Paul A. Checchia

Noninvasive positive-pressure ventilation in children with lower airway obstruction

Study Objectives: Mechanical ventilation of patients with severe lower airway obstruction presents significant risks; therefore, avoiding the intubation in these patients has been a principal goal of clinical management. Noninvasive positive-pressure ventilation has been shown to be effective in treating adults with chronic obstructive pulmonary disease, but its use has not been studied prospectively in children with acute obstructive lower airways disease. The objective of this study was to determine whether noninvasive mask ventilation improved respiratory function in children with asthma and other obstructive lower airways diseases. Study Design: A prospective, randomized, crossover study. Patients: A total of 20 children admitted to the pediatric intensive care unit with acute lower airway obstruction. Methods: Children were randomized to receive either 2 hrs of non-invasive ventilation followed by crossover to 2 hrs of standard therapy or 2 hrs of standard therapy followed by 2 hrs of noninvasive ventilation. Results: Using a Clinical Asthma Score, we found that noninvasive ventilation decreased signs of work of breathing such as respiratory rate, accessory muscle use, and dyspnea as compared with standard therapy. There was no serious morbidity associated with noninvasive ventilation. Conclusions: We conclude that noninvasive ventilation can be an effective treatment for children with acute lower airway obstruction.

Steroid use before pediatric cardiac operations using cardiopulmonary bypass: an international survey of 36 centers.

Objective: Steroid administration before pediatric cardiac operations using cardiopulmonary bypass has been shown to modulate the inflammatory response and reduce myocardial injury. We hypothesized that current steroid administration practices among pediatric cardiac surgical centers are highly variable. Design: Questionnaire survey. Setting: Pediatric intensive care units. Subjects: All members of the Pediatric Cardiac Intensive Care Society. Interventions: A self-administered survey was sent to >130 members and 70 institutions participating in the Pediatric Cardiac Intensive Care Society. Measurements and Main Results: Thirty-six questionnaires were returned: 14 international and 22 domestic centers. Cumulatively, these centers treat >11,000 pediatric cardiac patients per year. Ninety-seven percent (35 of 36) of these centers report the use of steroids before cardiopulmonary bypass, yet only 40% (14 of 35) administer steroids with every case. Of the 21 centers that selectively use steroids, 12 do so only for neonates, five administer steroids based on surgeon preference, and four administer steroids for cases anticipated to involve bypass time >2 hrs or deep hypothermic circulatory arrest. Of the 35 centers using steroids, 11 deliver a single dose in the circuit prime, 18 administer a single dose to the patient, and six give multiple doses. The timing of the steroid dose to the patient is variable; 12 centers administer a dose on induction of anesthesia; six centers administer the dose 2–12 hrs before operation. Regimens in the six centers using multiple doses of steroids before cardiopulmonary bypass are as follows: administration at induction and in the prime (two centers); 12 hrs preoperatively and at induction (one center); prime, induction, and 6 hrs preoperatively (one center); prime and midnight preoperatively (one center); and prime plus 2 and 8 hrs preoperatively (one center). Eight centers continue steroid administration following bypass. Conclusion: Although nearly all centers surveyed administer steroids before cardiopulmonary bypass, the type, dosing, route, and timing of administration are highly variable. The inconsistencies in these data and the pediatric literature would support the undertaking of a large, multiple-center clinical trial to evaluate the risks and benefits of steroid administration before pediatric cardiopulmonary bypass.

Identification of pediatric septic shock subclasses based on genome-wide expression profiling

BackgroundSeptic shock is a heterogeneous syndrome within which probably exist several biological subclasses. Discovery and identification of septic shock subclasses could provide the foundation for the design of more specifically targeted therapies. Herein we tested the hypothesis that pediatric septic shock subclasses can be discovered through genome-wide expression profiling.MethodsGenome-wide expression profiling was conducted using whole blood-derived RNA from 98 children with septic shock, followed by a series of bioinformatic approaches targeted at subclass discovery and characterization.ResultsThree putative subclasses (subclasses A, B, and C) were initially identified based on an empiric, discovery-oriented expression filter and unsupervised hierarchical clustering. Statistical comparison of the three putative subclasses (analysis of variance, Bonferonni correction, P < 0.05) identified 6,934 differentially regulated genes. K-means clustering of these 6,934 genes generated 10 coordinately regulated gene clusters corresponding to multiple signaling and metabolic pathways, all of which were differentially regulated across the three subclasses. Leave one out cross-validation procedures indentified 100 genes having the strongest predictive values for subclass identification. Forty-four of these 100 genes corresponded to signaling pathways relevant to the adaptive immune system and glucocorticoid receptor signaling, the majority of which were repressed in subclass A patients. Subclass A patients were also characterized by repression of genes corresponding to zinc-related biology. Phenotypic analyses revealed that subclass A patients were younger, had a higher illness severity, and a higher mortality rate than patients in subclasses B and C.ConclusionGenome-wide expression profiling can identify pediatric septic shock subclasses having clinically relevant phenotypes.

Fatality rates in published reports of RSV hospitalizations among high-risk and otherwise healthy children

Abstract Objective: To review the fatalities among children hospitalized with respiratory syncytial virus (RSV) infection, and identify factors leading to a fatal outcome. Research design and methods: Review of literature identified from a structured search of PubMed (1966−2009) using the following Medical Subject Headings: respiratory syncytial virus infection; hospitalized; infants; and risk factors. Publications were restricted to: English language; full papers; inclusion of ≥10 subjects; children aged ≤18 years, hospitalization for RSV infection; and deaths reported. Case fatality rates were defined as number of deaths divided by number of children hospitalized for RSV and were calculated for each study. Results: Thirty-six studies met the inclusion and exclusion criteria. Case fatality rates among children hospitalized for RSV ranged from 0 to 33%. In general, studies showed that subgroups of high-risk children (chronic lung disease [CLD] 3.5–23%, congenital heart disease [CHD] 2–37%, and prematurity 0–6.1%) had higher fatality rates than older or otherwise healthy children (consistently <1%). Presence of severe underlying comorbidities such as neuromuscular disease, immunosuppression, and malignancies was associated with death among term and/or older (>1 year) children. Higher fatality rates were reported for infants receiving intensive unit care (1.1–8.6%), extracorporeal life support (33%) or for those who acquired nosocomial RSV infection (0–12.2%). The majority of studies did not report cause of death and clinical details of the fatal cases were often not provided. Other limitations of this review include our search limits, the possibility of inherent bias in our methodology that could result in an under or over estimation of case-fatality rates, and potential publication bias. Conclusions: Children at high risk for RSV (CLD, CHD and prematurity), those with severe underlying comorbidities, or those with nosocomial RSV appear to be at increased risk for death after RSV hospitalization. More data are needed on cause of death and how much is directly attributable to RSV.

Dexamethasone reduces postoperative troponin levels in children undergoing cardiopulmonary bypass.

OBJECTIVE We previously demonstrated that dexamethasone treatment before cardiopulmonary bypass in children reduces the postoperative systemic inflammatory response. The purpose of this study was to test the hypothesis that dexamethasone administration before cardiopulmonary bypass in children correlates with a lesser degree of myocardial injury as measured by a decrease in cardiac troponin I release. DESIGN A prospective, randomized, double-blind study. SETTING The cardiac surgery operating room and intensive care unit of a pediatric referral hospital. SUBJECTS Twenty-eight patients who underwent open-heart surgery for congenital heart defects. INTERVENTIONS Patients received either placebo (group I, n = 13) or dexamethasone, 1 mg/kg iv (group II, n = 15), 1 hr before initiation of cardiopulmonary bypass. Plasma cardiac troponin I samples were obtained at three time points: immediately before study agent (sample 1), 10 mins after protamine sulfate administration after cardiopulmonary bypass (sample 2), and 24 hrs postoperatively (sample 3). MEASUREMENTS AND MAIN RESULTS Mean cardiac troponin I levels (+/-sd) were significantly lower at sample time 3 in group II (dexamethasone; 33.4 +/- 20.0 ng/mL) vs. group I (control; 86.9 +/- 81.1) (p =.04). CONCLUSION Dexamethasone administration before cardiopulmonary bypass in children resulted in a significant decrease in cardiac troponin I levels at 24 hrs postoperatively. We postulate that this may represent a decrease in myocardial injury, and, thus, a possible cardioprotective effect produced by dexamethasone.

Validating the genomic signature of pediatric septic shock

We previously generated genome-wide expression data (microarray) from children with septic shock having the potential to lead the field into novel areas of investigation. Herein we seek to validate our data through a bioinformatic approach centered on a validation patient cohort. Forty-two children with a clinical diagnosis of septic shock and 15 normal controls served as the training data set, while 30 separate children with septic shock and 14 separate normal controls served as the test data set. Class prediction modeling using the training data set and the previously reported genome-wide expression signature of pediatric septic shock correctly identified 95-100% of controls and septic shock patients in the test data set, depending on the class prediction algorithm and the gene selection method. Subjecting the test data set to an identical filtering strategy as that used for the training data set, demonstrated 75% concordance between the two gene lists. Subjecting the test data set to a purely statistical filtering strategy, with highly stringent correction for multiple comparisons, demonstrated <50% concordance with the previous gene filtering strategy. However, functional analysis of this statistics-based gene list demonstrated similar functional annotations and signaling pathways as that seen in the training data set. In particular, we validated that pediatric septic shock is characterized by large-scale repression of genes related to zinc homeostasis and lymphocyte function. These data demonstrate that the previously reported genome-wide expression signature of pediatric septic shock is applicable to a validation cohort of patients.

The influence of developmental age on the early transcriptomic response of children with septic shock.

Septic shock is a frequent and costly problem among patients in the pediatric intensive care unit (PICU) and is associated with high mortality and devastating survivor morbidity. Genome-wide expression patterns can provide molecular granularity of the host response and offer insight into why large variations in outcomes exist. We derived whole-blood genome-wide expression patterns within 24 h of PICU admission from children with septic shock. We compared the transcriptome between septic shock developmental-age groups defined as neonates (≤28 d, n = 17), infants (1 month to 1 year, n = 62), toddlers (2–5 years, n = 54) and school-age (≥6 years, n = 47) and age-matched controls. Direct intergroup comparisons demonstrated profound changes in neonates, relative to older children. Neonates with septic shock demonstrated reduced expression of genes representing key pathways of innate and adaptive immunity. In contrast to the largely upregulated transcriptome in all other groups, neonates exhibited a predominantly downregulated transcriptome when compared with controls. Neonates and school-age subjects had the most uniquely regulated genes relative to controls. Age-specific studies of the host response are necessary to identify developmentally relevant translational opportunities that may lead to improved sepsis outcomes.

Validation of a gene expression-based subclassification strategy for pediatric septic shock

Objective:Septic shock heterogeneity has important implications for clinical trial implementation and patient management. We previously addressed this heterogeneity by identifying three putative subclasses of children with septic shock based exclusively on a 100-gene expression signature. Here we attempted to prospectively validate the existence of these gene expression-based subclasses in a validation cohort. Design:Prospective observational study involving microarray-based bioinformatics. Setting:Multiple pediatric intensive care units in the United States. Patients:Separate derivation (n = 98) and validation (n = 82) cohorts of children with septic shock. Interventions:None other than standard care. Measurements and Main Results:Gene expression mosaics of the 100 class-defining genes were generated for 82 individual patients in the validation cohort. Using computer-based image analysis, patients were classified into one of three subclasses (“A,” “B,” or “C”) based on color and pattern similarity relative to reference mosaics generated from the original derivation cohort. After subclassification, the clinical database was mined for phenotyping. Subclass A patients had higher illness severity relative to subclasses B and C as measured by maximal organ failure, fewer intensive care unit-free days, and a higher Pediatric Risk of Mortality score. Patients in subclass A were characterized by repression of genes corresponding to adaptive immunity and glucocorticoid receptor signaling. Separate subclass assignments were conducted by 21 individual clinicians using visual inspection. The consensus classification of the clinicians had modest agreement with the computer algorithm. Conclusions:We have validated the existence of subclasses of children with septic shock based on a biologically relevant, 100-gene expression signature. The subclasses have relevant clinical differences.

Report of the Pediatric Heart Network and National Heart, Lung, and Blood Institute Working Group on the Perioperative Management of Congenital Heart Disease

The survival of patients with congenital heart disease (CHD) has significantly improved during the past several decades (the Figure). This accomplishment is directly attributable to the net effect of individual therapeutic successes from the innovative work of surgeons and cardiologists and the courageous devotion of patients and families. However, as the field moves forward, the need for evidence-based medicine derived from multi-institutional collaborations to address more subtle and complex questions such as functional outcome and quality of life and to provide data to guide individual practitioners has become paramount. Recognizing this, the National Heart, Lung, and Blood Institute (NHLBI) established the Pediatric Heart Network (PHN) in 2001 to provide a collaborative platform for conducting clinical studies. The need for evidence-based care and the ability of the PHN to provide this evidence were demonstrated by recent developments in the surgical management of hypoplastic left heart syndrome. Hypoplastic left heart syndrome was a uniformly fatal defect before Norwood’s innovative surgical approach in which the diminutive aorta is reconstructed using the pulmonary artery trunk and pulmonary blood flow is provided by a Blalock-Taussig shunt. 2 Recently, a previously described modification to this procedure in which pulmonary blood flow is provided by a right ventricle to pulmonary artery shunt has seen renewed interest. 3 This modification has been widely adopted but has yielded conflicting results. 4–7 In May 2005, the PHN launched the Single Ventricle Reconstruction (SVR) trial, a randomized trial comparing these 2 surgical strategies. 8 In just over 3 years, 555 infants were

Care Models and Associated Outcomes in Congenital Heart Surgery

OBJECTIVE: Recently, there has been a shift toward care of children undergoing heart surgery in dedicated pediatric cardiac intensive care units (CICU). The impact of this trend on patient outcomes is unclear. We evaluated postoperative outcomes associated with a CICU versus other ICU models. PATIENTS AND METHODS: Society of Thoracic Surgeons Congenital Heart Surgery Database participants (2007–2009) who completed an ICU survey were included. In multivariable analysis, we evaluated outcomes associated with a CICU versus other ICUs, adjusting for center volume, patient factors, and Society of Thoracic Surgeons–European Association for Cardiothoracic Surgery surgical risk category. RESULTS: A total of 20 922 patients (47 centers; 25 with a CICU) were included. Overall unadjusted mortality was 3.8%, median length of stay was 6 days (interquartile range: 4–13), and 21% had 1 or more complications. In multivariable analysis, there was no difference in mortality comparing CICUs versus other ICUs (odds ratio: 0.88 [95% confidence interval: 0.65–1.19]). In stratified analysis, CICUs were associated with lower mortality only among those in Society of Thoracic Surgeons–European Association for Cardiothoracic Surgery category 3 (odds ratio: 0.47 [95% confidence interval: 0.25–0.86]), primarily related to atrioventricular canal repair and arterial switch operation. There was no difference in length of stay or complications overall or in stratified analysis. CONCLUSIONS: We were not able to detect a difference in postoperative morbidity or mortality associated with the presence of a dedicated CICU for children undergoing heart surgery. There may be a survival benefit in certain subgroups .