Erika Stalets

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.

Toward a clinically feasible gene expression-based subclassification strategy for septic shock: proof of concept.

Objective:To develop a clinically feasible stratification strategy for pediatric septic shock, using gene expression mosaics and a 100-gene signature representing the first 24 hrs of admission to the pediatric intensive care unit. Design:Prospective, observational study involving microarray-based bioinformatics. Setting:Multiple pediatric intensive care units in the United States. Patients:Ninety-eight children with septic shock. Interventions:None other than standard care. Measurements and Main Results:Patients were classified into three previously published, genome-wide, expression-based subclasses (subclasses A, B, and C) having clinically relevant phenotypic differences. The class-defining 100-gene signature was depicted for each individual patient, using mosaics generated by the Gene Expression Dynamics Inspector (GEDI). Composite mosaics were generated representing the average expression patterns for each of the three subclasses. Nine individual clinicians served as blinded evaluators. Each evaluator was shown the 98 individual patient mosaics and asked to classify each patient into one of the three subclasses, using the composite mosaics as the reference point. The respective sensitivities, specificities, positive predictive values, and negative predictive values of the subclassification strategy were ≥84% across the three subclasses. The classification strategy also generated positive likelihood ratios of ≥16.8 and negative likelihood ratios of ≤0.2 across the three subclasses. The &kgr; coefficient across all possible interevaluator comparisons was 0.81. Conclusions:We have provided initial evidence (proof of concept) for a clinically feasible and robust stratification strategy for pediatric septic shock based on a 100-gene signature and gene expression mosaics.

A Case-Control Study on the Impact of Ventilator-Associated Tracheobronchitis in the PICU.

Objectives: Hospital-acquired infections increase morbidity, mortality, and charges in the PICU. We implemented a quality improvement bundle directed at ventilator-associated pneumonia in our PICU in 2005. We observed an increase in ventilator-associated tracheobronchitis coincident with the near-elimination of ventilator-associated pneumonia. The impact of ventilator-associated tracheobronchitis on critically ill children has not been previously described. Accordingly, we hypothesized that ventilator-associated tracheobronchitisis associated with increased length of stay, mortality, and hospital charge. Design: Retrospective case-control study. Patients: Critically ill children admitted to a quaternary PICU at a free-standing academic children’s hospital in the United States. Interventions: None. Measurements and Main Results: We conducted a retrospective case control study, with institutional review board approval, of 77 consecutive cases of ventilator-associated tracheobronchitis admitted to our PICU from 2004-2010. We matched each case with a control based on the following criteria (in rank order): age range (< 30 d, 30 d to 24 mo, 24 mo to 12 yr, > 12 yr), admission Pediatric Risk of Mortality III score ± 10, number of ventilator days of control group (> 75% of days until development of ventilator-associated tracheobronchitis), primary diagnosis, underlying organ system dysfunction, surgical procedure, and gender. The primary outcome measured was PICU length of stay. Secondary outcomes included ventilator days, hospital length of stay, mortality, and PICU and hospital charges. Data was analyzed using chi square analysis and p less than 0.05 was considered significant. We successfully matched 45 of 77 ventilator-associated tracheobronchitis patients with controls. There were no significant differences in age, gender, diagnosis, or Pediatric Risk of Mortality III score between groups. Ventilator-associated tracheobronchitis patients had a longer PICU length of stay (median, 21.5 d, interquartile range, 24 d) compared to controls (median, 18 d; interquartile range, 17 d), although not statistically significant (p = 0.13). Ventilator days were also longer in the ventilator-associated tracheobronchitis patients (median, 17 d; IQR, 22 d) versus control (median, 10.5 d; interquartile range, 13 d) (p = 0.01). There was no significant difference in total hospital length of stay (54 d vs 36 d; p = 0.69). PICU mortality was higher in the ventilator-associated tracheobronchitis group (15% vs 5%; p = 0.14), although not statistically significant. There was an increase in both median PICU charges (

Staffing and workforce issues in the pediatric intensive care unit

197,393 vs

Time to antibiotics and outcomes in pediatric septic shock

172,344; p < 0.05) and hospital charges (

424: EVALUATION OF THE USE OF A RESPIRATORY THERAPIST DRIVEN PROTOCOL IN THE PEDIATRIC ICU

421,576 vs

670: CATHETER ASSOCIATED URINARY TRACT INFECTION IN THE PEDIATRIC ICU

350,649; p < 0.05) for ventilator-associated tracheobronchitis patients compared with controls. Conclusions: Ventilator-associated tracheobronchitis is a clinically significant hospital-acquired infection in the PICU and is associated with longer duration of mechanical ventilation and healthcare costs, possibly through causing a longer PICU length of stay. Quality improvement efforts should be directed at reducing the incidence of ventilator-associated tracheobronchitis in the PICU.

481: DELAYED ANTIBIOTIC ADMINISTRATION IN PEDIATRIC SEPTIC SHOCK IS ASSOCIATED WITH INCREASED ORGAN FAILURE DURATION

The health care industry is in the midst of incredible change, and unfortunately, change is not easy. The intensive care unit (ICU) plays a critical role in the overall delivery of care to patients in the hospital. Care in the ICU is expensive. One of the best ways of improving the value of care delivered in the ICU is to focus greater attention on the needs of the critical care workforce. Herein, we highlight three major areas of concern-the changing model of care delivery outside of the traditional four walls of the ICU, the need for greater diversity in the pediatric critical care workforce, and the widespread problem of professional burnout and its impact on patient care.