Stress-strain curve and elastic behavior of the fibrotic lung with usual interstitial pneumonia pattern during protective mechanical ventilation

Abstract

Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress-strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO₂/FiO₂ ratio) during a PEEP trial performed within 24 h from intubation. Patient's stress-strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8-33.2] cmH₂O versus 11.4 [10.3-14.6] cmH₂O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress-strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.

Keywords: Acute respiratory distress syndrome; Acute respiratory failure; End-expiratory transpulmonary pressure; End-inspiratory transpulmonary pressure; Idiopathic pulmonary fibrosis; Interstitial lung disease; Invasive mechanical ventilation; Lung elastance; Lung fibrosis; Respiratory mechanics; Specific elastance; Strain; Stress; Transpulmonary pressure; Usual interstitial pneumonia; Ventilator-induced lung injury.

Figure 1

(Panel A) geometry of the three-layered shell modeling an alveolus. Dark gray indicates a layer of collagen interposed between two layers composed of elastin and ground substance, colored in light gray. The shell is inflated by an inner pressure $P.$ The inset shows the stress components acting at each point of the shell material: the radial stress component, ${\sigma }_r$, is in the radial direction, and the circumferential (or hoop) stress components, ${\sigma }_{\theta }$ and ${\sigma }_{\phi }$ (here ${\sigma }_{\phi }={\sigma }_{\theta },$ due to axial symmetry), are in the tangential direction of the meridians and the parallels of the sphere. (Panel B) For a homogeneous shell, force equilibrium requires the resultant of ${\sigma }_{\theta },$ acting on the small area depicted in gray, to be much larger than the resultant of the pressure $P$ acting on the dashed larger area.

Figure 2

Measured individual values of specific elastance of EUIP and ARDS patients at each PEEP level. For EUIP patients specific elastance was 28.9 (24.8 – 33.2) cmH₂O, 22.8 (16.6–27.8) cmH₂O and 33.2 (28.8–41.6) cmH₂O at ZEEP, PEEP_LOW and PEEP_TITRATED respectively. For ARDS patients specific elastance was 11.4 (11.1–14.5) cmH₂O, 14.6 (7.9–22) cmH₂O and 10.6 (9.5–12.2) cmH₂O respectively. Specific elastance was different among group at each PEEP level. EUIP, Acute exacerbation of interstitial lung disease with usual interstitial pneumonia pattern; ARDS, Acute respiratory distress syndrome.

Figure 3

(Panel A) Pressure–volume curves for EUIP, ARDS and healthy patients^, obtained by using Eq. (18). The VILI risk thresholds for stress and strain values derived from ARDS literature are indicated according to Tonetti et al. and Protti et al.. None of the 5 EUIP patients reached global strain values above 1, irrespective of the PEEP applied. For ARDS patients, the highest stress values were reached for strain levels between 1.5 and 2. The same was described when plotting data in healthy lungs^,. With reference to the mechanical model, strain and stress indicate the relative volume change and the pressure applied inside the composite sphere, respectively. (Panel B) Partitioned analysis of the pressure–volume curves for EUIP, ARDS and healthy patients^, obtained by using Eq. (18) showing the behavior of the secant modulus (specific elastance). When fitting EUIP data, the minimum point was reached for strain = 0.55. (Panel C) Partitioned analysis of the pressure–volume curves for EUIP, ARDS and healthy patients^, obtained by using Eq. (18) illustrating the behavior of the tangent modulus. When fitting EUIP data, the minimum point was reached for strain = 0.35. EUIP, Acute exacerbation of interstitial lung disease with usual interstitial pneumonia pattern; ARDS, Acute respiratory distress syndrome.

Figure 4

(Panel A) Isolated contributions of elastin and ground substance (thin lines) and collagen (thick lines) in the pressure–volume fitting curves. Elastin’s contribution in lung inflation was prevalent at lower strains, while the contribution of collagen was significant at higher strains. With reference to the mechanical model, strain and stress here indicate the relative volume change and the pressure applied inside the composite sphere, respectively. The partitioned analysis of the secant modulus (elastance) and tangent modulus for collagen and elastin of for EUIP, ARDS and healthy patients^, is shown in (panels B and C), respectively. For strain value > 0.5 the tangent modulus of elastin showed a steep decrease, and the tangent modulus of collagen showed a marked increase. At strain = 0.9 the modulus of elastin resulted 3.8 cmH₂O and the modulus of collagen 50.0 cmH₂O. EUIP, acute exacerbation of interstitial lung disease with usual interstitial pneumonia pattern; ARDS, acute respiratory distress syndrome.

Figure 5

Simplified diagram illustrating the strain threshold predisposing to VILI for EUIP and ARDS. For these latter the risk of VILI starts increasing at 1.5 and becomes significant above 2^,, resulting in lung inflammation and alveolar rupture. Our data show that in patients with UIP-lung the harmful strain threshold starts for strain value of 0.35 and could be reached slightly above 0.5. EUIP, Acute exacerbation of interstitial lung disease with usual interstitial pneumonia pattern; ARDS, Acute respiratory distress syndrome.