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

doi:10.21203/rs.3.rs-3585487/v1

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

https://doi.org/10.21203/rs.3.rs-3585487/v1

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published 07 Jun, 2024

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Background

Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (AE-ILD-UIP) 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 AE-ILD-UIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung.

Methods

Partitioned lung and chest wall mechanics were assessed for patients with AE-ILD-UIP and primary ARDS (1:1 matched based on BMI 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 (ECM).

Results

Five patients with AE-ILD-UIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Specific elastance was significantly higher in AE-ILD-UIP as compared to ARDS (28.9 [24.8–33.2] cmH₂O/l versus 11.4 [11.1–14.5] cmH₂O/l, respectively). Compared to ARDS and healthy lung, the stress/strain curve of AE-ILD-UIP showed a steeper increase, crossing the VILI threshold 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 AE-ILD-UIP lungs.

Conclusions

During MV, patients with AE-ILD-UIP 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 AE-ILD-UIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.

Health sciences/Medical research

Health sciences/Diseases/Respiratory tract diseases

Health sciences/Diseases/Respiratory tract diseases/Respiratory distress syndrome

Interstitial lung disease

idiopathic pulmonary fibrosis

lung fibrosis

stress

strain

lung elastance

specific elastance

usual interstitial pneumonia

acute respiratory failure

acute respiratory distress syndrome

respiratory mechanics

end-inspiratory transpulmonary pressure

end-expiratory transpulmonary pressure

invasive mechanical ventilation

ventilator-induced lung injury

transpulmonary pressure

Patients with fibrotic interstitial lung disease (ILD) may experience acute worsening of their clinical status leading to severe acute hypoxic respiratory failure that needs respiratory assistance¹. Although acute exacerbations (AE) of disease represent a major cause of death in patients with idiopathic pulmonary fibrosis (IPF), the elastic properties of the fibrotic lung and its interplay with non-invasive and invasive respiratory support remains largely unknown². What is known from clinical practice is that the tissue architecture of the fibrotic lung with usual interstitial pneumonia (UIP) pattern limits parenchymal deformation and increases the risk of ventilator-induced lung injury (VILI) when mechanical ventilation (MV) is required³. In lung physiology, stress is defined as the pressure developed within the lung structures onto which a distending force (namely transpulmonary pressure) is applied whereas strain is the ratio of the change in lung volume to the resting lung volume during lung inflation^4,5. Lung tissue exhibits a heterogenous nonlinear stress-strain behavior arising from the mechanical interaction between the extra cellular matrix (ECM) constituents, collagen and elastin fibers^6,7,8. In previous studies, we hypothesized static strain as a major determinant of VILI for these patients⁹.

Studies focused on early acute respiratory distress syndrome (ARDS) patients, showed that ARDS-lungs exhibit a specific lung elastance that is similar to healthy lungs, suggesting that the elastic properties of the aerated lung regions are not affected by diffuse alveolar damage (DAD)¹⁰. ARDS, like IPF, is characterized by a heterogeneous elasticity of the lung parenchyma. However and unlike IPF, the pathological alterations behind ARDS are due to the alveolar inflammatory exudation that affects an otherwise healthy lung³ and are influenced by gravitational phenomena. By contrast, UIP represents an intrinsic architectural alteration of the lung structure due to the quantitative and qualitative changes in the collagen and elastin networks in alveolar wall tissue¹¹.

Understanding the mechanical behavior of the fibrotic lung during passive lung inflation could help critical care physicians to tailor controlled MV and prevent detrimental stress-strain interaction resulting in VILI¹². The first explorative aim of this study was to investigate the stress-strain behavior and the specific elastance in a cohort of patients with ILD and UIP pattern undergoing lung protective MV during AE of disease (AE-ILD-UIP), compared it to that of patients with ARDS and healthy lung. The secondary aim was to propose a novel mathematical model to describe ventilator-induced stress and strain in the fibrotic lung.

Study design

The present study has been designed and conducted in two sequential phases: initially, we have retrospectively collected data of patients with UIP pattern that underwent MV during acute exacerbation of disease and protocolized respiratory mechanics assessment and compared them with data from an ARDS matched cohort. In the second phase, we have firstly elaborated a new mathematical model of the lung that describes its deformation during MV. Then, we have used the respiratory mechanics data of our cohorts and available data in literature on healthy lung to fit the model. Finally, based on our mathematical model, we investigated the contributions of elastin and collagen fibers to ventilator-induced lung deformation and illustrated the distributions of the radial and hoop stress components in a three-dimensional shell model.

First phase

Study setting

The study was carried out at the Respiratory Intensive Care Unit (RICU) of the University Hospital of Modena (Italy) and conducted in accordance with the Ethics Committee “Area Vasta Emilia Nord” approval (registered protocol number 327/2022). The study has been registered on ClinicalTrial.gov (ID NCT05098717). Informed consent to participate in the study and to allow their clinical data to be analyzed and published were obtained from participants, as appropriate.

Study population

Patients with ILD and UIP pattern developing acute hypoxic respiratory failure (AHR) due to acute exacerbation (AE) of disease and consecutively admitted to the RICU of the University Hospital of Modena over the period August 1st, 2016 to July 1th, 2022 were considered eligible for enrollment.

Inclusion criteria were as follows: age > 18 years; previously established diagnosis of ILD with a UIP pattern on a high-resolution computed tomography (HRCT) scan; invasive MV in volume-controlled mode; end-expiratory lung volume assessment. According to our institutional protocol, patients with severe AE-ILD-UIP requiring MV are submitted to a standard standardized protocol of partitioned respiratory mechanics measurements at three different level of positive end expiratory pressure (PEEP), i.e. zero PEEP (ZEEP), LOW PEEP (4–8 cmH₂O) and esophageal pressure (P_es)-guided PEEP titration to obtain positive end expiratory transpulmonary pressure (P_L,EE) (TITRATED PEEP).

Patients were excluded if they presented any of the followings: chronic obstructive pulmonary disease; neuromuscular disease; chest wall deformities; missing core data (i.e. data on partitioned respiratory mechanics) at medical record analysis.

AE-ILD-UIP population was then compared with a group of patients with pulmonary ARDS (namely lung infection) under MV extracted from our dataset, treated between 2016 and 2022. BMI and PaO₂/FIO₂ used for matching the AE-ILD-UIP and the pulmonary ARDS groups were those measured at the time of RICU admission.

The stress/strain curve of both populations was compared to that of patients with healthy lung derived from data published by D’Angelo et al.⁹ and Levy et al.¹⁴, hereafter denoted as DA and L data.

Data collection

Medical reports, electronical charts and available clinical and physiological datasets were investigated to collect data on demographics, clinical characteristics, arterial blood gases, PaO₂/FiO₂ ratio, clinical severity (as assessed by the APACHE II score on RICU admission), standardized partitioned respiratory mechanics assessment and end-expiratory lung volume measurements at each PEEP level.

Measurements

On admission, patients were ventilated with a Vt of 6 ml/kg of predicted body weight (PBW) computed as in¹⁵. PEEP was initially set between 5–8 cmH₂O. All patients underwent esophageal manometry (NutriVent^™, nasogastric polyfunctional catheter; SIDAM, Mirandola, Italy), according to standard procedures¹⁶.

According to our local protocol, respiratory mechanics were further assessed in supine position within 24 hours from admission in three consecutive phases at different PEEP levels.

In the first phase (ZEEP phase), measurements of static respiratory mechanics were performed a zero end-expiratory pressure (ZEEP phase).
In the second phase (PEEP_LOW phase), static respiratory mechanics were assessed with PEEP set between 4 and 8 cmH₂O.
In the third phase (PEEP_TITRATED phase), PEEP was titrated in order to achieve a P_L,EE > 0 cmH₂O and according to oxygenation¹⁷.

At each phase, PEEP level was maintained for 30 min before recording all respiratory parameters and blood withdrawal for blood gas analysis. Respiratory mechanics were performed using the end-inspiratory occlusion technique during constant flow inflation and the end-expiratory occlusion method¹⁸.

The mechanical variables were computed according to the formulas reported in the Supplementary materials^{5,10,19–27,}.

Second phase

Mechanical model development

We propose a computational model for the lung based on the mechanical behavior of a single alveolus. Alveolar models and their generalizations have been successfully proposed to explain the pressure-volume response of the normal lung [21,28,29]. In particular, they allow to relate the macroscopic response of the lung (the pressure-volume curve) and the mechanical behavior of the alveolus. This is useful to assess the stresses and local elastance in the alveolar walls in order to investigate the risk of overdistension and epithelial cell damage when the macroscopic strain is at safe values. Moreover, the alveolar model proposed in the present paper is analytical, leading to an exact and thus computationally fast pressure-volume relationship (Eq. (18), Supplementary materials).

In our approach, the alveolus is modeled as an inflated thin-walled hollow spherical shell schematically shown in eFigure 1 (Supplementary materials). The shell is initially stress-free, and it is subject to the internal pressure \(P\). As shown in previous studies^19–28,29 elastin and collagen dominate the elastic behavior of the alveolar tissue, the contribution of interstitial cells being negligible^30,31. It is well known that collagen and elastin fibers form an interlinked random mesh in lung parenchyma. In our alveolar model, the microstructure of the two types of fibers is smeared out, as usual in homogenization approaches [32,33].

Accordingly, we assume that the shell is composed of alternating layers of possible dissimilar thickness, as shown in eFigure 1. Each layer is composed of a different nonlinear hyper-elastic, isotropic and incompressible material, modelling a different fiber contribution, Even though the analysis is performed for any number of layers, in the end we consider only three layers, two external ones composed of elastin fibers and ground substance and an inner layer modeling collagen fibers and their interaction with elastin. The responses in traction of the materials composing the two types of layers are specified by the strain energy functions in Equations (16) and (17), Supplementary materials[21,23,24]. Strain energy functions of this type have been experimentally validated via uniaxial tension tests on living precision-cut rat lung slices [23,24]. In addition, it can be easily verified that the stress-strain curve associated to the strain energy function for collagen (Eq. (17)) has a vanishing slope at the origin followed by a steep ascending branch, mimicking the initial flaccidness and the progressive recruitment of collagen fibers as strain increases [25–28].

The model focuses on the elastic effects on mechanical fields for static inflation, so viscoelasticity is not included in the present analysis.

The development of the mechanical model was carried out according to the following steps:

First, we have mathematically assessed the equilibrium state of a multilayered pressurized sphere and deduced the corresponding pressure-volume response (see Equation (13), Supplementary materials)²².
Using the shell model, we have analytically computed the pressure-volume relationship (see Equation (18), Supplementary materials), which was fitted to the patients’ data.
Finally we assessed the piecewise distribution of radial and hoop stress along the thickness of the shell model (see Equation (24) and (29), Supplementary materials).

Analysis plan

Data were displayed as median and IQR (interquartile range) for continuous variables and numbers and percentages for dichotomous variables. The paired Student’s t-test was used to assess the difference between variables measured at different PEEP levels, when distributed normally; otherwise, the Wilcoxon test was used. As an exploratory analysis, we compared the mechanical variables of AE-ILD-UIP patients with an ARDS population extracted from our dataset, between 2016 and 2022. The ARDS comparison cohort was built using a case-control matching procedure according to body mass index (BMI) and PaO₂/FiO₂ ratio. Comparison between continuous variables was performed with Student’s t-test distributed normally; otherwise, the Wilcoxon test was used. Dichotomous variables were compared using the χ² test or Fisher's exact test, where appropriate. ANOVA and Kruskal-Wallis were used to test an interaction for whether the change in strain according to PEEP levels were different between groups.

For normal lung, the model was fit to average deflationary static pressure–volume data from literature (DA¹³ and L¹⁴). Data were digitized by means of WebPlotDigitizer ( https://automeris.io/WebPlotDigitizer, version 4.6, Pacifica, California, USA). After having digitized data, the curve fitting toolbox in MATLAB R2023a (MathWorks, CA, USA) was used to fit the shell model given by Eq. (18). Analogous fitting was performed for the data collected on AE-ILD-UIP and ARDS and patients¹⁰,³². Further, the stress-strain curve was graphed, and a partitioned analysis of the secant (specific elastance) and tangent modulus was performed to study the curves behavior. The isolated global and partitioned contributions of elastin and collagen were further investigated according to the constitutive model and considering data on multiscale modeling of collagen and elastin proteins available in literature^{23,24,27,29,33}. Statistics was performed using SPSS version 25.0 with PSMATCHING3 R Extension command (IBM Corp., Armonk, NY, USA) and GraphPad Prism version 8.0 (GraphPad Software, Inc., La Jolla, Ca, USA) unless otherwise indicated.

Clinical features and respiratory mechanics of study population

The flowchart of this study is shown in eFigure 2, Supplementary materials. Over the study period a total of 21 patients with AE-ILD-UIP resulted eligible for enrollment. Of these, 5 patients were analyzed according to inclusion criteria. All of them showed a definite UIP pattern on HRCT scan. Patients were prevalently male (n = 4) with a median age of 62 years (56–68) (eTable 1, Supplementary materials). Two of them were diagnosed with IPF. Among the others, one had rheumatoid arthritis associated ILD, one had chronic hypersensitivity pneumonitis and one presented an undetermined ILD. All patients died as inpatients while on MV. AE-ILD-UIP and matched ARDS groups were similar for clinical severity scores (APACHE and SAPS II, eTable 1, Supplementary materials). All ARDS patients presented a pulmonary ARDS occurring from lung infection.

Respiratory mechanics of AE-ILD-UIP and matched ARDS groups at different PEEP levels are showed in Table 1. The PEEP_LOW level was similar, whereas PEEP TITRATED resulted in higher PEEP level in the AE-ILD-UIP group (Table 1).

Table 1

Blood gas analyses and respiratory mechanics of the AE-ILD-UIP and the ARDS population at different PEEP levels. Data are presented as median value and IQR.
Variable	AE-ILD-UIP	ARDS	p-value
ZEEP phase
E_L, cmH₂O/L	43.2 (39.9–54.4)	21 (17.3–35.6)	0.01
E_cw, cmH₂O/L	3.3 (2.8–7)	4.5 (4–6.3)	0.72
E_tot, cmH₂O/L	50 (43.8–57.4)	26.4 (21.6–41.2)	0.01
P_L,EI, cmH₂O	16.1 (13.3–18.5)	7 (4.9–7)	0.0002
P_L,EE, cmH₂O	-4.3 (-7.7 – -2.9)	-4 (-7.5 – -1.2)	0.71
ΔP_aw, cmH₂O	17.5 (16.3–19.3)	21.2 (17.5–22.8)	0.13
ΔP_L, cmH₂O	21.3 (18.1–23.8)	9.4 (8.9–13.2)	0.0003
EELV, ml	693 (588–717)	820 (599–1047)	0.18
Strain, ration	0.58 (0.49–0.62)	0.5 (0.39–0.67)	0.68
pH, value	7.42 (7.39–7.44)	7.39 (7.37–7.41)	0.17
pO2, cmH₂O	75 (72–80)	80 (65–90)	0.73
pCO2, cmH₂O	38 (35–41)	39 (38–42)	0.35
PEEP_LOW phase
E_L, cmH₂O/L	44 (38.8–57.8)	18.3 (15.4–29.5)	0.003
E_cw, cmH₂O/L	3.6 (2.7–7)	4.3 (4–6.4)	0.73
E_tot, cmH₂O/L	52 (42.3–60.9)	23.6 (19.5–35.3)	0.005
P_L,EI, cmH₂O	14 (10.9–18.8)	12 (8.7–15)	0.26
P_L,EE, cmH₂O	-2.2 (-6.5 – -1)	-2.1 (-5.4 – -0.6)	0.78
ΔP_aw, cmH₂O	18.2 (14.8–18.8)	20.8 (16.2–26)	0.18
ΔP_L, cmH₂O	18.4 (15.6–21.8)	16.1 (9.3–19.4)	0.32
PEEP, cmH₂O	4 (4–4)	4 (4–5)	0.71
EELV, ml	702 (625–762)	1010 (733–1175)	0.04
Strain, ratio	0.62 (0.6–0.74)	0.96 (0.63–1.1)	0.08
pH, value	7.4 (7.38–7.43)	7.39 (7.35–7.4)	0.18
pO₂, cmH₂O	75 (72–78.5)	80 (69.5–95.5)	0.31
pCO₂, cmH₂O	39 (36–42.5)	40 (38.5–44)	0.39
PEEP_TITRATED phase
E_L, cmH₂O/L	50 (42.8–60.5)	15.4 (14.4–20.9)	< 0.0001
E_cw, cmH₂O/L	3.9 (3.4–7.2)	4.3 (4–6.5)	0.97
E_tot, cmH₂O/L	59 (47.3–64.2)	21 (18.6–26.6)	< 0.0001
P_L,EI, cmH₂O	26.2 (19.9–29.8)	18.2 (16.5–20.3)	0.03
P_L,EE, cmH₂O	0.3 (0.3–1.4)	0.6 (0.1–1)	0.63
ΔP_aw, cmH₂O	20 (17.3–21.8)	16.5 (14–18.4)	0.06
ΔP_L, cmH₂O	25 (19–29.5)	17.6 (15.6–20.2)	0.04
PEEP, cmH₂O	12 (10–14)	14 (12–17.5)	0.03
EELV, ml	714 (635–755)	1260 (912–1575)	0.01
Strain, ratio	0.69 (0.63–0.83)	1.8 (1.5–1.9)	< 0.0001
pH, value	7.39 (7.36–7.42)	7.36 (7.32–7.39)	0.14
pO2, cmH₂O	78 (55–85)	80 (73–91)	0.3
pCO2, cmH₂O	40 (37–44)	42 (40–48)	0.27
AE-ILD-UIP, acute exacerbation of interstitial lung disease with usual interstitial pneumonia pattern; ARDS, acute respiratory distress syndrome; IQR, interquartile range; ΔP_L, transpulmonary driving pressure; P_L,EI, end-inspiratory transpulmonary pressure; P_L,EE, end-expiratory transpulmonary pressure; ΔP_aw, driving pressure; E_tot, respiratory system elastance; E_cw, chest wall elastance; E_L, lung elastance; PEEP, positive end-expiratory pressure

Table 2

shows the fitting results for the elasticity parameters, \({c}_{1}\) and \({c}_{2}\), and the collagen thickness fraction \({\chi }_{2}\) in the shell model. The estimates indicate a range of variation of 53–189 cmH₂O (≅5.2–18.5 kPa) for the elastic parameter \({c}_{1}\) of elastin and ground substance, 365–702 cmH₂O (about 35.8–68.8 kPa) for the elastic parameter \({c}_{2}\) of collagen.
Data source	Adj-R²	SSE	Elastin and ground substance	Collagen
Data source	Adj-R²	SSE	\({\varvec{c}}_{1}\) (cmH₂O)	\({\varvec{c}}_{2}\) (cmH₂O)	\({\varvec{\chi }}_{2}\) (-)
Healthy lung (D’Angelo et al.)¹³	0.9774	2.458	53.29 [39.71–66.87]	365.0 [246–483.9]	0.05 [-0.19–0.29]
Healthy lung (Levy et al.)¹⁴	0.9754	8.07	74.64 [66.21–83.06]	392.9 [315.7–470.0]	0.04 [-0.07–0.15]
ARDS	0.7435	135.0	95.0 [70.0–120.0]	212.0 [91.05–333.0]	0.08 [-0.16–0.32]
AE-ILD-UIP	0.5743	340.9	189.4 [102.1–276.7]	702.3 [370.7–1034]	0.31 [-0.01–0.63]

At ZEEP, AE-ILD-UIP patients had higher E_L (43.2 [39.9–54.4] cmH₂O/L, p = 0.01), P_L,EI (16.1 [13.3–18.5] cmH₂O, p = 0.0002) and ΔP_L (21.3 [18.1–23.8] cmH₂O, p = 0.0003) as compared to ARDS patients (Table 1). Conversely, ΔP_aw (17.5 cmH₂O/L VS 21.2 cmH₂O/L, p = 0.1), P_L,EE (-4.3 cmH₂O/L VS -4 cmH₂O/L, p = 0.7) and EELV (693 ml VS 820 ml, p = 0.18) were not different between the two groups (Table 1). During the PEEP_LOW and the PEEP_TITRATED phases, AE-ILD-UIP patients had higher E_L (44 cmH₂O/L VS 18.3 cmH₂O/L, p = 0.003 and 50 cmH₂O/L VS 15.4 cmH₂O/L, p = 0.0001, respectively) and lower EELV (702 ml VS 1010 ml, p = 0.04 and 714 ml VS 1260 ml, p = 0.01, respectively) as compared to ARDS (Table 1). Strain was not different at ZEEP and PEEP_LOW between the groups (0.58 VS 0.5 cmH₂O/L, p = 0.68 and 0.62 VS 0.96, p = 0.08, respectively), while AE-ILD-UIP patients showed significantly lower strain values during the PEEP_TITRATED phases (0.62 VS 1.8, p < 0.0001). Figure 1 illustrates and compares the changes in strain according to incremental PEEP values in the two groups. Whereas AE-ILD-UIP and ARDS patients presented an increase in strain during the PEEP_TITRATED phase as compared to both ZEEP and PEEP_LOW phases, this resulted significantly higher for the latter group (p = 0.003, Fig. 1).

Specific elastance was significantly higher in AE-ILD-UIP as compared to ARDS (28.9 [24.8–33.2] cmH₂O versus 11.4 [11.1–14.5] cmH₂O, respectively) (Fig. 2).

Stress/strain curve and model fitting

The stress/strain curve according to Eq. (18) (Supplementary materials) for AE-ILD-UIP and ARDS patients and for healthy subjects^13,14 is illustrated in Fig. 3, panel A. None of the AE-ILD-UIP patients reached global strain above 1. Four out 5 patients with AE-ILD-UIP reached levels of strain above 0.5 that corresponded to stress values higher than 12.5 cmH₂O, irrespective of the selected PEEP. For ARDS patients and healthy subjects, the highest stress values were reached for strain levels between 1.5 and 2. The partitioned analysis of the secant and tangent modulus of AE-ILD-UIP patients showed that the minimum point was reached for strain value of 0.55 (Fig. 3, panel B) and 0.35 (Fig. 3, panel C) respectively.

Figure 4, panel A shows the isolated contributions of elastin plus ground substance and collagen in the pressure-volume curves. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was significant at higher strains. The curve for collagen showed an upward shift passing from normal to AE-ILD-UIP lungs. The partitioned analysis of the secant and tangent modulus for collagen and elastin of AE-ILD-UIP patients is showed in panel B and panel 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 two moduli resulted 3.8 cmH₂O for elastin and 50.0 cmH₂O for collagen.

The piecewise distributions of the radial and hoop stress components, \({\sigma }_{r}\) and \({\sigma }_{\theta }\) respectively, in three deformed (inflated) configurations of the alveolus, corresponding to three different values of the relative volume change \(\frac{{\Delta }V}{V}\) is shown in eFigure 3 and eFigure 4, Supplementary materials for AE-ILD-UIP and ARDS patients respectively.

In this study, we proposed a constitutive model for lung deformation during mechanical ventilation, accounting for the contributions of elastin and collagen – the main components of the ECM. This model was developed with stress/strain data from patients with AE-ILD-UIP and ARDS undergoing MV and fills a theoretical knowledge gap concerning the risk of VILI underwent by patients with AE-ILD-UIP during MV.

Are data on respiratory mechanics of UIP-lung really needed?

Although the use of MV in patients with AE-ILD and UIP pattern is limited due to unfavorable outcome³, the use of invasive respiratory assistance is required in certain cases (bridge to transplantation, ILD of unknown etiology presenting with AE at its onset, overlap with potentially revertible infectious disease)⁹. In this scenario, current guidelines on IPF (the most frequent ILD with UIP pattern) management do not provide any recommendation regarding the use of MV³⁴. This may be due by the lack of data on the interplay between ventilatory assistance and the mechanical response of the fibrotic lung with UIP pattern. Comparing the effect of a protective ventilation strategy on respiratory mechanics of ARDS and AE-ILD-UIP patients, we firstly report evidence of lung elastance derangement for these latter. These data may help in reducing the gap of knowledge on the interaction between MV and lung fibrosis.

To what extent is the specific elastance different between AE-ILD-UIP and ARDS?

Studies in patients with early-phase ARDS, found that specific elastance falls within ranges comparable to healthy lungs (about 12 cmH₂O/L)^5,8, which is confirmed by our data. The specific lung elastance of AE-ILD-UIP is significantly higher, probably reflecting the intrinsic mechanical features of the lung parenchyma which depends on lung structural composition (i.e. ECM). Following the mechanical laws at the basis of VILI, we know that the complete unfolding of the collagen fibers at the molecular level, limits the safe maximum lung inflation at total lung capacity (TLC) and corresponds to a specific elastance that is two-fold the resting value (around 24 cmH₂O/L)⁵. Yet, we show a specific elastance of nearly 30 cmH₂O/L. Thus, according to our results, the latter concept does not seem applicable to the fibrotic lung with UIP pattern, as the value of specific elastance reported for the UIP lung is per se nearly critical to cause lung damage. That is to say that in patients with lung fibrosis the limit to safe inflation during MV should not be based on specific elastance.

Is there a harmful strain threshold for UIP-lung?

Studies conducted on patients with acute lung injury reported that the harmful value of global strain is around 2^5,35. This is confirmed by our data where ARDS patients showed the highest stress values for strain between 1.5 and 2. Conversely, none of the AE-ILD-UIP reached levels of strain above 1, not even for higher PEEP values. As such, the classical paradigm derived from ARDS in which MV produces clinically relevant VILI for strain ≥ 1³⁶ could not fit for the UIP-lung. The global and partitioned analysis of the model fit with AE-ILD-UIP data shows that the stress-strain curve starts rearing up thus deranging its mechanical behavior for values of global strain within 0.35 and 0.55; further, when assessing the contribution of elastin and collagen to lung deformation, our data show that for strain value > 0.5 the tangent moduli start diverging significantly. Thus, we propose it as a threshold risk for VILI development in UIP-lung. Furthermore, we must also consider that in ARDS patients undergoing MV lethal strain values are rarely applied in clinical practice; indeed, VILI is usually explained through the mechanism of lung parenchyma heterogeneity acting as a “stress riser” at the interface areas between healthy and diseased lung. This is even more true for the parenchymal inhomogeneity characterizing the UIP lung, (causing the rise of local stress, cf. the stress distributions shown in Figs. 3 and 4) where stress raisers take place at the interface of regions characterized by different elastic recoil (also with a “squishy” behavior, which could occur at the microscale³⁷). Thus, it is not surprising that the stress-strain curve that we reported for patients with AE-ILD-UIP shows how harmful strain threshold could be reached slightly above 0.5, which is a value commonly applied in clinical practice. Based on the presented data and model, it seems not possible to invasively ventilate patients with AE-ILD-UIP without provoking a certain degree of VILI. This concept is illustrated in a simplified graphic diagram in Fig. 5. For detailed discussion on the mechanical characteristics and implications of the model^21,31, we refer to the Supplementary materials.

Study limitations

Our study suffers from several limitations. First, our analysis has been conducted on just 5 patients with AE-ILD-UIP. However, given that patients with ILD-UIP rarely undergo MV, to our knowledge no data on respiratory mechanics in this subset are available. Secondly, we limited our investigation to patients experiencing AE of disease. Third, we did not provide data on CT images at different PEEP levels nor on biomarkers of lung damage. Additionally, the mathematical model has several simplifying aspects. First, the analysis is conducted at the scale of a single alveolus, so regional heterogeneities caused by gravity or intrinsic local tissue variability are neglected. Next, the model focuses on elastic effects on mechanical fields for static inflation, so viscoelasticity is not included in this analysis. Finally, the effect of lung surfactant is not considered in the model.

Despite these limitations, we believe that our results could pave the way for further research in the clinical management of patients with AE-ILD-UIP in need of IMV. Indeed, our data seem to suggest that even when the principles of protective MV are applied, patients with AE-ILD-UIP still are at high risk of VILI. This raises the issue on how to manage ILD-UIP patients with no ceiling of escalation to MV (i.e. bridge to transplantation). In this scenario whether alternative strategies (i.e. ultra-protective ventilation, extra-corporeal membrane oxygenation) may limit the application of harmful airways pressure to support vital function should be matter of further research.

The stress/strain curve of patients with fibrotic lung and UIP pattern explains why these patients may experience harmful values of lung stress during invasive ventilatory assistance even when the principles of lung protective MV developed for ARDS are applied. According to our novel mathematical model, we suggest that the peculiar model of deformation in patients with fibrotic lung and UIP might be due to the different contribution of the main ECM components. Our model fills a theoretical research gap and encourage research on a tailored management of UIP-lung during AHRF.

ILD, interstitial lung disease; AE-ILD, acute exacerbation of ILD; UIP, usual interstitial pneumonia; ARDS, acute respiratory distress syndrome; AHRF, acute hypoxic respiratory failure; bpm, breaths per minute; MV, invasive mechanical ventilation; ETI, endotracheal intubation; PEEP, positive end-expiratory pressure; PBW, predicted body weight; PSV, pressure support; APACHE II, acute physiology and chronic health evaluation II; SAPS II, Simplified Acute Physiology Score; IPF, idiopathic pulmonary fibrosis; RICU, respiratory intensive care unit; ICU, intensive care unit; P_es, esophageal pressure; P_es,EI, end-inspiratory esophageal pressure; P_es,EE, end-expiratory esophageal pressure; P_L, transpulmonary pressure; DP_L, transpulmonary driving pressure; P_L,EI, end-inspiratory transpulmonary pressure; P_L,EE, end-expiratory transpulmonary pressure; P_plat,end-inspiratory plateau pressure; DP_aw, driving pressure; E_tot, respiratory system elastance; E_cw, chest wall elastance; E_L, lung elastance; Vt, tidal volume; IQR, interquartile range.

Authors’ contributions

RT, RR, AM designed the study, enrolled the patients, analyzed the data, and wrote the paper and should be considered as first authors. SG, AC, LBall, AVS, RF, GB, LT, SC, LM, DA, FG, IC, M.R. S, FP;L Boss made substantial contributions to the literature review, data collection, and paper writing. SG, AM reviewed the literature, wrote the manuscript and produced the figures. AC, LBoss, AM, RR analyzed data and produced figures. RR elaborated the analysis and wrote the paper. A Marchioni and EC designed the study, wrote, reviewed, and edited the manuscript and share senior authorship. All authors have read and approved the final version of the manuscript. RT and RR share first authorship. AM and EC share senior authorship.

Data availability statement

Clinical data available upon request contacting

Roberto Tonelli, MD, PhD
Researcher

Conflict of interest

None.

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No competing interests reported.

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

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Journal Publication

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Abstract

Figures

INTRODUCTION

MATERIALS AND METHODS

Study design

First phase

Study setting

Study population

Data collection

Measurements

Second phase

Mechanical model development

Analysis plan

RESULTS

Clinical features and respiratory mechanics of study population

Stress/strain curve and model fitting

DISCUSSION

Are data on respiratory mechanics of UIP-lung really needed?

To what extent is the specific elastance different between AE-ILD-UIP and ARDS?

Is there a harmful strain threshold for UIP-lung?

Study limitations

CONCLUSION

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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