Lisa A. Asaro

Protocolized Sedation vs Usual Care in Pediatric Patients Mechanically Ventilated for Acute Respiratory Failure: A Randomized Clinical Trial

IMPORTANCE Protocolized sedation improves clinical outcomes in critically ill adults, but its effect in children is unknown. OBJECTIVE To determine whether critically ill children managed with a nurse-implemented, goal-directed sedation protocol experience fewer days of mechanical ventilation than patients receiving usual care. DESIGN, SETTING, AND PARTICIPANTS Cluster randomized trial conducted in 31 US pediatric intensive care units (PICUs). A total of 2449 children (mean age, 4.7 years; range, 2 weeks to 17 years) mechanically ventilated for acute respiratory failure were enrolled in 2009-2013 and followed up until 72 hours after opioids were discontinued, 28 days, or hospital discharge. INTERVENTION Intervention PICUs (17 sites; n = 1225 patients) used a protocol that included targeted sedation, arousal assessments, extubation readiness testing, sedation adjustment every 8 hours, and sedation weaning. Control PICUs (14 sites; n = 1224 patients) managed sedation per usual care. MAIN OUTCOMES AND MEASURES The primary outcome was duration of mechanical ventilation. Secondary outcomes included time to recovery from acute respiratory failure, duration of weaning from mechanical ventilation, neurological testing, PICU and hospital lengths of stay, in-hospital mortality, sedation-related adverse events, measures of sedative exposure (wakefulness, pain, and agitation), and occurrence of iatrogenic withdrawal. RESULTS Duration of mechanical ventilation was not different between the 2 groups (intervention: median, 6.5 [IQR, 4.1-11.2] days; control: median, 6.5 [IQR, 3.7-12.1] days). Sedation-related adverse events including inadequate pain and sedation management, clinically significant iatrogenic withdrawal, and unplanned endotracheal tube/invasive line removal were not significantly different between the 2 groups. Intervention patients experienced more postextubation stridor (7% vs 4%; P = .03) and fewer stage 2 or worse immobility-related pressure ulcers (<1% vs 2%; P = .001). In exploratory analyses, intervention patients had fewer days of opioid administration (median, 9 [IQR, 5-15] days vs 10 [IQR, 4-21] days; P = .01), were exposed to fewer sedative classes (median, 2 [IQR, 2-3] classes vs 3 [IQR, 2-4] classes; P < .001), and were more often awake and calm while intubated (median, 86% [IQR, 67%-100%] of days vs 75% [IQR, 50%-100%] of days; P = .004) than control patients, respectively; however, intervention patients had more days with any report of a pain score ≥ 4 (median, 50% [IQR, 27%-67%] of days vs 23% [IQR, 0%-46%] of days; P < .001) and any report of agitation (median, 60% [IQR, 33%-80%] vs 40% [IQR, 13%-67%]; P = .003), respectively. CONCLUSIONS AND RELEVANCE Among children undergoing mechanical ventilation for acute respiratory failure, the use of a sedation protocol compared with usual care did not reduce the duration of mechanical ventilation. Exploratory analyses of secondary outcomes suggest a complex relationship among wakefulness, pain, and agitation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00814099.

White matter microstructure and cognition in adolescents with congenital heart disease.

OBJECTIVE To describe the relationship between altered white matter microstructure and neurodevelopment in children with dextro-transposition of the great arteries (d-TGA). STUDY DESIGN We report correlations between regional white matter microstructure as measured by fractional anisotropy (FA) and cognitive outcome in a homogeneous group of adolescents with d-TGA. Subjects with d-TGA (n = 49) and controls (n = 29) underwent diffusion tensor imaging and neurocognitive testing. In the group with d-TGA, we correlated neurocognitive scores with FA in 14 composite regions of interest in which subjects with d-TGA had lower FA than controls. RESULTS Among the patients with d-TGA, mathematics achievement correlated with left parietal FA (r = 0.39; P = .006), inattention/hyperactivity symptoms correlated with right precentral FA (r = -0.39; P = .006) and left parietal FA (r = -0.30; P = .04), executive function correlated with right precentral FA (r = -0.30; P = .04), and visual-spatial skills correlated with right frontal FA (r = 0.30; P = .04). We also found an unanticipated correlation between memory and right posterior limb of the internal capsule FA (r = 0.29; P = .047). CONCLUSION Within the group with d-TGA, regions of reduced white matter microstructure are associated with cognitive performance in a pattern similar to that seen in healthy adolescents and adults. Diminished white matter microstructure may contribute to cognitive compromise in adolescents who underwent open-heart surgery in infancy.

Tight glycemic control in critically Ill children

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.)

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

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.

Tight Glycemic Control after Pediatric Cardiac Surgery in High-Risk Patient Populations: A Secondary Analysis of the Safe Pediatric Euglycemia after Cardiac Surgery Trial

Background— Our previous randomized, clinical trial showed that postoperative tight glycemic control (TGC) for children undergoing cardiac surgery did not reduce the rate of health care–associated infections compared with standard care (STD). Heterogeneity of treatment effect may exist within this population. Methods and Results— We performed a post hoc exploratory analysis of 980 children from birth to 36 months of age at the time of cardiac surgery who were randomized to postoperative TGC or STD in the intensive care unit. Significant interactions were observed between treatment group and both neonate (age ⩽30 days; P=0.03) and intraoperative glucocorticoid exposure (P=0.03) on the risk of infection. The rate and incidence of infections in subjects ⩽60 days old were significantly increased in the TGC compared with the STD group (rate: 13.5 versus 3.7 infections per 1000 cardiac intensive care unit days, P=0.01; incidence: 13% versus 4%, P=0.02), whereas infections among those >60 days of age were significantly reduced in the TGC compared with the STD group (rate: 5.0 versus 14.1 infections per 1000 cardiac intensive care unit days, P=0.02; incidence: 2% versus 5%, P=0.03); the interaction of treatment group by age subgroup was highly significant (P=0.001). Multivariable logistic regression controlling for the main effects revealed that previous cardiac surgery, chromosomal anomaly, and delayed sternal closure were independently associated with increased risk of infection. Conclusions— This exploratory analysis demonstrated that TGC may lower the risk of infection in children >60 days of age at the time of cardiac surgery compared with children receiving STD. Meta-analyses of past and ongoing clinical trials are necessary to confirm these findings before clinical practice is altered. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00443599.Background— Our previous randomized, clinical trial showed that postoperative tight glycemic control (TGC) for children undergoing cardiac surgery did not reduce the rate of health care–associated infections compared with standard care (STD). Heterogeneity of treatment effect may exist within this population. Methods and Results— We performed a post hoc exploratory analysis of 980 children from birth to 36 months of age at the time of cardiac surgery who were randomized to postoperative TGC or STD in the intensive care unit. Significant interactions were observed between treatment group and both neonate (age ≤30 days; P =0.03) and intraoperative glucocorticoid exposure ( P =0.03) on the risk of infection. The rate and incidence of infections in subjects ≤60 days old were significantly increased in the TGC compared with the STD group (rate: 13.5 versus 3.7 infections per 1000 cardiac intensive care unit days, P =0.01; incidence: 13% versus 4%, P =0.02), whereas infections among those >60 days of age were significantly reduced in the TGC compared with the STD group (rate: 5.0 versus 14.1 infections per 1000 cardiac intensive care unit days, P =0.02; incidence: 2% versus 5%, P =0.03); the interaction of treatment group by age subgroup was highly significant ( P =0.001). Multivariable logistic regression controlling for the main effects revealed that previous cardiac surgery, chromosomal anomaly, and delayed sternal closure were independently associated with increased risk of infection. Conclusions— This exploratory analysis demonstrated that TGC may lower the risk of infection in children >60 days of age at the time of cardiac surgery compared with children receiving STD. Meta-analyses of past and ongoing clinical trials are necessary to confirm these findings before clinical practice is altered. Clinical Trial Registration— URL: . Unique identifier: [NCT00443599][1]. # CLINICAL PERSPECTIVE {#article-title-34} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00443599&atom=%2Fcirculationaha%2F129%2F22%2F2297.atom

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

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.

Dexmedetomidine Use in Critically Ill Children with Acute Respiratory Failure

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.

White Matter Volume Predicts Language Development in Congenital Heart Disease

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.

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

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.

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

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.