key: cord-0843098-zn5pxp0n
authors: Tobin, Martin J.; Jubran, Amal; Laghi, Franco
title: Respiratory Drive Measurements Do Not Signify Conjectural Patient Self-inflicted Lung Injury
date: 2021-01-01
journal: Am J Respir Crit Care Med
DOI: 10.1164/rccm.202009-3630le
sha: ed33077fee40e43a8bb20da234ddf9831d333e7f
doc_id: 843098
cord_uid: zn5pxp0n

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6R complex associates with a second protein, gp130 (5, 6) . Signaling via membrane-bound IL-6R is termed classic signaling. Though gp130 is present in all cells, IL-6R is only expressed by a select few, most notably hepatocytes and macrophages. Therefore, only certain cells are IL-6 responsive under usual circumstances. However, during acute inflammatory states, IL-6R is cleaved by ADAM-17, creating a soluble receptor, sIL-6R, which is capable of binding IL-6. The IL-6/sIL-6R complexes that subsequently form are capable of binding gp130. This process, known as trans-signaling, thereby enables cells that do not express IL-6R to become IL-6 responsive.

Critically, the antiinflammatory and antibacterial activities of IL-6 are mediated via classical signaling, whereas the proinflammatory activities of IL-6 are mediated by transsignaling (5, 6) . This is important, as monoclonal antibodies against IL-6R do not discriminate between classical or trans but instead block both types of IL-6R signaling. This is the rationale for increased bacterial infection in patients treated with tocilizumab. IL-6 is also necessary for resolution of H1N1 influenza infection by protecting neutrophils from virusinduced death in the lung and by promoting neutrophilmediated viral clearance (7) .

In addition to pathogen clearance, the acute phase proteins such as a-1 antitrypsin (AAT) are also induced via classical IL-6 signaling. A treatment that ablates the AAT response altogether would seem risky. Tocilizumab cannot be reversed once administered and has a terminal half-life of approximately 21.5 days. Furthermore, the safest way to wean patients with COVID-19 from this therapy has yet to be agreed upon. We believe that treatment aimed at changing the level or activity of a specific cytokine such as IL-6 may represent a double-edged sword and that therapeutic approaches that address the underlying cause of changes in IL-6 and other mediators are more likely to be successful. In the event that inhibition of the inflammation driven by IL-6 alone is required, specific blockade of IL-6 trans-signaling would preserve cytokine balance and bacterial clearance and might therefore be a superior strategy. n

To the Editor:

We read with interest the editorial by Gattinoni and colleagues on the role of respiratory drive in the application of mechanical ventilation in patients with coronavirus disease (COVID-19) (1).

Gattinoni and colleagues conclude that measurements of airway occlusion pressure (P 0.1 ) and maximal deflection in airway pressure during end-expiratory airway occlusion (DPocc) "displayed good prognostic performance in predicting respiratory deterioration at 24 hours" and can forewarn against patient selfinflicted lung injury (P-SILI).

Apart from the arbitrary definition of respiratory deterioration, the scatter plot in Figure 1 of the article by Esnault and colleagues (2) shows that the vast majority of data overlap between the two groups: 66% of P 0.1 values in nine "Relapse" patients overlap with 74% of P 0.1 values in 19 "Non-Relapse" patients. Only one value of DPocc in the "Relapse" group does not overlap with values in the "Non-Relapse" group. Gattinoni and colleagues fail to point out that the "break-points" were selected in a post hoc manner-a step known to markedly overestimate the accuracy of predictive indexes (3) . No conclusions about reliability of a predictive index can be reached without the threshold being prospectively tested with a validation data set.

In addition to methodological problems, there is no justification for judging P 0.1 4 cm H 2 O as a worrisome high value. Such values are seen in patients with stable chronic obstructive pulmonary disease and in patients successfully weaned from mechanical ventilation (4) . There is no biological rationale for proposing that this level of respiratory motor output likely causes structural injury of the lung or respiratory muscles. The claim by Gattinoni and colleagues that P 0.1 >4 cm H 2 O "portends subsequent worsening of respiratory function" constitutes major overinterpretation of the data.

Gattinoni and colleagues convey that P 0.1 provides a reliable measure of respiratory motor output in individual patients. For decades, it has been known that numerous difficult-to-control factors alter the relationship between P 0.1 and inspiratory muscle pressure output (4). Moreover, P 0.1 exhibits a coefficient of variation as high as 38% in critically ill patients.

Gattinoni and colleagues claim that P 0.1 and DPocc "correlate well with relatively more precise methods for effort estimation." On the contrary, P 0.1 z4 cm H 2 O is associated with a wide range of pressure-time product: z110 to z420 cm H 2 O $ s $ min 21 ( Figure 3H of Reference 5). P 0.1 z1 cm H 2 O is associated with a wide range of peak electrical activity of the diaphragm: z5 to z20 mV $ s 21 ( Figure 3B Gattinoni and colleagues draw conclusions based on observed rapid shallow breathing index of 49 breaths/min/L. It has been known for decades that measurements of rapid shallow breathing index in the presence of un-estimated levels of respiratory workinevitable with pressure support ranging between ,4 and .11 cm H 2 O and positive end-expiratory pressure ,10 to .14 cm H 2 Oare uninterpretable (3).

Gattinoni and colleagues continue to claim that the study by Tonelli and colleagues supports the existence of P-SILI (7). If inspiratory efforts were causing P-SILI, one would expect a decrease in VT-to-transpulmonary pressure swing ratio-a surrogate of lung compliance; yet, VT-to-transpulmonary pressure swing ratio remained constant across 24 hours of noninvasive ventilation. Chest radiography cannot be linked mechanistically to P-SILI because radiologists were not blinded.

Mechanical ventilation plays a crucial role in the management of patients with COVID-19. Conducting rigorous research is vital to enlighten clinicians at the bedside. A pandemic is no time to engage in speculation and broad generalizations based on dubious interpretations of small data sets. On the contrary, ventilator research in COVID-19 needs to aspire to the highest internal validity. n

Characterization of the inflammatory response to severe COVID-19 illness

Clinical and virological data of the first cases of COVID-19 in Europe: a case series

Cytokine assays: an assessment of the preparation and treatment of blood and tissue samples

Influence of collection and separation of blood samples on plasma IL-1, IL-6 and TNF-alpha concentrations

Interleukin-6: designing specific therapeutics for a complex cytokine

Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer

Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung

The respiratory drive: an overlooked tile of COVID-19 pathophysiology

High respiratory drive and excessive respiratory efforts predict relapse of respiratory failure in critically ill patients with COVID-19

Principles and practice of mechanical ventilation

Principles and practice of intensive care monitoring

Airway occlusion pressure as an estimate of respiratory drive and inspiratory effort during assisted ventilation

A novel non-invasive method to detect excessively high respiratory effort and dynamic transpulmonary driving pressure during mechanical ventilation

P-SILI is not justification for intubation of COVID-19 patients

Author disclosures are available with the text of this letter at www.atsjournals.org. 

Reply to Tobin et al.

We read with some perplexity the comments by Tobin and colleagues to our editorial (1). Indeed, many of their questions or concerns should be more properly addressed to Esnault and colleagues, the authors of the original paper (2) .We believe that an important role of an editorial is first to bring fresh ideas to the fore and place them against an engaging conceptual background. Regarding the specific concerns of Tobin and colleagues, we find it fruitless to argue whether 4 cm H 2 O of occlusion pressure at 100 milliseconds is tolerable or not in