Busana M.

Chiumello D.

Coppola S.

Cressoni M.

Gattinoni L.

Rossi S.

English

AIR Universita degli studi di Milano

Author disclosures are available with the text of this letter atwww.atsjournals.org.Philippe Haouzi, M.D., Ph.D.*Areeb Zamir, M.D.Eduardo Villarreal-Fernandez, M.D.Dana Stauffer, M.S.Lauren Ventola, M.D.Danish Ahmad, M.D.Ami Dewaters, M.D.Muhammad Khalid, M.D.Margaret Wojnar, M.D., M.Ed.Pennsylvania State UniversityState College, PennsylvaniaORCID ID: 0000-0002-0251-0122 (E.V.-F.).*Corresponding author (e-mail: phaouzi@pennstatehealth.psu.edu).References1. Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D.COVID-19 does not lead to a “typical” acute respiratory distresssyndrome [letter]. Am J Respir Crit Care Med 2020;201:1299–1300.2. Liu X, Liu X, Xu Y, Xu Z, Huang Y, Chen S, et al. Ventilatory ratio inhypercapnic mechanically ventilated patients with COVID-19-associated acute respiratory distress syndrome [letter]. Am J RespirCrit Care Med 2020;201:1297–1299.3. Pan C, Chen L, Lu C, Zhang W, Xia JA, Sklar MC, et al. Lung recruitabilityin COVID-19-associated acute respiratory distress syndrome: asingle-center observational study [letter]. Am J Respir Crit Care Med2020;201:1294–1297.4. Bernasconi M, Ploysongsang Y, Gottfried SB, Milic-Emili J, Rossi A.Respiratory compliance and resistance in mechanically ventilatedpatients with acute respiratory failure. Intensive Care Med 1988;14:547–553.5. Gattinoni L, Caironi P, Cressoni M, Chiumello D, Ranieri VM, Quintel M,et al. Lung recruitment in patients with the acute respiratory distresssyndrome. N Engl J Med 2006;354:1775–1786.Copyright © 2020 by the American Thoracic SocietyReply by Gattinoni et al. to Hedenstierna et al., to Maleyet al., to Fowler et al., to Bhatia and Mohammed,to Bos, to Koumbourlis and Motoyama, and to Haouziet al.From the Authors:The strong controversies raised by our 400-word letter (1) reflect theunderlying conflict through which medical knowledge and scienceproceed: on one side, the need for evidence regarding a treatment,for which the apex is randomized trials, and on the other side,the need for evidence to elucidate the mechanisms of disease, forwhich the apex is the reproducible observation of phenomena andtheir interactions (2). As suggested by Fowler and colleagues, ina pandemic the real problem is to “balance the tradeoff betweenlearning (evidence of mechanism) and doing (evidence of responseto treatment).” In any case, the process of acquiring knowledgeabout a novel disease or treatment ideally begins with observations(generating the hypothesis) and ends with the experiments(to prove or disprove the hypothesis).However, as evidenced by this correspondence, our scientificcommunity seems divided into two broad categories: On one side arethe believers that coronavirus disease (COVID-19) pneumonia mustbe defined as acute respiratory distress syndrome (ARDS)—and thatis it. If so, we have nothing to learn about its respiratory treatment,just to do (lung-protective strategy, positive end-expiratory pressure[PEEP]–FIO2 table, etc.) (3). On the other side are the believers thatCOVID-19 is a specific disease that is somehow different fromARDS, with manifestations that may change over time. As such, wehave much to learn regarding mechanisms and what a “lung-protective” approach should mean in this setting (4).It is from collecting hundreds of consistent observations (the so-despised anecdotes) from Milan, Parma, Turin, and London that weproposed two phenotypes, which represent the extremes of a broadspectrum of the respiratory manifestations in COVID-19 pneumonia:an early phenotype, L (i.e., the “atypical” ARDS of our letter,characterized by lower elastance, lower _VA/ _Q, lower recruitability,and lower lung weight), and a late phenotype, H (i.e., the typicalARDS, characterized by higher lung elastance, higher right-to-leftshunt, higher recruitability, and higher lung weight) (5).Dr. Bos, Dr. Maley and colleagues, and Dr. Haouzi and colleaguesin their letters conclude, as domany others in our scientific community,that COVID-19 pneumonia is not atypical but fits the conventionalARDS definition and that higher respiratory system compliance (Crs)may be a normal finding in the syndrome. Dr. Bos, in particular, reportsa “striking similarity” between the common presentation of patientswith severe COVID-19 pneumonia and the ARDS originallydescribed by Ashbaugh in 1967, namely, “acute onset of tachypnea,hypoxemia and loss of compliance.” Actually, the L patientspresenting to the hospital are in 50% of the cases eupneic, with arespiratory rate of approximately 20 breaths/min (approximately40 breaths/min in the Ashbaugh paper [6]) with near a normal Crsof .50 ml/cm H2O (,20 ml/cm H2 in Ashbaugh [6]).Maley and colleagues suggest that our small cohort (16 patientswith a mean Crs of 50.26 14.3 ml/cm H2O) cannot meaningfullybe compared with the series of Seattle (24 patients with a medianCrs of 29 ml/cm H2O [25–36]). Finally, Haouzi and colleaguescritique the large range of Crs values we reported (20–90 ml/cm H2O). Because the disease is the same all around the world, theobservations also should be similar. Actually, we believe that theapparent contradictory results stem from the time of observation,with type L being more likely early on and type H being morelikely in the late phase. We suspect that many ICUs are treatingpatients at a more advanced H stage. The pivotal role of time isdemonstrated in Figure 1, in which we show, in a series of 28patients, that Crs, measured at 5 cm H2O of PEEP is a function ofthe days elapsed from the initial symptoms (Figure 1A), regardlessthe venous admixture (Figure 1B).The striking feature of the COVID-19 pneumonia in the L stateis not the Crs per se but the remarkable hypoxemia associated witha lung gas volume far greater than what is found in the ARDS“baby lung.” Because the gas and ventilation side are relativelyThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage andreprints, please contact Diane Gern (dgern@thoracic.org).Originally Published in Press as DOI: 10.1164/rccm.202004-1052LE on June24, 2020CORRESPONDENCE628 American Journal of Respiratory and Critical Care Medicine Volume 202 Number 4 | August 15 2020preserved, the hypoxemia must primarily derive from the perfusionside (7). Indeed, a growing number of observations showendothelial involvement (8), which initiates hypercoagulability(9), and the lung perfusion dysregulation that causes severehypoxemia because of _VA/ _Q mismatch. However, as pointed out byBhatia and Mohammed, microthrombosis are likely part of thisphenomenon. In this context, Hedenstierna and colleaguessuggested that inhaled nitric oxide could be of interest to correcthypoxemia. This is rational and certainly possible, but only furtherobservations may tell us the value of inhaled nitric oxide in thedifferent stages of the disease. Given that the hypoxemia is mainlydetermined by a pathology on the endothelial side of the alveolarmembrane, the use of exogenous surfactant suggested byKoumbourlis and Motoyama lacks physiological rationale.Thus, so far, we have learned that COVID-19 is a systemic diseasein which the viral assault is primarily focused on the endothelium,which accounts for both the pulmonary vascular dysregulation and thehypercoagulable state. Are these insights sufficient to rethink andchange our practice, and if so, at which stage? Fowler and colleagues,recognizing the difficulties of promptly organizing randomizedcontrolled trials, propose a direct acyclic graph to evaluate thehypothetical risks and benefits of conventional therapies for the twoextreme phenotypes. In the meantime, how should we manage type Lpatients? The transition from L to H status, in which the ARDS criteriaand therapies fully apply, may be due both to the natural course of thedisease and to the patient self-induced lung injury (10). There is littlethat can be done to alleviate the first factor, but we can certainlyintervene to prevent patient self-induced lung injury. If, despitenoninvasive support, the patient continues to make vigorousinspiratory efforts, we believe that mechanical ventilation should beapplied without delay. During the mechanical ventilation of these earlyphase L patients, higher PEEP is not advisable despite the severehypoxemia because recruitability is relatively low, the lung is alreadyfull of gas, and the consequences on hemodynamics may beremarkable. We also proposed in these L patients a VT higher than 6ml/kg, provoking a strong disagreement by Maley and colleagues, forwhom the conventionally low VT ventilation is the precise strategy forgentle lung ventilation. However, in those patients with higher Crs,the tradeoff is between possible ventilator-induced lung injury andpossible hypoventilation, with an increased need for sedation and riskof atelectasis. We believe that in the L patients the risk of ventilator-induced lung injury is minimized, as plateau, driving pressure, andmechanical power are far from their conventionally acceptedthresholds. In addition, we would like to respectfully remind ourcorrespondents that in three large randomized controlled trials, nodifferences were found between patients treated with 7.1 ml/kg versus10.3 ml/kg ideal body weight (IBW) (11), 7.2 ml/kg versus 10.8 ml/kgIBW (12), 7.3 ml/kg versus 10.2 ml/kg IBW (13).ARDS is of fundamental importance in the ICU community,which developed in parallel to the understanding of the syndrome(14). Many people have argued that the term “ARDS” is too genericbecause it encompasses too many conditions and etiologies to haveany credible diagnostic and prognostic validity. It is therefore ironicto see how many try to turn strongly in favor of preserving thediagnosis of ARDS in COVID-19 disease, particularly becauseCOVID-19 is a single-etiology disease (unlike ARDS), and theventilatory management is independent from the degree ofhypoxemia (unlike ARDS). Standard ARDS treatment in such casesshould be deeply reconsidered, taking also in account that themortality rate in different ICUs around the world ranges from 10%to 90% (personal communications). Because the disease is thesame, this disparity underlines the impact of treatment. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Luciano Gattinoni, M.D.*Medical University of GöttingenGöttingen, GermanySilvia Coppola, M.D.University of MilanMilan, Italy90807060504030203 96 12 15 18 21 24 27Days from symptoms onsetRespiratorysysytem compliance (ml/cmH2O)A0.70.60.50.40.30.23 96 12 15 18 21 24 27Days from symptoms onsetBVenous admixtureFigure 1. (A) Respiratory system compliance measured at 5 cm H2O of positive end-expiratory pressure within 48 hours after admission to the ICU as afunction of the days elapsed since the onset of symptoms (P, 0.001). (B) Venous admixture fraction (measured in the same conditions) as a function ofthe days elapsed since the onset of symptoms (P=0.964).CORRESPONDENCECorrespondence 629Massimo Cressoni, M.D.University of Milan-BicoccaMilan, ItalyMattia Busana, M.D.Medical University of GöttingenGöttingen, GermanySandra Rossi, M.D.University HospitalParma, ItalyDavide Chiumello, M.D.University of MilanMilan, ItalyORCID IDs: 0000-0001-5380-2494 (L.G.); 0000-0002-1626-1278 (M.B.).*Corresponding author (e-mail: gattinoniluciano@gmail.com).References1. Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D.COVID-19 does not lead to a “typical” acute respiratory distresssyndrome [letter]. Am J Respir Crit Care Med 2020;201:1299–1300.2. Gattinoni L, Giomarelli P. Acquiring knowledge in intensive care: meritsand pitfalls of randomized controlled trials. Intensive Care Med 2015;41:1460–1464.3. Ziehr DR, Alladina J, Petri CR, Maley JH, Moskowitz A, Medoff BD, et al.Respiratory pathophysiology of mechanically ventilated patients withCOVID-19: a cohort study. Am J Respir Crit Care Med 2020;201:1560–1564.4. Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress.JAMA [online ahead of print] 24 Apr 2020; DOI: 10.1001/jama.2020.6825.5. Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, et al.COVID-19 pneumonia: different respiratory treatment for differentphenotypes. Intensive Care Med 2020;46:1099–1102.6. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratorydistress in adults. Lancet 1967;2:319–323.7. Lang M, Som A, Mendoza DP, Flores EJ, Reid N, Carey D, et al.Hypoxaemia related to COVID-19: vascular and perfusionabnormalities on dual-energy CT. Lancet Infect Dis [online ahead ofprint] 30 Apr 2020; DOI: 10.1016/S1473-3099(20)30367-4.8. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R,Zinkernagel AS, et al. Endothelial cell infection and endotheliitis inCOVID-19. Lancet 2020;395:1417–1418.9. Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C,Chantarangkul V, et al. Hypercoagulability of COVID-19 patients inintensive care unit: a report of thromboelastography findings andother parameters of hemostasis. J Thromb Haemost [online ahead ofprint] 17 Apr 2020; DOI: 10.1111/jth.14850.10. Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to minimizeprogression of lung injury in acute respiratory failure. Am J RespirCrit Care Med 2017;195:438–442.11. Brochard L, Roudot-Thoraval F, Roupie E, Delclaux C, Chastre J,Fernandez-Mondéjar E, et al. Tidal volume reduction forprevention of ventilator-induced lung injury in acute respiratorydistress syndrome: the Multicenter Trail Group on TidalVolume reduction in ARDS. Am J Respir Crit Care Med 1998;158:1831–1838.12. Stewart TE, Meade MO, Cook DJ, Granton JT, Hodder RV, LapinskySE, et al.; Pressure- and Volume-Limited Ventilation StrategyGroup. Evaluation of a ventilation strategy to prevent barotraumain patients at high risk for acute respiratory distress syndrome.N Engl J Med 1998;338:355–361.13. Brower RG, Shanholtz CB, Fessler HE, Shade DM, White P Jr, WienerCM, et al. Prospective, randomized, controlled clinical trialcomparing traditional versus reduced tidal volume ventilation in acuterespiratory distress syndrome patients. Crit Care Med 1999;27:1492–1498.14. Gattinoni L, Quintel M. Fifty years of research in ARDS why is acuterespiratory distress syndrome so important for critical care? Am JRespir Crit Care Med 2016;194:1051–1052.Copyright © 2020 by the American Thoracic SocietyReply by Pan et al. to Haouzi et al.From the Authors:We appreciate Dr. Haouzi and his colleagues for their interest inour research letter (1). They reanalyzed our reported data andfound a possible but nonsignificant coupling between lowercompliance and greater alveolar PO2 (PAO2)–PaO2 gradient. Theythen suggested that positive end-expiratory pressure (PEEP)should be titrated by reaching the highest compliance and lowestPAO2–PaO2 gradient.We want to point out that a possible association between complianceand PAO2–PaO2 gradient among different patients makes physiologicalsense but may not be applied for PEEP titration in a given individual; thePEEP providing the highest compliance can be completely different fromthe PEEP providing the lowest PAO2–PaO2 gradient. Actually, we haveobserved that patients with coronavirus disease (COVID-19)–associatedacute respiratory distress syndrome (ARDS) from Wuhan often present“better” compliance and “worse” PAO2–PaO2 gradient at low PEEP. Wethus will discuss the optimal compliance and the optimal PAO2–PaO2gradient as two respective PEEP strategies.Titrating PEEP by the optimal compliance has been proposedfor several decades, but years of research have shown manypitfalls and limitations. 1) Plateau pressure can be measured byperforming varied durations of end-inspiratory occlusion, and thepressure value can change according to viscoelastic properties,pendelluft, or simply the presence of leaks. This technical issue isnot trivial. A preset 0.2- to 0.3-second end-inspiratory pauseminimizes this issue, providing more reliable plateau pressure as anindicator of the maximal lung distension (2). 2) Some physiologicalstudies using electrical-impedance tomography suggested that ahigh PEEP guided by “best” compliance of the whole respiratorysystem can be substantially higher than the PEEP based on regionalcompliance or on the dorsal fraction of ventilation reaching 50%and that the chest wall could play a role in these discrepancies (3).3) In contrast, when substantial tidal recruitment is present at lowPEEP, compliance may be increased by this tidal recruitment (4).Using this “best” compliance would therefore favor ongoingrepeated recruitment and collapse. 4) The optimal complianceapproach has been tested in a large randomized controlled trial,showing no benefit on outcome (5).The PAO2–PaO2 gradient can be a useful physiological indicatorduring clinical practice, but we cannot rely on it for PEEP titrationbecause of the following considerations. 1) Calculating theThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage andreprints, please contact Diane Gern (dgern@thoracic.org).Originally Published in Press as DOI: 10.1164/rccm.202005-2045LE on June24, 2020CORRESPONDENCE630 American Journal of Respiratory and Critical Care Medicine Volume 202 Number 4 | August 15 2020

Reply by Gattinoni et al. to Hedenstierna et al., to Maley et al., to Fowler et al., to Bhatia and Mohammed, to Bos, to Koumbourlis and Motoyama, and to Haouzi et al.

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Reply by Gattinoni et al. to Hedenstierna et al., to Maley et al., to Fowler et al., to Bhatia and Mohammed, to Bos, to Koumbourlis and Motoyama, and to Haouzi et al.

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