Ventilator and viral induced inflammation

This thesis expands current knowledge on ventilator induced lung injury and provides insights on the immunological effects of mechanical ventilation during viral respiratory infections. The experimental studies in the first part of this thesis improve our understanding of how mechanical ventilation induces lung injury in healthy lungs. It is shown that mechanical ventilation causes pulmonary endothelial activation and inflammation as well as inflammation in organs distal to the lungs. In addition we demonstrate that lung protective ventilation (aimed at limiting peak pressures and tidal volumes with sufficient PEEP), attenuates but not completely abolishes pulmonary inflammation. We investigated the effects of 2 drugs (dexamethasone and angiopoietin-1) in the treatment and/or prevention of ventilator induced lung injury (VILI). Neither drug had a beneficial effect on ventilator induced vascular leakage and lung dysfunction despite a clear down regulation of neutrophil infiltration and protein expression of pro-inflammatory mediators. Interestingly, none of the pharmacological interventions studied by others have been successful in either treating or preventing VILI. To date, only lung protective mechanical ventilation has proven to be effective in preventing VILI. In the second section part of this thesis, we focus on ‘virus induced inflammation’ and its possible interaction with ventilator induced inflammation. First, factors associated with turning an essentially trivial community acquired RSV infection into a life-threatening disease are reviewed. In addition, we show that mechanical ventilation during experimental RSV infection enhances pulmonary inflammation, reflected by increased influx of cells and pro-inflammatory cytokines in the bronchoalveolar space. Gene expression analysis demonstrates that this enhanced inflammation is attributable to the ventilator induced distinct molecular stress response additive to, but not aggravating, the innate immune response seen in RSV. Furthermore, we show that the use of low tidal volumes (6 ml/kg), as compared to high tidal volumes (12 ml/kg), partially prevents ventilation-induced cellular and cytokine influx into the bronchoalveolar space during experimental RSV LRTI. Previous clinical studies showed increased levels of inflammatory mediators in airways of RSV infected ventilated children. In these studies cytokine analysis was performed on samples collected while patients were already ventilated. We demonstrate that the need for mechanical ventilation in RSV-infected infants is not associated with enhanced virus-induced pulmonary inflammation at baseline. Using pre- and post-intubation observations we show that endotracheal intubation and subsequent mechanical ventilation induces additional inflammation expressed by increased levels of cytokine concentrations in nasopharyngeal aspirates after 24 hours. This is in concordance with results from our experimental studies. Finally, using a human genetic study as well as an experimental model we demonstrate that opioid receptor signaling has a potential beneficial role in the outcome of respiratory viral disease. We show that opioid receptor signaling is required to control RSV replication and thereby to control disease severity. As opioids are frequently used for sedative and analgesic purposes during mechanical ventilation for severe viral infection in infancy, opioid receptors might offer powerful novel pharmacologic targets to ameliorate virus-induced airway inflammatio

Development of entrustable professional activities for paediatric intensive care fellows: A national modified Delphi study

Contains fulltext : 232752.pdf (Publisher’s version ) (Open Access)Entrustable professional activities (EPAs), as a focus of learner assessment, are supported by validity evidence. An EPA is a unit of professional practice requiring proficiency in multiple competencies simultaneously, that can be entrusted to a sufficiently competent learner. Taken collectively, a set of EPAs define and inform the curriculum of a specialty training. The goal of this study was to develop a set of EPAs for Dutch PICU fellows. A multistage methodology was employed incorporating sequential input from task force members, a medical education expert, PICU fellowship program directors, and PICU physicians and fellows via a modified three-round Delphi study. In the first modified Delphi round, experts rated indispensability and clarity of preliminary EPAs. In the subsequent rounds, aggregated scores for each EPA and group comments were provided. In round two, respondents rated indispensability and clarity of revised EPAs. Round three was used to gain explicit confirmation of suitability to implement these EPAs. Based on median ratings and content validity index (CVI) analysis for indispensability in the first two rounds, all nine preliminary EPAs covered activities that were deemed essential to the clinical practice of PICU physicians. Based on median ratings and CVI analysis for clarity however, four EPAs needed revision. With an agreement percentage of 93-100% for all individual EPAs as well as the set as a whole, a high degree of consensus among experts was reached in the third round. The resulting nine PICU EPAs provide a succinct overview of the core tasks of Dutch PICU physicians. These EPAs were created as an essential first step towards developing an assessment system for PICU fellows, grounded in core professional activities. The robust methodology used, may have broad applicability for other (sub)specialty training programs aiming to develop specialty specific EPAs

Life-threatening human herpes virus-6 infection in early childhood : presenting symptom of a primary immunodeficiency?

OBJECTIVE: To report two previously healthy children with a life-threatening course of human herpes virus type 6 (HHV-6) infection and prolonged pediatric intensive care treatment. DESIGN: Case reports. SETTING: A 16 bed pediatric intensive care unit at a tertiary care children's hospital. PATIENTS: Two children with life-threatening HHV-6 disease. INTERVENTIONS: Both children were mechanically ventilated because of respiratory failure. A detailed viral and immunologic workup was performed and treatment with antiviral medication started. MEASUREMENTS: Polymerase chain reaction assays of plasma, cerebrospinal fluid, bronchoalveolar lavage, and lung biopsies yielded HHV-6 in both patients. Immunophenotyping and lymphocyte stimulation tests with both mitogens and antigens indicated an immunodeficiency in both patients. CONCLUSION: HHV-6 infection should be considered in infants and young children with respiratory failure or meningo-encephalitis without clear causative agent or failure to respond to empirical treatment. A thorough immunologic workup and early start with antiviral therapy in any patient with a life-threatening course of HHV-6 infection is mandatory, because a severe HHV-6 infection can be the first indication of a primary immunodeficiency

Development of entrustable professional activities for paediatric intensive care fellows: A national modified Delphi study

Entrustable professional activities (EPAs), as a focus of learner assessment, are supported by validity evidence. An EPA is a unit of professional practice requiring proficiency in multiple competencies simultaneously, that can be entrusted to a sufficiently competent learner. Taken collectively, a set of EPAs define and inform the curriculum of a specialty training. The goal of this study was to develop a set of EPAs for Dutch PICU fellows. A multistage methodology was employed incorporating sequential input from task force members, a medical education expert, PICU fellowship program directors, and PICU physicians and fellows via a modified three-round Delphi study. In the first modified Delphi round, experts rated indispensability and clarity of preliminary EPAs. In the subsequent rounds, aggregated scores for each EPA and group comments were provided. In round two, respondents rated indispensability and clarity of revised EPAs. Round three was used to gain explicit confirmation of suitability to implement these EPAs. Based on median ratings and content validity index (CVI) analysis for indispensability in the first two rounds, all nine preliminary EPAs covered activities that were deemed essential to the clinical practice of PICU physicians. Based on median ratings and CVI analysis for clarity however, four EPAs needed revision. With an agreement percentage of 93-100% for all individual EPAs as well as the set as a whole, a high degree of consensus among experts was reached in the third round. The resulting nine PICU EPAs provide a succinct overview of the core tasks of Dutch PICU physicians. These EPAs were created as an essential first step towards developing an assessment system for PICU fellows, grounded in core professional activities. The robust methodology used, may have broad applicability for other (sub)specialty training programs aiming to develop specialty specific EPAs