Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza.

Background: Influenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection. Methods: We measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q<0.05). Results: Comparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week. Conclusion: Thus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome.

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

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.

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.

Vancomycin Monotherapy May Be Insufficient to Treat Methicillin-resistant Staphylococcus aureus Coinfection in Children With Influenza-related Critical Illness.

Background: Coinfection with influenza virus and methicillin-resistant Staphylococcus aureus (MRSA) causes life-threatening necrotizing pneumonia in children. Sporadic incidence precludes evaluation of antimicrobial efficacy. We assessed the clinical characteristics and outcomes of critically ill children with influenza-MRSA pneumonia and evaluated antibiotic use. Methods: We enrolled children (<18 years) with influenza infection and respiratory failure across 34 pediatric intensive care units 11/2008-5/2016. We compared baseline characteristics, clinical courses, and therapies in children with MRSA coinfection, non-MRSA bacterial coinfection, and no bacterial coinfection. Results: We enrolled 170 children (127 influenza A, 43 influenza B). Children with influenza-MRSA pneumonia (N = 30, 87% previously healthy) were older than those with non-MRSA (N = 61) or no (N = 79) bacterial coinfections. Influenza-MRSA was associated with increased leukopenia, acute lung injury, vasopressor use, extracorporeal life support, and mortality than either group (P ≤ .0001). Influenza-related mortality was 40% with MRSA compared to 4.3% without (relative risk [RR], 9.3; 95% confidence interval [CI], 3.8-22.9). Of 29/30 children with MRSA who received vancomycin within the first 24 hours of hospitalization, mortality was 12.5% (N = 2/16) if treatment also included a second anti-MRSA antibiotic compared to 69.2% (N = 9/13) with vancomycin monotherapy (RR, 5.5; 95% CI, 1.4, 21.3; P = .003). Vancomycin dosing did not influence initial trough levels; 78% were <10 µg/mL. Conclusions: Influenza-MRSA coinfection is associated with high fatality in critically ill children. These data support early addition of a second anti-MRSA antibiotic to vancomycin in suspected severe cases.

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.

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.

U.S. attitudes and perceived practice for noninvasive ventilation in pediatric acute respiratory failure.

OBJECTIVE: Few pediatric studies exist regarding the use of noninvasive positive-pressure ventilation for acute respiratory failure; however, those that do suggest a role. This study seeks to describe attitudes and perceived practices of pediatric intensivists regarding the use of noninvasive positive-pressure ventilation in children with acute respiratory failure. DESIGN: Electronic survey. SETTING: Medical institutions. PARTICIPANTS: Of the 932 physicians approached, 353 (38%) responded to the survey. Respondents included U.S. physicians practicing pediatric critical care (90%), pediatric anesthesia critical care (4%), pediatric pulmonary critical care (4%), and other disciplines (2%). INTERVENTIONS: Survey. MEASUREMENTS AND MAIN RESULTS: The survey contained questions regarding 1) practitioner demographics, 2) patient characteristics, and 3) clinical cases designed to assess noninvasive positive-pressure ventilation use in certain patient scenarios. Noninvasive positive-pressure ventilation was used by 99% of the respondents, with 60% using noninvasive positive-pressure ventilation as initial support >10% of the time. Respondents reported use of noninvasive positive-pressure ventilation for acute respiratory failure in lower airway disease (70%), asthma (51%), acute lung injury/acute respiratory distress syndrome (43%), and upper airway obstruction (31%). In clinical scenarios, respondents reported that the factors associated with nonuse of noninvasive positive-pressure ventilation as initial support were disease process (31%), oxygenation (19%), ventilation severity (15%), expectation that the patient was likely to worsen (12%), and age or inability to cooperate (11%). CONCLUSIONS: Noninvasive positive-pressure ventilation is widely used and most frequently utilized in patients with acute lower airway disease. Factors such as severe defects in oxygenation and ventilation, disease progression, and patient tolerability decreased the likelihood of use. These findings may help direct further studies of noninvasive positive-pressure ventilation in children with acute respiratory failure.

Cumulative fluid intake minus output is not associated with ventilator weaning duration or extubation outcomes in children.

OBJECTIVE: The effect of fluid balance on respiratory outcomes for critically ill children has not been evaluated. The only indicator of fluid balance routinely recorded across our intensive care units was estimated fluid intake and output. We sought to determine whether cumulative intake minus output (I-O) at the start of weaning predicted weaning duration and whether cumulative I-O at extubation predicted extubation failure. DESIGN: Prospective observational study. SETTING: Ten pediatric intensive care units. PATIENTS: Cumulative I-O was recorded daily for 301 mechanically ventilated children (<18 yrs of age) from November 1999 through April 2001. INTERVENTIONS: Cumulative I-O was recorded during a study of weaning strategies and extubation failure in which mechanical ventilation of the majority of patients during weaning and extubation was managed according to a protocol that did not include fluid balance indicators. Outcomes were the time to successful removal of ventilatory support and the rate of initial extubation failure. MEASUREMENTS AND MAIN RESULTS: Relationships between cumulative I-O and outcomes were assessed by means of proportional hazards and logistic regression. The mean cumulative I-O per kilogram of ideal body weight at the start of weaning was 101 mL (sd, 180). Cumulative I-O at the time weaning was initiated did not predict duration of mechanical ventilator weaning. The mean cumulative I-O per kilogram of ideal body weight at extubation was 136 mL (sd, 237). Cumulative I-O at extubation did not predict extubation outcome. There was an association between cumulative I-O at extubation and the duration of weaning in cases not managed by a protocol. CONCLUSION: Although routinely recorded, cumulative fluid I-O does not appear to have clinical utility in cases managed according to a mechanical ventilator protocol in which tidal volume and oxygenation on minimal levels of ventilator support are systematically tested.

The feasibility of conducting clinical trials in infants and children with acute respiratory failure.

Designing robust clinical trials in critically ill, mechanically ventilated children requires an understanding of the epidemiology and course of pediatric respiratory failure. As part of a clinical trial, we screened all mechanically ventilated children in nine large pediatric intensive care units (ICUs) across North America for 6 consecutive months. Of 6,403 total ICU admissions, 1,096 (17.1%) required mechanical ventilator support for a minimum of 24 hours. Of these, 701 (64%) met one or more exclusion criteria for trial enrollment. Common reasons for exclusion were upper airway obstruction (13.5%) and cyanotic congenital heart disease (11.5%). Life support interventions were restricted for 9.7% of patients, and 5.5% were chronically ventilator dependent. In the patients who were eligible for respiratory failure studies, 62.4% had an acute primary diagnosis of pulmonary disease, 14.2% neurologic disease, and 8.9% cardiac disease. Chronic underlying conditions were present in 43.2% of the patients. The most common acute diagnosis was bronchiolitis in infants (43.6%) and pneumonia in children 1 year old and older (24.5%). Mortality was rare (1.6%), and the median duration of ventilation was 7 days. The design of clinical trials in critically ill children is feasible but must account for the diverse population, infrequent mortality, and short duration of mechanical ventilation.

Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children: a randomized controlled trial.

CONTEXT: Ventilator management protocols shorten the time required to wean adult patients from mechanical ventilation. The efficacy of such weaning protocols among children has not been studied. OBJECTIVE: To evaluate whether weaning protocols are superior to standard care (no defined protocol) for infants and children with acute illnesses requiring mechanical ventilator support and whether a volume support weaning protocol using continuous automated adjustment of pressure support by the ventilator (ie, VSV) is superior to manual adjustment of pressure support by clinicians (ie, PSV). DESIGN AND SETTING: Randomized controlled trial conducted in the pediatric intensive care units of 10 children's hospitals across North America from November 1999 through April 2001. PATIENTS: One hundred eighty-two spontaneously breathing children (<18 years old) who had been receiving ventilator support for more than 24 hours and who failed a test for extubation readiness on minimal pressure support. INTERVENTIONS: Patients were randomized to a PSV protocol (n = 62), VSV protocol (n = 60), or no protocol (n = 60). MAIN OUTCOME MEASURES: Duration of weaning time (from randomization to successful extubation); extubation failure (any invasive or noninvasive ventilator support within 48 hours of extubation). RESULTS: Extubation failure rates were not significantly different for PSV (15%), VSV (24%), and no protocol (17%) (P =.44). Among weaning successes, median duration of weaning was not significantly different for PSV (1.6 days), VSV (1.8 days), and no protocol (2.0 days) (P =.75). Male children more frequently failed extubation (odds ratio, 7.86; 95% confidence interval, 2.36-26.2; P<.001). Increased sedative use in the first 24 hours of weaning predicted extubation failure (P =.04) and, among extubation successes, duration of weaning (P<.001). CONCLUSIONS: In contrast with adult patients, the majority of children are weaned from mechanical ventilator support in 2 days or less. Weaning protocols did not significantly shorten this brief duration of weaning.