Reply to Pérez

From the Authors:

We thank the editors for giving us the opportunity to reply to the issues raised in the letter by Dr. Pérez (1) in response to our recent study published in the Journal (2). Strong respiratory effort is recognized as a potential “second hit” in acute lung injury (ALI) and acute respiratory distress syndrome, introducing the concept of “patient self-inflicted lung injury” (P-SILI) (3). It is pertinent to note that, even though P-SILI differs conceptually from the lung injury induced by hyperventilation in healthy lungs, unfortunately, it is often misconstrued. Our findings were consistent with the “solid-like behavior” of injured lungs. Figure 1A in our paper (2) clearly shows that the lung injury in the P-SILI group was predominant in regions adjacent to the diaphragm. Also, the vascular damage in P-SILI was greater than in the protective mechanical ventilation (MV) group, specifically hyperemia and edema (figure 1C in our paper [2]). In the regional analysis, both parameters were higher in P-SILI in the basal region, in striking contrast to the other groups (data not shown). In a previous report (4), using the same P-SILI model, mapping the lung regional volumetric strain with a tomographic-based biomechanical analysis, we found a progression of regional strain, mainly in basal regions. Also, the nonaerated tissue compartment increased in dependent areas, although the tidal volume was close to 6 mL/kg. Controlled MV prevented these alterations (4).

The injury mechanisms proposed in P-SILI may bear similarities to those classically described in ventilator-induced lung injury (VILI) (5). Still, topographic distribution and specific damaged structures may differ between them. Our study aimed to describe the histological lung damage superimposed by unmodulated respiratory effort on injured lungs (2). The thought process of the MV setting was to maintain an equivalent minute ventilation between groups, avoiding hyperventilation as a confounding factor, with a positive end-expiratory pressure that is unlikely to cause overdistention in a model of alveolar instability. Contrary to Pérez’s interpretation, the most relevant comparison is between the P-SILI and protective MV groups. Through this analysis, we assessed the extent of additional damage (i.e., second hit) caused by the respiratory effort in comparison with a conservative ventilatory approach. The VILI group was established only as a positive control of mechanical damage. Thus, the magnitude of injury in this group is not the most meaningful finding.

Although interesting, it is difficult to study the contribution of the blood CO₂ concentration to inflammation or other parameters in our model because small-animal models have intrinsic limitations that preclude serial blood sampling for common analytic techniques. However, we did not find differences in the inflammatory response between the P-SILI and protective MV groups in our experiment (figure 1C [2]). Additionally, it is essential to clarify that the “dead space” follows a U-shaped function, with increases at the low and high ends of tidal volume.

Another concept to have in mind is that the consequences of respiratory effort will depend on factors such as the magnitude and timeline of respiratory effort (6), the alveolar–capillary barrier indemnity, and the distribution of regional deformation.

In summary, our data suggest that respiratory effort adds a characteristic pattern of damage in acutely injured lungs despite the absence of hyperventilation. However, just like VILI, P-SILI has more than two aspects. To understand in depth the expansion of knowledge of this fascinating topic in recent years, a thorough review of previous research, particularly the methodology and analysis, is crucial. Numerous faces and dimensions have emerged to form a complex polyhedron that requires a multifaceted approach to comprehend fully.