Prospective Evaluation of Sedation-Related Adverse Events in Pediatric Patients Ventilated for Acute Respiratory Failure

Objectives: Sedation-related adverse events in critically ill pediatric patients lack reproducible operational definitions and reference standards. Understanding these adverse events is essential to improving the quality of patient care and for developing prevention strategies in critically ill children. The purpose of this study was to test operational definitions and estimate the rate and site-to-site heterogeneity of sedation-related adverse events. Design: Prospective cohort study. Setting: Twenty-two pediatric intensive care units in the United States enrolling baseline patients into a prerandomization phase of a multicenter trial on sedation management. Patients: Pediatric patients intubated and mechanically ventilated for acute respiratory failure. Data Extraction: Analysis of adverse event data using consistent operational definitions from a Web-based data management system. Measurements and Main Results: There were 594 sedation-related adverse events reported in 308 subjects, for a rate of 1.9 adverse events per subject and 16.6 adverse events per 100 pediatric intensive care unit days. Fifty-four percent of subjects had at least one adverse event. Seven (1%) adverse events were classified as severe, 347 (58%) as moderate, and 240 (40%) as mild. Agitation (30% of subjects, 41% of events) and pain (27% of subjects, 29% of events) were the most frequently reported events. Eight percent of subjects (n = 24) experienced 54 episodes of clinically significant iatrogenic withdrawal. Unplanned endotracheal tube extubation occurred at a rate of 0.82 per 100 ventilator days, and 32 subjects experienced postextubation stridor. Adverse events with moderate intraclass correlation coefficients included: Inadequate sedation management (intraclass correlation coefficient = 0.130), clinically significant iatrogenic withdrawal (intraclass correlation coefficient = 0.088), inadequate pain management (intraclass correlation coefficient = 0.080), and postextubation stridor (intraclass correlation coefficient = 0.078). Conclusions: Operational definitions for sedation-related adverse events were consistently applied across multiple pediatric intensive care units. Adverse event rates were different from what has been previously reported in single-center studies. Many adverse events have moderate intraclass correlation coefficients, signaling site-to-site heterogeneity

Defining Sedation-Related Adverse Events in the Pediatric Intensive Care Unit

Background Clinical trials exploring optimal sedation management in critically ill pediatric patients are urgently needed to improve both short- and long-term outcomes. Concise operational definitions that define and provide best-available estimates of sedation-related adverse events (AE) in the pediatric population are fundamental to this line of inquiry. Objectives To perform a multiphase systematic review of the literature to identify, define, and provide estimates of sedation-related AEs in the pediatric ICU setting for use in a multicenter clinical trial. Methods In Phase One, we identified and operationally defined the AE. OVID-MEDLINE and CINAHL databases were searched from January 1998 to January 2012. Key terms included sedation, intensive and critical care. We limited our search to data-based clinical trials from neonatal to adult age. In Phase Two, we replicated the search strategy for all AEs and identified pediatric-specific AE rates. Results We reviewed 20 articles identifying sedation-related adverse events and 64 articles on the pediatric-specific sedation-related AE. A total of eleven sedation-related AEs were identified, operationally defined and estimated pediatric event rates were derived. AEs included: inadequate sedation management, inadequate pain management, clinically significant iatrogenic withdrawal, unplanned endotracheal tube extubation, post-extubation stridor with chest-wall retractions at rest, extubation failure, unplanned removal of invasive tubes, ventilator-associated pneumonia, catheter-associated bloodstream infection, Stage II+ pressure ulcers and new tracheostomy. Conclusions Concise operational definitions that defined and provided best-available event rates of sedation-related AEs in the pediatric population are presented. Uniform reporting of adverse events will improve subject and patient safety

Prone Positioning can be Safely Performed in Critically Ill Infants and Children

Objective: To describe the effects of prone positioning on airway management, mechanical ventilation, enteral nutrition, pain and sedation management, and staff utilization in infants and children with acute lung injury. Design: Secondary analysis of data collected in a multiple-center, randomized, controlled clinical trial of supine vs. prone positioning. Setting: Seven pediatric intensive care units located in the United States. Patients: One hundred and two pediatric patients (51 prone and 51 supine) with acute lung injury. Interventions: Patients randomized to the supine group remained supine. Patients randomized to the prone group were positioned prone per protocol during the acute phase of their illness for a maximum of 7 days. Both groups were managed using ventilator and sedation protocols and nutrition and skin care guidelines. Measurements and Main Results: Airway management and mechanical ventilatory variables before and after repositioning, enteral nutrition management, pain and sedation management, staff utilization, and adverse event data were collected for up to 28 days after enrollment. There were a total of 202 supine-prone-supine cycles. There were no differences in the incidence of endotracheal tube leak between the two groups (p = .30). Per protocol, 95% of patients remained connected to the ventilator during repositioning. The inadvertent extubation rate was 0.85 for the prone group and 1.03 for the supine group per 100 ventilator days (p = 1.00). There were no significant differences in the initiation of trophic (p = .24), advancing (p = .82), or full enteral feeds (p = .80) between the prone and supine groups; in the average pain (p = .81) and sedation (p = .18) scores during the acute phase; and in the amount of comfort medications received between the two groups (p = .91). There were no critical events during a turn procedure. While prone, two patients experienced an obstructed endotracheal tube. One patient, supported on high-frequency oscillatory ventilation, experienced persistent hypercapnea when prone and was withdrawn from the study. The occurrence of pressure ulcers was similar between the two groups (p = .71). Compared with the supine group, more staff (p ≤ .001) and more time were necessary to reposition patients in the prone group. Conclusions: Our data show that prone positioning can be safely performed in critically ill pediatric patients and that these patients can be safely managed while in the prone position for prolonged periods of time

Hemodynamic Effects of a High-Frequency Oscillatory Ventilation Open-Lung Strategy in Critically Ill Children With Acquired or Congenital Cardiac Disease

OBJECTIVES: To study the hemodynamic consequences of an open-lung high-frequency oscillatory ventilation (HFOV) strategy in patients with an underlying cardiac anomaly with or without intracardiac shunt or primary pulmonary hypertension with severe lung injury.DESIGN: Secondary analysis of prospectively collected data.SETTING: Medical-surgical PICU.PATIENTS: Children less than 18 years old with cardiac anomalies (± intracardiac shunt) or primary pulmonary hypertension.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: Data from 52 subjects were analyzed, of whom 39 of 52 with cardiac anomaly (23/39 with intracardiac shunt) and 13 of 52 with primary pulmonary hypertension. Fourteen patients were admitted postoperatively, and 26 patients were admitted with acute respiratory failure. Five subjects (9.6%) were canulated for ECMO (of whom four for worsening respiratory status). Ten patients (19.2%) died during PICU stay. Median conventional mechanical ventilation settings prior to HFOV were peak inspiratory pressure 30 cm H 2 O (27-33 cm H 2 O), positive end-expiratory pressure 8 cm H 2 O (6-10 cm H 2 O), and F io2 0.72 (0.56-0.94). After transitioning to HFOV, there was no negative effect on mean arterial blood pressure, central venous pressure, or arterial lactate. Heart rate decreased significantly over time ( p &lt; 0.0001), without group differences. The percentage of subjects receiving a fluid bolus decreased over time ( p = 0.003), especially in those with primary pulmonary hypertension ( p = 0.0155) and without intracardiac shunt ( p = 0.0328). There were no significant differences in the cumulative number of daily boluses over time. Vasoactive Infusion Score did not increase over time. Pa co2 decreased ( p &lt; 0.0002) and arterial pH significantly improved ( p &lt; 0.0001) over time in the whole cohort. Neuromuscular blocking agents were used in all subjects switched to HFOV. Daily cumulative sedative doses were unchanged, and no clinically apparent barotrauma was found.CONCLUSIONS: No negative hemodynamic consequences occurred with an individualized, physiology-based open-lung HFOV approach in patients with cardiac anomalies or primary pulmonary hypertension suffering from severe lung injury.</p

State Behavioral Scale (SBS) A Sedation Assessment Instrument for Infants and Young Children Supported on Mechanical Ventilation

Objective: To develop and test the reliability and validity of the State Behavioral Scale for use in describing sedation/agitation levels in young intubated patients supported on mechanical ventilation. Design: In this prospective, psychometric evaluation, pairs of trained pediatric critical care nurse evaluators simultaneously and independently assessed a convenience sample of pediatric intensive care unit patients along eight state/behavioral dimensions and a numeric rating scale (NRS) of 0 (extremely sedated) to 10 (extremely agitated). The eight dimensions were derived from the sedation/agitation literature and expert opinion and included respiratory drive, response to ventilation, coughing, best response to stimulation, attentiveness to careprovider, tolerance to care, consolability, and movement after consoled, each with 3–5 levels. Setting: An 18-bed pediatric medical–surgical intensive care unit and 26-bed pediatric cardiovascular intensive care unit in a university-affiliated academic children’s hospital. Patients: A total of 91 intubated mechanically ventilated patients 6 wks to 6 yrs of age provided a median of two observations (interquartile range, 1–3) for a total of 198 sets of observations. Excluded were postoperative patients or those receiving neuromuscular blockade. Interventions: Patients were observed for 1 min, and then incremental levels of stimulation were applied until patient response. After 2 mins of consoling, the state behavioral assessment and NRS were completed. Measurements: Weighted kappa and intraclass coefficients were generated to assess interrater reliability of the eight dimension and NRS ratings. Distinct state behavior profiles were empirically identified from the dimension ratings using hierarchical cluster analysis using a squared Euclidean distance measure and between-groups linkage. Construct validity of these profiles was assessed by comparing group mean NRS scores using one-way analysis of variance. Main Results: Weighted kappa scores for all 198 dimension ratings ranged from .44 to .76, indicating moderate to good interrater reliability. The intraclass coefficient of .79 was high for NRS ratings. Cluster analysis revealed five distinct state profiles, with mean NRS ratings of 1.1, 2.5, 4.0, 5.3, and 7.6, all of which differed significantly from each other (F = 75.8, p \u3c .001), supporting the profiles’ construct validity. Conclusions: Based on empirically derived state behavior profiles, we have constructed the State Behavioral Scale to allow systematic description of the sedation–agitation continuum in young pediatric patients supported on mechanical ventilation. Further studies including prospective validation and describing the effect of State Behavioral Scale implementation on clinical outcomes, including the quality of sedation and length of mechanical ventilation, are warranted

The Withdrawal Assessment Tool–1 (WAT–1): An Assessment Instrument for Monitoring Opioid and Benzodiazepine Withdrawal Symptoms in Pediatric Patients

Objective: To develop and test the validity and reliability of the Withdrawal Assessment Tool–1 for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Design: Prospective psychometric evaluation. Pediatric critical care nurses assessed eligible at-risk pediatric patients for the presence of 19 withdrawal symptoms and rated the patient’s overall withdrawal intensity using a Numeric Rating Scale where zero indicated no withdrawal and 10 indicated worst possible withdrawal. The 19 symptoms were derived from the Opioid and Benzodiazepine Withdrawal Score, the literature and expert opinion. Setting: Two pediatric intensive care units in university-affiliated academic children’s hospitals. Patients: Eighty-three pediatric patients, median age 35 mos (interquartile range: 7 mos−10 yrs), recovering from acute respiratory failure who were being weaned from more than 5 days of continuous infusion or round-the-clock opioid and benzodiazepine administration. Interventions: Repeated observations during analgesia and sedative weaning. A total of 1040 withdrawal symptom assessments were completed, with a median (interquartile range) of 11 (6–16) per patient over 6.6 (4.8−11) days. Measurements and Main Results: Generalized linear modeling was used to analyze each symptom in relation to withdrawal intensity ratings, adjusted for site, subject, and age group. Symptoms with high redundancy or low levels of association with withdrawal intensity ratings were dropped, resulting in an 11-item (12-point) scale. Concurrent validity was indicated by high sensitivity (0.872) and specificity (0.880) for Withdrawal Assessment Tool–1 \u3e 3 predicting Numeric Rating Scale \u3e 4. Construct validity was supported by significant differences in drug exposure, length of treatment and weaning from sedation, length of mechanical ventilation and intensive care unit stay for patients with Withdrawal Assessment Tool–1 scores \u3e 3 compared with those with lower scores. Conclusions: The Withdrawal Assessment Tool–1 shows excellent preliminary psychometric performance when used to assess clinically important withdrawal symptoms in the pediatric intensive care unit setting. Further psychometric evaluation in diverse at-risk groups is needed

Defining Acute Lung Disease in Children With the Oxygenation Saturation Index

Objective: To evaluate whether a formula could be derived using oxygen saturation (Spo2) to replace Pao2 that would allow identification of children with acute lung injury and acute respiratory distress syndrome. Definitions of acute lung injury and acute respiratory distress syndrome require arterial blood gases to determine the Pao2/Fio2 ratio of 300 (acute lung injury) and 200 (acute respiratory distress syndrome). Design: Post hoc data analysis of measurements abstracted from two prospective databases of randomized controlled trials. Setting: Academic pediatric intensive care units. Patients: A total of 255 children enrolled in two large prospective trials of therapeutic intervention for acute lung disease: calfactant and prone positioning. Interventions: Data were abstracted including Pao2, Paco2, pH, Fio2, and mean airway pressure. Repeated-measures analyses, using linear mixed-effects models, were used to build separate prediction equations for the Spo2/Fio2 ratio, oxygenation index [(Fio2 × Mean Airway Pressure)/Pao2], and oxygen saturation index [(Fio2 × Mean Airway Pressure)/Spo2]. A generalization of R2 was used to measure goodness-of-fit. Generalized estimating equations with a logit link were used to calculate the sensitivity and specificity for the cutoffs of Pao2/Fio2 ratio of 200 and 300 and equivalent values of Spo2/Fio2 ratio, oxygenation index, and oxygen saturation index. Measurements and Main Results: An Spo2/Fio2 ratio of 253 and 212 would equal criteria for acute lung injury and acute respiratory distress syndrome, respectively. An oxygenation index of 5.3 would equal acute lung injury criteria, and an oxygenation index of 8.1 would qualify for acute respiratory distress syndrome. An oxygen saturation index, which includes the mean airway pressure and the noninvasive measure of oxygenation, of 6.5 would be equivalent to the acute lung injury criteria, and an oxygen saturation index of 7.8 would equal acute respiratory distress syndrome criteria. Conclusions: Noninvasive methods of assessing oxygenation may be utilized with reasonable sensitivity and specificity to define acute lung injury and acute respiratory distress syndrome, and, with prospective validation, have the potential to increase the number of children enrolled into clinical trials

Early Neuromuscular Blockade in Moderate-to-Severe Pediatric Acute Respiratory Distress Syndrome

Objectives: The use of neuromuscular blocking agents (NMBAs) in pediatric acute respiratory distress syndrome (PARDS) is common but unsupported by efficacy data. We sought to compare the outcomes between patients with moderate-to-severe PARDS receiving continuous NMBA during the first 48 hours of endotracheal intubation (early NMBA) and those without. Design: Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial, a pediatric multicenter cluster randomized trial of sedation. Setting: Thirty-one PICUs in the United States. Patients: Children 2 weeks to 17 years receiving invasive mechanical ventilation (MV) for moderate-to-severe PARDS (i.e., oxygenation index >= 8 and bilateral infiltrates on chest radiograph on days 0-1 of endotracheal intubation). Interventions: NMBA for the entire duration of days 1 and 2 after intubation. Measurements and Main Results: Among 1,182 RESTORE patients with moderate-to-severe PARDS, 196 (17%) received early NMBA for a median of 50.0% ventilator days (interquartile range, 33.3-60.7%). The propensity score model predicting the probability of receiving early NMBA included high-frequency oscillatory ventilation on days 0-2 (odds ratio [OR], 7.61; 95% CI, 4.75-12.21) and severe PARDS on days 0-1 (OR, 2.16; 95% CI, 1.50-3.12). After adjusting for risk category, early use of NMBA was associated with a longer duration of MV (hazard ratio, 0.57; 95% CI, 0.48-0.68; p < 0.0001), but not with mortality (OR, 1.62; 95% CI, 0.92-2.85; p = 0.096) compared with no early use of NMBA. Other outcomes including cognitive, functional, and physical impairment at 6 months post-PICU discharge were similar. Outcomes did not differ when comparing high versus low NMBA usage sites or when patients were stratified by baseline PaO2/FIO2 less than 150. Conclusions: Early NMBA use was associated with a longer duration of MV. This propensity score analysis underscores the need for a randomized controlled trial in pediatrics

Tight Glycemic Control After Pediatric Cardiac Surgery in High-Risk Patient Populations

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 \u3e60 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 \u3e60 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