Publications by authors named "Lisa A Asaro"

35 Publications

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

Crit Care Med 2021 Feb 15. Epub 2021 Feb 15.

Department of Pediatrics, Sacred Hearts Children's Hospital, Spokane, WA. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI. Section of, Critical Care, Children's Hospital of Wisconsin, Milwaukee, WI. Department of Cardiology, Boston Children's Hospital, Boston, MA. Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA. Department of Pediatrics, Harvard Medical School, Boston, MA. Family and Community Health, School of Nursing, University of Pennsylvania, Philadelphia, PA. Department of Anesthesia and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA.

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
February 2021

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

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

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

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

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

Sedation Management for Critically Ill Children with Pre-Existing Cognitive Impairment.

J Pediatr 2019 03 5;206:204-211.e1. Epub 2018 Dec 5.

The Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Family and Community Health, School of Nursing, Department of Anesthesia and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address:

Objective: To compare current analgesia and sedation management practices between critically ill children with pre-existing cognitive impairment and critically ill neurotypical children, including possible indicators of therapeutic efficacy.

Study Design: This study used secondary analysis of prospective data from the RESTORE clinical trial, with 2449 children admitted to the pediatric intensive care unit and receiving mechanical ventilation for acute respiratory failure. Subjects with a baseline Pediatric Cerebral Performance Category ≥3 were defined as subjects with cognitive impairment, and differences between groups were explored using regression methods accounting for pediatric intensive care unit as a cluster variable.

Results: This study identified 412 subjects (17%) with cognitive impairment. Compared with neurotypical subjects, subjects with cognitive impairment were older (median, years, 6.2 vs 1.4; P < .001) with more severe pediatric acute respiratory distress syndrome (40% vs 33%; P = .009). They received significantly lower cumulative doses of opioids (median, mg/kg, 14.2 vs 16.2; P < .001) and benzodiazepines (10.6 vs 14.4; P < .001). Three nonverbal subjects with cognitive impairment received no analgesia or sedation. Subjects with cognitive impairment were assessed as having more study days awake and calm and fewer study days with an episode of pain. They were less likely to be assessed as having inadequate pain/sedation management or unplanned endotracheal/invasive tube removal. Subjects with cognitive impairment had more documented iatrogenic withdrawal symptoms than neurotypical subjects.

Conclusions: Subjects with cognitive impairment in this study received less medication, but it is unclear whether they have authentically lower analgesic and/or sedative requirements or are vulnerable to inadequate assessment of discomfort because of the lack of validated assessment tools. We recommend the development of pain and sedation assessment tools specific to this patient population.
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http://dx.doi.org/10.1016/j.jpeds.2018.10.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389364PMC
March 2019

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

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

Face and content validity of variables associated with the difficult-to-sedate child in the paediatric intensive care unit: A survey of paediatric critical care clinicians.

Aust Crit Care 2018 05 19;31(3):167-173. Epub 2018 Mar 19.

University of Pennsylvania School of Nursing, 418 Curie Boulevard, Philadelphia, PA 19104, USA; Children's Hospital of Philadelphia Research Institute, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA. Electronic address:

Background: Clinicians recognise that some critically ill children are difficult-to-sedate. It may be possible to identify this clinical phenotype for sedation response using statistical modelling techniques adopted from machine learning. This requires identification of a finite number of variables to include in the statistical model.

Objective: To establish face and content validity for 17 candidate variables identified in the international literature as characteristic of the difficult-to-sedate child phenotype.

Methods: Paediatric critical care clinicians rated the relevance of 17 variables characterising the difficult-to-sedate child using a four-point scale ranging from not (1) to highly relevant (4). Face and content validity of these variables were assessed by calculating a mean score for each item and computing an item-level content validity index. Items with a mean score >1 were rated as having adequate face validity. An item-level content validity index ≥0.70 indicated good to excellent content validity.

Setting And Participants: Web-based survey emailed to members of the Pediatric Acute Lung Injury and Sepsis Investigators Network or the Society of Critical Care Medicine Pediatric Sedation Study Group.

Results: Of 411 possible respondents, 121 useable surveys were returned for a response rate of 29%. All items had a mean score >1, indicating adequate face validity. Ten of 17 items scored an item-level content validity index ≥0.70. The highest scoring items were requiring three or more sedation classes simultaneously, daily modal sedation score indicating agitation, sedation score indicating agitation for 2 consecutive hours, receiving sedatives at a dose >90th percentile of the usual starting dose, and receiving intermittent paralytic doses for sedation.

Conclusions: Computation of an item-level content validity index validated variables to include in statistical modelling of the difficult-to-sedate phenotype. The results indicate consensus among paediatric critical care clinicians that the majority of candidate variables identified through literature review are characteristic of the difficult-to-sedate child.
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http://dx.doi.org/10.1016/j.aucc.2017.12.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936660PMC
May 2018

Physiologic response to pre-arrest bolus dilute epinephrine in the pediatric intensive care unit.

Resuscitation 2018 05 8;126:137-142. Epub 2018 Mar 8.

Division of Critical Care Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.

Aim: To quantify the physiologic effects of pre-arrest bolus dilute epinephrine in the pediatric intensive care unit.

Methods: Patients <18 years old and ≥37 weeks gestation who received an intravenous bolus of dilute epinephrine (10 mcg/mL) in the pediatric intensive care units at our institution from January 2011 to March 2017 were retrospectively identified. Patients were excluded if doses exceeded 20 mcg/kg, or under the following circumstances: orders limiting resuscitation, extracorporeal membrane oxygenation, active chest compressions, simultaneous administration of other blood pressure-altering interventions or documented normotension prior to epinephrine. The primary outcome was change in systolic blood pressure within 5 min of epinephrine. Patients were categorized as non-responders if the change in systolic blood pressure was ≤10 mmHg.

Results: One hundred forty-four patients were analyzed. The median index dose was 0.7 mcg/kg (IQR, 0.3-2.0), and the mean increase in systolic blood pressure was 31 mmHg (95% CI, 25-36; P < 0.001). Thirty-nine (27%) patients were classified as non-responders. Compared to responders, non-responders had higher rates of cardiac arrest or extracorporeal membrane oxygenation within 6 h (26% vs 10%; relative risk, 2.69; 95% CI, 1.21-5.97; P = 0.03), and had higher in-hospital mortality (51% vs 21%; relative risk, 2.45; 95% CI, 1.51-3.96; P < 0.001).

Conclusions: In the majority of pre-arrest pediatric patients, bolus dilute epinephrine resulted in an increase in systolic blood pressure, and lack of blood pressure response was associated with poor outcomes. Optimal dosing of dilute epinephrine remains unclear.
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http://dx.doi.org/10.1016/j.resuscitation.2018.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441975PMC
May 2018

Long-Term Outcomes after Protocolized Sedation versus Usual Care in Ventilated Pediatric Patients.

Am J Respir Crit Care Med 2018 06;197(11):1457-1467

12 Critical Care and Cardiovascular Program, Boston Children's Hospital, Boston, Massachusetts.

Rationale: Whether a nurse-implemented goal-directed sedation protocol resulting in more awake yet calm intubated children affects postdischarge functional status, health-related quality of life, or risk for post-traumatic stress disorder is unknown.

Objectives: To compare postdischarge outcomes in children with acute respiratory failure cluster-randomized to a sedation protocol or usual care.

Methods: A stratified random sample of 1,360 patients from 31 centers in the RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure) trial was assessed by mail, electronically, and/or telephone 6 months after ICU discharge. In treatment group comparisons, we controlled for age, baseline functional status, and severity of illness.

Measurements And Main Results: We used the Pediatric Overall Performance Category and the Pediatric Cerebral Performance Category to characterize functional status, the Infant and Toddler Quality of Life Questionnaire (97-item full-length version) (<2 yr old) or Pediatric Quality of Life Inventory (≥2 yr old), and the Child Post-traumatic Stress Disorder Symptom Scale (≥8 yr old and developmentally able). Functional status worsened from baseline to follow-up in 20%. Decline in functional status did not differ by treatment arm and was more common among those with baseline impairment than those with baseline normal function (27 vs. 18%; P < 0.001). There were no significant differences in health-related quality of life total scores by treatment arm. Scores indicating risk of post-traumatic stress disorder occurred in 30%, with no difference between treatment arms.

Conclusions: A sedation strategy that allows patients to be more awake and exposes them to fewer sedative and analgesic medications produces no long-term harm. However, postdischarge morbidity after acute respiratory failure is common. Clinical trial registered with www.clinicaltrials.gov (NCT00814099).
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http://dx.doi.org/10.1164/rccm.201708-1768OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005554PMC
June 2018

Sedation Management in Children Supported on Extracorporeal Membrane Oxygenation for Acute Respiratory Failure.

Crit Care Med 2017 10;45(10):e1001-e1010

1Division of Pediatric Critical Care Medicine, Department of Pediatrics, Cohen Children's Medical Center, Hofstra-Northwell School of Medicine, New York, NY. 2Department of Cardiology, Boston Children's Hospital, Boston, MA. 3Division of Pediatric Critical Care Medicine, Oregon Health & Science University School of Medicine, Portland, OR. 4Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA. 5Department of Pediatrics, Harvard Medical School, Boston, MA. 6Department of Family and Community Health, School of Nursing, University of Pennsylvania, Philadelphia, PA. 7Division of Anesthesia and Critical Care Medicine at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 8Critical Care and Cardiovascular Program, Boston Children's Hospital, Boston, MA.

Objectives: To describe sedation management in children supported on extracorporeal membrane oxygenation for acute respiratory failure.

Design: Secondary analysis of prospectively collected data from a multicenter randomized trial of sedation (Randomized Evaluation of Sedation Titration for Respiratory Failure).

Setting: Twenty-one U.S. PICUs.

Patients: One thousand two hundred fifty-five children, 2 weeks to 17 years old, with moderate/severe pediatric acute respiratory distress syndrome.

Interventions: Sedation managed per usual care or Randomized Evaluation of Sedation Titration for Respiratory Failure protocol.

Measurements And Main Results: Sixty-one Randomized Evaluation of Sedation Titration for Respiratory Failure patients (5%) with moderate/severe pediatric acute respiratory distress syndrome were supported on extracorporeal membrane oxygenation, including 29 managed per Randomized Evaluation of Sedation Titration for Respiratory Failure protocol. Most extracorporeal membrane oxygenation patients received neuromuscular blockade (46%) or were heavily sedated with State Behavioral Scale scores -3/-2 (34%) by extracorporeal membrane oxygenation day 3. Median opioid and benzodiazepine doses on the day of cannulation, 0.15 mg/kg/hr (3.7 mg/kg/d) and 0.11 mg/kg/hr (2.8 mg/kg/d), increased by 36% and 58%, respectively, by extracorporeal membrane oxygenation day 3. In the 41 patients successfully decannulated prior to study discharge, patients were receiving 0.40 mg/kg/hr opioids (9.7 mg/kg/d) and 0.39 mg/kg/hr benzodiazepines (9.4 mg/kg/d) at decannulation, an increase from cannulation of 108% and 192%, respectively (both p < 0.001). Extracorporeal membrane oxygenation patients experienced more clinically significant iatrogenic withdrawal than moderate/severe pediatric acute respiratory distress syndrome patients managed without extracorporeal membrane oxygenation support (p < 0.001). Compared to extracorporeal membrane oxygenation patients managed per Randomized Evaluation of Sedation Titration for Respiratory Failure protocol, usual care extracorporeal membrane oxygenation patients received more opioids during the study period (mean cumulative dose of 183.0 vs 89.8 mg/kg; p = 0.02), over 6.5 greater exposure days (p = 0.002) with no differences in wakefulness or agitation.

Conclusions: In children, the initiation of extracorporeal membrane oxygenation support is associated with deep sedation, substantial sedative exposure, and increased frequency of iatrogenic withdrawal syndrome. A standardized, goal-directed, nurse-driven sedation protocol may help mitigate these effects.
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http://dx.doi.org/10.1097/CCM.0000000000002540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600656PMC
October 2017

The authors reply.

Crit Care Med 2017 06;45(6):e623-e624

Cardiac Intensive Care Unit, Department of Nursing, Respiratory Care and Neurodiagnostic Services, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Cardiology, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA; and Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Cardiology, Boston Children's Hospital, Boston, MA; Ellen and Robert Kapito Professor of Nursing Science, Department of Family and Community Health in the School of Nursing at the University of Pennsylvania, Philadelphia, PA; and Department of Anesthesia and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1097/CCM.0000000000002417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538028PMC
June 2017

Acute Kidney Injury After Pediatric Cardiac Surgery: A Secondary Analysis of the Safe Pediatric Euglycemia After Cardiac Surgery Trial.

Pediatr Crit Care Med 2017 Jul;18(7):638-646

1Division of Cardiac Critical Care, Department of Anesthesia/Critical Care, Children's Hospital of Philadelphia, Perelman School of Medicine, Philadelphia, PA. 2Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. 3Division of Critical Care Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA. 4Department of Pediatrics, University of Michigan Medical School, C.S. Mott Children's Hospital, Ann Arbor, MI. 5Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA.

Objectives: To understand the effect of tight glycemic control on cardiac surgery-associated acute kidney injury.

Design: Secondary analysis of data from the Safe Pediatric Euglycemia after Cardiac Surgery trial of tight glycemic control versus standard care.

Setting: Pediatric cardiac ICUs at University of Michigan, C.S. Mott Children's Hospital, and Boston Children's Hospital.

Patients: Children 0-36 months old undergoing congenital cardiac surgery.

Interventions: None.

Measurements And Main Results: Cardiac surgery-associated acute kidney injury was assigned using the Acute Kidney Injury Network criteria with the modification that a greater than 0.1 mg/dL increase in serum creatinine was required to assign cardiac surgery-associated acute kidney injury. We explored associations between cardiac surgery-associated acute kidney injury and tight glycemic control and clinical outcomes. Of 799 patients studied, cardiac surgery-associated acute kidney injury occurred in 289 patients (36%), most of whom had stage II or III disease (72%). Cardiac surgery-associated acute kidney injury rates were similar between treatment groups (36% vs 36%; p = 0.99). Multivariable modeling showed that patients with cardiac surgery-associated acute kidney injury were younger (p = 0.002), underwent more complex surgery (p = 0.005), and had longer cardiopulmonary bypass times (p = 0.002). Cardiac surgery-associated acute kidney injury was associated with longer mechanical ventilation and ICU and hospital stays and increased mortality. Patients at University of Michigan had higher rates of cardiac surgery-associated acute kidney injury compared with Boston Children's Hospital patients (66% vs 15%; p < 0.001), but University of Michigan patients with cardiac surgery-associated acute kidney injury had shorter time to extubation and ICU and hospital stays compared with Boston Children's Hospital patients.

Conclusions: Tight glycemic control did not reduce the cardiac surgery-associated acute kidney injury rate in this trial cohort. We observed significant differences in cardiac surgery-associated acute kidney injury rates between the two study sites, and there was a differential effect of cardiac surgery-associated acute kidney injury on clinical outcomes by site. These findings warrant further investigation to identify causal variation in perioperative practices that affect cardiac surgery-associated acute kidney injury epidemiology.
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http://dx.doi.org/10.1097/PCC.0000000000001185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503840PMC
July 2017

The authors reply.

Crit Care Med 2017 03;45(3):e333-e334

Department of Pediatrics, Yale School of Medicine, New Haven, CT; Department of Pediatrics, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI; Department of Critical Care, Children's Hospital of Orange County, Orange, CA; Department of Cardiology, Boston Children's Hospital, Boston, MA; Family and Community Health, School of Nursing, University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1097/CCM.0000000000002224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319485PMC
March 2017

Multiple Organ Dysfunction in Children Mechanically Ventilated for Acute Respiratory Failure.

Pediatr Crit Care Med 2017 Apr;18(4):319-329

1Department of Anesthesiology and Critical Care, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 2Department of Cardiology, Boston Children's Hospital, Boston, MA. 3Division of Pediatric Critical Care, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI. 4Division of Critical Care, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO. 5Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA. 6Department of Pediatrics, Harvard Medical School, Boston, MA. 7School of Nursing, University of Pennsylvania, Philadelphia, PA. 8Critical Care and Cardiovascular Program, Boston Children's Hospital, Boston, MA.

Objectives: The impact of extrapulmonary organ dysfunction, independent from sepsis and lung injury severity, on outcomes in pediatric acute respiratory failure is unclear. We sought to determine the frequency, timing, and risk factors for extrapulmonary organ dysfunction and the independent association of multiple organ dysfunction syndrome with outcomes in pediatric acute respiratory failure.

Design: Secondary observational analysis of the Randomized Evaluation of Sedation Titration for Respiratory Failure cluster-randomized prospective clinical trial conducted between 2009 and 2013.

Setting: Thirty-one academic PICUs in the United States.

Patients: Two thousand four hundred forty-nine children mechanically ventilated for acute respiratory failure enrolled in Randomized Evaluation of Sedation Titration for Respiratory Failure.

Measurements And Main Results: Organ dysfunction was defined using criteria published for pediatric sepsis. Multiple organ dysfunction syndrome was defined as respiratory dysfunction one or more extrapulmonary organ dysfunctions. We used multivariable logistic regression to identify risk factors for multiple organ dysfunction syndrome, and logistic or proportional hazards regression to compare clinical outcomes. All analyses accounted for PICU as a cluster variable. Overall, 73% exhibited extrapulmonary organ dysfunction, including 1,547 (63%) with concurrent multiple organ dysfunction syndrome defined by onset on day 0/1 and 244 (10%) with new multiple organ dysfunction syndrome with onset on day 2 or later. Most patients (93%) with indirect lung injury from sepsis presented with concurrent multiple organ dysfunction syndrome, whereas patients with direct lung injury had both concurrent (56%) and new (12%) multiple organ dysfunction syndrome. Risk factors for concurrent multiple organ dysfunction syndrome included older age, illness severity, sepsis, cancer, and moderate/severe lung injury. Risk factors for new multiple organ dysfunction syndrome were moderate/severe lung injury and neuromuscular blockade. Both concurrent and new multiple organ dysfunction syndrome were associated with 90-day in-hospital mortality (concurrent: adjusted odds ratio, 6.54; 95% CI, 3.00-14.25 and new: adjusted odds ratio, 3.21; 95% CI, 1.48-6.93) after adjusting for sepsis, moderate/severe lung injury, and other baseline characteristics.

Conclusions: Extrapulmonary organ dysfunction was common, generally occurred concurrent with respiratory dysfunction (especially in sepsis), and was a major risk factor for mortality in pediatric acute respiratory failure.
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http://dx.doi.org/10.1097/PCC.0000000000001091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380520PMC
April 2017

Tight Glycemic Control in Critically Ill Children.

N Engl J Med 2017 02 24;376(8):729-741. Epub 2017 Jan 24.

From the Division of Medicine Critical Care (M.S.D.A., J.L.A., G.M.S.) and the Department of Cardiology (D.W., L.A.A.), Boston Children's Hospital and Harvard Medical School, Boston; the Division of Pediatric Critical Care, University of Utah Medical School, Primary Children's Hospital, Salt Lake City, and Intermountain Medical Center, Murray - both in Utah (E.L.H.); Children's Hospital of Philadelphia (V.S., V.M.N.) and the Perelman School of Medicine (V.S., M.A.Q.C., V.M.N.) and the School of Nursing (M.A.Q.C.), University of Pennsylvania - all in Philadelphia; Yale School of Medicine, New Haven, CT (E.V.F.); and Children's Medical Center Dallas and the University of Texas Southwestern Medical School, Dallas (P.M.L.).

Background: In multicenter studies, tight glycemic control targeting a normal blood glucose level has not been shown to improve outcomes in critically ill adults or children after cardiac surgery. Studies involving critically ill children who have not undergone cardiac surgery are lacking.

Methods: In a 35-center trial, we randomly assigned critically ill children with confirmed hyperglycemia (excluding patients who had undergone cardiac surgery) to one of two ranges of glycemic control: 80 to 110 mg per deciliter (4.4 to 6.1 mmol per liter; lower-target group) or 150 to 180 mg per deciliter (8.3 to 10.0 mmol per liter; higher-target group). Clinicians were guided by continuous glucose monitoring and explicit methods for insulin adjustment. The primary outcome was the number of intensive care unit (ICU)-free days to day 28.

Results: The trial was stopped early, on the recommendation of the data and safety monitoring board, owing to a low likelihood of benefit and evidence of the possibility of harm. Of 713 patients, 360 were randomly assigned to the lower-target group and 353 to the higher-target group. In the intention-to-treat analysis, the median number of ICU-free days did not differ significantly between the lower-target group and the higher-target group (19.4 days [interquartile range {IQR}, 0 to 24.2] and 19.4 days [IQR, 6.7 to 23.9], respectively; P=0.58). In per-protocol analyses, the median time-weighted average glucose level was significantly lower in the lower-target group (109 mg per deciliter [IQR, 102 to 118]; 6.1 mmol per liter [IQR, 5.7 to 6.6]) than in the higher-target group (123 mg per deciliter [IQR, 108 to 142]; 6.8 mmol per liter [IQR, 6.0 to 7.9]; P<0.001). Patients in the lower-target group also had higher rates of health care-associated infections than those in the higher-target group (12 of 349 patients [3.4%] vs. 4 of 349 [1.1%], P=0.04), as well as higher rates of severe hypoglycemia, defined as a blood glucose level below 40 mg per deciliter (2.2 mmol per liter) (18 patients [5.2%] vs. 7 [2.0%], P=0.03). No significant differences were observed in mortality, severity of organ dysfunction, or the number of ventilator-free days.

Conclusions: Critically ill children with hyperglycemia did not benefit from tight glycemic control targeted to a blood glucose level of 80 to 110 mg per deciliter, as compared with a level of 150 to 180 mg per deciliter. (Funded by the National Heart, Lung, and Blood Institute and others; HALF-PINT ClinicalTrials.gov number, NCT01565941 .).
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http://dx.doi.org/10.1056/NEJMoa1612348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444653PMC
February 2017

Suspected Cerebral Edema in Diabetic Ketoacidosis: Is There Still a Role for Head CT in Treatment Decisions?

Pediatr Crit Care Med 2017 Mar;18(3):207-212

1Division of Medicine Critical Care, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA. 2Division of Endocrinology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA. 3Department of Cardiology, Boston Children's Hospital, Boston, MA.

Objectives: Neurologic deterioration associated with cerebral edema in diabetic ketoacidosis is typically sudden in onset, progresses rapidly, and requires emergent treatment. The utility of brain imaging by head CT in decisions to treat for cerebral edema has not been previously studied. The objective of this study was to describe the characteristics of pediatric patients with diabetic ketoacidosis who develop altered mental status and evaluate the role of head CT in this cohort.

Design: Retrospective analysis of clinical, biochemical, and radiologic data.

Setting: Tertiary care children's hospital (2004-2010).

Patients: Six hundred eighty-six admissions of patients (< 26 yr) with diabetic ketoacidosis.

Interventions: None.

Measurements And Main Results: Altered mental status was documented during 96 of 686 diabetic ketoacidosis admissions (14%). Compared with alert patients, those with altered mental status were younger (median, 12.0 vs 13.1 yr; p = 0.007) and more acidotic (pH, 7.04 vs 7.19; p < 0.001), with higher serum osmolality (328 vs 315 mOsm/kg; p < 0.001) and longer hospital length of stay (4.5 vs 3 d; p = 0.002). Head CT was performed during 60 of 96 diabetic ketoacidosis admissions with altered mental status (63%), 16 (27%) of which had abnormal results. Hyperosmolar therapy for cerebral edema was given during 23 of the 60 admissions (38%), during which 12 (52%) had normal head CT results, eight of these 12 (67%) after cerebral edema treatment and four (33%) before. Of the 11 admissions with abnormal head CT results that received hyperosmolar therapy, four head CT scan (36%) occurred after hyperosmolar treatment and seven (64%) before. For the 11 admissions with head CT before cerebral edema treatment, there was a median 2-hour delay between head CT and hyperosmolar therapy.

Conclusions: In this single-center retrospective study, there was no evidence that decisions about treatment of patients with diabetic ketoacidosis and suspected cerebral edema were enhanced by head CT, and head CT may have led to a significant delay in hyperosmolar therapy.
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http://dx.doi.org/10.1097/PCC.0000000000001027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336411PMC
March 2017

Design and rationale of Heart and Lung Failure - Pediatric INsulin Titration Trial (HALF-PINT): A randomized clinical trial of tight glycemic control in hyperglycemic critically ill children.

Contemp Clin Trials 2017 02 30;53:178-187. Epub 2016 Dec 30.

The Children's Hospital of Philadelphia, University of Pennsylvania, 3401 Civic Center Blvd., Philadelphia, PA 19104, United States. Electronic address:

Objectives: Test whether hyperglycemic critically ill children with cardiovascular and/or respiratory failure experience more ICU-free days when assigned to tight glycemic control with a normoglycemic versus hyperglycemic blood glucose target range.

Design: Multi-center randomized clinical trial.

Setting: Pediatric ICUs at 35 academic hospitals.

Patients: Children aged 2weeks to 17years receiving inotropic support and/or acute mechanical ventilation, excluding cardiac surgical patients.

Interventions: Patients receive intravenous insulin titrated to either 80-110mg/dL (4.4-6.1mmol/L) or 150-180mg/dL (8.3-10.0mmol/L). The intervention begins upon confirmed hyperglycemia and ends when the patient meets study-defined ICU discharge criteria or after 28days. Continuous glucose monitoring, a minimum glucose infusion, and an explicit insulin infusion algorithm are deployed to achieve the BG targets while minimizing hypoglycemia risk.

Measurements And Main Results: The primary outcome is ICU-free days (equivalent to 28-day hospital mortality-adjusted ICU length of stay). Secondary outcomes include 90-day hospital mortality, organ dysfunction scores, ventilator-free days, nosocomial infection rate, neurodevelopmental outcomes, and nursing workload. To detect an increase of 1.25 ICU-free days (corresponding to a 20% relative reduction in 28-day hospital mortality and a one-day reduction in ICU length of stay), 1414 patients are needed for 80% power using a two-sided 0.05 level test.

Conclusions: This trial tests whether hyperglycemic critically ill children randomized to 80-110mg/dL benefit more than those randomized to 150-180mg/dL. This study implements validated bedside support tools including continuous glucose monitoring and a computerized algorithm to enhance patient safety and ensure reproducible bedside decision-making in achieving glycemic control.
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http://dx.doi.org/10.1016/j.cct.2016.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5285511PMC
February 2017

White Matter Volume Predicts Language Development in Congenital Heart Disease.

J Pediatr 2017 02 9;181:42-48.e2. Epub 2016 Nov 9.

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

Objective: To determine whether brain volume is reduced at 1 year of age and whether these volumes are associated with neurodevelopment in biventricular congenital heart disease (CHD) repaired in infancy.

Study Design: Infants with biventricular CHD (n = 48) underwent brain magnetic resonance imaging (MRI) and neurodevelopmental testing with the Bayley Scales of Infant Development-II and the MacArthur-Bates Communicative Development Inventories at 1 year of age. A multitemplate based probabilistic segmentation algorithm was applied to volumetric MRI data. We compared volumes with those of 13 healthy control infants of comparable ages. In the group with CHD, we measured Spearman correlations between neurodevelopmental outcomes and the residuals from linear regression of the volumes on corrected chronological age at MRI and sex.

Results: Compared with controls, infants with CHD had reductions of 54 mL in total brain (P = .009), 40 mL in cerebral white matter (P <.001), and 1.2 mL in brainstem (P = .003) volumes. Within the group with CHD, brain volumes were not correlated with Bayley Scales of Infant Development-II scores but did correlate positively with MacArthur-Bates Communicative Development Inventory language development.

Conclusions: Infants with biventricular CHD show total brain volume reductions at 1 year of age, driven by differences in cerebral white matter. White matter volume correlates with language development, but not broader developmental indices. These findings suggest that abnormalities in white matter development detected months after corrective heart surgery may contribute to language impairment.

Trial Registration: ClinicalTrials.gov: NCT00006183.
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http://dx.doi.org/10.1016/j.jpeds.2016.09.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5274582PMC
February 2017

Dexmedetomidine Use in Critically Ill Children With Acute Respiratory Failure.

Pediatr Crit Care Med 2016 12;17(12):1131-1141

1Department of Pediatric Critical Care, Primary Children's Hospital, Salt Lake City, UT.2Division of Pediatric Critical Care Medicine, Cohen Children's Medical Center, Hofstra-Northwell School of Medicine, New York, NY.3Department of Cardiology, Boston Children's Hospital, Boston, MA.4Department of Pharmacy, Boston Children's Hospital, Boston, MA.5Department of Pharmacy, UC Davis Medical Center, Sacramento, CA.6Department of Pediatric Critical Care, University of Maryland Medical Center, Baltimore, MD.7Division of Pediatric Critical Care Medicine, Connecticut Children's Medical Center, Hartford, CT.8Division of Pediatric Critical Care Medicine, Department of Pediatric Critical Care, Phoenix Children's Hospital, University of Arizona College of Medicine, Phoenix, AZ.9Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.10Department of Pediatrics, Harvard Medical School, Boston, MA.11Department of Family and Community Health, School of Nursing and Department of Anesthesia and Critical Care Medicine, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.12Department of Critical Care and Cardiovascular Nursing, Boston Children's Hospital, Boston, MA.

Objective: Care of critically ill children includes sedation but current therapies are suboptimal. To describe dexmedetomidine use in children supported on mechanical ventilation for acute respiratory failure.

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

Setting: Thirty-one PICUs.

Patients: Data from 2,449 children; 2 weeks to 17 years old.

Interventions: Sedation practices were unrestrained in the usual care arm. Patients were categorized as receiving dexmedetomidine as a primary sedative, secondary sedative, periextubation agent, or never prescribed. Dexmedetomidine exposure and sedation and clinical profiles are described.

Measurements And Main Results: Of 1,224 usual care patients, 596 (49%) received dexmedetomidine. Dexmedetomidine as a primary sedative patients (n = 138; 11%) were less critically ill (Pediatric Risk of Mortality III-12 score median, 6 [interquartile range, 3-11]) and when compared with all other cohorts, experienced more episodic agitation. In the intervention group, time in sedation target improved from 28% to 50% within 1 day of initiating dexmedetomidine as a primary sedative. Dexmedetomidine as a secondary sedative usual care patients (n = 280; 23%) included more children with severe pediatric acute respiratory distress syndrome or organ failure. Dexmedetomidine as a secondary sedative patients experienced more inadequate pain (22% vs 11%) and sedation (31% vs 16%) events. Dexmedetomidine as a periextubation agent patients (n = 178; 15%) were those known to not tolerate an awake, intubated state and experienced a shorter ventilator weaning process (2.1 vs 2.3 d).

Conclusions: Our data support the use of dexmedetomidine as a primary agent in low criticality patients offering the benefit of rapid achievement of targeted sedation levels. Dexmedetomidine as a secondary agent does not appear to add benefit. The use of dexmedetomidine to facilitate extubation in children intolerant of an awake, intubated state may abbreviate ventilator weaning. These data support a broader armamentarium of pediatric critical care sedation.
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http://dx.doi.org/10.1097/PCC.0000000000000941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5138139PMC
December 2016

Accuracy of an Extubation Readiness Test in Predicting Successful Extubation in Children With Acute Respiratory Failure From Lower Respiratory Tract Disease.

Crit Care Med 2017 Jan;45(1):94-102

1Department of Pediatrics, Yale School of Medicine, New Haven, CT. 2Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI. 3Department of Critical Care, Children's Hospital of Orange County, Orange, CA. 4Department of Cardiology, Boston Children's Hospital, Boston, MA. 5Family and Community Health, School of Nursing, University of Pennsylvania, Philadelphia, PA.

Objective: Identifying children ready for extubation is desirable to minimize morbidity and mortality associated with prolonged mechanical ventilation and extubation failure. We determined the accuracy of an extubation readiness test (Randomized Evaluation of Sedation Titration for Respiratory Failure extubation readiness test) in predicting successful extubation in children with acute respiratory failure from lower respiratory tract disease.

Design: Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure clinical trial, a pediatric multicenter cluster randomized trial of sedation.

Setting: Seventeen PICUs in the intervention arm.

Patients: Children 2 weeks to 17 years receiving invasive mechanical ventilation for lower respiratory tract disease.

Intervention: Extubation readiness test in which spontaneously breathing children with oxygenation index less than or equal to 6 were placed on FIO2 of 0.50, positive end-expiratory pressure of 5 cm H2O, and pressure support.

Measurements And Main Results: Of 1,042 children, 444 (43%) passed their first extubation readiness test. Of these, 295 (66%) were extubated within 10 hours of starting the extubation readiness test, including 272 who were successfully extubated, for a positive predictive value of 92%. Among 861 children who were extubated for the first time within 10 hours of performing an extubation readiness test, 788 passed their extubation readiness test and 736 were successfully extubated for a positive predictive value of 93%. The median time of day for extubation with an extubation readiness test was 12:15 hours compared with 14:54 hours for extubation without an extubation readiness test within 10 hours (p < 0.001).

Conclusions: In children with acute respiratory failure from lower respiratory tract disease, an extubation readiness test, as described, should be considered at least daily if the oxygenation index is less than or equal to 6. If the child passes the extubation readiness test, there is a high likelihood of successful extubation.
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http://dx.doi.org/10.1097/CCM.0000000000002024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541896PMC
January 2017

Patient, Process, and System Predictors of Iatrogenic Withdrawal Syndrome in Critically Ill Children.

Crit Care Med 2017 Jan;45(1):e7-e15

1Hillman Scholar in Nursing Innovation, University of Pennsylvania School of Nursing, Nurse Resident, The Children's Hospital of Philadelphia, Philadelphia, PA. 2Department of Cardiology, Boston Children's Hospital, Boston, MA. 3Department of Pediatrics, Harvard Medical School, Boston, MA. 4Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA. 5Ellen and Robert Kapito Professor in Nursing Science, School of Nursing, Anesthesia and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Objective: To generate a multidimensional predictive model of risk factors for iatrogenic withdrawal syndrome in critically ill children.

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

Setting: PICU.

Patients: Children who received greater than or equal to 5 days of sedation during mechanical ventilation for acute respiratory failure.

Interventions: The Randomized Evaluation of Sedation Titration for Respiratory Failure study tested the effect of a nurse-led, goal-directed sedation protocol on clinical outcomes. There was no additional intervention in this secondary analysis.

Measurements And Main Results: Data included 1,157 children from 31 PICUs. Iatrogenic withdrawal syndrome was defined as having at least two Withdrawal Assessment Tool-Version 1 scores greater than or equal to 3 after the start of opioid weaning. Logistic regression with generalized estimating equations to account for clustering by site was used to evaluate patient, process, and healthcare system risk factors for iatrogenic withdrawal syndrome. Subjects with iatrogenic withdrawal syndrome (544/1,157; 47%) were younger and more likely to have preexisting cognitive or functional impairment. They also received higher sedative doses and longer exposure periods. In multivariable analyses, significant predictors of iatrogenic withdrawal syndrome included younger age, preexisting cognitive impairment, higher preweaning mean daily opioid dose, longer duration of sedation, receipt of three or more preweaning sedative classes, higher nursing workload, and more one-to-one nurse staffing.

Conclusions: Iatrogenic withdrawal syndrome is common in children recovering from critical illness, and several risk factors are predictive, including patient characteristics, sedative exposure, additional sedative agents, and system-level factors. High-risk patients could be identified before weaning to better prevent iatrogenic withdrawal syndrome among at-risk patients.
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http://dx.doi.org/10.1097/CCM.0000000000001953DOI Listing
January 2017

Impact of Tight Glycemic Control on Neurodevelopmental Outcomes at 1 Year of Age for Children with Congenital Heart Disease: A Randomized Controlled Trial.

J Pediatr 2016 07 23;174:193-198.e2. Epub 2016 Apr 23.

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

Objective: To assess the association of postoperative tight glycemic control and hypoglycemia in children undergoing cardiac surgery with neurodevelopmental outcomes at 1 year of age.

Study Design: A 2-center, prospective, randomized trial of postoperative tight glycemic control vs standard care was conducted in 980 children undergoing cardiac surgery. Neurodevelopmental outcomes were assessed at nine to 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), the Adaptive Behavior Assessment System, Second Edition, the Ages and Stages Questionnaire, Third Edition, and the Brief Infant Toddler Social-Emotional Assessment.

Results: Neurodevelopmental follow-up was performed on 237 patients with a mean age of 13 months. No significant treatment group differences were found in the Bayley-III and Adaptive Behavior Assessment System, Second Edition composite scores or percentage at risk based on the Ages and Stages Questionnaire, Third Edition and the Brief Infant Toddler Social-Emotional Assessment. Patients who experienced moderate to severe hypoglycemia (n = 8) had lower Bayley-III composite scores compared with patients with no to mild hypoglycemia, even after controlling for factors known to be associated with poorer neurodevelopmental outcomes.

Conclusion: For infants undergoing cardiac surgery, tight glycemic control did not impact neurodevelopmental outcomes compared with standard care. These data suggest a possible association between moderate to severe hypoglycemia and poorer neurodevelopmental outcomes at 1 year of age.

Trial Registration: ClinicalTrials.gov: NCT00443599.
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http://dx.doi.org/10.1016/j.jpeds.2016.03.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925287PMC
July 2016

Altered Gray Matter in Adolescents with d-Transposition of the Great Arteries.

J Pediatr 2016 Feb 6;169:36-43.e1. Epub 2015 Nov 6.

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

Objective: To investigate the structural brain characteristics of adolescent patients with d-transposition of the great arteries (d-TGA), repaired with the arterial switch operation in early infancy, using quantitative volumetric magnetic resonance imaging.

Study Design: Ninety-two patients with d-TGA from the Boston Circulatory Arrest Study (76% male; median age at scan 16.1 years) and 49 control subjects (41% male; median age at scan 15.7 years) were scanned using a 1.5-Tesla magnetic resonance imaging system. Subcortical and cortical gyral volumes and cortical gyral thicknesses were measured using surface-based morphometry. Group differences were assessed with linear regression.

Results: Compared with controls, patients with d-TGA demonstrated significantly reduced subcortical volumes bilaterally in the striatum and pallidum. Cortical regions that showed significant volume and thickness differences between groups were distributed throughout parietal, medial frontoparietal, cingulate, and temporal gyri. Among adolescents with d-TGA, volumes and thicknesses correlated with several perioperative variables, including age at surgery, cooling duration, total support time, and days in the cardiac intensive care unit.

Conclusions: Adolescents with d-TGA repaired early in life exhibit widespread differences from control adolescents in gray matter volumes and thicknesses, particularly in parietal, midline, and subcortical brain regions, corresponding to white matter regions already known to demonstrate altered microstructure. These findings complement observations made in white matter in this group and suggest that the adolescent d-TGA cognitive profile derives from altered brain development involving both white and gray matter.
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http://dx.doi.org/10.1016/j.jpeds.2015.09.084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854486PMC
February 2016

Patterns of Sedation Weaning in Critically Ill Children Recovering From Acute Respiratory Failure.

Pediatr Crit Care Med 2016 Jan;17(1):19-29

1University of Pennsylvania, Philadelphia, PA. 2Department of Cardiology, Boston Children's Hospital, Boston, MA. 3Department of Family Health Care Nursing, University of California, San Francisco, CA. 4Department of Pediatrics, Harvard Medical School, Boston, MA. 5Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA. 6Department of Family and Community Health in the School of Nursing, and the Department of Anesthesia and Critical Care Medicine in the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 7Critical Care/Cardiovascular Nursing Program, Boston Children's Hospital, Boston, MA.

Objective: To characterize sedation weaning patterns in typical practice settings among children recovering from critical illness.

Design: A descriptive secondary analysis of data that were prospectively collected during the prerandomization phase (January to July 2009) of a clinical trial of sedation management.

Setting: Twenty-two PICUs across the United States.

Patients: The sample included 145 patients, aged 2 weeks to 17 years, mechanically ventilated for acute respiratory failure who received at least five consecutive days of opioid exposure.

Interventions: None.

Measurements And Main Results: Group comparisons were made between patients with an intermittent weaning pattern, defined as a 20% or greater increase in daily opioid dose after the start of weaning, and the remaining patients defined as having a steady weaning pattern. Demographic and clinical characteristics, tolerance to sedatives, and iatrogenic withdrawal symptoms were evaluated. Sixty-six patients (46%) were intermittently weaned; 79 patients were steadily weaned. Prior to weaning, intermittently weaned patients received higher peak and cumulative doses and longer exposures to opioids and benzodiazepines, demonstrated more sedative tolerance (58% vs 41%), and received more chloral hydrate and barbiturates compared with steadily weaned patients. During weaning, intermittently weaned patients assessed for withdrawal had a higher incidence of Withdrawal Assessment Tool-version 1 scores of greater than or equal to 3 (85% vs 46%) and received more sedative classes compared with steadily weaned patients.

Conclusions: This study characterizes sedative administration practices for pediatric patients prior to and during weaning from sedation after critical illness. It provides a novel methodology for describing weaning in an at-risk pediatric population that may be helpful in future research on weaning strategies to prevent iatrogenic withdrawal syndrome.
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http://dx.doi.org/10.1097/PCC.0000000000000572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703577PMC
January 2016

Early High-Frequency Oscillatory Ventilation in Pediatric Acute Respiratory Failure. A Propensity Score Analysis.

Am J Respir Crit Care Med 2016 Mar;193(5):495-503

10 Department of Cardiovascular and Critical Care Services, Boston Children's Hospital, Boston, Massachusetts.

Rationale: The use of high-frequency oscillatory ventilation (HFOV) for acute respiratory failure in children is prevalent despite the lack of efficacy data.

Objectives: To compare the outcomes of patients with acute respiratory failure managed with HFOV within 24-48 hours of endotracheal intubation with those receiving conventional mechanical ventilation (CMV) and/or late HFOV.

Methods: This is a secondary analysis of data from the RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure) study, a prospective cluster randomized clinical trial conducted between 2009 and 2013 in 31 U.S. pediatric intensive care units. Propensity score analysis, including degree of hypoxia in the model, compared the duration of mechanical ventilation and mortality of patients treated with early HFOV matched with those treated with CMV/late HFOV.

Measurements And Main Results: Among 2,449 subjects enrolled in RESTORE, 353 patients (14%) were ever supported on HFOV, of which 210 (59%) had HFOV initiated within 24-48 hours of intubation. The propensity score model predicting the probability of receiving early HFOV included 1,064 patients (181 early HFOV vs. 883 CMV/late HFOV) with significant hypoxia (oxygenation index ≥ 8). The degree of hypoxia was the most significant contributor to the propensity score model. After adjusting for risk category, early HFOV use was associated with a longer duration of mechanical ventilation (hazard ratio, 0.75; 95% confidence interval, 0.64-0.89; P = 0.001) but not with mortality (odds ratio, 1.28; 95% confidence interval, 0.92-1.79; P = 0.15) compared with CMV/late HFOV.

Conclusions: In adjusted models including important oxygenation variables, early HFOV was associated with a longer duration of mechanical ventilation. These analyses make supporting the current approach to HFOV less convincing.
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http://dx.doi.org/10.1164/rccm.201507-1381OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824923PMC
March 2016