High Tidal Volume, High Positive End Expiratory Pressure and Apneic Breath Hold Strategies (Lung Navigation Ventilation Protocol) With Cone Beam Computed Tomography Bronchoscopic Biopsy of Peripheral Lung Lesions: Results in 100 Patients.

BACKGROUND: A dedicated anesthesia protocol for bronchoscopic lung biopsy-lung navigation ventilation protocol (LNVP)-specifically designed to mitigate atelectasis and reduce unnecessary respiratory motion, has been recently described. LNVP demonstrated significantly reduced dependent ground glass, sublobar/lobar atelectasis, and atelectasis obscuring target lesions compared with conventional ventilation. METHODS: In this retrospective, single-center study, we examine the impact of LNVP on 100 consecutive patients during peripheral lung lesion biopsy. We report the incidence of atelectasis using cone beam computed tomography imaging, observed ventilatory findings, anesthesia medications, and outcomes, including diagnostic yield, radiation exposure, and complications. RESULTS: Atelectasis was observed in a minority of subjects: ground glass opacity atelectasis was seen in 30 patients by reader 1 (28%) and in 18 patients by reader 2 (17%), with good agreement between readers (κ = 0.78). Sublobar/lobar atelectasis was observed in 23 patients by reader 1 and 26 patients by reader 2, also demonstrating good agreement (κ = 0.67). Atelectasis obscured target lesions in very few cases: 0 patients (0%, reader 1) and 3 patients (3%, reader 2). Diagnostic yield was 85.9% based on the AQuIRE definition. Pathology demonstrated 57 of 106 lesions (54%) were malignant, 34 lesions (32%) were benign, and 15 lesions (14%) were nondiagnostic. CONCLUSION: Cone beam computed tomography images confirmed low rates of atelectasis, high tool-in-lesion confirmation rate, and high diagnostic yield. LNVP has a similar safety profile to conventional bronchoscopy. Most patients will require intravenous fluid and vasopressor support. Further study of LNVP and other ventilation protocols are necessary to understand the impact of ventilation protocols on bronchoscopic peripheral lung biopsy.

GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress.

We have previously demonstrated that mice exposed to sublethal hyperoxia (an atmosphere of >95% oxygen for 4 days, followed by return to room air) have significantly impaired pulmonary innate immune response. Alveolar macrophages (AM) from hyperoxia-exposed mice exhibit significantly diminished antimicrobial activity and markedly reduced production of inflammatory cytokines in response to stimulation with LPS compared with AM from control mice in normoxia. As a consequence of these defects, mice exposed to sublethal hyperoxia are more susceptible to lethal pneumonia with Klebsiella pneumoniae than control mice. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a growth factor produced by normal pulmonary alveolar epithelial cells that is critically involved in maintenance of normal AM function. We now report that sublethal hyperoxia in vivo leads to greatly reduced alveolar epithelial cell GM-CSF expression. Systemic treatment of mice with recombinant murine GM-CSF during hyperoxia exposure preserved AM function, as indicated by cell surface Toll-like receptor 4 expression and by inflammatory cytokine secretion following stimulation with LPS ex vivo. Treatment of hyperoxic mice with GM-CSF significantly reduced lung bacterial burden following intratracheal inoculation with K. pneumoniae, returning lung bacterial colony-forming units to the level of normoxic controls. These data point to a critical role for continuous GM-CSF activity in the lung in maintenance of normal AM function and demonstrate that lung injury due to hyperoxic stress results in significant impairment in pulmonary innate immunity through suppression of alveolar epithelial cell GM-CSF expression.

Transgenic overexpression of granulocyte macrophage-colony stimulating factor in the lung prevents hyperoxic lung injury.

Granulocyte macrophage-colony stimulating factor (GM-CSF) plays an important role in pulmonary homeostasis, with effects on both alveolar macrophages and alveolar epithelial cells. We hypothesized that overexpression of GM-CSF in the lung would protect mice from hyperoxic lung injury by limiting alveolar epithelial cell injury. Wild-type C57BL/6 mice and mutant mice in which GM-CSF was overexpressed in the lung under control of the SP-C promoter (SP-C-GM mice) were placed in >95% oxygen. Within 6 days, 100% of the wild-type mice had died, while 70% of the SP-C-GM mice remained alive after 10 days in hyperoxia. Histological assessment of the lungs at day 4 revealed less disruption of the alveolar wall in SP-C-GM mice compared to wild-type mice. The concentration of albumin in bronchoalveolar lavage fluid after 4 days in hyperoxia was significantly lower in SP-C-GM mice than in wild-type mice, indicating preservation of alveolar epithelial barrier properties in the SP-C-GM mice. Alveolar fluid clearance was preserved in SP-C-GM mice in hyperoxia, but decreased significantly in hyperoxia-exposed wild-type mice. Staining of lung tissue for caspase 3 demonstrated increased apoptosis in alveolar wall cells in wild-type mice in hyperoxia compared to mice in room air. In contrast, SP-C-GM mice exposed to hyperoxia demonstrated only modest increase in alveolar wall apoptosis compared to room air. Systemic treatment with GM-CSF (9 micro g/kg/day) during 4 days of hyperoxic exposure resulted in decreased apoptosis in the lungs compared to placebo. In studies using isolated murine type II alveolar epithelial cells, treatment with GM-CSF greatly reduced apoptosis in response to suspension culture. In conclusion, overexpression of GM-CSF enhances survival of mice in hyperoxia; this effect may be explained by preservation of alveolar epithelial barrier function and fluid clearance, at least in part because of reduction in hyperoxia-induced apoptosis of cells in the alveolar wall.

Sublethal hyperoxia impairs pulmonary innate immunity.

Supplemental oxygen is often required in the treatment of critically ill patients. The impact of hyperoxia on pulmonary host defense is not well-established. We hypothesized that hyperoxia directly impairs pulmonary host defense, beyond effects on alveolar wall barrier function. C57BL/6 mice were kept in an atmosphere of >95% O(2) for 4 days followed by return to room air. This exposure does not lead to mortality in mice subsequently returned to room air. Mice kept in room air served as controls. Mice were intratracheally inoculated with Klebsiella pneumoniae and followed for survival. Alveolar macrophages (AM) were harvested by bronchoalveolar lavage after 4 days of in vivo hyperoxia for ex vivo experiments. Mortality from pneumonia increased significantly in mice exposed to hyperoxia compared with infected mice in room air. Burden of organisms in the lung and dissemination of infection were increased in the hyperoxia group whereas accumulation of inflammatory cells in the lung was impaired. Hyperoxia alone had no impact on AM numbers, viability, or ability to phagocytize latex microbeads. However, following in vivo hyperoxia, AM phagocytosis and killing of Gram-negative bacteria and production of TNF-alpha and IL-6 in response to LPS were significantly reduced. AM surface expression of Toll-like receptor-4 was significantly decreased following in vivo hyperoxia. Thus sublethal hyperoxia increases Gram-negative bacterial pneumonia mortality and has a significant adverse effect on AM host defense function. Impaired AM function due to high concentrations of supplemental oxygen may contribute to the high rate of ventilator-associated pneumonia seen in critically ill patients.