Patients with acute exacerbation (AE) of interstitial lung disease (ILD) and usual interstitial pneumonia (UIP) pattern may experience severe acute hypoxic respiratory failure, even requiring ventilatory assistance. Patho-physiologically, AE-ILD resembles an acute respiratory distress syndrome (ARDS), since it mainly consists of diffuse alveolar damage (DAD) superimposed on a background of fibrosing ILD. While protective ventilatory strategies have contributed to significant improvements in ARDS mortality mitigating the risk of ventilator induced lung injury, specific evidence concerning lung mechanics and optimal ventilatory setting during AE-ILD are lacking. Given that pulmonary fibrosis may be the trajectory towards which a wide variety of clinical conditions (e.g. ARDS) are directed, understanding the peculiar physiological changes occurring in the fibrotic lung while subjected to ventilatory support, could help critical care physicians to tailor respiratory assistance and optimize ventilatory strategies. Thus, the purpose of this 3-years research project was to explore the mechanical properties and elastic behavior of the fibrotic lung with UIP pattern under invasive and non-invasive respiratory assistance for AE of disease. First and as introduction, we explore and discuss similarities and differences between AE of idiopathic pulmonary fibrosis (IPF) and ARDS and we analyse the available evidence on physiopathology, mechanical ventilation settings and other treatments available for AE-IPF. In the second chapter, we review the effects of MV in AE-ILD to increase the knowledge on the characteristics of fibrotic lung during artificial ventilation and we introduce and detail the concept of “squishy ball lung” to illustrate the mechanical behavior of the fibrotic lung with UIP pattern when subjected to positive end-expiratory pressure (PEEP). In the third chapter, we analyse available evidence on the relationship between mechanical forces acting on the lung and biological responses in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support. In the fourth chapter, we quantify the inspiratory effort as assessed by esophageal manometry and the respiratory mechanics of 10 consecutive AE-IPF patients before and after a 2-hour non-invasive ventilation (NIV) trial and compare it with a historic matched cohort of ARDS patients, showing that patients with AE-IPF show a high inspiratory effort, whose intensity is reduced by NIV application without any significant improvement in respiratory mechanics, at difference with ARDS patients. In the fifth chapter, we explore the mechanical behavior of the fibrotic lung with UIP pattern while on AE, once subjected to MV and PEEP titration based on end-expiratory transpulmonary pressure (PLEEX) and we compare the mechanical response of AE-ILD-UIP lungs with that of pulmonary ARDS during MV. We show that positive value of PLEEX may be achieved in the lung of patients with AE-ILD-UIP when PEEP is increased, despite a significant worsening in lung mechanics. Overall, with this project we have reviewed clinical data regarding the interaction between mechanical forces and the lung of patients with a UIP pattern. Starting from this evidence, we have elaborated an original theoretical model that might explain the mechanical behavior of the fibrotic lung when subjected to MV and its implication on clinical outcomes and unfavorable mechanotransduction and fibrosis progression. Finally, we have given clinical evidence to confirm the “squishy ball” lung model in patients with lung fibrosis and UIP pattern experiencing AE of disease that require non-invasive and invasive ventilatory assistance.

I pazienti con riacutizzazione di interstiziopatia polmonare (AE-ILD) e pattern di polmonite interstiziale specifica (UIP) possono sviluppare una grave insufficienza respiratoria ipossiemica che richiede assistenza ventilatoria. Da un punto di vista fisiopatologico, le AE-ILD possono essere paragonate alla sindrome da distress respiratorio acuto (ARDS), in quanto si osserva la sovrapposizione di un danno alveolare diffuso (DAD) su un substrato di ILD fibrosante. Se le strategie di ventilazione protettiva hanno ridotto il rischio di danno indotto da ventilazione e la mortalità dei pazienti con ARDS, mancano evidenze specifiche sulla meccanica polmonare e sulle strategie ventilatorie durante le AE-ILD. Considerando che la fibrosi polmonare può essere la traiettoria verso cui evolvono diverse condizioni cliniche (ad esempio l’ARDS), la comprensione dei cambiamenti fisiologici che intervengono nel polmone fibrotico sottoposto a supporto ventilatorio, potrebbe aiutare gli intensivisti a sviluppare strategie ventilatorie adeguate per questa tipologia di pazienti. In questo scenario, l’obiettivo del presente progetto di ricerca è stato quello di esplorare le proprietà meccaniche e il comportamento elastico del polmone interessato da fibrosi a pattern UIP sottoposto ad assistenza respiratoria invasiva e non invasiva per riacutizzazione di malattia. Nel primo capitolo abbiamo discusso analogie e differenze fra riacutizzazione di fibrosi polmonare idiopatica (IPF) e ARDS, analizzando le evidenze disponibili sulla fisiopatologia e sulle impostazioni della ventilazione meccanica (MV) nelle AE-IPF. Nel secondo capitolo, abbiamo revisionato gli effetti della MV nelle AE-ILD e abbiamo introdotto e dettagliato il concetto del polmone “squishy-ball” per illustrare il comportamento meccanico del polmone fibrotico a pattern UIP quando sottoposto a pressione positiva tele-espiratoria (PEEP). Nel terzo capitolo, abbiamo analizzato i dati disponibili sulla relazione fra le forze meccaniche agenti sul polmone e la risposta biologica del polmone fibrotico, focalizzandoci sulla progressione del danno durante il respiro spontaneo assistito e non assistito. Nel quarto capitolo, abbiamo quantificato lo sforzo inspiratorio e la meccanica respiratoria (misurati mediante manometria esofagea) di 10 pazienti con AE-IPF prima e dopo un trial di 2 ore di ventilazione non-invasiva (NIV) confrontandoli con una coorte appaiata di pazienti ARDS e dimostrando come i pazienti con AE-IPF presentino un elevato sforzo respiratorio, la cui intensità è, a differenza dei pazienti ARDS, ridotta dall’applicazione della NIV senza miglioramento dei parametri di meccanica. Nel quinto capitolo, abbiamo esplorato il comportamento meccanico del polmone con pattern UIP sottoposto a titolazione della PEEP sulla base della pressione transpolmonare di fine espirio (PLEEX), confrontando la risposta meccanica dei pazienti con AE-ILD-UIP con i pazienti ARDS. Abbiamo dimostrato che nei pazienti con AE-ILD-UIP è possibile ottenere valori positivi di PLEEX incrementando i valori di PEEP, a prezzo di un significativo peggioramento della meccanica polmonare. In conclusione, con questa ricerca abbiamo revisionato le evidenze riguardanti l’interazione fra stress meccanico e polmone fibrotico a pattern UIP per poi elaborare un modello teorico originale che spieghi il comportamento meccanico del polmone fibrotico sottoposto a ventilazione e le sue implicazioni sugli outcome clinici e sulla progressione della fibrosi. Abbiamo infine fornito evidenza clinica per confermare il modello del polmone “squishy ball” nei pazienti con fibrosi polmonare a pattern UIP che richiedono assistenza ventilatoria invasiva e non-invasiva

Proprietà meccaniche e comportamento elastico del polmone affetto da fibrosi con pattern "polmonite interstiziale tipica" in corso di ventilazione meccanica: sviluppo e significato clinico della teoria del polmone "squishy ball" / Roberto Tonelli , 2023 May 19. 35. ciclo, Anno Accademico 2021/2022.

Proprietà meccaniche e comportamento elastico del polmone affetto da fibrosi con pattern "polmonite interstiziale tipica" in corso di ventilazione meccanica: sviluppo e significato clinico della teoria del polmone "squishy ball"

TONELLI, ROBERTO
2023

Abstract

Patients with acute exacerbation (AE) of interstitial lung disease (ILD) and usual interstitial pneumonia (UIP) pattern may experience severe acute hypoxic respiratory failure, even requiring ventilatory assistance. Patho-physiologically, AE-ILD resembles an acute respiratory distress syndrome (ARDS), since it mainly consists of diffuse alveolar damage (DAD) superimposed on a background of fibrosing ILD. While protective ventilatory strategies have contributed to significant improvements in ARDS mortality mitigating the risk of ventilator induced lung injury, specific evidence concerning lung mechanics and optimal ventilatory setting during AE-ILD are lacking. Given that pulmonary fibrosis may be the trajectory towards which a wide variety of clinical conditions (e.g. ARDS) are directed, understanding the peculiar physiological changes occurring in the fibrotic lung while subjected to ventilatory support, could help critical care physicians to tailor respiratory assistance and optimize ventilatory strategies. Thus, the purpose of this 3-years research project was to explore the mechanical properties and elastic behavior of the fibrotic lung with UIP pattern under invasive and non-invasive respiratory assistance for AE of disease. First and as introduction, we explore and discuss similarities and differences between AE of idiopathic pulmonary fibrosis (IPF) and ARDS and we analyse the available evidence on physiopathology, mechanical ventilation settings and other treatments available for AE-IPF. In the second chapter, we review the effects of MV in AE-ILD to increase the knowledge on the characteristics of fibrotic lung during artificial ventilation and we introduce and detail the concept of “squishy ball lung” to illustrate the mechanical behavior of the fibrotic lung with UIP pattern when subjected to positive end-expiratory pressure (PEEP). In the third chapter, we analyse available evidence on the relationship between mechanical forces acting on the lung and biological responses in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support. In the fourth chapter, we quantify the inspiratory effort as assessed by esophageal manometry and the respiratory mechanics of 10 consecutive AE-IPF patients before and after a 2-hour non-invasive ventilation (NIV) trial and compare it with a historic matched cohort of ARDS patients, showing that patients with AE-IPF show a high inspiratory effort, whose intensity is reduced by NIV application without any significant improvement in respiratory mechanics, at difference with ARDS patients. In the fifth chapter, we explore the mechanical behavior of the fibrotic lung with UIP pattern while on AE, once subjected to MV and PEEP titration based on end-expiratory transpulmonary pressure (PLEEX) and we compare the mechanical response of AE-ILD-UIP lungs with that of pulmonary ARDS during MV. We show that positive value of PLEEX may be achieved in the lung of patients with AE-ILD-UIP when PEEP is increased, despite a significant worsening in lung mechanics. Overall, with this project we have reviewed clinical data regarding the interaction between mechanical forces and the lung of patients with a UIP pattern. Starting from this evidence, we have elaborated an original theoretical model that might explain the mechanical behavior of the fibrotic lung when subjected to MV and its implication on clinical outcomes and unfavorable mechanotransduction and fibrosis progression. Finally, we have given clinical evidence to confirm the “squishy ball” lung model in patients with lung fibrosis and UIP pattern experiencing AE of disease that require non-invasive and invasive ventilatory assistance.
Mechanical properties and elastic behaviour of the fibrotic lung with usual interstitial pneumonia pattern under mechanical ventilation: development and clinical significance of the “squishy ball” lung theory
19-mag-2023
CLINI, Enrico
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