions: None. Measurements and Main Results: Maximal expiratory flow at functional residual capacity and functional residual capacity were measured with Masterscreen Babybody. Z-scores were calculated for maximal expiratory flow at functional residual capacity. Mean maximal expiratory flow at functional residual capacity values at 6 and 12 months were significantly below the expected values (mean z-score −1.4 and −1.5, respectively) without a significant change between both time points. Values did not significantly differ between extracorporeal membrane oxygenation and nonextracorporeal membrane oxygenation-treated patients. Functional residual capacity values were generally high, 47% were above the suggested normal range, and did not change significantly over time. Mean functional residual capacity values in extracorporeal membrane oxygenation-treated patients were significantly higher than in nonextracorporeal membrane oxygenation-treated patients (p = .006). The difference (5.1 mL/kg ± 1.8 SE) did not change significantly between the two time points. Higher mean airway pressure and longer duration of ventilation were associated with higher functional residual capacity. None of the perinatal characteristics was associated with maximal expiratory flow at functional residual capacity. Mean weight z-scores were significantly below zero at both time points (p < .001). Mean weight z-score in extracorporeal membrane oxygenation-treated patients were lower than in nonextracorporeal membrane oxygenation-treated patients (p = .046). Conclusions: Infants with congenital diaphragmatic hernia have decreased expiratory flows and increased functional residual capacity within the first year of life. Extracorporeal membrane oxygenation-treated patients with congenital diaphragmatic hernia may have more respiratory morbidity and concomitant growth impairment. Close follow-up beyond the neonatal period is therefore required.

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.

CKD and Hypertension during Long-Term Follow-Up in Children and Adolescents Previously Treated with Extracorporeal Membrane Oxygenation

BACKGROUND AND OBJECTIVES Many children receiving extracorporeal membrane oxygenation develop AKI. If AKI leads to permanent nephron loss, it may increase the risk of developing CKD. The prevalence of CKD and hypertension and its predictive factors during long-term follow-up of children and adolescents previously treated with neonatal extracorporeal membrane oxygenation were determined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Between November of 2010 and February of 2014, neonatal survivors of extracorporeal membrane oxygenation who visited the prospective follow-up program at 1, 2, 5, 8, 12, and 18 years of age were screened for CKD and hypertension (BP≥95th percentile of reference values). CKD was suspected in children with either an eGFR<90 ml/min per 1.73 m(2) or proteinuria (urinary protein-to-creatinine ratio >0.50 for children ages ≤24 months and >0.20 at >24 months). The RIFLE classification (risk, injury, or failure as 150%, 200%, or 300% of serum creatinine reference values) was used to define AKI during extracorporeal membrane oxygenation without preemptive hemofiltration. RESULTS Median follow-up of 169 screened participants was 8.2 years (interquartile range=5.2-12.1 years). Nine children had a lower eGFR, but all rates were >60 ml/min per 1.73 m(2). Proteinuria was observed in 20 children (median=0.26 mg protein/mg creatinine; interquartile range=0.23-0.32 mg protein/mg creatinine), and 32 children had hypertension. Only history of AKI was associated with CKD (P=0.004). Children with RIFLE scores injury and failure had 4.3 times higher odds of CKD signs or hypertension than those without AKI (95% confidence interval, 1.6 to 12.1; P=0.004). CONCLUSIONS Altogether, 54 participants (32%) had at least one sign of CKD and/or hypertension. However, most values were marginally abnormal, with no immediate consequences for clinical care. Nevertheless, a prevalence of 32% clearly indicates that survivors of neonatal extracorporeal membrane oxygenation, especially those with AKI, are at risk of a more rapid decline of kidney function with increasing age. Therefore, screening for CKD development in adulthood is recommended.

Motor performance after neonatal extracorporeal membrane oxygenation: a longitudinal evaluation

OBJECTIVE: To assess longitudinally children’s motor performance 5 to 12 years after neonatal extracorporeal membrane oxygenation (ECMO) and to evaluate associations between clinical characteristics and motor performance. METHODS: Two hundred fifty-four neonatal ECMO survivors in the Netherlands were tested with the Movement Assessment Battery for Children at 5, 8, and/or 12 years. Percentile scores were transformed to z scores for longitudinal evaluation (norm population mean = 0 and SD = 1). Primary diagnoses: meconium aspiration syndrome (n = 137), congenital diaphragmatic hernia (n = 49), persistent pulmonary hypertension of the newborn (n = 36), other diagnoses (n = 32). RESULTS: Four hundred fifty-six tests were analyzed. At 5, 8, and 12 years motor performance was normal in 73.7, 74.8, and 40.5%, respectively (vs 85% expected based on reference values; P < .001 at all ages). In longitudinal analyses mean (95% confidence interval [CI]) z scores were –0.42 (–0.55 to –0.28), –0.25 (–0.40 to –0.10) and –1.00 (–1.26 to –0.75) at 5, 8, and 12 years, respectively. Mean score at 8 years was significantly higher than at 5 years (difference 0.16, 95% CI 0.02 to 0.30), and mean score at 12 years was significantly lower than at both other ages (differences –0.59 and –0.75; 95% CI –0.33 to –0.84 and –0.49 to –1.00, respectively). Children with congenital diaphragmatic hernia encountered problems at all ages. The presence of chronic lung disease was negatively related with outcome. CONCLUSIONS: Motor problems in neonatal ECMO survivors persist throughout childhood and become more obvious with time.

Sensorineural hearing loss and language development following neonatal extracorporeal membrane oxygenation

Objectives: To determine the prevalence of hearing loss in school-age children who have undergone neonatal extracorporeal membrane oxygenation treatment and to identify any effects of hearing loss on speech and language development. Design: Prospective longitudinal follow-up study within the framework of a structured post-extracorporeal membrane oxygenation follow-up program. Setting: Outpatient clinic of a level III university hospital. Results: Tone audiometry was performed by standardized protocol in 136 children aged 5–12 yrs. Hearing loss was considered clinically significant when >20 dB. Hearing was normal in 75.7% of children. Five children (3.7%) had bilateral sensorineural or combined hearing loss; three of them received special audiological care (2.2% of total sample). Of the 24 children with congenital diaphragmatic hernia, 19 (79.2%) had normal hearing and only two (8.3%) had mild sensorineural hearing loss, unilateral in one of them. Follow-up at 24 months of age had shown normal verbal and nonverbal developmental scores. Language development and intelligence median (range) scores at 5 yrs of age were also normal: receptive language development 104 (55–133), syntactical development 104 (68–132), and lexical development 101 (50–141) for 89 children; intelligence quotient 104 (68–132) for 106 children. Scores did not differ among those with normal hearing, mild hearing loss, and moderate-to-severe hearing loss (p = 0.800, p = 0.639, p = 0.876, and p = 0.886, for the respective developmental tests). Conclusions: We found normal language development and intelligence in a cohort of neonatal extracorporeal membrane oxygenation survivors. The prevalence of bilateral sensorineural hearing loss was in accordance with that of a larger series in the United States—which exceeds the prevalence in the normal population.