Mechanical ventilation triggers hippocampal apoptosis by vagal and dopaminergic pathways. (Fortenberry)

González-López A, López-Alonso I, Aguirre A, et al. Mechanical ventilation triggers hippocampal apoptosis by vagal and dopaminergic pathways. Am J Respir Crit Care Med. 2013 Sep 15;188(6):693-702.

Rationale: Critically ill patients frequently develop neuropsychological disturbances including acute delirium or memory impairment. The need for mechanical ventilation is a risk factor for these adverse events, but a mechanism that links lung stretch and brain injury has not been identified.

Objectives: To identify the mechanisms that lead to brain dysfunction during mechanical ventilation.

Methods: Brains from mechanically ventilated mice were harvested, and signals of apoptosis and alterations in the Akt survival pathway were studied. These measurements were repeated in vagotomized or haloperidol-treated mice, and in animals intracerebroventricularly injected with selective dopamine-receptor blockers. Hippocampal slices were cultured and treated with micromolar concentrations of dopamine, with or without dopamine receptor blockers. Last, levels of dysbindin, a regulator of the membrane availability of dopamine receptors, were assessed in the experimental model and in brain samples from ventilated patients.

Measurements and Main Results: Mechanical ventilation triggers hippocampal apoptosis as a result of type 2 dopamine receptor activation in response to vagal signaling. Activation of these receptors blocks the Akt/GSK3β prosurvival pathway and activates the apoptotic cascade, as demonstrated in vivo and in vitro. Vagotomy, systemic haloperidol, or intracerebroventricular raclopride (a type 2 dopamine receptor blocker) ameliorated this effect. Moreover, ventilation induced a concomitant change in the expression of dysbindin-1C. These results were confirmed in brain samples from ventilated patients.

Conclusions: These results prove the existence of a pathogenic mechanism of lung stretch-induced hippocampal apoptosis that could explain the neurological changes in ventilated patients and may help to identify novel therapeutic approaches.

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Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. (Fortenberry)

Klinger JR, Abman SH, Gladwin MT. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013 Sep 15;188(6):639-46.

Nitric oxide (NO) signaling plays a major role in modulating vascular tone and remodeling in the pulmonary circulation, but its role in the pathogenesis of pulmonary vascular diseases is still not completely understood. Numerous abnormalities of NO synthesis and signaling have been identified in animal models of pulmonary vascular disease and in humans with pulmonary hypertension. Many of these abnormalities have become targets of new therapies for the treatment of pulmonary hypertension. However, it is unclear to what extent alterations in NO signaling contribute to pulmonary hypertensive responses or merely reflect abnormalities induced by the underlying disease. This perspective examines the current understanding of altered NO signaling in pulmonary hypertensive diseases and discusses how these alterations may contribute to the pathogenesis of pulmonary hypertension. The efficacy and limitations of presently available therapies for pulmonary hypertension that target NO signaling are reviewed along with an update on investigational therapies that use this pathway to reverse pulmonary hypertensive changes.

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Effects of prone positioning on lung protection in patients with acute respiratory distress syndrome. (Fortenberry)

Am J Respir Crit Care Med. 2013 Jan 24. [Epub ahead of print] PMID: 23348974

Rationale: Positive end-expiratory pressure (PEEP) and prone positioning may induce lung recruitment and affect alveolar dynamics in acute respiratory distress syndrome (ARDS). However, whether there is any interdependence between the effects of PEEP and prone positioning on these variables is unknown. Objectives: To determine the effects of high PEEP and prone positioning on lung recruitment, cyclic recruitment/derecruitment and tidal-hyperinflation, and how these effects are influenced by lung recruitability. Methods: Mechanically ventilated patients (VT 6 ml/kg IBW) underwent whole-lung computed tomography (CT) during breath-holding sessions at airway pressures of 5, 15, and 45-cmH2O, and Cine-CTs on a fixed thoracic transverse slice at PEEP 5 and 15-cmH2O. CT-images were repeated in supine and prone. A recruitment maneuver at 45- cmH2O was performed before each PEEP change. Lung recruitability was defined as the difference in percentage of non-aerated tissue between 5 and 45-cmH2O. Cyclic recruitment/derecruitment and tidal-hyperinflation were determined as tidal changes in percentage of non-aerated and hyperinflated tissue, respectively Main Results: 24 ARDS patients were included. Increasing PEEP from 5 to 15-cmH2O decreased non-aerated tissue (501±201 to 322±132grs, p<0.001) and increased tidal-hyperinflation (0.41±0.26 to 0.57±0.30%, p=0.004) in supine. Prone positioning further decreased non-aerated tissue (322±132 to 290±141grs, p=0.028), and reduced tidal-hyperinflation observed at PEEP 15 in supine (0.57±0.30 to 0.41±0.22%). Cyclic recruitment/derecruitment only decreased when high PEEP and prone were applied together (4.1±1.9 to 2.9±0.9%, p=0.003), particularly in patients with high lung recruitability. Conclusions: Prone positioning enhances lung recruitment and decreases alveolar instability and hyperinflation observed at high PEEP in ARDS patients.

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Implementation of an evidence-based extubation readiness bundle in 499 brain-injured patients – a before-after evaluation of a quality Improvement project. (Fortenberry)

Am J Respir Crit Care Med. 2013 Aug 8. [Epub ahead of print] PMID: 23927561

Rationale: Mechanical ventilation is associated with morbidity in brain-injured patients. This study aims to assess the effectiveness of an extubation readiness bundle to decrease ventilator time in brain-injured patients. Methods: Before/after design in two intensive care units (ICUs) in one university hospital. Brain-injured patients ventilated > 24 hours were evaluated during two phases (a 3-year control phase followed by a 22-month intervention phase). Bundle components were: protective ventilation, early enteral nutrition, standardization of antibiotherapy for hospital-acquired pneumonia and systematic approach to extubation. The primary endpoint was the duration of mechanical ventilation. Results: 299 and 200 patients respectively were analyzed in the control and the intervention phases of this before/after study. The intervention phase was associated with lower tidal volume (P<0.01), higher PEEP (P<0.01), and higher enteral intake in the first 7 days (P=0.01). The duration of mechanical ventilation was 14.9±11.7 days in the control phase and 12.6±10.3 days in the intervention phase (P=0.02). The hazard ratio (HR) for extubation was 1.28 (95% confidence interval (95%CI) 1.04-1.57; P=0.02) in the intervention phase. Adjusted HR was 1.40 (95%CI, 1.12-1.76, P<0.01) in multivariate analysis and 1.34 (95%CI, 1.03-1.74; P=0.02) in propensity score-adjusted analysis. ICU-free days at day-90 increased from 50±33 in the control phase versus 57±29 in the intervention phase (P<0.01). Mortality at day 90 was 28.4% in the control phase and 23.5% in the intervention phase (P=0.22). Conclusion: The implementation of an evidence-based extubation readiness bundle was associated with a reduction in the duration of ventilation in brain-injured patients.

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