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

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.

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

BACKGROUND: Few papers discuss the pragmatics of conducting large, cluster randomized clinical trials. Here we describe the sequential steps taken to develop methods to implement the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) trial that tested the effect of a nurse-implemented, goal-directed, comfort algorithm on clinical outcomes in pediatric patients with acute respiratory failure. METHODS: After development in a single institution, the RESTORE intervention was pilot-tested in two pediatric intensive care units (PICUs) to evaluate safety and feasibility. After the pilot, the RESTORE intervention was simplified to enhance reproducibility across multiple PICUs. The final RESTORE trial was developed as a cluster randomized clinical trial where the unit of randomization was the PICU, stratified by PICU size, and the unit of inference was the patient. Study execution was revised based on our Data and Safety Monitoring Board's recommendation to consult with the Department of Health and Human Services' Office of Human Research Protection (OHRP) on how best to consent eligible subjects. OHRP deemed that the RESTORE intervention posed greater than minimal risk and that all enrolled subjects provide consent reflecting their level of participation. RESULTS: Thirty-one PICUs of varying size, organization and academic affiliation participated and over 2800 critically ill infants and children supported on mechanical ventilation for acute pulmonary disease were enrolled. The primary outcome for the trial was the duration of mechanical ventilation; secondary outcomes included time awake and comfortable, total sedative exposure and iatrogenic withdrawal symptoms. Throughout the clinical trial the investigative team worked to maintain treatment fidelity, enrollment milestones and co-investigator enthusiasm. We considered the potential impact of competing clinical trials through a decision-making framework. CONCLUSIONS: The RESTORE clinical trial was a large and complex multicenter study that has provided the necessary evidence to guide sedation practices in the field of pediatric critical care. Specific issues that were unique to this trial included level of consent, adding clinical sites to augment enrollment and evaluating the potential impact of competing clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov , Identifiers: Pilot trial: NCT00142766 ; Retrospectively registerd on 2 September 2005. Cluster randomized trial: NCT00814099 . Registered on 23 December 2008.

An Investigation of Drug-Drug Interaction Alert Overrides at a Pediatric Hospital.

OBJECTIVES: Drug-drug interactions (DDIs) can result in patient harm. DDI alerts are intended to help prevent harm; when the majority of alerts presented to providers are being overridden, their value is diminished. Our objective was to evaluate the overall rates of DDI alert overrides and how rates varied by specialty, clinician type, and patient complexity. METHODS: A retrospective study of DDI alert overrides that occurred during 2012 and 2013 within the inpatient setting described at the medication-, hospital-, provider-, and patient encounter-specific levels was performed at an urban, quaternary-care, pediatric hospital. RESULTS: There were >41 000 DDI alerts presented to clinicians; ∼90% were overridden. The 5 DDI pairs that were most frequently presented and overridden included the following: potassium chloride-spironolactone, methadone-ondansetron, ketorolac-ibuprofen, cyclosporine-fluconazole, and potassium chloride-enalapril, each with an alert override rate of ≥0.89. Override rates across provider groups ranged between 0.84 and 0.97. In general, patients with high complexity had a higher frequency of alert overrides, but the rates of alert overrides for each DDI pairing did not differ significantly. CONCLUSIONS: High rates of DDI alert overrides occur across medications, provider groups, and patient encounters. Methods to decrease DDI alerts which are likely to be overridden exist, but it is also clear that more robust and intelligent tools are needed. Characteristics exist at the medication, hospital, provider, and patient levels that can be used to help specialize and enhance information transmission.

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.

Quality improvement program reduces venous thromboembolism in infants and children with long-gap esophageal atresia (LGEA).

PURPOSE: Patients with long-gap esophageal atresia (LGEA) treated with the Foker process are at increased risk of venous thromboembolism (VTE). An institutional quality improvement program to decrease VTE risk factor exposure and utilize prophylactic anticoagulation was implemented. We aim to evaluate the efficacy and safety of a VTE risk-reduction program in patients with LGEA. METHODS: Implementation and evaluation of a VTE risk-reduction program in patients with LGEA from 2012 to 2015 was performed. Symptomatic VTE with radiographic confirmation were defined as events. Post-program characteristics were evaluated and compared to a historical cohort. RESULTS: Sixty-seven patients were identified. Two developed VTE (7 %) post-program implementation; compared to 13/40 (33 %) VTE incidence in the historical cohort (p = 0.018). Baseline demographics were similar, including age, esophageal atresia type and gap length. Post-protocol patients had fewer paralysis episodes (p = 0.004), paralysis days (p = 0.003), central venous catheters (p = 0.003), thoracotomies (p < 0.001), ventilator hours (p = 0.02), and decreased hospital (p < 0.001) and ICU stay (p < 0.001). All patients in the VTE risk-reduction program were exposed to prophylactic anticoagulation. No bleeding complications and/or thrombosis-related mortality occurred. CONCLUSION: VTE risk-reduction program implementation decreased symptomatic VTE incidence with associated decreases in ICU and hospital length of stay. Prophylactic anticoagulation can be utilized safely in a complicated pediatric surgical population.

Paravertebral nerve block catheters using chloroprocaine in infants with prolonged mechanical ventilation for treatment of long-gap esophageal atresia.

BACKGROUND: Infants with long-gap esophageal atresia (LGEA) undergo repeated thoracotomies for staged surgical repair known as the Foker process (FP). Associated prolonged mechanical ventilation results in exposure to high doses of opioids and benzodiazepines, and prolonged weaning times and ICU stays. AIM: The aim of this study was to determine the effectiveness of short-term paravertebral nerve block (PVNB) catheters in reducing opioid/benzodiazepine exposure and effects on clinical variables. METHODS: The medical records of seventeen infants were retrospectively reviewed; 11 with PVNB and six without (CG). PVNB were placed using ultrasound-guidance and chloroprocaine infusions implemented in the ICU. Opioids and benzodiazepines were administered via the protocol for 5 days following thoracotomies for Foker-I and Foker-II. RESULTS: Foker-I: Average reduction in morphine and midazolam consumption was 36% (2.18 vs 3.40 mg·kg(-1) ·day(-1) ; P < 0.001) and 31% (2.25 vs 3.25 mg·kg(-1) ·day(-1) ; P = 0.033), respectively, in the PVNB compared with CG. Foker-II: Average reduction in morphine and midazolam consumption was 39% (3.19 vs 5.27 mg·kg(-1) ·day(-1) ) and 38% (3.46 mg·kg(-1) ·day(-1) vs 5.62; P < 0.001), respectively in the PVNB compared with CG. 24-h prior to extubation: Average reduction in morphine and midazolam consumption was 50% (2.91 vs 5.85 mg·kg(-1) ·24 h(-1) ; p = 0.023) and 61% (2.27 vs 5.83 mg·kg(-1) ·24 h(-1) ; P = 0.004), respectively, in the PVNB compared with CG. Infusion wean time, (independence from opioid/midazolam infusions) following extubation was 5 days in the PVNB group and 15 days in CG (P = 0.005). Median ICU stay (IQR) was 40 days (34-45 days) in PVNB patients and 71 days (42-106 days) in controls (P = 0.02). PVNB catheters were left an average of 7 days and there were no complications associated with the nerve blocks. CONCLUSION: Short-term PVNB placement decreases opioid and benzodiazepine exposure, weaning days and ICU stay in infants undergoing prolonged mechanical ventilation for LGEA repair in this small pilot study. Larger studies are warranted to confirm results.

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.

High incidence of fracture events in patients with Long-Gap Esophageal Atresia (LGEA): A retrospective review prompting implementation of standardized protocol.

PURPOSE: To identify factors associated with an increased risk of fractures in Long-Gap Esophageal Atresia (LGEA) patients. Following implementation of a risk-stratified program, we hypothesized a reduction in fracture incidence within this potentially high-risk population. METHODS: A retrospective review of LGEA-patients admitted between 2005 and 2014 was conducted. Symptomatic fractures with radiographic confirmation were defined as events. Univariate and multivariable analysis evaluated factors including admission weight-for-age z-score, primary versus secondary Foker process (FP), weight at Foker Stage I, days and episodes of paralysis, number of parenteral nutrition (PN) days, cumulative dose of loop diuretics adjusted for body weight and days exposed, and exposure to non-loop diuretics. A fracture-prevention protocol was initiated in 2012; incidence was evaluated pre and post-intervention. RESULTS: Fifty-nine patients met inclusion criteria. Twenty-three (39%) patients in the entire cohort incurred at least one fracture during their hospitalization utilizing the Foker process. Given this high percentage, a targeted fracture-prevention protocol was initiated in 2012. Fracture incidence decreased from 48% prior to the protocol to 21% following the protocol (P = 0.046). Several variables that were associated with an increased risk of fractures on univariate analysis included prior esophageal anastomosis attempt (P = 0.008), number of separate episodes of paralysis (P = 0.002), exposure to non-loop diuretics (P = 0.006), cumulative loop diuretic dose (P < 0.001), as well as cumulative loop diuretic over days exposed (P < 0.001). Intensive care unit (ICU) stay (P = 0.002) and total length of hospitalization (P < 0.001) were also significantly longer among patients with a fracture. Number of separate episodes of paralysis was the only independent risk factor for the development of a fracture; patients having more than 3 episodes of paralysis had an estimated risk of fracture 15 times higher than those patients paralyzed only once or twice (O.R. 15.87, 95% C.I.: 1.47-171.23, P = 0.008). CONCLUSION: Episodes of paralysis appeared to be the most significant risk factor for fractures in patients with LGEA who underwent the Foker procedure. The incidence of symptomatic fractures decreased significantly following implementation of a standardized protocol in this series of LGEA patients with continued prospective evaluation.

Impact of needleless connector change frequency on central line-associated bloodstream infection rate.

BACKGROUND: Bloodstream infection is the most common pediatric health care-associated infection and is strongly associated with catheter use. These infections greatly increase the cost of hospital stay. METHODS: To assess the association between needleless connector (NC) change frequency and central line-associated bloodstream infection (CLABSI) rate, we modeled monthly pediatric stem cell transplant (SCT) CLABSI rate in 3 periods: baseline period during which NC were changed every 96 hours regardless of infusate (period 1); trial period in which NC were changed every 24 hours with blood or lipid infusions (period 2); and a return to NC change every 96 hours regardless of infusate (period 3). Data on potential confounders were collected retrospectively. Autocorrelated segmented regression models were used to compare SCT CLABSI rates in each period, adjusting for potential confounders. CLABSI rates were also assessed for a nonequivalent control group (oncology unit) in which NC were changed every 24 hours with blood or lipid use in periods 2 and 3. RESULTS: SCT CLABSI rates were 0.41, 3.56, and 0.03 per 1,000 central line-days in periods 1, 2, and 3, respectively. In multivariable analysis, the CLABSI rate was significantly higher in period 2 compared with both period 1 (P = .01) and period 3 (P = .003). In contrast, CLABSI rates on the oncology unit were not significantly different among periods. CONCLUSION: In pediatric SCT patients, changing needleless connectors every 24 hours when blood or lipids are infused is associated with increased CLABSI rates. National recommendations regarding NC change frequency should be clarified.

High incidence of catheter-associated venous thromboembolic events in patients with long gap esophageal atresia treated with the Foker process.

PURPOSE: To determine the incidence of catheter-associated venous thromboembolic events (VTE) in long gap esophageal atresia (LGEA) patients treated at Boston Children's Hospital (BCH) and to identify possible risk factors associated with their development. METHODS: We performed a retrospective analysis of LGEA patients from 2005 to 2012. Symptomatic VTEs with radiographic confirmation were defined as events. Potential risk factors were assessed by univariate analysis and multivariate logistic regression. Covariates included age, weight, initial gap length, cumulative days of pharmacologic paralysis and paralytic episodes, number and type of central venous catheters (CVCs), and number of operations. RESULTS: Forty-four LGEA patients were identified. The incidence of CVC associated VTE was 34%. Univariate analysis identified age at Foker 1 (P=.03), paralysis duration (P=.01), episodes of paralysis (P=.001), cumulative number of CVC (P=.007) and length of stay (P=.03) as significant. Multivariate logistic regression identified the number of paralytic episodes as the only significant independent risk factor for VTE (P<.0001). CONCLUSIONS: The incidence of symptomatic VTE was 34%, significantly higher than the VTE incidence of 4.5% reported for our other hospitalized children. These data have led to multidisciplinary discussions regarding thromboprophylaxis and development of a consensus-driven protocol. Since the initiation of this protocol, no VTEs have been identified.

Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment.

OBJECTIVE: Using an ex vivo simulation model we set out to estimate the amount of drug lost due to sequestration within the extracorporeal circuit over time. DESIGN: Simulated closed-loop extracorporeal membrane oxygenation (ECMO) circuits were prepared using a 1.5-m2 silicone membrane oxygenator. Group A consisted of heparin, dopamine, ampicillin, vancomycin, phenobarbital and fentanyl. Group B consisted of epinephrine, cefazolin, hydrocortisone, fosphenytoin and morphine. Drugs were tested in crystalloid and blood-primed circuits. After administration of a one-time dose of drugs in the priming fluid, baseline drug concentrations were obtained (P0). A simultaneous specimen was stored for stability testing at 24 h (P4). Serial post-membrane drug concentrations were then obtained at 30 min (P1), 3 h (P2) and 24 h (P3) from circuit fluid. MEASUREMENTS AND RESULTS: One hundred and one samples were analyzed. At the end of 24 h in crystalloid-primed circuits, 71.8% of ampicillin, 96.7% of epinephrine, 17.6% of fosphenytoin, 33.3% of heparin, 17.5% of morphine and 87% of fentanyl was lost. At the end of 24 h in blood-primed extracorporeal circuits, 15.4% of ampicillin, 21% of cefazolin, 71% of voriconazole, 31.4% of fosphenytoin, 53.3% of heparin and 100% of fentanyl was lost. There was a significant decrease in overall drug concentrations from 30 min to 24 h for both crystalloid-primed circuits (p = 0.023) and blood-primed circuits (p = 0.04). CONCLUSIONS: Our ex vivo study demonstrates serial losses of several drugs commonly used during ECMO therapy. Therapeutic concentrations of fentanyl, voriconazole, antimicrobials and heparin cannot be guaranteed in patients on ECMO.

Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children.

OBJECTIVE: To determine the relationship between estimated free, measured free, and measured total phenytoin levels in critically ill pediatric patients, assess the utility of the Sheiner-Tozer equation in predicting free phenytoin levels, and identify comedications that may influence phenytoin binding or confound attempts to maintain therapeutic concentrations. DESIGN: Retrospective chart review. SETTING: Twenty-four-bed medical-surgical pediatric intensive care unit. PATIENTS: Sixty critically ill pediatric patients receiving phenytoin for treatment of seizures in a large multidisciplinary intensive care unit. INTERVENTIONS AND MAIN RESULTS: The linear correlation between free and total phenytoin concentrations was moderate (r = .795), but the mean difference between actual free concentrations and those estimated from total concentrations using the Sheiner-Tozer equation was -0.31 +/- 0.5 microg/mL (95% confidence interval, -1.3 to 0.7). This difference was of concern, as 10% of patients had toxic free levels (>2 microg/mL) when simultaneously measured total levels were therapeutic (<20 microg/mL). The mean free/total phenytoin ratio was 0.13 +/- 0.07 (range, 0.06-0.42) and varied considerably among patients. Free fractions were particularly elevated in children whose serum albumin concentrations were <2.5 g/dL (0.22, p < .001). However, the relationship between free phenytoin and serum albumin concentration appeared to be nonlinear. Coadministration of valproic acid and cefazolin also increased free fraction (p < .001). CONCLUSIONS: Measured total phenytoin concentrations are unreliable for directing therapy in critically ill children. In part, this is because phenytoin binding shows greater variability in this population than has been reported in adults. This phenomenon is exacerbated by coadministration of other highly protein-bound drugs. Instead, free phenytoin concentrations should be routinely measured in critically ill children to prevent possible intoxications and ensure therapeutic dosing. Corrections using the Sheiner-Tozer equation were unreliable.

Pentobarbital desensitization in a 3-month-old child.

Barbiturates, a class of medications commonly used as antiepileptics and sedatives, are known to cause adverse reaction, with the most commonly reported immune-mediated reactions being anticonvulsant hypersensitivity syndrome. Other types of allergic reactions such as immediate hypersensitivity reactions also can occur. We present a 3-month-old child with refractory generalized convulsive status epilepticus who required pentobarbital therapy in the context of phenobarbital sensitivity because of progressive generalized seizures unresponsive to other aggressive therapies. Skin tests to pentobarbital and phenobarbital were negative. In the intensive care unit setting, intravenous pentobarbital desensitization was performed without reaction. To our knowledge, this is the first reported protocol for pentobarbital desensitization.