Effects of mechanical ventilation on the interstitial extracellular matrix in healthy lungs and lungs affected by acute respiratory distress syndrome: a narrative review.

BACKGROUND: Mechanical ventilation, a lifesaving intervention in critical care, can lead to damage in the extracellular matrix (ECM), triggering inflammation and ventilator-induced lung injury (VILI), particularly in conditions such as acute respiratory distress syndrome (ARDS). This review discusses the detailed structure of the ECM in healthy and ARDS-affected lungs under mechanical ventilation, aiming to bridge the gap between experimental insights and clinical practice by offering a thorough understanding of lung ECM organization and the dynamics of its alteration during mechanical ventilation. MAIN TEXT: Focusing on the clinical implications, we explore the potential of precise interventions targeting the ECM and cellular signaling pathways to mitigate lung damage, reduce inflammation, and ultimately improve outcomes for critically ill patients. By analyzing a range of experimental studies and clinical papers, particular attention is paid to the roles of matrix metalloproteinases (MMPs), integrins, and other molecules in ECM damage and VILI. This synthesis not only sheds light on the structural changes induced by mechanical stress but also underscores the importance of cellular responses such as inflammation, fibrosis, and excessive activation of MMPs. CONCLUSIONS: This review emphasizes the significance of mechanical cues transduced by integrins and their impact on cellular behavior during ventilation, offering insights into the complex interactions between mechanical ventilation, ECM damage, and cellular signaling. By understanding these mechanisms, healthcare professionals in critical care can anticipate the consequences of mechanical ventilation and use targeted strategies to prevent or minimize ECM damage, ultimately leading to better patient management and outcomes in critical care settings.

Stress & strain in mechanically nonuniform alveoli using clinical input variables: a simple conceptual model.

Clinicians currently monitor pressure and volume at the airway opening, assuming that these observations relate closely to stresses and strains at the micro level. Indeed, this assumption forms the basis of current approaches to lung protective ventilation. Nonetheless, although the airway pressure applied under static conditions may be the same everywhere in healthy lungs, the stresses within a mechanically non-uniform ARDS lung are not. Estimating actual tissue stresses and strains that occur in a mechanically non-uniform environment must account for factors beyond the measurements from the ventilator circuit of airway pressures, tidal volume, and total mechanical power. A first conceptual step for the clinician to better define the VILI hazard requires consideration of lung unit tension, stress focusing, and intracycle power concentration. With reasonable approximations, better understanding of the value and limitations of presently used general guidelines for lung protection may eventually be developed from clinical inputs measured by the caregiver. The primary purpose of the present thought exercise is to extend our published model of a uniform, spherical lung unit to characterize the amplifications of stress (tension) and strain (area change) that occur under static conditions at interface boundaries between a sphere's surface segments having differing compliances. Together with measurable ventilating power, these are incorporated into our perspective of VILI risk. This conceptual exercise brings to light how variables that are seldom considered by the clinician but are both recognizable and measurable might help gauge the hazard for VILI of applied pressure and power.

The place of positive end expiratory pressure in ventilator-induced lung injury generation.

PURPOSE OF REVIEW: Describe the rationale for concern and accumulating pathophysiologic evidence regarding the adverse effects of high-level positive end expiratory pressure (PEEP) on excessive mechanical stress and ventilator-induced lung injury (VILI). RECENT FINDINGS: Although the inclusion of PEEP in numerical estimates of mechanical power may be theoretically debated, its potential to increase stress, strain, and mean airway pressure are not. Recent laboratory data in a variety of animal models demonstrate that higher levels of PEEP coupled with additional fluids needed to offset its impediment of hemodynamic function are associated with increased VILI. Moreover, counteracting end-tidal hyperinflation by external chest wall pressure may paradoxically improve respiratory mechanics, indicating that lower PEEP helps protect the small 'baby lung' of advanced acute respiratory distress syndrome (ARDS). SUMMARY: The potentially adverse effects of PEEP on VILI can be considered in three broad categories. First, the contribution of PEEP to total mechanical energy expressed through mechanical power, raised mean airway pressure, and end-tidal hyperinflation; second, the hemodynamic consequences of altered cardiac loading, heightened pulmonary vascular stress and total lung water; and third, the ventilatory consequences of compromised carbon dioxide eliminating efficiency. Minimizing ventilation demands, optimized body positioning and care to avoid unnecessary PEEP are central to lung protection in all stages of ARDS.

From pressure to tension: a model of damaging inflation stress.

Although the stretch that generates ventilator-induced lung injury (VILI) occurs within the peripheral tissue that encloses the alveolar space, airway pressures and volumes monitor the gas within the interior core of the lung unit, not its cellular enclosure. Measured pressures (plateau pressure, positive end-expiratory pressure, and driving pressure) and tidal volumes paint a highly relevant but incomplete picture of forces that act on the lung tissues themselves. Convenient and clinically useful measures of the airspace, such as pressure and volume, neglect the partitioning of tidal elastic energy into the increments of tension and surface area that constitute actual stress and strain at the alveolar margins. More sharply focused determinants of VILI require estimates of absolute alveolar dimension and morphology and the lung's unstressed volume at rest. We present a highly simplified but informative mathematical model that translates the radial energy of pressure and volume of the airspace into its surface energy components. In doing so it elaborates conceptual relationships that highlight the forces tending to cause end-tidal hyperinflation of aerated units within the 'baby lung' of acute respiratory distress syndrome (ARDS).

Optimized ventilation power to avoid VILI.

The effort to minimize VILI risk must be multi-pronged. The need to adequately ventilate, a key determinant of hazardous power, is reduced by judicious permissive hypercapnia, reduction of innate oxygen demand, and by prone body positioning that promotes both efficient pulmonary gas exchange and homogenous distributions of local stress. Modifiable ventilator-related determinants of lung protection include reductions of tidal volume, plateau pressure, driving pressure, PEEP, inspiratory flow amplitude and profile (using longer inspiration to expiration ratios), and ventilation frequency. Underappreciated conditional cofactors of importance to modulate the impact of local specific power may include lower vascular pressures and blood flows. Employed together, these measures modulate ventilation power with the intent to avoid VILI while achieving clinically acceptable targets for pulmonary gas exchange.

Practical assessment of risk of VILI from ventilating power: a conceptual model.

At the bedside, assessing the risk of ventilator-induced lung injury (VILI) requires parameters readily measured by the clinician. For this purpose, driving pressure (DP) and end-inspiratory static 'plateau' pressure ([Formula: see text]) of the tidal cycle are unquestionably useful but lack key information relating to associated volume changes and cumulative strain. 'Mechanical power', a clinical term which incorporates all dissipated ('non-elastic') and conserved ('elastic') energy components of inflation, has drawn considerable interest as a comprehensive 'umbrella' variable that accounts for the influence of ventilating frequency per minute as well as the energy cost per tidal cycle. Yet, like the raw values of DP and [Formula: see text], the absolute levels of energy and power by themselves may not carry sufficiently precise information to guide safe ventilatory practice. In previous work we introduced the concept of 'damaging energy per cycle'. Here we describe how-if only in concept-the bedside clinician might gauge the theoretical hazard of delivered energy using easily observed static circuit pressures ([Formula: see text] and positive end expiratory pressure) and an estimate of the maximally tolerated (threshold) non-dissipated ('elastic') airway pressure that reflects the pressure component applied to the alveolar tissues. Because its core inputs are already in use and familiar in daily practice, the simplified mathematical model we propose here for damaging energy and power may promote deeper comprehension of the key factors in play to improve lung protective ventilation.

Clinical Outcomes Among Children With Standard-Risk Medulloblastoma Treated With Proton and Photon Radiation Therapy: A Comparison of Disease Control and Overall Survival.

PURPOSE: The purpose of this study was to compare long-term disease control and overall survival between children treated with proton and photon radiation therapy (RT) for standard-risk medulloblastoma. METHODS AND MATERIALS: This multi-institution cohort study includes 88 children treated with chemotherapy and proton (n=45) or photon (n=43) RT between 2000 and 2009. Overall survival (OS), recurrence-free survival (RFS), and patterns of failure were compared between the 2 cohorts. RESULTS: Median (range) age was 6 years old at diagnosis (3-21 years) for proton patients versus 8 years (3-19 years) for photon patients (P=.011). Cohorts were similar with respect to sex, histology, extent of surgical resection, craniospinal irradiation (CSI) RT dose, total RT dose, whether the RT boost was delivered to the posterior fossa (PF) or tumor bed (TB), time from surgery to RT start, or total duration of RT. RT consisted of a median (range) CSI dose of 23.4 Gy (18-27 Gy) and a boost of 30.6 Gy (27-37.8 Gy). Median follow-up time is 6.2 years (95% confidence interval [CI]: 5.1-6.6 years) for proton patients versus 7.0 years (95% CI: 5.8-8.9 years) for photon patients. There was no significant difference in RFS or OS between patients treated with proton versus photon RT; 6-year RFS was 78.8% versus 76.5% (P=.948) and 6-year OS was 82.0% versus 87.6%, respectively (P=.285). On multivariate analysis, there was a trend for longer RFS with females (P=.058) and higher CSI dose (P=.096) and for longer OS with females (P=.093). Patterns of failure were similar between the 2 cohorts (P=.908). CONCLUSIONS: Disease control with proton and photon radiation therapy appears equivalent for standard risk medulloblastoma.

Endocrine outcomes with proton and photon radiotherapy for standard risk medulloblastoma.

BACKGROUND: Endocrine dysfunction is a common sequela of craniospinal irradiation (CSI). Dosimetric data suggest that proton radiotherapy (PRT) may reduce radiation-associated endocrine dysfunction but clinical data are limited. METHODS: Seventy-seven children were treated with chemotherapy and proton (n = 40) or photon (n = 37) radiation between 2000 and 2009 with ≥3 years of endocrine screening. The incidence of multiple endocrinopathies among the proton and photon cohorts is compared. Multivariable analysis and propensity score adjusted analysis are performed to estimate the effect of radiotherapy type while adjusting for other variables. RESULTS: The median age at diagnosis was 6.2 and 8.3 years for the proton and photon cohorts, respectively (P = .010). Cohorts were similar with respect to gender, histology, CSI dose, and total radiotherapy dose and whether the radiotherapy boost was delivered to the posterior fossa or tumor bed. The median follow-up time was 5.8 years for proton patients and 7.0 years for photon patients (P = .010). PRT was associated with a reduced risk of hypothyroidism (23% vs 69%, P < .001), sex hormone deficiency (3% vs 19%, P = .025), requirement for any endocrine replacement therapy (55% vs 78%, P = .030), and a greater height standard deviation score (mean (± SD) -1.19 (± 1.22) vs -2 (± 1.35), P = .020) on both univariate and multivariate and propensity score adjusted analysis. There was no significant difference in the incidence of growth hormone deficiency (53% vs 57%), adrenal insufficiency (5% vs 8%), or precocious puberty (18% vs 16%). CONCLUSIONS: Proton radiotherapy may reduce the risk of some, but not all, radiation-associated late endocrine abnormalities.

Proton therapy for low-grade gliomas: Results from a prospective trial.

BACKGROUND: In this prospective study, the authors evaluated potential treatment toxicity and progression-free survival in patients with low-grade glioma who received treatment with proton radiation therapy. METHODS: Twenty patients with World Health Organization grade 2 glioma who were eligible for radiation therapy were enrolled in a prospective, single-arm trial of proton therapy. The patients received proton therapy at a dose of 54 Gy (relative biological effectiveness) in 30 fractions. Comprehensive baseline and regular post-treatment evaluations of neurocognitive function, neuroendocrine function, and quality of life (QOL) were performed. RESULTS: All 20 patients (median age, 37.5 years) tolerated treatment without difficulty. The median follow-up after proton therapy was 5.1 years. At baseline, intellectual functioning was within the normal range for the group and remained stable over time. Visuospatial ability, attention/working memory, and executive functioning also were within normal limits; however, baseline neurocognitive impairments were observed in language, memory, and processing speed in 8 patients. There was no overall decline in cognitive functioning over time. New endocrine dysfunction was detected in 6 patients, and all but 1 had received direct irradiation of the hypothalamic-pituitary axis. QOL assessment revealed no changes over time. The progression-free survival rate at 3 years was 85%, but it dropped to 40% at 5 years. CONCLUSIONS: Patients with low-grade glioma tolerate proton therapy well, and a subset develops neuroendocrine deficiencies. There is no evidence for overall decline in cognitive function or QOL.