Publications by authors named "David Wypij"

146 Publications

Grandmothers' endocrine disruption during pregnancy, low birth weight, and preterm birth in third generation.

Int J Epidemiol 2021 Apr 5. Epub 2021 Apr 5.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Diethylstilbestrol (DES) is an endocrine-disrupting pharmaceutical prescribed to pregnant women to prevent pregnancy complications between the 1940s and 1970s. Although DES has been shown in animal studies to have multigenerational effects, only two studies have investigated potential multigenerational effects in humans on preterm birth (PTB), and none on low birthweight (LBW)-major determinants of later life health.

Methods: Nurses' Health Study (NHS) II participants (G1; born 1946-64) reported their mothers' (G0) use of DES while pregnant with them. We used cluster-weighted generalized estimating equations to estimate odds ratios (OR) and 95% confidence intervals (CI) for risk of LBW and PTB among the grandchildren by grandmother use of DES. G1 birthweight and gestational age were considered to explore confounding by indication.

Results: Among 54 334 G0-G1/grandmother-mother pairs, 973 (1.8%) G0 used DES during pregnancy with G1. Of the 128 275 G2 children, 4369 (3.4%) were LBW and 7976 (6.2%) premature. Grandmother (G0) use of DES during pregnancy was associated with an increased risk of G2 LBW [adjusted OR (aOR) = 3.09; 95% CI: 2.57, 3.72], that was reduced when restricted to term births (aOR = 1.59; 95% CI: 1.08, 2.36). The aOR for PTB was 2.88 (95% CI: 2.46, 3.37). Results were essentially unchanged when G1 birthweight and gestational age were included in the model, as well as after adjusting for other potential intermediate variables, such as G2 pregnancy-related factors.

Conclusions: Grandmother use of DES during pregnancy is associated with an increased risk of LBW, predominantly through an increased risk of PTB. Results when considering G1 birth outcomes suggest this does not result from confounding by indication.
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http://dx.doi.org/10.1093/ije/dyab065DOI Listing
April 2021

The Impact of Preintubation Noninvasive Ventilation on Outcomes in Pediatric Acute Respiratory Distress Syndrome.

Crit Care Med 2021 May;49(5):816-827

Department of Pediatrics, Sacred Hearts Children's Hospital, Spokane, WA.

Objectives: There is evidence that noninvasive ventilation decreases the need for invasive mechanical ventilation. However, children with pediatric acute respiratory distress syndrome who fail noninvasive ventilation may have worse outcomes than those who are intubated without exposure to noninvasive ventilation. Our objective was to evaluate the impact of preintubation noninvasive ventilation on children with pediatric acute respiratory distress syndrome.

Design: Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure trial.

Setting: Thirty-one PICUs in the United States.

Patients: Children 2 weeks to 17 years old with pediatric acute respiratory distress syndrome receiving invasive mechanical ventilation, excluding those admitted with tracheostomies.

Interventions: None.

Measurements And Main Results: Of 2,427 subjects receiving invasive mechanical ventilation, preintubation noninvasive ventilation was used in 995 (41%). Compared with subjects without preintubation noninvasive ventilation use, subjects with preintubation noninvasive ventilation use were more likely to have a history of seizures (10% vs 8%; p = 0.04) or cancer (11% vs 6%; p < 0.001) and have moderate or severe pediatric acute respiratory distress syndrome by the end of their first full day of invasive mechanical ventilation (68% vs 60%; p < 0.001). Adjusting for age, severity of illness on PICU admission, and baseline functional status, preintubation noninvasive ventilation use resulted in longer invasive mechanical ventilation duration (median 7.0 vs 6.0 d), longer PICU (10.8 vs 8.9 d), and hospital (17 vs 14 d) lengths of stay, and higher 28-day (5% vs 4%) and 90-day (8% vs 5%) inhospital mortalities (all comparisons p < 0.001). Longer duration of noninvasive ventilation before intubation was associated with worse outcomes.

Conclusions: In children with pediatric acute respiratory distress syndrome, preintubation noninvasive ventilation use is associated with worse outcomes when compared with no preintubation noninvasive ventilation use. These data can be used to inform the design of clinical studies to evaluate best noninvasive ventilation practices in children with pediatric acute respiratory distress syndrome.
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http://dx.doi.org/10.1097/CCM.0000000000004819DOI Listing
May 2021

Nurses' Perceptions of Workload Burden in Pediatric Critical Care.

Am J Crit Care 2021 01;30(1):27-35

Martha A. Q. Curley is the Ruth M. Colket Endowed Chair in Pediatric Nursing, Department of Family and Community Health, School of Nursing, University of Pennsylvania, Department of Anesthesiology and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, and Research Institute, Children's Hospital of Philadelphia.

Background: Quantifying nurses' perceptions of workload burden when managing critically ill patients is essential for designing interventions to ease nurses' workday.

Objectives: To explore pediatric intensive care unit (PICU) nurses' perceptions of their workload when caring for critically ill patients and managing protocolized therapies.

Methods: This study was embedded in a multicenter randomized clinical trial where participants were assigned to receive either lower-target or higher-target glucose control. Nurses from 35 participating PICUs completed a baseline survey containing questions about their perceptions of PICU workload in general. They completed an intervention survey after caring for a study patient. Two workload measurement instruments, the Subjective Workload Assessment Technique (SWAT) and the National Aeronautics and Space Administration-Task Load Index (NASA-TLX), were embedded in these surveys.

Results: Baseline surveys were completed by 1476 PICU nurses, predominantly female with a bachelor's degree and a median (interquartile range) of 6 (3-11) years of nursing experience and 4 (2-9) years of PICU experience. Most nurses (65%) rated time burden as the most important component of their workload, followed by cognitive (22%) or psychological stress (13%) burden. Work performance was selected most often as contributing to workload, followed by cognitive demand, time pressure, effort, and physical demand. Intervention surveys were completed by 73% of enrolled participants (505 of 693). Nurses managing the lower glucose target group reported higher levels of workload burden as measured by the SWAT (P = .002) and NASA-TLX (P < .001).

Conclusions: This study describes the workload burden perceived by PICU nurses when managing critically ill patients in general and when managing protocolized therapies.
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http://dx.doi.org/10.4037/ajcc2021725DOI Listing
January 2021

A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures.

Ann Neurol 2021 02 3;89(2):327-340. Epub 2020 Dec 3.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Objective: In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard-therapy control group.

Methods: A randomized, double-blind, dose-escalation design was employed. Neonates with postmenstrual age 33 to 44 weeks at risk of or with seizures were eligible. Subjects with electroencephalography (EEG)-confirmed seizures after ≥20 and <40mg/kg phenobarbital were randomized to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg/kg bumetanide (treatment). Continuous EEG monitoring data from ≥2 hours before to ≥48 hours after study drug administration (SDA) were analyzed for seizures.

Results: Subjects were randomized to treatment (n = 27) and control (n = 16) groups. Pharmacokinetics were highly variable among subjects and altered by hypothermia. The only statistically significant adverse event was diuresis in treated subjects (48% vs 13%, p = 0.02). One treated (4%) and 3 control subjects died (19%, p = 0.14). Among survivors, 2 of 26 treated subjects (8%) and 0 of 13 control subjects had hearing impairment, as did 1 nonrandomized subject. Total seizure burden varied widely, with much higher seizure burden in treatment versus control groups (median = 3.1 vs 1.2 min/h, p = 0.006). There was significantly greater reduction in seizure burden 0 to 4 hours and 2 to 4 hours post-SDA (both p < 0.01) compared with 2-hour baseline in treatment versus control groups with adjustment for seizure burden.

Interpretation: Although definitive proof of efficacy awaits an appropriately powered phase 3 trial, this randomized, controlled, multicenter trial demonstrated an additional reduction in seizure burden attributable to bumetanide over phenobarbital without increased serious adverse effects. Future trials of bumetanide and other drugs should include a control group and balance seizure severity. ANN NEUROL 2021;89:327-340.
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http://dx.doi.org/10.1002/ana.25959DOI Listing
February 2021

Variations in practice in cardiac neurodevelopmental follow-up programs.

Cardiol Young 2020 Nov 23;30(11):1603-1608. Epub 2020 Oct 23.

Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Over the last two decades, heart centres have developed strategies to meet the neurodevelopmental needs of children with congenital heart disease. Since the publication of guidelines in 2012, cardiac neurodevelopmental follow-up programmes have become more widespread. Local neurodevelopmental programmes, however, have been developed independently in widely varying environments. We sought to characterise variation in structure and personnel in cardiac neurodevelopmental programmes. A 31-item survey was sent to all member institutions of the Cardiac Neurodevelopmental Outcome Collaborative. Multidisciplinary teams at each centre completed the survey. Responses were compiled in a descriptive fashion. Of the 29 invited centres, 23 responded to the survey (79%). Centres reported more anticipated neurodevelopment visits between birth and 5 years of age (median 5, range 2-8) than 5-18 years (median 2, range 0-10) with 53% of centres lacking any standard for routine neurodevelopment evaluations after 5 years of age. Estimated annual neurodevelopment clinic volume ranged from 85 to 428 visits with a median of 16% of visits involving children >5 years of age. Among responding centres, the Bayley Scales of Infant and Toddler Development and Wechsler Preschool and Primary Scale of Intelligence were the most routinely used tests. Neonatal clinical assessment was more common (64%) than routine neonatal brain imaging (23%) during hospitalisation. In response to clinical need and published guidelines, centres have established formal cardiac neurodevelopment follow-up programmes. Centres vary considerably in their approaches to routine screening and objective testing, with many centres currently focussing their resources on evaluating younger patients.
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http://dx.doi.org/10.1017/S1047951120003522DOI Listing
November 2020

Regional Brain Growth Trajectories in Fetuses with Congenital Heart Disease.

Ann Neurol 2021 01 4;89(1):143-157. Epub 2020 Nov 4.

Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.

Objective: Congenital heart disease (CHD) is associated with abnormal brain development in utero. We applied innovative fetal magnetic resonance imaging (MRI) techniques to determine whether reduced fetal cerebral substrate delivery impacts the brain globally, or in a region-specific pattern. Our novel design included two control groups, one with and the other without a family history of CHD, to explore the contribution of shared genes and/or fetal environment to brain development.

Methods: From 2014 to 2018, we enrolled 179 pregnant women into 4 groups: "HLHS/TGA" fetuses with hypoplastic left heart syndrome (HLHS) or transposition of the great arteries (TGA), diagnoses with lowest fetal cerebral substrate delivery; "CHD-other," with other CHD diagnoses; "CHD-related," healthy with a CHD family history; and "optimal control," healthy without a family history. Two MRIs were obtained between 18 and 40 weeks gestation. Random effect regression models assessed group differences in brain volumes and relationships to hemodynamic variables.

Results: HLHS/TGA (n = 24), CHD-other (50), and CHD-related (34) groups each had generally smaller brain volumes than the optimal controls (71). Compared with CHD-related, the HLHS/TGA group had smaller subplate (-13.3% [standard error = 4.3%], p < 0.01) and intermediate (-13.7% [4.3%], p < 0.01) zones, with a similar trend in ventricular zone (-7.1% [1.9%], p = 0.07). These volumetric reductions were associated with lower cerebral substrate delivery.

Interpretation: Fetuses with CHD, especially those with lowest cerebral substrate delivery, show a region-specific pattern of small brain volumes and impaired brain growth before 32 weeks gestation. The brains of fetuses with CHD were more similar to those of CHD-related than optimal controls, suggesting genetic or environmental factors also contribute. ANN NEUROL 2021;89:143-157.
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http://dx.doi.org/10.1002/ana.25940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970443PMC
January 2021

Medical Device-Related Pressure Injuries in Infants and Children.

J Wound Ostomy Continence Nurs 2020 Sep/Oct;47(5):459-469

Judith J. Stellar, MSN, CRNP, PPCNP-BC, CWOCN, Department of Nursing and General Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Natalie R. Hasbani, MPH, Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts. Lindyce A. Kulik, PhD, RN, CWON, Cardiovascular Nursing Patient Services, Boston Children's Hospital, Boston, Massachusetts. Stacey S. Shelley, RN, DNP, Intermountain Healthcare, Salt Lake City, Utah. Sandy Quigley, RN, MSN, CPNP, CWOCN, Department of Nursing and Patient Care Services, Boston Children's Hospital, Boston, Massachusetts. David Wypij, PhD, Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Martha A. Q. Curley, PhD, RN, FAAN, Department of Family and Community Health, School of Nursing, and Department of Anesthesia and Critical Care, Perelman School of Medicine, University of Pennsylvania and the Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Purpose: The purpose of this study was to describe medical device-related pressure injuries (MDRPIs) in hospitalized pediatric patients.

Design: A prospective, descriptive study.

Sample/subjects And Setting: The sample comprised 625 patients cared for in 8 US pediatric hospitals. Participants were aged preterm to 21 years, on bed rest for at least 24 hours, and had a medical device in place.

Methods: Two nursing teams, blinded to the other's assessments, worked in tandem to assess pressure injury risk, type of medical devices in use, and preventive interventions for each medical device. They also identified the presence, location, and stage of MDRPI. Subjects were observed up to 8 times over 4 weeks, or until discharge, whichever occurred first.

Results: Of 625 enrolled patients, 42 (7%) developed 1 or more MDRPIs. Two-thirds of patients with MDRPIs were younger than 8 years. Patients experiencing MDRPIs had higher acuity scores on hospital admission, were more frequently cognitively and/or functionally impaired, or were extreme in body mass index. Respiratory devices caused the most injuries (6.19/1000 device-days), followed by immobilizers (2.40/1000 device-days), gastric tubes (2.24/1000 device-days), and external monitoring devices (1.77/1000 device-days). Of the 6336 devices in place, 36% did not have an MDRPI preventive intervention in place. Clinical variables contributing to MDRPI development included intensive care unit care (odds ratio [OR] 8.9, 95% confidence interval [CI] 1.9-43.6), use of neuromuscular blockade (OR 3.7, 95% CI 1.7-7.8), and inotropic/vasopressor medications (OR 2.7, 95% CI 1.7-4.3). Multivariable analysis indicated that Braden QD scores alone predicted MDRPI development.

Conclusion: Medical devices are common in hospitalized infants and children and these medical devices place patients at risk for MDRPI.
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http://dx.doi.org/10.1097/WON.0000000000000683DOI Listing
September 2020

Randomized Controlled Trial of Working Memory Intervention in Congenital Heart Disease.

J Pediatr 2020 12 19;227:191-198.e3. Epub 2020 Aug 19.

Department of Psychiatry, Boston Children's Hospital, Boston, MA; Department of Psychiatry, Harvard Medical School, Boston, MA; Department of Neurology, Boston Children's Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA.

Objectives: To evaluate the efficacy of Cogmed Working Memory Training compared with the standard of care to improve executive function and social outcomes in adolescents with congenital heart disease (CHD) who underwent open-heart surgery in infancy and to identify factors associated with changes in outcomes following the intervention.

Study Design: In a single-center, randomized controlled trial, adolescents (13-16 years) with CHD were randomly assigned to either Cogmed (home-based 45-minutes sessions for 5-8 weeks) or to a control group. The primary outcome was working memory. Secondary outcomes included inhibitory control and cognitive flexibility as well as parent-reported executive function, symptoms of attention deficit hyperactivity disorder, and social outcomes. All measures were assessed at baseline, post-treatment (1-3 weeks post-training) and at 3-month follow-up. Data were analyzed using an intention-to-treat approach.

Results: Sixty adolescents with CHD participated (28 assigned to Cogmed). No improvement at the post-treatment or 3-month follow-up assessments was found for the primary outcome measure of working memory. Compared with the control group, participants assigned to the intervention demonstrated benefits in inhibitory control and attention at the 3-month follow-up (P = .02) and in parent-reported cognitive regulatory skills at post-treatment and 3-month follow-up (P = .02 and P = .04, respectively). Preterm birth, biventricular CHD, and history of attention deficit hyperactivity disorder diagnosis were associated with improved response to the intervention.

Conclusions: Cogmed intervention produced improvements in the self-regulatory control abilities of adolescents with CHD. The training did not enhance other areas of executive function or behavioral outcomes. Further studies are needed to evaluate the longer-term potential benefits to other domains.

Trial Registration: Clinicaltrials.gov: NCT02759263.
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http://dx.doi.org/10.1016/j.jpeds.2020.08.038DOI Listing
December 2020

Association of Race and Ethnicity with Sedation Management in Pediatric Intensive Care.

Ann Am Thorac Soc 2021 01;18(1):93-102

School of Nursing and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.

Racial disparities in pain management have been previously reported for children receiving emergency care. To determine whether patient race or ethnicity is associated with the broader goal of pain management and sedation among pediatric patients mechanically ventilated for acute respiratory failure. Planned secondary analysis of RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure). RESTORE, a cluster-randomized clinical trial conducted in 31 U.S. pediatric intensive care units, compared protocolized sedation management (intervention arm) with usual care (control arm). Participants included 2,271 children identified as non-Hispanic white (white,  = 1,233), non-Hispanic Black (Black,  = 502), or Hispanic of any race (Hispanic,  = 536). Within each treatment arm, neither opioid nor benzodiazepine selection, nor cumulative dosing, differed significantly among race and ethnicity groups. Black patients experienced fewer days with an episode of pain (compared with white patients in the control arm and with Hispanic patients in the intervention arm) and experienced less iatrogenic withdrawal syndrome (compared with white patients in either arm or with Hispanic patients in the intervention arm). The percentage of days awake and calm while intubated was not significantly different in pairwise comparisons by race and ethnicity groups in either the control arm (median: white, 75%; Black, 71%; Hispanic, 75%) or the intervention arm (white, 86%; Black, 88%; Hispanic, 85%). Across multiple measures, our study found scattered differences in sedation management among critically ill Black, Hispanic, and white children that did not consistently favor any group. However, racial disparities related to implicit bias cannot be completely ruled out.Clinical trial registered with clinicaltrials.gov (NCT00814099).
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http://dx.doi.org/10.1513/AnnalsATS.201912-872OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780975PMC
January 2021

Long-Term Neurobehavioral and Quality of Life Outcomes of Critically Ill Children after Glycemic Control.

J Pediatr 2020 03 3;218:57-63.e5. Epub 2020 Jan 3.

Division of Medical Critical Care, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA.

Objectives: To investigate adaptive skills, behavior, and quality health-related quality of life in children from 32 centers enrolling in the Heart And Lung Failure-Pediatric INsulin Titration randomized controlled trial.

Study Design: This prospective longitudinal cohort study compared the effect of 2 tight glycemic control ranges (lower target, 80-100 mg/dL vs higher target, 150-180 mg/dL) 1-year neurobehavioral and health-related quality of life outcomes. Subjects had confirmed hyperglycemia and cardiac and/or respiratory failure. Patients aged 2-16 years old enrolled between April 2012 and September 2016 were studied at 1 year after intensive care discharge. The primary outcome, adaptive skills, was assessed using the Vineland Adaptive Behavior Scale. Behavior and health-related quality of life outcomes were assessed as secondary outcomes using the Pediatric Quality of Life and Child Behavior Checklist at baseline and 1-year follow-up. Group differences were evaluated using regression models adjusting for age category, baseline overall performance, and risk of mortality.

Results: Of 369 eligible children, 358 survived after hospital discharge and 214 (60%) completed follow-up. One-year Vineland Adaptive Behavior Scale-II composite scores were not different (mean ± SD, 79.9 ± 25.5 vs 79.4 ± 26.9, lower vs higher target; P = .20). Improvement in Pediatric Quality of Life total health from baseline was greater in the higher target group (adjusted mean difference, 8.2; 95% CI, 1.1-15.3; P = .02).

Conclusions: One-year adaptive behavior in critically ill children with lower vs higher target glycemic control did not differ. The higher target group demonstrated improvement from baseline in overall health. This study affirms the lack of benefit of lower glucose targeting.

Trial Registration: ClinicalTrials.gov: NCT01565941.
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http://dx.doi.org/10.1016/j.jpeds.2019.10.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122648PMC
March 2020

Outcomes Associated With Multiple Organ Dysfunction Syndrome in Critically Ill Children With Hyperglycemia.

Pediatr Crit Care Med 2019 12;20(12):1147-1156

Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.

Objectives: Patterns and outcomes of multiple organ dysfunction syndrome are unknown in critically ill children with hyperglycemia. We aimed to determine whether tight glycemic control to a lower vs. higher range influenced timing, duration, or resolution of multiple organ dysfunction syndrome as well as characterize the clinical outcomes of subgroups of multiple organ dysfunction syndrome in children enrolled in the Heart And Lung Failure-Pediatric INsulin Titration trial.

Design: Planned secondary analysis of the multicenter Heart And Lung Failure-Pediatric INsulin Titration trial.

Setting: Thirty-five PICUs.

Patients: Critically ill children with hyperglycemia who received the Heart And Lung Failure-Pediatric INsulin Titration protocol from 2012 to 2016.

Interventions: Randomization to a lower versus higher glucose target group.

Measurements And Main Results: Of 698 patients analyzed, 48 (7%) never developed multiple organ dysfunction syndrome, 549 (79%) had multiple organ dysfunction syndrome without progression, 32 (5%) developed new multiple organ dysfunction syndrome, and 69 (10%) developed progressive multiple organ dysfunction syndrome. Of those whose multiple organ dysfunction syndrome resolved, 192 (34%) experienced recurrent multiple organ dysfunction syndrome. There were no significant differences in the proportion of multiple organ dysfunction syndrome subgroups between Heart And Lung Failure-Pediatric INsulin Titration glucose target groups. However, patients with new or progressive multiple organ dys function syndrome had fewer ICU-free days through day 28 than those without new or progressive multiple organ dysfunction syndrome, and progressive multiple organ dysfunction syndrome patients had fewer ICU-free days than those with new multiple organ dysfunction syndrome: median 25.1 days for never multiple organ dysfunction syndrome, 20.2 days for multiple organ dysfunction syndrome without progression, 18.6 days for new multiple organ dysfunction syndrome, and 0 days for progressive multiple organ dysfunction syndrome (all comparisons p < 0.001). Patients with recurrent multiple organ dysfunction syndrome experienced fewer ICU-free days than those without recurrence (median, 11.2 vs 22.8 d; p < 0.001).

Conclusions: Tight glycemic control target range was not associated with differences in the proportion of new, progressive, or recurrent multiple organ dysfunction syndrome. New or progressive multiple organ dysfunction syndrome was associated with poor clinical outcomes, and progressive multiple organ dysfunction syndrome was associated with worse outcomes than new multiple organ dysfunction syndrome. In future studies, new multiple organ dysfunction syndrome and progressive multiple organ dysfunction syndrome may need to be considered separately, as they represent distinct subgroups with different, potentially modifiable risk factors. Patients with recurrent multiple organ dysfunction syndrome represent a newly characterized, high-risk group which warrants attention in future research.
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http://dx.doi.org/10.1097/PCC.0000000000002151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895434PMC
December 2019

Early Enteral Nutrition Is Associated With Improved Clinical Outcomes in Critically Ill Children: A Secondary Analysis of Nutrition Support in the Heart and Lung Failure-Pediatric Insulin Titration Trial.

Pediatr Crit Care Med 2020 03;21(3):213-221

Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA.

Objectives: The impact of early enteral nutrition on clinical outcomes in critically ill children has not been adequately described. We hypothesized that early enteral nutrition is associated with improved clinical outcomes in critically ill children.

Design: Secondary analysis of the Heart and Lung Failure-Pediatric Insulin Titration randomized controlled trial.

Setting: Thirty-five PICUs.

Patients: Critically ill children with hyperglycemia requiring inotropic support and/or invasive mechanical ventilation who were enrolled for at least 48 hours with complete nutrition data.

Interventions: Subjects received nutrition via guidelines that emphasized enteral nutrition and were classified into early enteral nutrition (enteral nutrition within 48 hr of study randomization) and no early enteral nutrition (enteral nutrition after 48 hr of study randomization, or no enteral nutrition at any time).

Measurements And Main Results: Of 608 eligible subjects, 331 (54%) received early enteral nutrition. Both early enteral nutrition and no early enteral nutrition groups had similar daily caloric intake over the first 8 study days (median, 36 vs 36 kcal/kg/d; p = 0.93). After controlling for age, body mass index z scores, primary reason for ICU admission, severity of illness, and mean Vasopressor-Inotrope Score at the time of randomization, and adjusting for site, early enteral nutrition was associated with lower 90-day hospital mortality (8% vs 17%; p = 0.007), more ICU-free days (median, 20 vs 17 d; p = 0.02), more hospital-free days (median, 8 vs 0 d; p = 0.003), more ventilator-free days (median, 21 vs 19 d; p = 0.003), and less organ dysfunction (median maximum Pediatric Logistic Organ Dysfunction, 11 vs 12; p < 0.001).

Conclusions: In critically ill children with hyperglycemia requiring inotropic support and/or mechanical ventilation, early enteral nutrition was independently associated with better clinical outcomes.
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http://dx.doi.org/10.1097/PCC.0000000000002135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060827PMC
March 2020

Hospital-Acquired Pressure Injuries in Children With Congenital Heart Disease: Prevalence and Associated Factors.

Pediatr Crit Care Med 2019 11;20(11):1048-1056

Department of Family and Community Health, School of Nursing, University of Pennsylvania, Philadelphia, PA.

Objectives: To explore the prevalence, location, and clinical factors associated with hospital-acquired pressure injuries among pediatric patients with congenital heart disease.

Design: Secondary analysis of data from a multicenter prospective cohort study of pediatric pressure injury risk, including patients with congenital heart disease.

Setting: Eight acute care academic pediatric hospitals.

Patients: Patients were preterm to 21 years old with congenital heart disease and on bed rest for at least 24 hours after hospital admission with a medical device attached to or traversing the skin or mucous membrane.

Interventions: None.

Measurements And Main Results: Patients were evaluated for a maximum of eight observations during a 4-week period to identify Braden QD risk and pressure injury development. Hospital-acquired pressure injuries were staged according to the National Pressure Ulcer Advisory Panel guidelines. Stepwise logistic regression was used to explore risk factors associated with hospital-acquired pressure injuries development, accounting for site as a cluster variable using generalized estimating equations. Overall, 279 pediatric cardiac patients provided 919 observations (median, 2 per patient [interquartile range, 2-5 per patient]). Thirty-eight hospital-acquired pressure injuries occurred in 27 patients (9.7%). Most injuries (28/38 [74%]) were related to medical devices. The most common medical devices that caused injury were oxygen saturation probes. The remaining hospital-acquired pressure injuries were immobility-related pressure injuries (10/38 [26%]) located primarily on the buttock, sacrum, or coccyx (5/10 [50%]). In multivariable analyses, being non-Hispanic white (odds ratio, 3.54; 95% CI, 2.15-5.84), experiencing operating room time greater than 4 hours (odds ratio, 2.91; 95% CI, 1.13-7.49), having oxygen saturation levels less than 85% (odds ratio, 2.65; 95% CI, 1.01-6.96), and having worse Braden QD scores (odds ratio, 1.25 per 1 point increase; 95% CI, 1.17-1.34) were significantly associated with hospital-acquired pressure injuries development.

Conclusions: In this multicenter observational study of pediatric patients with congenital heart disease, we describe a hospital-acquired pressure injury prevalence of 9.7% with approximately 75% of injuries related to medical devices. These data can be used to inform practice and target interventions to decrease pressure injury risk and prevent pressure injuries in this vulnerable pediatric population.
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http://dx.doi.org/10.1097/PCC.0000000000002077DOI Listing
November 2019

Abnormal Left-Hemispheric Sulcal Patterns Correlate with Neurodevelopmental Outcomes in Subjects with Single Ventricular Congenital Heart Disease.

Cereb Cortex 2020 03;30(2):476-487

Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA.

Neurodevelopmental abnormalities are the most common noncardiac complications in patients with congenital heart disease (CHD). Prenatal brain abnormalities may be due to reduced oxygenation, genetic factors, or less commonly, teratogens. Understanding the contribution of these factors is essential to improve outcomes. Because primary sulcal patterns are prenatally determined and under strong genetic control, we hypothesized that they are influenced by genetic variants in CHD. In this study, we reveal significant alterations in sulcal patterns among subjects with single ventricle CHD (n = 115, 14.7 ± 2.9 years [mean ± standard deviation]) compared with controls (n = 45, 15.5 ± 2.4 years) using a graph-based pattern-analysis technique. Among patients with CHD, the left hemisphere demonstrated decreased sulcal pattern similarity to controls in the left temporal and parietal lobes, as well as the bilateral frontal lobes. Temporal and parietal lobes demonstrated an abnormally asymmetric left-right pattern of sulcal basin area in CHD subjects. Sulcal pattern similarity to control was positively correlated with working memory, processing speed, and executive function. Exome analysis identified damaging de novo variants only in CHD subjects with more atypical sulcal patterns. Together, these findings suggest that sulcal pattern analysis may be useful in characterizing genetically influenced, atypical early brain development and neurodevelopmental risk in subjects with CHD.
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http://dx.doi.org/10.1093/cercor/bhz101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306172PMC
March 2020

Early Neurodevelopmental Outcomes in Children Supported with ECMO for Cardiac Indications.

Pediatr Cardiol 2019 Jun 11;40(5):1072-1083. Epub 2019 May 11.

Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.

Extracorporeal membrane oxygenation (ECMO) is lifesaving for many critically ill children with congenital heart disease (CHD). However, limited information is available about their ensuing neurodevelopmental (ND) outcomes. We describe early ND outcomes in a cohort of children supported with ECMO for cardiac indications. Twenty-eight patients supported with ECMO at age < 36 months underwent later ND testing at 12-42 months of age using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). ND scores were compared with normative means and with ND outcomes of a matched cohort of 79 children with CHD undergoing cardiac surgery but not requiring ECMO support. Risk factors for worse ND outcomes were identified using multivariable linear regression models. Cardiac ECMO patients had ND scores at least one standard deviation below the normative mean in the gross motor (61%), language (43%), and cognitive (29%) domains of the Bayley-III. Cardiac ECMO patients had lower scores on the motor, language, and cognitive domains as compared to the matched non-ECMO group and clinically important (1/2 SD) differences in the motor domain persisted after controlling for primary caregiver education and number of cardiac catheterizations. Risk factors of worse ND outcomes among cardiac ECMO patients in more than one developmental domain included older age at first cannulation and more cardiac catheterization and cardiac surgical procedures prior to ND assessment. Overall, children supported on ECMO for cardiac indications have significant developmental delays and warrant close ND follow-up.
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http://dx.doi.org/10.1007/s00246-019-02115-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876703PMC
June 2019

Risk Factors for Functional Decline and Impaired Quality of Life after Pediatric Respiratory Failure.

Am J Respir Crit Care Med 2019 10;200(7):900-909

School of Nursing and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.

Poor outcomes of adults surviving critical illness are well documented, but data in children are limited. To identify factors associated with worse postdischarge function and health-related quality of life (HRQL) after pediatric acute respiratory failure. We assessed functional status at baseline, discharge, and 6 months after pediatric ICU discharge and HRQL 6 months after discharge in 2-week- to 17-year-olds mechanically ventilated for acute respiratory failure in the (Randomized Evaluation of Sedation Titration for Respiratory Failure) trial. We assessed HRQL via Infant and Toddler Quality of Life Questionnaire-97 (<2 yr old) or Pediatric Quality of Life Inventory (≥2 yr old). We categorized patients with normal baseline function as having impaired HRQL if scores were greater than 1 SD below mean norms for Infant and Toddler Quality of Life Questionnaire-97 growth and development or Pediatric Quality of Life Inventory total score. One-fifth ( = 192) of 949 patients declined in function from baseline to postdischarge; 20% (55/271) had impaired growth and development; 19% (64/343) had impaired HRQL. In multivariable analyses, decline in function was associated with baseline impaired function, prematurity, cancer, respiratory failure etiology, ventilation duration, and clonidine (odds ratio [OR] = 2.14; 95% confidence interval [CI] = 1.22-3.76). Independent predictors of impaired growth and development included methadone (OR = 2.27; 95% CI = 1.18-4.36) and inadequate pain management (OR = 2.94; 95% CI = 1.39-6.19). Impaired HRQL was associated with older age, non-white or Hispanic race, cancer, and inadequate sedation management (OR = 3.15; 95% CI = 1.74-5.72). Postdischarge morbidity after respiratory failure is common and associated with admission factors, exposure to critical care therapies, and pain and sedation management.
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http://dx.doi.org/10.1164/rccm.201810-1881OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812438PMC
October 2019

The Bayley-III scale may underestimate neurodevelopmental disability after cardiac surgery in infants.

Eur J Cardiothorac Surg 2020 01;57(1):63-71

Department of Cardiothoracic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Objectives: Neurodevelopmental disability is the most common complication among congenital heart surgery survivors. The Bayley scales are standardized instruments to assess neurodevelopment. The most recent edition (Bayley Scales of Infant and Toddler Development 3rd Edition, Bayley-III) yields better-than-expected scores in typically developing and high-risk infants than the second edition (Bayley Scales of Infant Development 2nd Edition, BSID-II). We compared BSID-II and Bayley-III scores in infants undergoing cardiac surgery.

Methods: We evaluated 2198 infants who underwent operations with cardiopulmonary bypass between 1996 and 2009 at 26 institutions. We used propensity score matching to limit confounding by indication in a subset of patients (n = 705).

Results: Overall, unadjusted Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores (90.7 ± 17.2 vs 77.6 ± 18.8, P < 0.001), and unadjusted Bayley-III composite cognitive and language scores were higher than BSID-II Mental Development Index scores (92.0 ± 15.4 vs 88.2 ± 16.7, P < 0.001). In the propensity-matched analysis, Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores [absolute difference 14.1, 95% confidence interval (CI) 11.7-17.6; P < 0.001] and the Bayley-III classified fewer children as having severe [odds ratio (OR) 0.24; 95% CI 0.14-0.42] or mild-to-moderate impairment (OR 0.21; 95% CI 0.14-0.32). The composite of Bayley-III cognitive and language scores was higher than BSID-II Mental Development Index scores (absolute difference 4.0, 95% CI 1.4-6.7; P = 0.003), but there was no difference between Bayley editions in the proportion of children classified as having severe cognitive and language impairment.

Conclusions: The Bayley-III yielded higher scores than the BSID-II and classified fewer children as severely impaired. The systematic bias towards higher scores with the Bayley-III precludes valid comparisons between early and contemporary cardiac surgery cohorts.
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http://dx.doi.org/10.1093/ejcts/ezz123DOI Listing
January 2020

Short-Term Adverse Outcomes Associated With Hypoglycemia in Critically Ill Children.

Crit Care Med 2019 05;47(5):706-714

Division of Medical Critical Care, Department of Pediatrics, Boston Children's Hospital, Boston, MA.

Objectives: Previous studies report worse short-term outcomes with hypoglycemia in critically ill children. These studies relied on intermittent blood glucose measurements, which may have introduced detection bias. We analyzed data from the Heart And Lung Failure-Pediatric INsulin Titration trial to determine the association of hypoglycemia with adverse short-term outcomes in critically ill children.

Design: Nested case-control study.

Setting: Thirty-five PICUs. A computerized algorithm that guided the timing of blood glucose measurements and titration of insulin infusion, continuous glucose monitors, and standardized glucose infusion rates were used to minimize hypoglycemia.

Patients: Nondiabetic children with cardiovascular and/or respiratory failure and hyperglycemia. Cases were children with any hypoglycemia (blood glucose < 60 mg/dL), whereas controls were children without hypoglycemia. Each case was matched with up to four unique controls according to age group, study day, and severity of illness.

Interventions: None.

Measurements And Main Results: A total of 112 (16.0%) of 698 children who received the Heart And Lung Failure-Pediatric INsulin Titration protocol developed hypoglycemia, including 25 (3.6%) who developed severe hypoglycemia (blood glucose < 40 mg/dL). Of these, 110 cases were matched to 427 controls. Hypoglycemia was associated with fewer ICU-free days (median, 15.3 vs 20.2 d; p = 0.04) and fewer hospital-free days (0 vs 7 d; p = 0.01) through day 28. Ventilator-free days through day 28 and mortality at 28 and 90 days did not differ between groups. More children with insulin-induced versus noninsulin-induced hypoglycemia had zero ICU-free days (35.8% vs 20.9%; p = 0.008). Outcomes did not differ between children with severe versus nonsevere hypoglycemia or those with recurrent versus isolated hypoglycemia.

Conclusions: When a computerized algorithm, continuous glucose monitors and standardized glucose infusion rates were used to manage hyperglycemia in critically ill children with cardiovascular and/or respiratory failure, severe hypoglycemia (blood glucose < 40 mg/dL) was uncommon, but any hypoglycemia (blood glucose < 60 mg/dL) remained common and was associated with worse short-term outcomes.
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http://dx.doi.org/10.1097/CCM.0000000000003699DOI Listing
May 2019

Improving neurodevelopmental outcomes in children with congenital heart disease: protocol for a randomised controlled trial of working memory training.

BMJ Open 2019 02 19;9(2):e023304. Epub 2019 Feb 19.

Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.

Introduction: Executive function (EF) impairments are among the most prevalent neurodevelopmental morbidities in youth with congenital heart disease (CHD). To date, no studies have investigated the efficacy of cognitive interventions to improve EF outcomes in children with CHD.

Methods And Analysis: This is a single-centre, single-blinded, two-arm randomised controlled trial to test the efficacy of Cogmed Working Memory Training (Cogmed) versus standard of care in children with CHD after open-heart surgery in infancy. Participants will consist of 100 children with CHD aged 7-12 years who underwent open-heart surgery before the age of 12 months. Participants are randomly allocated to either an intervention group including training on the home-based Cogmed intervention for a duration of approximately 5 weeks or a control group who receive the standard of care. We will evaluate the efficacy of Cogmed at post-treatment and 3 months after completion of the intervention. Baseline, post-treatment and 3-month follow-up assessments will include specific measures of EF, cognitive and social functioning, and attention deficit hyperactivity disorder (ADHD) symptoms. The primary outcome of this study is the change in standardised mean score on the List Sorting Working Memory test from the National Institutes of Health Toolbox for the Assessment of Neurological and Behavioral Function. Secondary outcomes include measures of social skills, inhibitory control, cognitive flexibility and behavioural EF as well as ADHD symptoms as measured by the Behavior Rating Inventory of Executive Function, Second Edition, and the Conners Third Edition. The efficacy of the intervention will be evaluated by comparing within-subject differences (baseline to post-treatment, baseline to 3-month follow-up) between the two groups using an intention-to-treat analysis.

Ethics And Dissemination: This study has received Institutional Review Board (IRB) approval from Boston's Children's Hospital IRB (P00022440) and the Human Protection Agency from the US Department of Defense.

Trial Registration Number: NCT03023644; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-023304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377570PMC
February 2019

Statistical Analysis of Dependent Observations in the Orthopaedic Sports Literature.

Orthop J Sports Med 2019 Jan 2;7(1):2325967118818410. Epub 2019 Jan 2.

Division of Sports Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.

Background: Orthopaedic research may involve multiple observations from the same patient because of bilateral joint involvement, multiple disease sites, or recurrent disease episodes. These situations violate statistical independence and need to be accounted for via appropriate statistical techniques. Failing to account for nonindependence may lead to biased and overly precise effect estimates.

Purpose: To determine the degree to which orthopaedic sports medicine studies analyze dependent observations and the proportion of these failing to account for nonindependence.

Study Design: Cross-sectional study.

Methods: Clinical studies published in from 2012 to 2017 were reviewed. Studies reporting nonindependent observations because of multiple extremity involvement or multiple disease episodes were identified. Methods to account for nonindependence were recorded. Studies violating the assumption of independence were identified and stratified by study design, level of evidence, body part involved, and inclusion of a statistician coauthor. Univariate logistic regression was used to determine whether these factors were associated with violations of statistical independence.

Results: After screening 1016 articles, 886 clinical studies were reviewed. A total of 135 (15%) studies analyzed dependent observations, and 111 (82%) of these failed to account for nonindependence. Relative to the knee, studies of the hip (odds ratio [OR], 0.21; = .02) and the thigh or leg (OR, 0.03; = .004) were less likely to violate statistical independence. Study design ( = .03) was also associated with violations of statistical independence. Among studies that analyzed dependent observations, the median proportion of dependent observations relative to the total number of observations in each study was 0.07 (interquartile range, 0.04-0.12).

Conclusion: The analysis of dependent observations is common in the orthopaedic sports literature, but most studies do not adjust for nonindependence in these situations. Investigators should be aware of incorrect inferences arising from nonindependence and how to statistically adjust for dependent data.
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http://dx.doi.org/10.1177/2325967118818410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317150PMC
January 2019

Correction to: Methods in the design and implementation of the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial.

Trials 2019 01 7;20(1):17. Epub 2019 Jan 7.

Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.

AbstractFollowing publication of the original article [1], the authors notified us of a typing error in spelling Dr. Asario's name. The original publication has been corrected.
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http://dx.doi.org/10.1186/s13063-018-3154-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323764PMC
January 2019

How Often Do Orthopaedic Matched Case-Control Studies Use Matched Methods? A Review of Methodological Quality.

Clin Orthop Relat Res 2019 03;477(3):655-662

D. G. LeBrun, Hospital for Special Surgery, New York, NY, USA D. G. LeBrun, T. Tran, D. Wypij , Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA T. Tran, Alpert Medical School of Brown University, Providence, RI, USA M. S. Kocher, Division of Sports Medicine, Boston Children's Hospital, Boston, MA, USA.

Background: Case-control studies are a common method of analyzing associations between clinical outcomes and potential risk factors. Matching cases to controls based on known confounding variables can decrease bias and allow investigators to assess the association of interest with increased precision. However, the analysis of matched data generally requires matched statistical methods, and failure to use these methods can lead to imprecise or biased results. The appropriate use of matched statistical methods in orthopaedic case-control studies has not been documented.

Questions/purposes: (1) What proportion of matched orthopaedic case-control studies use the appropriate matched statistical analyses? (2) What study factors are associated with the use of appropriate matched statistical tests?

Methods: All matched case-control studies published in the top 10 orthopaedic journals according to impact factor from 2007 to 2016 were identified by literature review. Studies using appropriate statistical techniques were identified by two independent evaluators; discrepancies were settled by a third evaluator, all with advanced training in biostatistics. The number of studies using appropriate matched statistical methods was compared with the number of studies reviewed. Logistic regression was used to identify key study factors (including journal, publication year, rank according to impact factor, number of matching factors, number of controls per case, and the inclusion of a biostatistician coauthor) associated with the use of appropriate statistical methods. Three hundred nineteen articles that were initially classified as case-control studies were screened, yielding 83 matched case-control studies. One hundred two of the excluded articles were cohort or cross-sectional studies that were misclassified as case-control studies. The median number of matching factors was 3.0 (range, 1-10) and the median number of controls per case was 1.0 (range, 0.5-6.0). Thirty studies (36%) had a statistician coauthor.

Results: Thirty of the 83 included studies (36%) used appropriately matched methods throughout, 11 (13%) used matched methods for multivariable but not univariable analyses, and 42 (51%) used only unmatched methods, which we considered inappropriate. After controlling for the number of controls per case and publication year, we found that the inclusion of a statistician coauthor (70% versus 38%; odds ratio, 3.6; 95% confidence interval, 1.4-20.3; p = 0.01) and journal were associated with the use of appropriate methods.

Conclusions: Although matched case-control studies can be statistically more efficient study designs, in that they are capable of generating more precise effect size estimates than other kinds of retrospective research, most orthopaedic case-control studies use inappropriate statistical methods in their analyses. Additionally, the high degree of study misclassification indicates a need to more rigorously define differences among case-control, cohort, and cross-sectional study designs.

Clinical Relevance: Failing to use matched statistical tests may lead to imprecise and/or biased effect estimates, which may lead to a tendency to overestimate or underestimate associations between possible risk factors and clinically relevant outcomes. Orthopaedic researchers should be cognizant of the risks and benefits of matching and should consult individuals with biostatistical expertise as needed to ensure that their statistical methods are appropriate and methodologically rigorous.
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http://dx.doi.org/10.1097/CORR.0000000000000612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382197PMC
March 2019

Ascending Aorta Size at Birth Predicts White Matter Microstructure in Adolescents Who Underwent Fontan Palliation.

J Am Heart Assoc 2018 12;7(24):e010395

2 Department of Neurology Boston Children's Hospital Boston MA.

Background In neonates with single ventricle, smaller ascending aorta diameter is associated with cerebral white matter ( WM ) microstructural abnormalities. We sought to determine whether this association persists into adolescence. Methods and Results Ascending aorta Z scores were obtained from first postnatal echocardiogram. Brain magnetic resonance imaging with diffusion tensor imaging was acquired in adolescence and used to obtain fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity in 33 WM tract regions of interest. Partial Pearson correlation coefficients were evaluated for associations between ascending aorta Z scores and WM microstructure measures, adjusting for sex, age at magnetic resonance imaging, scanner field strength, and Norwood status. Among 42 single ventricle patients aged 10 to 19 years, 31 had undergone the Norwood procedure as neonates. Lower ascending aorta Z scores were associated with lower fractional anisotropy in bilateral pontine crossing tracts ( P=0.02), inferior fronto-occipital fasciculus ( P=0.02), and inferior longitudinal fasciculus ( P=0.01); left cingulum-cingulate bundle ( P=0.01), superior longitudinal fasciculus ( P=0.04), and superior longitudinal fasciculus-temporal component ( P=0.01); and right cingulum-hippocampal bundle (P=0.009) and inferior cerebellar peduncle ( P=0.01). Lower ascending aorta Z scores were associated with higher radial diffusivity and mean diffusivity in a similar regional pattern but not with axial diffusivity. Conclusions In adolescents with single ventricle, smaller aorta diameter at birth is associated with abnormalities of WM microstructure in a subset of WM tracts, mostly those located in deeper brain regions. Our findings suggest that despite multiple intervening medical or surgical procedures, prenatal cerebral blood flow may have a lasting influence on WM microstructure in single-ventricle patients.
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http://dx.doi.org/10.1161/JAHA.118.010395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405606PMC
December 2018

Methods in the design and implementation of the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial.

Trials 2018 12 17;19(1):687. Epub 2018 Dec 17.

Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.

Background: Few papers discuss the pragmatics of conducting large, cluster randomized clinical trials. Here we describe the sequential steps taken to develop methods to implement the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) trial that tested the effect of a nurse-implemented, goal-directed, comfort algorithm on clinical outcomes in pediatric patients with acute respiratory failure.

Methods: After development in a single institution, the RESTORE intervention was pilot-tested in two pediatric intensive care units (PICUs) to evaluate safety and feasibility. After the pilot, the RESTORE intervention was simplified to enhance reproducibility across multiple PICUs. The final RESTORE trial was developed as a cluster randomized clinical trial where the unit of randomization was the PICU, stratified by PICU size, and the unit of inference was the patient. Study execution was revised based on our Data and Safety Monitoring Board's recommendation to consult with the Department of Health and Human Services' Office of Human Research Protection (OHRP) on how best to consent eligible subjects. OHRP deemed that the RESTORE intervention posed greater than minimal risk and that all enrolled subjects provide consent reflecting their level of participation.

Results: Thirty-one PICUs of varying size, organization and academic affiliation participated and over 2800 critically ill infants and children supported on mechanical ventilation for acute pulmonary disease were enrolled. The primary outcome for the trial was the duration of mechanical ventilation; secondary outcomes included time awake and comfortable, total sedative exposure and iatrogenic withdrawal symptoms. Throughout the clinical trial the investigative team worked to maintain treatment fidelity, enrollment milestones and co-investigator enthusiasm. We considered the potential impact of competing clinical trials through a decision-making framework.

Conclusions: The RESTORE clinical trial was a large and complex multicenter study that has provided the necessary evidence to guide sedation practices in the field of pediatric critical care. Specific issues that were unique to this trial included level of consent, adding clinical sites to augment enrollment and evaluating the potential impact of competing clinical trials.

Trial Registration: ClinicalTrials.gov , Identifiers: Pilot trial: NCT00142766 ; Retrospectively registerd on 2 September 2005. Cluster randomized trial: NCT00814099 . Registered on 23 December 2008.
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http://dx.doi.org/10.1186/s13063-018-3075-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296093PMC
December 2018

Timing of Antibiotic Administration in Pediatric Sepsis.

Pediatr Emerg Care 2020 Oct;36(10):464-467

From the Boston Children's Hospital, Boston, MA.

Objectives: Antibiotic administration within 1 hour of hypotension has been shown to reduce mortality. It is unknown whether antibiotics before hypotension in children who eventually meet criteria for septic shock improves outcomes. This study assesses whether antibiotic timing from the time of meeting criteria for sepsis in children with septic shock impacts morbidity and mortality.

Methods: This is a retrospective study of children 18 years or younger presenting to a tertiary free-standing children's hospital emergency department with sepsis that subsequently progressed to septic shock and were admitted to an intensive care unit from 2008 to 2012. The time when the patient met criteria for sepsis to the time of first antibiotic administration was assessed and correlated with patient morbidity and mortality.

Results: Among 135 children (median age, 13.1 years), 34 (25%) were previously healthy, whereas 49 (36%) had 2 or more medical comorbidities. Twenty-seven children (20%) had positive blood cultures, 17 (13%) had positive urine cultures, and 34 (25%) had chest x-ray findings that were interpreted as pneumonia. Among the 42 (31%) with antibiotics within 1 hour from criteria for sepsis, there was higher mortality (4/42 vs 0/93, P = 0.009), more organ dysfunction, longer time on a vasoactive infusion, and increased intensive care unit and hospital lengths of stay (all P < 0.05).

Conclusions: Children with criteria for sepsis who subsequently progressed to septic shock who received antibiotics within 1 hour of meeting sepsis criteria had increased mortality, length of stay, and organ dysfunction.
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http://dx.doi.org/10.1097/PEC.0000000000001663DOI Listing
October 2020

Neurodevelopmental assessment of infants with congenital heart disease in the early postoperative period.

Congenit Heart Dis 2019 Mar 15;14(2):236-245. Epub 2018 Oct 15.

Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.

Objective: Mortality rates for children with congenital heart disease (CHD) have significantly declined, resulting in a growing population with associated neurodevelopmental disabilities. American Heart Association guidelines recommend systematic developmental screening for children with CHD. The present study describes results of inpatient newborn neurodevelopmental assessment of infants after open heart surgery.

Outcome Measures: We evaluated the neurodevelopment of a convenience sample of high-risk infants following cardiac surgery but before hospital discharge using an adaptation of the Newborn Behavioral Observation. Factor analysis examined relationships among assessment items and consolidated them into domains of development.

Results: We assessed 237 infants at a median of 11 days (interquartile range [IQR]: 7-19 days) after cardiac surgery and median corrected age of 21 days (IQR: 13-33 days). Autonomic regulation was minimally stressed or well organized in 14% of infants. Upper and lower muscle tone was appropriate in 33% and 35%, respectively. Appropriate response to social stimulation ranged between 7% and 12% depending on task, and state regulation was well organized in 14%. The vast majority (87%) required enhanced examiner facilitation for participation. Factor analyses of assessment items aligned into four domains of development (autonomic, motor, oral motor, and attention organization).

Conclusion: At discharge, postoperative infants with CHD had impairments in autonomic, motor, attention, and state regulation following cardiac surgery. Findings highlight the challenges faced by children with CHD relative to healthy peers, suggesting that neurodevelopmental follow-up and intervention should begin early in infancy.
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http://dx.doi.org/10.1111/chd.12686DOI Listing
March 2019

Longitudinal Associations between Neurodevelopment and Psychosocial Health Status in Patients with Repaired D-Transposition of the Great Arteries.

J Pediatr 2019 01 28;204:38-45.e1. Epub 2018 Sep 28.

Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Cardiology, Boston Children's Hospital, Boston, MA. Electronic address:

Objective: To examine associations between measurements of neurodevelopment and psychosocial health status at age 8 and 16 years in patients with repaired dextro-transposition of the great arteries.

Study Design: In the 16-year follow-up of the Boston Circulatory Arrest Study, 137 parents completed the Child Health Questionnaire-Parent Form-50, of whom 135 had completed the Child Health Questionnaire-Parent Form-50 when their child was age 8 years. Psychosocial and physical summary scores were used to assess change in health status from age 8 to 16 years. A comprehensive battery of neurodevelopmental testing was performed at ages 8 and 16 years to examine associations with adolescent health status.

Results: Lower psychosocial summary scores of 16 year old subjects with dextro-transposition of the great arteries were highly associated with numerous concurrent domains of neurodevelopmental function, most notably with higher (worse) scores on the Conners' Attention Deficit Hyperactivity Disorder/Diagnostic and Statistical Manual-4th Edition Scales (parent: r = -0.62, P < .001; adolescent: r = -0.43, P < .001) and the Behavior Rating Inventory of Executive Function Global Executive Composite (parent: r = -0.66, P < .001; adolescent: r = -0.39, P < .001). Psychosocial and physical summary scores tracked from ages 8 to 16 years (r = 0.44 and 0.47, respectively, P < .001 for each). Higher (worse) scores of multiple attention measures at age 8 years predicted worse psychosocial summary scores at age 16 years.

Conclusions: Attention deficits at age 8 years were highly predictive of worse psychosocial health status in adolescence. Further studies are needed to assess whether treatment of childhood attention deficit hyperactivity disorder could improve adolescent well-being.
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http://dx.doi.org/10.1016/j.jpeds.2018.08.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309657PMC
January 2019

Design and rationale of the "Sedation strategy and cognitive outcome after critical illness in early childhood" study.

Contemp Clin Trials 2018 09 11;72:8-15. Epub 2018 Jul 11.

Department of Psychiatry, University of Pittsburgh School of Medicine, United States.

There is increasing concern that sedatives commonly used during critical illness may be neurotoxic during the period of early brain development. The Sedation strategy and cognitive outcome after critical illness in early childhood (RESTORE-cognition) study is a prospective cohort study designed to examine the relationships between sedative exposure during pediatric critical illness and long-term neurocognitive outcomes. We assess multiple domains of neurocognitive function 2.5-5 years post-hospital discharge, at a single time point and depending on participant and clinician availability, in up to 500 subjects who had normal baseline cognitive function, were aged 2 weeks to 8 years at pediatric intensive care unit admission, and were enrolled in a cluster randomized controlled trial of a sedation protocol (the RESTORE trial; U01 HL086622 and HL086649). In addition, to provide comparable data on an unexposed group with similar baseline biological characteristics and environment, we are studying matched, healthy siblings of RESTORE patients. Our goal is to increase understanding of the relationships between sedative exposure, critical illness, and long-term neurocognitive outcomes in infants and young children by studying these subjects 2.5 to 5 years after their index hospitalization. This paper highlights the design challenges in conducting comprehensive neurocognitive assessment procedures across a broad age span at multiple testing centers across the United States. Our approach, which includes building interprofessional teams and novel cohort retention strategies, may be of help in future longitudinal trials.
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http://dx.doi.org/10.1016/j.cct.2018.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914341PMC
September 2018

Altered White Matter Microstructure Correlates with IQ and Processing Speed in Children and Adolescents Post-Fontan.

J Pediatr 2018 09 19;200:140-149.e4. Epub 2018 Jun 19.

Department of Neurology, Boston Children's Hospital, Boston, MA; Department of Psychiatry, Boston Children's Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Department of Radiology, Boston Children's Hospital, Boston, MA. Electronic address:

Objective: To compare white matter microstructure in children and adolescents with single ventricle who underwent the Fontan procedure with healthy controls, and to explore the association of white matter injury with cognitive performance as well as patient and medical factors.

Study Design: Fontan (n = 102) and control subjects (n = 47) underwent diffusion tensor imaging (DTI) at ages 10-19 years. Mean DTI measures (fractional anisotropy, radial diffusivity, axial diffusivity, and mean diffusivity) were calculated for 33 fiber tracts from standard white matter atlases. Voxel-wise group differences in DTI measures were assessed using Tract-Based Spatial Statistics. Associations of regional fractional anisotropy with IQ and processing speed as well as medical characteristics were examined.

Results: Subjects with Fontan, compared with controls, had reduced bilateral regional and voxel-wise fractional anisotropy in multiple white matter tracts along with increased regional radial diffusivity in several overlapping tracts; regional mean diffusivity differed in 2 tracts. The groups did not differ in voxel-wise radial diffusivity or mean diffusivity. Among subjects with Fontan, fractional anisotropy in many tracts correlated positively with Full-Scale Intelligence Quotient and processing speed, although similar findings were absent in controls. Lower mean fractional anisotropy in various tracts was associated with more complications in the first operation, a greater number of total operations, and history of neurologic event.

Conclusions: Children and adolescents who have undergone the Fontan procedure have widespread abnormalities in white matter microstructure. Furthermore, white matter microstructure in several tracts is associated with cognitive performance and operative and medical history characteristics.
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http://dx.doi.org/10.1016/j.jpeds.2018.04.022DOI Listing
September 2018