A physiological approach to understand the role of respiratory effort in the progression of lung injury in SARS-CoV-2 infection

Abstract

Deterioration of lung function during the first week of COVID-19 has been observed when patients remain with insufficient respiratory support. Patient self-inflicted lung injury (P-SILI) is theorized as the responsible, but there is not robust experimental and clinical data to support it. Given the limited understanding of P-SILI, we describe the physiological basis of P-SILI and we show experimental data to comprehend the role of regional strain and heterogeneity in lung injury due to increased work of breathing.In addition, we discuss the current approach to respiratory support for COVID-19 under this point of view.

Keywords: COVID-19; Lung strain; Mechanical ventilation; P-SILI; SARS-CoV2; Work of breathing.

Fig. 1

Electrical impedance tomography maps of ventilation in one ARDS patient before (superior line) and after intubation using volume-controlled ventilation (VCV) mode (inferior line). Images correspond to one complete respiratory cycle, and it was divided since beginning of inspiration to end-expiration. Observe differences in the inflation pattern. At beginning of inspiration ventilation starts in the most dependent lung regions in spontaneous breathing (SB) and more central regions in VCV. At the end of inspiration ventilation is predominantly dorsal in SB and predominantly central in VCV. The beginning of expiration presents a displacement of center of ventilation directed to ventral in SB and maintaining central in VCV. At the end of expiration, it is observed that ventilation ended in the ventral part of lungs in case of SB, and in the intermediate lung region of VCV. Modified from: Bachmann MC, Basoalto R, Soto, et al. Intensive Care Med Exp. 2018;6(Suppl 2):0274

Fig. 2

Regional volumetric strain maps in a 3-h murine model of patient self-inflicted lung injury randomized to two groups: Group I: subjects with induced lung injury on low tidal volume mechanical ventilation at the beginning of the experiment (T1) and at the end of the experiment (T3) (upper left and right panels). Group II: subjects with induced lung injury on spontaneous breathing (no mechanical ventilation) at the beginning of the experiment (T1) and at the end of the experiment (T3) (lower left and right panels). Progression of regional strain and heterogeneity in time is observed in spontaneous breathing, which reaches volumetric strain levels of up to 80%. Regional strain distribution remains more uniform and homogeneous in low tidal volume mechanical ventilation

Fig. 3

Variation of gene expression in high strain and low strain regions of the lung in a murine model of patient self-inflicted lung injury. a Representative images of in vivo/ex vivo fit between tomographic maps of regional strain and 3D digitized frozen lungs. Red areas represent high strain regions, while the green/blue areas represent low strain regions in spontaneous breathing. Low and high strain regions from the same frozen lung were cut, homogenized, and the RNA purified. b Gene expression variation of inflammation/pathological mechanotransduction between regions of high and low regional strain. The genes that increased their expression in regions of high deformation were TNF Superfamily Member 13b (Tnfsf13b, > 8 times), Interleukin-2 receptor subunit beta (Il2rb, > 6 times), Phosphodiesterase 4A (Pde4A, ~ 3 times), 5-hydroxytryptamine receptor 3A (Htr3a), Plasma kallikrein (Klkb1), and Leukotriene C4 Synthase (Ltc4s). These genes are involved in apoptosis, IL-2 signaling, G-protein signaling, activation of ligand-activated ion channels, coagulation, and inflammation, respectively

Fig. 4

Representative images of lung histology of a 3-h murine experimental study where subjects were randomized to three groups: Group I: subjects with normal (uninjured lungs) on spontaneous breathing (no mechanical ventilation) (a, b). Group II: subjects with induced lung injury on low Vt mechanical ventilation (c, d). Group III: subjects with induced lung injury on spontaneous breathing (no mechanical ventilation) (f–j). In the first image set, no edema or perivascular infiltration is appreciated at ×100 (a) and ×200 (b). In the second image set, minimal amount of perivascular fluid is occasionally observed at ×100 (c–e). In the third image set, we observed alveolar wall disruption and hemorrhage at ×400 (f), perivascular edema and hemorrhage at ×200 (g), intense hyperemia in lung parenchyma vascular bed with signs of initial perivascular edema and leucocyte infiltration at ×200 (h), intense hyperemia and perivascular accumulation of leucocytes at ×100 (i), and perivascular accumulation of polymorphonuclear cell leucocytes and lymphoid cells at ×400 (j)