Burnout in Pediatric Critical Care Medicine Fellows.

OBJECTIVES: Assess the overall level of burnout in pediatric critical care medicine fellows and examine factors that may contribute to or protect against its development. DESIGN: Cross-sectional observational study. SETTING: Accreditation Council for Graduate Medical Education-accredited pediatric critical care medicine fellowship programs across the United States. SUBJECTS: Pediatric critical care medicine fellows and program directors. INTERVENTIONS: Web-based survey that assessed burnout via the Maslach Burnout Inventory, as well as other measures that elicited demographics, sleepiness, social support, perceptions about prior training, relationships with colleagues, and environmental burnout. MEASUREMENTS AND MAIN RESULTS: One-hundred eighty-seven fellows and 47 program directors participated. Fellows from 30% of programs were excluded due to lack of program director participation. Average values on each burnout domain for fellows were higher than published values for other medical professionals. Personal accomplishment was greater (lower burnout) among fellows more satisfied with their career choice (ß 9.319; p ≤ 0.0001), spiritual fellows (ß 1.651; p = 0.0286), those with a stress outlet (ß 3.981; p = 0.0226), those comfortable discussing educational topics with faculty (ß 3.078; p = 0.0197), and those comfortable seeking support from their co-fellows (ß 3.762; p = 0.0006). Depersonalization was higher for second year fellows (ß 2.034; p = 0.0482), those with less educational debt (ß -2.920; p = 0.0115), those neutral/dissatisfied with their career choice (ß -6.995; p = 0.0031), those with nursing conflict (ß -3.527; p = 0.0067), those who perceived burnout among co-fellows (ß 1.803; p = 0.0352), and those from ICUs with an increased number of patient beds (ß 5.729; p ≤ 0.0001). Emotional exhaustion was higher among women (ß 2.933; p = 0.0237), those neutral/dissatisfied with their career choice (ß -7.986; p = 0.0353), and those who perceived burnout among co-fellows (ß 5.698; p ≤ 0.0001). Greater sleepiness correlated with higher burnout by means of lower personal accomplishment (r = -1.64; p = 0.0255) and higher emotional exhaustion (r = 0.246; p = 0.0007). Except for tangible support, all other forms of social support showed a small to moderate correlation with lower burnout. CONCLUSIONS: Pediatric critical care medicine fellows in the United States are experiencing high levels of burnout, which appears to be influenced by demographics, fellow perceptions of their work environment, and satisfaction with career choice. The exclusion of fellows at 30% of the programs may have over or underestimated the actual level of burnout in these trainees.

Extracellular Hsp72, an endogenous DAMP, is released by virally infected airway epithelial cells and activates neutrophils via Toll-like receptor (TLR)-4.

BACKGROUND: Neutrophils play an important role in the pathophysiology of RSV, though RSV does not appear to directly activate neutrophils in the lower airways. Therefore locally produced cytokines or other molecules released by virally-infected airway epithelial cells are likely responsible for recruiting and activating neutrophils. Heat shock proteins (HSPs) are generally regarded as intracellular proteins acting as molecular chaperones; however, HSP72 can also be released from cells, and the implications of this release are not fully understood. METHODS: Human bronchial epithelial cells (16HBE14o-) were infected with RSV and Hsp72 levels were measured by Western blot and ELISA. Tracheal aspirates were obtained from critically ill children infected with RSV and analyzed for Hsp72 levels by ELISA. Primary human neutrophils and differentiated HL-60 cells were cultured with Hsp72 and supernatants analyzed for cytokine production. In some cases, cells were pretreated with polymyxin B prior to treatment with Hsp72. IkappaBalpha was assessed by Western blot and EMSA's were performed to determine NF-kappaB activation. HL-60 cells were pretreated with neutralizing antibody against TLR4 prior to Hsp72 treatment. Neutrophils were harvested from the bone marrow of wild type or TLR4-deficient mice prior to treatment with Hsp72. RESULTS: Infection of 16HBE14o- with RSV showed an induction of intracellular Hsp72 levels as well as extracellular release of Hsp72. Primary human neutrophils from normal donors and differentiated HL-60 cells treated with increasing concentrations of Hsp72 resulted in increased cytokine (IL-8 and TNFalpha) production. This effect was independent of the low levels of endotoxin in the Hsp72 preparation. Hsp72 mediated cytokine production via activation of NF-kappaB translocation and DNA binding. Using bone marrow-derived neutrophils from wild type and TLR4-mutant mice, we showed that Hsp72 directly activates neutrophil-derived cytokine production via the activation of TLR4. CONCLUSION: Collectively these data suggest that extracellular Hsp72 is released from virally infected airway epithelial cells resulting in the recruitment and activation of neutrophils.

Hsp72 induces inflammation and regulates cytokine production in airway epithelium through a TLR4- and NF-kappaB-dependent mechanism.

Heat shock proteins are generally regarded as intracellular proteins acting as molecular chaperones; however, Hsp72 is also detected in the extracellular compartment. Hsp72 has been identified in the bronchoalveolar lavage fluid (BALF) of patients with acute lung injury. To address whether Hsp72 directly activated airway epithelium, human bronchial epithelial cells (16HBE14o-) were treated with recombinant Hsp72. Hsp72 induced a dose-dependent increase in IL-8 expression, which was inhibited by the NF-kappaB inhibitor parthenolide. Hsp72 induced activation of NF-kappaB, as evidenced by NF-kappaB trans-activation and by p65 RelA and p50 NF-kappaB1 binding to DNA. Endotoxin contamination of the Hsp72 preparation was not responsible for these effects. Next, BALB/c mice were challenged with a single intratracheal inhalation of Hsp72 and killed 4 h later. Hsp72 induced significant up-regulation of KC, TNF-alpha, neutrophil recruitment, and myeloperoxidase in the BALF. A similar challenge with Hsp72 in TLR4 mutant mice did not stimulate the inflammatory response, stressing the importance of TLR4 in Hsp72-mediated lung inflammation. Last, cultured mouse tracheal epithelial cells (MTEC) from BALB/c and TLR4 mutant and wild-type mice were treated ex vivo with Hsp72. Hsp72 induced a significant increase in KC expression from BALB/c and wild-type MTEC in an NF-kappaB-dependent manner; however, TLR4 mutant MTEC had minimal cytokine release. Taken together, these data suggest that Hsp72 is released and biologically active in the BALF and can regulate airway epithelial cell cytokine expression in a TLR4 and NF-kappaB-dependent mechanism.