Predictors of failure in infants with viral bronchiolitis treated with high-flow, high-humidity nasal cannula therapy*.

OBJECTIVES: Viral bronchiolitis is an acute infection and inflammatory disease of the respiratory tract, with infants typically presenting with the most severe symptoms. Medical management of bronchiolitis is mostly supportive. Several preliminary studies suggest potential benefit from the use of high-flow nasal cannula systems. Although high-flow nasal cannula is a well-established modality in the newborn intensive care unit, its use in the pediatric intensive care unit for acute respiratory failure is far less established. The objective of this study was to identify any laboratory and clinical variables that may predict high-flow nasal cannula failure in management of bronchiolitis in the pediatric intensive care unit. DESIGN: The study design was a retrospective chart review of all patients admitted to the pediatric intensive care unit from 2006 to 2010 with a diagnosis of viral bronchiolitis. Inclusion criteria included the initiation of high flow nasal cannula therapy at the time of admission and age ≤ 12 months. Exclusion criteria were intubation prior to admission, age >12 months, and the presence of a tracheostomy. PATIENTS: A total of 113 patients with viral bronchiolitis met the inclusion criteria. SETTING: Academic free standing Children's Hospital in the Midwest. INTERVENTIONS: Retrospective chart review. MEASUREMENTS AND MAIN RESULTS: The data were analyzed by comparing those patients who responded to high-flow nasal cannula (n = 92) with those who were nonresponders to high-flow nasal cannula and required intubation (n = 21). No differences were noted between the groups for age, sex, or ethnicity. Mean weight and weight-for-corrected-age percentiles were significantly lower for patients who failed high-flow nasal cannula (p = .016 and .031, respectively), but weight-for-corrected-age percentile was not significant in logistic regression controlling for other variables. Respiratory rate prior to the initiation of high-flow nasal cannula also correlated strongly with respiratory deterioration (p < .001). The PCO2 was significantly higher for both before (p < .001) and after (p < .001) initiation of therapy in the nonresponder group. Pediatric Risk of Mortality III scores for the patients who failed high-flow nasal cannula were significantly higher (p < .001) than those of patients who tolerated this therapy. CONCLUSIONS: History of prematurity and the patient's age did not increase a patient's risk of failure. Nonresponders to high-flow nasal cannula therapy were on the onset, more hypercarbic, were less tachypnic prior to the start of high-flow nasal cannula, and had no change in their respiratory rate after the initiation of high-flow nasal cannula therapy. Nonresponders had higher pediatric risk of mortality scores in the first 24 hrs.

The role of endogenously produced extracellular hsp72 in mononuclear cell reprogramming.

Intracellular heat shock protein 72 (Hsp72) is known to serve a broad cytoprotective role. Recent data indicate that stressed cells can release Hsp72 into the extracellular compartment, although the biological function of extracellular Hsp72 remains to be fully elucidated. Because extracellular Hsp72 has been demonstrated to interact with Toll-like receptor 4, we hypothesized that endogenously produced and released Hsp72 would reprogram the mononuclear cell responses to LPS. THP-1 cells treated with LPS were used as a model for nuclear factor (NF)-kappaB activation. Heat shock conditions consisted of incubation at 43 degrees C for 1 h. Control cells were incubated at 37 degrees C. Twenty four hours after incubation, heat shock conditioned media (HSCM) and control media (CM) were centrifuged, and the respective cells were discarded. A separate group of naive THP-1 cells were then incubated with either HSCM or CM for 18 h and then stimulated with LPS (1 mug/mL). Heat shock significantly increased Hsp72 in HSCM compared with CM. In THP-1 cells transfected with an NF-kappaB luciferase reporter plasmid, the addition of HSCM attenuated subsequent LPS-mediated luciferase activity compared with cells incubated in CM. The addition of HSCM also attenuated LPS-mediated NF-kappaB-DNA binding and IkappaBalpha degradation. Heat shock protein 72-mediated inhibition of NF-kappaB activation was further corroborated by a significant decrease in TNF-alpha production. When HSCM and CM were subjected to Hsp72 depletion via adenosine triphosphate-agarose binding, LPS-mediated activation of NF-kappaB was partially restored, suggesting that Hsp72 is partially responsible for cellular reprogramming in response to HSCM. These data demonstrate that endogenously produced and released extracellular Hsp72 has the ability to reprogram the in vitro response to endotoxin in cultured human mononuclear cells.

Therapeutic effect of epigallocatechin-3-gallate in a mouse model of colitis.

Epigallocatechin-3-gallate (EGCG), a green tea catechin, has been shown to inhibit signaling pathways involved in inflammation, including nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), which are important inducers of pro-inflammatory mediators. Aim of our study was to evaluate the therapeutic efficacy of EGCG in experimental colitis, which was induced by rectal administration of trinitrobenzenesulfonic acid (TNBS) in C57/BL6 mice. Mice were treated twice daily with vehicle or with EGCG (10 mg/kg) intraperitoneally, and sacrificed on days 1, 3, and 7 after TNBS administration. After induction of colitis, vehicle-treated mice experienced bloody diarrhea and loss of body weight. A remarkable colonic damage with hemorrhage, ulcers, and edema was observed and was associated with neutrophil infiltration as evaluated by myeloperoxidase (MPO) activity. Elevated plasma levels of tumor necrosis factor alpha, interleukin (IL)-6, IL-10 and keratinocyte-derived chemokine were also found. These events were paralleled by increased DNA binding of NF-kappaB and AP-1 in the colon of the vehicle-treated group. In contrast, the EGCG-treated mice experienced a very mild diarrhea and no weight loss. Damage of the colon was characterized by edema and hyperemia only. Tissue levels of MPO were also significantly reduced when compared to vehicle-treated mice. These beneficial effects of EGCG were associated with a significant reduction of NF-kappaB and AP-1 activation. However, treatment with EGCG did not reduce plasma cytokine levels. Our data demonstrate that EGCG may be beneficial in colitis through selective immunomodulatory effects, which may be mediated, at least in part, by inhibition of NF-kappaB and AP-1.

Impact of workflow-integrated corollary orders on aminoglycoside monitoring in children.

Computerized provider order entry (CPOE) and clinical decision support improve medication prescribing safety in adults. However, effective therapy for children requires dosing based on circulating medication levels. We examined the introduction of a computerized corollary order for aminoglycoside blood level monitoring. The study was divided into baseline (BP) and corollary order (CP) periods. In the CP, we implemented a workflow-integrated reminder to order blood levels and presented this to the clinician during each aminoglycoside ordering session. Appropriate laboratory monitoring was 128/159 (80.5%) courses in the BP and 146/177 (82.5%) courses in the CP. Thus introduction of the order did not significantly improve laboratory monitoring rates, nor did it result in a reduction in the rate of either toxic or subtherapeutic levels. However, aminoglycoside corollary orders may have an important role in institutions where pharmacists are not actively involved in monitoring therapy.