Cardiopulmonary resuscitation employing only abdominal compressions in infants after cardiac surgery: A secondary sub-analysis of the ICU-RESUS study.

Importance: Patients with underlying cardiac disease form a considerable proportion of pediatric patients who experience in-hospital cardiac arrest. In pediatric patients after cardiac surgery, CPR with abdominal compressions alone (AC-CPR) may provide an alternative to standard chest compression CPR (S-CPR) with additional procedural and physiologic advantages. Objective: Quantitatively describe hemodynamics during cardiopulmonary resuscitation (CPR) and outcomes of infants who received only abdominal compressions (AC-CPR). Design: This is a sub-group analysis of the prospective, observational cohort from the ICU-RESUS trial NCT028374497. Setting & Patients: A single site quaternary care pediatric cardiothoracic intensive care unit enrolled in the ICU-RESUS trial. Patients less than 1 year of age with congenital heart disease who required compressions during cardiac arrest. Interventions: Use of AC-CPR during cardiac arrest resuscitation. Measurements and Main Results: Invasive arterial line waveforms during CPR were analyzed for 11 patients (10 surgical cardiac and 1 medical cardiac). Median weight was 3.3 kg [IQR 3.0, 4.0]; and median duration of CPR was 5.0 [3.0, 20.0] minutes. Systolic (median 57 [IQR 48, 65] mmHg) and diastolic (median 32 [IQR 24, 43] mmHg) blood pressures were achieved with a median rate of 114 [IQR 100, 124] compressions per minute. Return of spontaneous circulation was obtained in 9 of 11 (82%) patients; 2 patients (18%) were cannulated for extracorporeal cardiopulmonary resuscitation (ECPR) and 6 (55%) survived to hospital discharge with favorable neurologic outcome. Conclusions: AC-CPR may offer an alternative method to maintain perfusion for infants who experience cardiac arrest. This may have particular benefit in pediatric patients after cardiac surgery for whom external chest compressions may be harmful due to anatomic and physiologic considerations.

A risk-based monitoring approach to source data monitoring and documenting monitoring findings.

BACKGROUND: Clinical trial monitoring is evolving from labor-intensive to targeted approaches. The traditional 100% Source Data Monitoring (SDM) approach fails to prioritize data by significance, diverting attention from critical elements. Despite regulatory guidance on Risk-Based Monitoring (RBM), its widespread implementation has been slow. METHODS: Our study teams assess the study's overall risk, document heightened and critical risks, and create a study-specific risk-based monitoring plan, integrating SDM and Central Data Monitoring (CDM). SDM combines a fixed list of pre-identified variables and a list of randomly identified variables to monitor. Identifying variables follows a two-step approach: first, a random sample of participants is selected, second, a random set of variables for each participant selected is identified. Sampling weights prioritize critical variables. Regular team meetings are held to discuss and compile significant findings into a Study Monitoring Report. RESULTS: We present a random SDM sample and a Study Monitoring Report. The random SDM output includes a look-up table for selected database elements. The report provides a holistic view of the study issues and overall health. CONCLUSIONS: The proposed random sampling method is used to monitor a representative set of critical variables, while the Study Monitoring Report is written to summarize significant monitoring findings and data trends. The report allows the sponsor to assess the current status of the study and data effectively. Communicating and sharing emerging insights facilitates timely adjustments of future monitoring activities, optimizing efficiencies, and study outcomes.

Outcomes of Extracorporeal Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest Among Children With Noncardiac Illness Categories.

OBJECTIVES: The objective of this study was to determine the association of the use of extracorporeal cardiopulmonary resuscitation (ECPR) with survival to hospital discharge in pediatric patients with a noncardiac illness category. A secondary objective was to report on trends in ECPR usage in this population for 20 years. DESIGN: Retrospective multicenter cohort study. SETTING: Hospitals contributing data to the American Heart Association's Get With The Guidelines-Resuscitation registry between 2000 and 2021. PATIENTS: Children (<18 yr) with noncardiac illness category who received greater than or equal to 30 minutes of cardiopulmonary resuscitation (CPR) for in-hospital cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Propensity score weighting balanced ECPR and conventional CPR (CCPR) groups on hospital and patient characteristics. Multivariable logistic regression incorporating these scores tested the association of ECPR with survival to discharge. A Bayesian logistic regression model estimated the probability of a positive effect from ECPR. A secondary analysis explored temporal trends in ECPR utilization. Of 875 patients, 159 received ECPR and 716 received CCPR. The median age was 1.0 [interquartile range: 0.2-7.0] year. Most patients (597/875; 68%) had a primary diagnosis of respiratory insufficiency. Median CPR duration was 45 [35-63] minutes. ECPR use increased over time ( p < 0.001). We did not identify differences in survival to discharge between the ECPR group (21.4%) and the CCPR group (16.2%) in univariable analysis ( p = 0.13) or propensity-weighted multivariable logistic regression (adjusted odds ratio 1.42 [95% CI, 0.84-2.40; p = 0.19]). The Bayesian model estimated an 85.1% posterior probability of a positive effect of ECPR on survival to discharge. CONCLUSIONS: ECPR usage increased substantially for the last 20 years. We failed to identify a significant association between ECPR and survival to hospital discharge, although a post hoc Bayesian analysis suggested a survival benefit (85% posterior probability).

Clinician-reported physiologic monitoring of cardiopulmonary resuscitation quality during pediatric in-hospital cardiac arrest: A propensity-weighted cohort study.

AIMS: The primary objective was to determine the association between clinician-reported use of end-tidal CO2 (ETCO2) or diastolic blood pressure (DBP) to monitor cardiopulmonary resuscitation (CPR) quality during pediatric in-hospital cardiac arrest (pIHCA) and survival outcomes. DESIGN: A retrospective cohort study was performed in two cohorts: (1) Patients with an invasive airway in place at the time of arrest to evaluate ETCO2 use, and (2) patients with an arterial line in place at the time of arrest to evaluate DBP use. The primary exposure was clinician-reported use of ETCO2 or DBP. The primary outcome was return of spontaneous circulation (ROSC). Propensity-weighted logistic regression evaluated the association between monitoring and outcomes. SETTING: Hospitals reporting to the American Heart Association's Get With The Guidelines®- Resuscitation registry (2007-2021). PATIENTS: Children with index IHCA with an invasive airway or arterial line at the time of arrest. RESULTS: Between January 2007 and May 2021, there were 15,280 pediatric CPR events with an invasive airway or arterial line in place at the time of arrest. Of 7159 events with an invasive airway, 6829 were eligible for analysis. Of 2978 events with an arterial line, 2886 were eligible. Clinicians reported using ETCO2 in 1335/6829 (20%) arrests and DBP in 1041/2886 (36%). Neither exposure was associated with ROSC. ETCO2 monitoring was associated with higher odds of 24-hour survival (aOR 1.17 [1.02, 1.35], p = 0.03). CONCLUSIONS: Neither clinician-reported ETCO2 monitoring nor DBP monitoring during pIHCA were associated with ROSC. Monitoring of ETCO2 was associated with 24-hour survival.

The Temporal Association of the COVID-19 Pandemic and Pediatric Cardiopulmonary Resuscitation Quality and Outcomes.

OBJECTIVES: The COVID-19 pandemic resulted in adaptations to pediatric resuscitation systems of care. The objective of this study was to determine the temporal association between the pandemic and pediatric in-hospital cardiac arrest (IHCA) process of care metrics, cardiopulmonary resuscitation (cardiopulmonary resuscitation) quality, and patient outcomes. DESIGN: Multicenter retrospective analysis of a dataset comprising observations of IHCA outcomes pre pandemic (March 1, 2019 to February 29, 2020) versus pandemic (March 1, 2020 to February 28, 2021). SETTING: Data source was the ICU-RESUScitation Project ("ICU-RESUS;" NCT028374497), a prospective, multicenter, cluster randomized interventional trial. PATIENTS: Children (≤ 18 yr) who received cardiopulmonary resuscitation while admitted to the ICU and were enrolled in ICU-RESUS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 429 IHCAs meeting inclusion criteria, occurrence during the pandemic period was associated with higher frequency of hypotension as the immediate cause of arrest. Cardiac arrest physiology, cardiopulmonary resuscitation quality metrics, and postarrest physiologic and quality of care metrics were similar between the two periods. Survival with favorable neurologic outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged from baseline) occurred in 102 of 195 subjects (52%) during the pandemic compared with 140 of 234 (60%) pre pandemic ( p = 0.12). Among survivors, occurrence of IHCA during the pandemic period was associated with a greater increase in Functional Status Scale (FSS) (i.e., worsening) from baseline (1 [0-3] vs 0 [0-2]; p = 0.01). After adjustment for confounders, IHCA survival during the pandemic period was associated with a greater increase in FSS from baseline (+1.19 [95% CI, 0.35-2.04] FSS points; p = 0.006) and higher odds of a new FSS-defined morbidity (adjusted odds ratio, 1.88 [95% CI, 1.03-3.46]; p = 0.04). CONCLUSIONS: Using the ICU-RESUS dataset, we found that relative to the year prior, pediatric IHCA during the first year of the COVID-19 pandemic was associated with greater worsening of functional status and higher odds of new functional morbidity among survivors.

Post-discharge rehabilitation and functional recovery after pediatric injury.

INTRODUCTION: Variability in rehabilitation disposition has been proposed as a trauma center quality metric. Benchmarking rehabilitation disposition is limited by a lack of objective measures of functional impairment at discharge. The primary aim of this study was to determine the relative contribution of patient characteristics and hospitalization factors associated with inpatient and outpatient rehabilitation after discharge. The secondary aims were to evaluate the sensitivity of the Functional Status Scale (FSS) score for identifying functional impairments at hospital discharge and track post-discharge recovery. PATIENTS AND METHODS: We report a planned secondary analysis of a prospective observational study of seriously injured children (<15 years old) enrolled at seven pediatric trauma centers. Functional Status Scale (FSS) score was measured for pre-injury, hospital discharge, and 6-month follow-up timepoints. Multinomial logistic regression identified factors associated with three dispositions: home without rehabilitation services, home with outpatient rehabilitation, and inpatient rehabilitation. Relative weight analysis was used to identify the impact of individual factors associated with inpatient or outpatient rehabilitation disposition. RESULTS: We analyzed 427 children with serious injuries. Functional impairment at discharge was present in 103 (24.1%) children, including 43/337 (12.8%) discharged without services, 12/38 (31.6%) discharged with outpatient rehabilitation, and 44/47 (93.6%) discharged to inpatient rehabilitation. In multivariable modeling, variables most contributing to prediction of inpatient rehabilitation were severe initial Glasgow coma scale (GCS), injured body region, and functional impairment at discharge. Severe initial GCS, private insurance, and extremity injury were independently associated with disposition with outpatient rehabilitation. Patients discharged without services or with outpatient rehabilitation most frequently had motor impairments that improved during the next 6 months. Patients discharged to inpatient rehabilitation had impairments in all domains, with many improving within 6 months. A higher proportion of patients discharged to inpatient rehabilitation had residual impairments at follow-up. CONCLUSION: Injury characteristics and discharge impairment were associated with discharge to inpatient rehabilitation. The FSS score identified impairments needing inpatient rehabilitation and characterized improvements after discharge. Less severe impairments needing outpatient rehabilitation were not identified by the FSS score.

All body region injuries are not equal: Differences in pediatric discharge functional status based on Abbreviated Injury Scale (AIS) body regions and severity scores.

PURPOSE: Functional outcomes have been proposed for assessing quality of pediatric trauma care. Outcomes assessments often rely on Abbreviated Injury Scale (AIS) severity scores to adjust for injury characteristics, but the relationship between AIS severity and functional impairment is unknown. This study's primary aim was to quantify functional impairment associated with increasing AIS severity scores within body regions. The secondary aim was to assess differences in impairment between body regions based on AIS severity. METHODS: Children with serious (AIS≥ 3) isolated body region injuries enrolled in a multicenter prospective study were analyzed. The primary outcome was functional status at discharge measured using the Functional Status Scale (FSS). Discharge FSS was compared (1) within each body region across increasing AIS severity scores, and (2) between body regions for injuries with matching AIS scores. RESULTS: The study included 266 children, with 16% having abnormal FSS at discharge. Worse FSS was associated with increasing AIS severity only for spine injuries. Abnormal FSS was observed in a greater proportion of head injury patients with a severely impaired initial Glasgow Coma Scale (GCS) (GCS< 9) compared to those with a higher GCS score (43% versus 9%; p < 0.01). Patients with AIS 3 extremity and severe head injuries had a higher proportion of abnormal FSS at discharge than AIS 3 abdomen or non-severe head injuries. CONCLUSIONS: AIS severity does not account for variability in discharge functional impairment within or between body regions. Benchmarking based on functional status assessment requires clinical factors in addition to AIS severity for appropriate risk adjustment. LEVEL OF EVIDENCE: 1 (Prognostic and Epidemiological).

Evaluating the association between obesity and discharge functional status after pediatric injury.

BACKGROUND: Children with obesity frequently have functional impairment after critical illness. Although obesity increases morbidity risk after trauma, the association with functional outcomes in children is unknown. OBJECTIVE: To evaluate the association of weight with functional impairment at hospital discharge in children with serious injuries. METHODS: This secondary analysis of a multicenter prospective study included children <15 years old with a serious injury. Four weight groups, underweight, healthy weight, overweight, and obesity/severe obesity were defined by body mass index z-scores. The functional status scale (FSS) measured impairment across six functional domains before injury and at hospital discharge. New domain morbidity was defined as a change ≥2 points. The association between weight and functional impairment was determined using logistic regression adjusting for demographics, physiological measures, injury details, presence of a severe head injury, and physical abuse. RESULTS: Although most patients discharged with good/unchanged functional status, new domain morbidity occurred in 74 patients (17%). New FSS domain morbidity occurred in 13% of underweight, 14% of healthy weight, 15% of overweight, and 26% of obese/severe obese patients. Compared to healthy weight patients, those with obesity had more frequent new domain morbidity (p = 0.01), while the other weight groups had similar morbidity. However, after adjustment for confounders, weight was not associated with new functional morbidity at discharge. CONCLUSION: Patients with obesity have greater frequency of new domain morbidity after a serious injury; however, after accounting for injury characteristics, weight group is not independently associated with new functional morbidity at hospital discharge after injury in children. LEVEL OF EVIDENCE: III.

Impact of ventricle size on neuropsychological outcomes in treated pediatric hydrocephalus: an HCRN prospective cohort study.

OBJECTIVE: In pediatric hydrocephalus, shunts tend to result in smaller postoperative ventricles compared with those following an endoscopic third ventriculostomy (ETV). The impact of the final treated ventricle size on neuropsychological and quality-of-life outcomes is currently undetermined. Therefore, the authors sought to ascertain whether treated ventricle size is associated with neurocognitive and academic outcomes postoperatively. METHODS: This prospective cohort study included children aged 5 years and older at the first diagnosis of hydrocephalus at 8 Hydrocephalus Clinical Research Network sites from 2011 to 2015. The treated ventricle size, as measured by the frontal and occipital horn ratio (FOR), was compared with 25 neuropsychological tests 6 months postoperatively after adjusting for age, hydrocephalus etiology, and treatment type (ETV vs shunt). Pre- and posttreatment grade point average (GPA), quality-of-life measures (Hydrocephalus Outcome Questionnaire [HOQ]), and a truncated preoperative neuropsychological battery were also compared with the FOR. RESULTS: Overall, 60 children were included with a mean age of 10.8 years; 17% had ≥ 1 comorbidity. Etiologies for hydrocephalus were midbrain lesions (37%), aqueductal stenosis (22%), posterior fossa tumors (13%), and supratentorial tumors (12%). ETV (78%) was more commonly used than shunting (22%). Of the 25 neuropsychological tests, including full-scale IQ (q = 0.77), 23 tests showed no univariable association with postoperative ventricle size. Verbal learning delayed recall (p = 0.006, q = 0.118) and visual spatial judgment (p = 0.006, q = 0.118) were negatively associated with larger ventricles and remained significant after multivariate adjustment for age, etiology, and procedure type. However, neither delayed verbal learning (p = 0.40) nor visual spatial judgment (p = 0.22) was associated with ventricle size change with surgery. No associations were found between postoperative ventricle size and either GPA or the HOQ. CONCLUSIONS: Minimal associations were found between the treated ventricle size and neuropsychological, academic, or quality-of-life outcomes for pediatric patients in this comprehensive, multicenter study that encompassed heterogeneous hydrocephalus etiologies.

Functional status impairment at six-month follow-up is independently associated with child physical abuse mechanism.

BACKGROUND: Children with abusive injuries have worse mortality, length-of-stay, complications, and healthcare costs compared to those sustaining an accidental injury. Long-term functional impairment is common in children with abusive head trauma but has not been examined in a cohort with heterogeneous body region injuries. OBJECTIVE: To assess for an independent association between child physical abuse and functional impairment at discharge and six-month follow-up. PARTICIPANTS AND SETTING: Seriously injured children (<15 years) treated at seven pediatric trauma centers. METHODS: Functional status was compared between child physical abuse and accidental injury groups at discharge and six-month follow-up. Functional impairment was defined at discharge ("new domain morbidity") as a change from pre-injury ≥2 points in any of the six domains of the Functional Status Scale (FSS), and impairment at six-month follow-up as an abnormal total FSS score. RESULTS: Children with abusive injuries accounted for 10.5% (n = 45) of the cohort. New domain morbidity was present in 17.8% (n = 8) of child physical abuse patients at discharge, with 10% (n = 3) of children having an abnormal FSS at six-months. There were no differences in new domain morbidity at hospital discharge between children injured by abuse and or accidental injury. However, children injured by physical abuse were 4.09 (2.15, 7.78) times more likely to have functional impairment at six months. CONCLUSIONS: Child physical abuse is an independent risk factor for functional impairment at six-month follow-up. Functional status measurement for this high-risk group of children should be routinely measured and incorporated into trauma center quality assessments.

Long-Term Outcomes after Pediatric Injury: Results of the Assessment of Functional Outcomes and Health-Related Quality of Life after Pediatric Trauma Study.

BACKGROUND: Disability and impaired health-related quality of life can persist for months among injured children. Previous studies of long-term outcomes have focused mainly on children with specific injury types rather than those with multiple injured body regions. This study's objective was to determine the long-term functional status and health-related quality of life after serious pediatric injury, and to evaluate the associations of these outcomes with features available at hospital discharge. STUDY DESIGN: We conducted a prospective observational study at 7 Level I pediatric trauma centers of children treated for at least 1 serious (Abbreviated Injury Scale severity 3 or higher) injury. Patients were sampled to increase the representation of less frequently injured body regions and multiple injured body regions. Six-month functional status was measured using the Functional Status Scale (FSS) and health-related quality of life using the Pediatric Quality of Life Inventory. RESULTS: Among 323 injured children with complete discharge and follow-up assessments, 6-month FSS score was abnormal in 33 patients (10.2%)-16 with persistent impairments and 17 previously normal at discharge. Increasing levels of impaired discharge FSS score were associated with impaired FSS and lower Pediatric Quality of Life Inventory scores at 6-month follow-up. Additional factors on multivariable analysis associated with 6-month FSS impairment included older age, penetrating injury type, severe head injuries, and spine injuries, and included older age for lower 6-month Pediatric Quality of Life Inventory scores. CONCLUSIONS: Older age and discharge functional status are associated with long-term impairment of functional status and health-related quality of life. Although most seriously injured children return to normal, ongoing disability and reduced health-related quality of life remained 6 months after injury. Our findings support long-term assessments as standard practice for evaluating the health impacts of serious pediatric injury.

Cerebrospinal fluid NCAM-1 concentration is associated with neurodevelopmental outcome in post-hemorrhagic hydrocephalus of prematurity.

OBJECTIVE: Efforts directed at mitigating neurological disability in preterm infants with intraventricular hemorrhage (IVH) and post hemorrhagic hydrocephalus (PHH) are limited by a dearth of quantifiable metrics capable of predicting long-term outcome. The objective of this study was to examine the relationships between candidate cerebrospinal fluid (CSF) biomarkers of PHH and neurodevelopmental outcomes in infants undergoing neurosurgical treatment for PHH. STUDY DESIGN: Preterm infants with PHH were enrolled across the Hydrocephalus Clinical Research Network. CSF samples were collected at the time of temporizing neurosurgical procedure (n = 98). Amyloid precursor protein (APP), L1CAM, NCAM-1, and total protein (TP) were compared in PHH versus control CSF. Fifty-four of these PHH subjects underwent Bayley Scales of Infant Development-III (Bayley-III) testing at 15-30 months corrected age. Controlling for false discovery rate (FDR) and adjusting for post-menstrual age (PMA) and IVH grade, Pearson's partial correlation coefficients were used to examine relationships between CSF proteins and Bayley-III composite cognitive, language, and motor scores. RESULTS: CSF APP, L1CAM, NCAM-1, and TP were elevated in PHH over control at temporizing surgery. CSF NCAM-1 was associated with Bayley-III motor score (R = -0.422, p = 0.007, FDR Q = 0.089), with modest relationships noted with cognition (R = -0.335, p = 0.030, FDR Q = 0.182) and language (R = -0.314, p = 0.048, FDR Q = 0.194) scores. No relationships were observed between CSF APP, L1CAM, or TP and Bayley-III scores. FOHR at the time of temporization did not correlate with Bayley-III scores, though trends were observed with Bayley-III motor (p = 0.0647 and R = -0.2912) and cognitive scores (p = 0.0506 and R = -0.2966). CONCLUSION: CSF NCAM-1 was associated with neurodevelopment in this multi-institutional PHH cohort. This is the first report relating a specific CSF protein, NCAM-1, to neurodevelopment in PHH. Future work will further investigate a possible role for NCAM-1 as a biomarker of PHH-associated neurological disability.

Predictors of fast and ultrafast shunt failure in pediatric hydrocephalus: a Hydrocephalus Clinical Research Network study.

OBJECTIVE: The primary objective of this study was to use the prospective Hydrocephalus Clinical Research Network (HCRN) registry to determine clinical predictors of fast time to shunt failure (≤ 30 days from last revision) and ultrafast time to failure (≤ 7 days from last revision). METHODS: Revisions (including those due to infection) to permanent shunt placements that occurred between April 2008 and November 2017 for patients whose entire shunt experience was recorded in the registry were analyzed. All registry data provided at the time of initial shunt placement and subsequent revision were reviewed. Key variables analyzed included etiology of hydrocephalus, age at time of initial shunt placement, presence of slit ventricles on imaging at revision, whether the ventricles were enlarged at the time of revision, and presence of prior fast failure events. Univariable and multivariable analyses were performed to find key predictors of fast and ultrafast failure events. RESULTS: A cohort of 1030 patients with initial shunt insertions experienced a total of 1995 revisions. Of the 1978 revision events with complete records, 1216 (61.5%) shunts remained functional for more than 1 year, and 762 (38.5%) failed within 1 year of the procedure date. Of those that failed within 1 year, 423 (55.5%) failed slowly (31-365 days) and 339 (44.5%) failed fast (≤ 30 days). Of the fast failures, 131 (38.6%) were ultrafast (≤ 7 days). In the multivariable analysis specified a priori, etiology of hydrocephalus (p = 0.005) and previous failure history (p = 0.011) were independently associated with fast failure. Age at time of procedure (p = 0.042) and etiology of hydrocephalus (p = 0.004) were independently associated with ultrafast failure. These relationships in both a priori models were supported by the data-driven multivariable models as well. CONCLUSIONS: Neither the presence of slit ventricle syndrome nor ventricular enlargement at the time of shunt failure appears to be a significant predictor of repeated, rapid shunt revisions. Age at the time of procedure, etiology of hydrocephalus, and the history of previous failure events seem to be important predictors of fast and ultrafast shunt failure. Further work is required to understand the mechanisms of these risk factors as well as mitigation strategies.

High-throughput investigation of molecular and cellular biomarkers in NMOSD.

OBJECTIVE: To identify candidate biomarkers associated with neuromyelitis optica spectrum disorder (NMOSD) using high-throughput technologies that broadly assay the concentrations of serum analytes and frequencies of immune cell subsets. METHODS: Sera, peripheral blood mononuclear cells (PBMCs), and matched clinical data from participants with NMOSD and healthy controls (HCs) were obtained from the Collaborative International Research in Clinical and Longitudinal Experience Study NMOSD biorepository. Flow cytometry panels were used to measure the frequencies of 39 T-cell, B-cell, regulatory T-cell, monocyte, natural killer (NK) cell, and dendritic cell subsets in unstimulated PBMCs. In parallel, multiplex proteomics assays were used to measure 46 serum cytokines and chemokines in 2 independent NMOSD and HC cohorts. Multivariable regression models were used to assess molecular and cellular profiles in NMOSD compared with HC. RESULTS: NMOSD samples had a lower frequency of CD16+CD56+ NK cells. Both serum cohorts and multivariable logistic regression revealed increased levels of B-cell activating factor associated with NMOSD. Interleukin 6, CCL22, and CCL3 were also elevated in 1 NMOSD cohort of the 2 analyzed. Multivariable linear regression of serum analyte levels revealed a correlation between CX3CL1 (fractalkine) levels and the number of days since most recent disease relapse. CONCLUSIONS: Integrative analyses of cytokines, chemokines, and immune cells in participants with NMOSD and HCs provide congruence with previously identified biomarkers of NMOSD and highlight CD16+CD56+ NK cells and CX3CL1 as potential novel biomarker candidates.

Surgical resource utilization after initial treatment of infant hydrocephalus: comparing ETV, early experience of ETV with choroid plexus cauterization, and shunt insertion in the Hydrocephalus Clinical Research Network.

OBJECTIVE: Few studies have addressed surgical resource utilization-surgical revisions and associated hospital admission days-following shunt insertion or endoscopic third ventriculostomy (ETV) with or without choroid plexus cauterization (CPC) for CSF diversion in hydrocephalus. Study members of the Hydrocephalus Clinical Research Network (HCRN) investigated differences in surgical resource utilization between CSF diversion strategies in hydrocephalus in infants. METHODS: Patients up to corrected age 24 months undergoing initial definitive treatment of hydrocephalus were reviewed from the prospectively maintained HCRN Core Data Project (Hydrocephalus Registry). Postoperative courses (at 1, 3, and 5 years) were studied for hydrocephalus-related surgeries (primary outcome) and hospital admission days related to surgical revision (secondary outcome). Data were summarized using descriptive statistics and compared using negative binomial regression, controlling for age, hydrocephalus etiology, and HCRN center. The study population was organized into 3 groups (ETV alone, ETV with CPC, and CSF shunt insertion) during the 1st postoperative year and 2 groups (ETV alone and CSF shunt insertion) during subsequent years due to limited long-term follow-up data. RESULTS: Among 1090 patients, the majority underwent CSF shunt insertion (CSF shunt, 83.5%; ETV with CPC, 10.0%; and ETV alone, 6.5%). Patients undergoing ETV with CPC had a higher mean number of revision surgeries (1.2 ± 1.6) than those undergoing ETV alone (0.6 ± 0.8) or CSF shunt insertion (0.7 ± 1.3) over the 1st year after surgery (p = 0.005). At long-term follow-up, patients undergoing ETV alone experienced a nonsignificant lower mean number of revision surgeries (0.7 ± 0.9 at 3 years and 0.8 ± 1.3 at 5 years) than those undergoing CSF shunt insertion (1.1 ± 1.9 at 3 years and 1.4 ± 2.6 at 5 years) and exhibited a lower mean number of hospital admission days related to revision surgery (3.8 ± 10.3 vs 9.9 ± 27.0, p = 0.042). CONCLUSIONS: Among initial treatment strategies for hydrocephalus, ETV with CPC yielded a higher surgical revision rate within 1 year after surgery. Patients undergoing ETV alone exhibited a nonsignificant lower mean number of surgical revisions than CSF shunt insertion at 3 and 5 years postoperatively. Additionally, the ETV-alone cohort demonstrated significantly fewer hospital admission days related to surgical management of hydrocephalus within 3 years after surgery. These findings suggest a time-dependent benefit of ETV over CSF shunt insertion regarding surgical resource utilization.

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

Predictors of success for combined endoscopic third ventriculostomy and choroid plexus cauterization in a North American setting: a Hydrocephalus Clinical Research Network study.

OBJECTIVE: Endoscopic third ventriculostomy combined with choroid plexus cauterization (ETV+CPC) has been adopted by many pediatric neurosurgeons as an alternative to placing shunts in infants with hydrocephalus. However, reported success rates have been highly variable, which may be secondary to patient selection, operative technique, and/or surgeon training. The objective of this prospective multicenter cohort study was to identify independent patient selection, operative technique, or surgical training predictors of ETV+CPC success in infants. METHODS: This was a prospective cohort study nested within the Hydrocephalus Clinical Research Network's (HCRN) Core Data Project (registry). All infants under the age of 2 years who underwent a first ETV+CPC between June 2006 and March 2015 from 8 HCRN centers were included. Each patient had a minimum of 6 months of follow-up unless censored by an ETV+CPC failure. Patient and operative risk factors of failure were examined, as well as formal ETV+CPC training, which was defined as traveling to and working with the experienced surgeons at CURE Children's Hospital of Uganda. ETV+CPC failure was defined as the need for repeat ETV, shunting, or death. RESULTS: The study contained 191 patients with a primary ETV+CPC conducted by 17 pediatric neurosurgeons within the HCRN. Infants under 6 months corrected age at the time of ETV+CPC represented 79% of the cohort. Myelomeningocele (26%), intraventricular hemorrhage associated with prematurity (24%), and aqueductal stenosis (17%) were the most common etiologies. A total of 115 (60%) of the ETV+CPCs were conducted by surgeons after formal training. Overall, ETV+CPC was successful in 48%, 46%, and 45% of infants at 6 months, 1 year, and 18 months, respectively. Young age (< 1 month) (adjusted hazard ratio [aHR] 1.9, 95% CI 1.0-3.6) and an etiology of post-intraventricular hemorrhage secondary to prematurity (aHR 2.0, 95% CI 1.1-3.6) were the only two independent predictors of ETV+CPC failure. Specific subgroups of ages within etiology categories were identified as having higher ETV+CPC success rates. Although training led to more frequent use of the flexible scope (p < 0.001) and higher rates of complete (> 90%) CPC (p < 0.001), training itself was not independently associated (aHR 1.1, 95% CI 0.7-1.8; p = 0.63) with ETV+CPC success. CONCLUSIONS: This is the largest prospective multicenter North American study to date examining ETV+CPC. Formal ETV+CPC training was not found to be associated with improved procedure outcomes. Specific subgroups of ages within specific hydrocephalus etiologies were identified that may preferentially benefit from ETV+CPC.

Endoscopic third ventriculostomy and choroid plexus cauterization in infant hydrocephalus: a prospective study by the Hydrocephalus Clinical Research Network.

OBJECTIVE High-quality data comparing endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) to shunt and ETV alone in North America are greatly lacking. To address this, the Hydrocephalus Clinical Research Network (HCRN) conducted a prospective study of ETV+CPC in infants. Here, these prospective data are presented and compared to prospectively collected data from a historical cohort of infants treated with shunt or ETV alone. METHODS From June 2014 to September 2015, infants (corrected age ≤ 24 months) requiring treatment for hydrocephalus with anatomy suitable for ETV+CPC were entered into a prospective study at 9 HCRN centers. The rate of procedural failure (i.e., the need for repeat hydrocephalus surgery, hydrocephalus-related death, or major postoperative neurological deficit) was determined. These data were compared with a cohort of similar infants who were treated with either a shunt (n = 969) or ETV alone (n = 74) by creating matched pairs on the basis of age and etiology. These data were obtained from the existing prospective HCRN Core Data Project. All patients were observed for at least 6 months. RESULTS A total of 118 infants underwent ETV+CPC (median corrected age 1.3 months; common etiologies including myelomeningocele [30.5%], intraventricular hemorrhage of prematurity [22.9%], and aqueductal stenosis [21.2%]). The 6-month success rate was 36%. The most common complications included seizures (5.1%) and CSF leak (3.4%). Important predictors of treatment success in the survival regression model included older age (p = 0.002), smaller preoperative ventricle size (p = 0.009), and greater degree of CPC (p = 0.02). The matching algorithm resulted in 112 matched pairs for ETV+CPC versus shunt alone and 34 matched pairs for ETV+CPC versus ETV alone. ETV+CPC was found to have significantly higher failure rate than shunt placement (p < 0.001). Although ETV+CPC had a similar failure rate compared with ETV alone (p = 0.73), the matched pairs included mostly infants with aqueductal stenosis and miscellaneous other etiologies but very few patients with intraventricular hemorrhage of prematurity. CONCLUSIONS Within a large and broad cohort of North American infants, our data show that overall ETV+CPC appears to have a higher failure rate than shunt alone. Although the ETV+CPC results were similar to ETV alone, this comparison was limited by the small sample size and skewed etiological distribution. Within the ETV+CPC group, greater extent of CPC was associated with treatment success, thereby suggesting that there are subgroups who might benefit from the addition of CPC. Further work will focus on identifying these subgroups.