Muders, Thomas

Petroff, David

Wrigge, Hermann

English

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Author disclosures are available with the text of this article atwww.atsjournals.org.Guy Brusselle, M.D., Ph.D.Department of Respiratory MedicineGhent University HospitalGhent, BelgiumandDepartments of Epidemiology and Respiratory MedicineErasmus Medical Center RotterdamRotterdam, The NetherlandsSebastian Riemann, M.D.Department of Respiratory MedicineGhent University HospitalGhent, BelgiumORCID IDs: 0000-0001-7021-8505 (G.B.); 0000-0003-1184-7234 (S.R.).References1. Gauvreau GM, Sehmi R, Ambrose CS, Griffiths JM. Thymic stromallymphopoietin: its role and potential as a therapeutic target in asthma.Expert Opin Ther Targets 2020;24:777–792.2. Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al.Tezepelumab in adults with uncontrolled asthma. N Engl J Med 2017;377:936–946.3. Menzies-Gow A, Corren J, Bourdin A, Chupp G, Israel E,Wechsler ME, et al. Tezepelumab in adults and adolescentswith severe, uncontrolled asthma. N Engl J Med 2021;384:1800–1809.4. Corren J, Menzies-Gow A, Chupp G, Israel E, Korn S, Cook B, et al.Efficacy of tezepelumab in severe, uncontrolled asthma: pooledanalysis of the PATHWAY and NAVIGATOR studies. Am J Respir CritCare Med 2023;208:13–24.5. Humbert M, Albers FC, Bratton DJ, Yancey SW, Liu MC, Hozawa S, et al.Effect of mepolizumab in severe eosinophilic asthma according toomalizumab eligibility. Respir Med 2019;154:69–75.6. Brusselle G, Quirce S, Papi A, Kuna P, Chipps BE, Hanania NA, et al.Dupilumab efficacy in patients with uncontrolled or oral corticosteroid-dependent allergic and nonallergic asthma. J Allergy Clin Immunol Pract2023;11:873–884.e11.7. Menzies-Gow A, Wechsler ME, Brightling CE, Korn S, Corren J, Israel E,et al. Long-term safety and efficacy of tezepelumab in people withsevere, uncontrolled asthma (DESTINATION): a randomised,placebo-controlled extension study. Lancet Respir Med 2023May;11(5):425–438.8. Brusselle GG, Koppelman GH. Biologic therapies for severe asthma.N Engl J Med 2022;386:157–171.9. Diver S, Khalfaoui L, Emson C, Wenzel SE, Menzies-Gow A, Wechsler ME,et al.; CASCADE Study Investigators. Effect of tezepelumab on airwayinflammatory cells, remodelling, and hyperresponsiveness in patients withmoderate-to-severe uncontrolled asthma (CASCADE): a double-blind,randomised, placebo-controlled, phase 2 trial. Lancet Respir Med 2021;9:1299–1312.10. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ,Pavord ID. Mast-cell infiltration of airway smooth muscle in asthma.N Engl J Med 2002;346:1699–1705.11. Gauvreau GM, O’Byrne PM, Boulet L-P, Wang Y, Cockcroft D, Bigler J,et al. Effects of an anti-TSLP antibody on allergen-induced asthmaticresponses. N Engl J Med 2014;370:2102–2110.12. Sverrild A, Hansen S, Hvidtfeldt M, Clausson CM, Cozzolino O, Cerps S,et al. The effect of tezepelumab on airway hyperresponsiveness tomannitol in asthma (UPSTREAM). Eur Respir J 2021;59:2101296.13. Pilette C, Brightling C, Lacombe D, Brusselle G. Urgent need for pragmatictrial platforms in severe asthma. Lancet Respir Med 2018;6:581–583.14. Lacombe D, O’Morain C, Casadei B, Hill K, Mateus E, Lories R, et al.Moving forward from drug-centred to patient-centred research: a whitepaper initiated by EORTC and developed together with the BioMedAlliance members. Eur Respir J 2019;53:1801870.15. Lommatzsch M, Brusselle GG, Canonica GW, Jackson DJ, Nair P,Buhl R, et al. Disease-modifying anti-asthmatic drugs. Lancet 2022;399:1664–1668.Copyright © 2023 by the American Thoracic SocietyElectrical Impedance Tomography: The Electrocardiogramfor the Lungs?Even patients with so-called mild acute respiratory distress syndrome(ARDS) have high 30-day mortality rates (1), and this has incitedlarge-scale international trials to explore means of improving clinicaloutcome, such as increasing positive end-expiratory pressure (PEEP)(2). Meta-analyses of randomized clinical trials suggest that higherconstant PEEP reduces mortality with estimates for the risk ratio of0.77 to 0.91 (3, 4) and better results without recruitment maneuvers(4). Our hopes are that, by individualizing PEEP, clinical outcomescan be improved further, but we have yet to find the “ECG for thelungs” to facilitate such optimization.In this issue of the Journal (pp. 25–38), Jonkman and colleagues(5) present data from patients with coronavirus disease (COVID-19)from the observational RECRUIT (Lung RecruitmEnt assessed byeleCtRical Impedance Tomography) trial. Intubated patients withmoderate to severe ARDS (PaO2/FIO2, 200mmHg) were recruitedfrom ICUs in North America and South America, as well as Europe,within 1week of ARDS diagnosis. With these inclusion criteria, theauthors ensured that the patients’ prognosis was predominantlydetermined by ARDS. Decremental PEEP titration was performed todetermine optimal PEEP on the basis of a balance between collapseand overdistension according to electrical impedance tomography(EIT). EITmay outperform other PEEP optimization strategies, suchas minimal driving pressure (or compliance) because it providesregional functional information on changes in aeration (6).This article is open access and distributed under the terms of theCreative Commons Attribution Non-Commercial No DerivativesLicense 4.0. For commercial usage and reprints, please e-mailDiane Gern (dgern@thoracic.org).Originally Published in Press as DOI: 10.1164/rccm.202305-0810EDon May 30, 2023Editorials 3EDITORIALS The RECRUIT trial was a physiological trial without clinicaloutcomes initially designed to study ARDS patients, but because ofthe high prevalence of COVID-19–associated ARDS (CARDS), thiseditorial presents an unplanned subgroup analysis midway in thestudy to discuss results from this interesting and potentiallyidiosyncratic patient cohort.Following a fairly complex ventilation protocol including aPEEP step with various respiratory mechanical and blood gasmeasurements, decremental PEEP titration started at 24 cmH2O witha driving pressure of 15 cmH2O above PEEP, and EIT tracings wererecorded at each step. As suggested by Costa and colleagues on thebasis of a proof-of-principle paper that examined two patients (7),collapse and hyperinflation curves were plotted by PEEP level, andthe optimumwas defined as the crossing point of the two. Theprotocol foresaw testing the patients’ tolerance for high pressure aftersafety issues observed in the Acute Respiratory Distress SyndromeTrial (2), and all but 4 of 108 patients tolerated the highest maximalpressure of 39 cmH2O.Although a compromise between collapse and overdistentionseems natural, the particular optimization can be questioned, and theconceptual foundations may require sharpening. The termsoverdistension, hyperinflation, overinflation, and overventilation allencompass fundamentally different concepts such as mechanicalstrain and stress of collagen fibers, flattening of a pressure-volumecurve, physiological dead space because of compression of perfusionin capillaries on an alveolar level, gray scales in a thoracic computedtomography scan, biotrauma to lung cells with a mechanicallyinduced boost in inflammation, and so forth. After choosing whichconcept is most relevant, one must a means of measuring andminimizing it. The definition of relative overdistention used in theRECRUIT trial led to values greater than 15% in some patients at aPEEP of 6 cmH2O (see Figure E3 in 5), whereas they would havebeen 0% by construction had the measurements from step 1(see Figure 1 in 5) not been counted. This and other propertiesdemonstrate a certain arbitrariness inherent to the crossing-pointmethod. Moreover, by optimizing a surrogate parameter such as anyEITmeasure, one does not necessarily arrive at the optimum for theintended parameter, whichever it may be. In addition, validation ofimaging methods for overdistention is complicated by the lack of agold standard.It is arguable that one should exploit the high temporalresolution inherent to EIT, typically 50Hz. Hundreds ofmeasurements per breath are thus available, although the method inthe RECRUIT trial uses only two. On the other hand, thisinformation is used to define regional ventilation delay (RVD) (8),where early filling may indicate overdistention toward the end ofeach breath, and delayed filling was shown to correspond to tidalrecruitment (9). Hence, an alternative EIT-optimization strategy isminimizing this inhomogeneity in delay by finding the PEEP with thelowest RVD index. In Figure 1, the computed tomography sliceshows a lung from a patient with viral pneumonia and bilateralinfiltrates. The tidal volume image shows the sum of impedancechanges over one breath cycle and visualizes nonventilated regions inthe dependent right lung. The two RVDmaps visualize the timedifferences in regional ventilation at the pixel level during a low-flowmaneuver (8). At a PEEP of 8 cmH2O, there is tidal recruitmentmainly in the middle part of the right lung, denoted by red and yellowsquares, whereas the blue colored pixels denote very early filling andmay indicate regions prone to overdistention. The RVDmap at thePEEP of 18 cmH2O is more homogeneous, indicating a betterbalance of avoiding tidal recruitment and overdistention.Beyond issues regarding the best measure, there is also thequestion as to whether optimization on the timescales of minutes canadequately capture the aforementioned biotraumas that may resultfrom cyclic processes over days. This leads to the question of whetherregular (daily) measurements and adjustments of ventilationparameters could be beneficial to clinical outcome.ARDS subsumes many pathophysiological etiologies, whereasCARDS is a single disease, and one might expect less heterogeneityamong this population. It is, thus, surprising at first sight thatrecruitability varied widely in this CARDS cohort (5). However,evidence shows that, in a first phase, COVID-19 is an endothelialinsult with arterial thrombosis, which includes pulmonary artery(micro)thromboses (10) and impaired oxygenation despite relativelylittle impaired respiratory system compliance (11), alveolar collapse(11, 12), and thus recruitment potential. In a second phase, the lungincurs inflammatory damage with consequences for recruitmentmore comparable with typical ARDS (13). The high range ofrecruitability, even in CARDS patients, highlights the need forindividualizing PEEP settings, and EIT has been shown to be aFigure 1. Effects of PEEP on RVD. CT=computed tomography; PEEP 8=positive end-expiratory pressure of 8 cm H2O; PEEP 18=positive end-expiratory pressure of 18 cm H2O; RVD= regioinal ventilation delay; VT= tidal ventilation image.4 American Journal of Respiratory and Critical Care Medicine Volume 208 Number 1 | July 1 2023EDITORIALS promising tool for doing so. Like ECG, EIT results are available atbedside after a brief processing time, albeit not yet entirely automatedin commercially available devices. The fact that the RECRUIT trialconstitutes a multicenter study using different EITmachines confirmsthat EIT is truly a viable option for use in clinical routine and couldbe used in future trials to select patients who could benefit most fromPEEP individualization. The high temporal resolution of EIT notedearlier also has the potential to measure changes in lung perfusion,especially if an “electrical contrast agent” such as saline solution isused (14). Some preliminary studies with bedside computation usenot only ventilation but also ventilation/perfusion ratios (6, 15–17).The RECRUIT trial is the largest EIT trial to date, and even thisCOVID-19 subgroup consists of 108 patients. It provides importantinformation on the logistic and clinical viability of EIT as well asphysiological data on a CARDS cohort, all of which help pave the waytoward EIT trials with patient-centered clinical outcomes. It showsthat recruitability differs substantially between CARDS patients,where those on the low end do not show an improved oxygenation atany PEEP setting in contrast to others. It will be of great interest tocompare with the ARDS patients once the data are available.Author disclosures are available with the text of this article atwww.atsjournals.org.Hermann Wrigge, M.D., Ph.D.Department of Anesthesiology, Intensive Care, Emergency Medicine, andPain TherapyBergmannstrost HospitalHalle, GermanyandMedical FacultyMartin-Luther University Halle-WittenbergHalle, GermanyThomas Muders, M.D.Department of Anesthesiology and Intensive Care MedicineUniversity Hospital BonnBonn, GermanyDavid Petroff, M.Sc., Ph.D.Clinical Trial CentreUniversity of LeipzigLeipzig, GermanyReferences1. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al.;LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, patternsof care, and mortality for patients with acute respiratory distresssyndrome in intensive care units in 50 countries. JAMA 2016;315:788–800.2. Cavalcanti AB, Suzumura EA, Laranjeira LN, Paisani DM, Damiani LP,Guimar~aes HP, et al.; Writing Group for the Alveolar Recruitment forAcute Respiratory Distress Syndrome Trial (ART) Investigators. Effect oflung recruitment and titrated positive end-expiratory pressure (PEEP) vslow PEEP on mortality in patients with acute respiratory distresssyndrome: a randomized clinical trial. JAMA 2017;318:1335–1345.3. Walkey AJ, Del Sorbo L, Hodgson CL, Adhikari NKJ, Wunsch H, MeadeMO, et al. Higher PEEP versus lower PEEP strategies for patients withacute respiratory distress syndrome. A systematic review and meta-analysis. Ann Am Thorac Soc 2017;14:S297–S303.4. Dianti J, Tisminetzky M, Ferreyro BL, Englesakis M, Del Sorbo L, Sud S,et al. Association of positive end-expiratory pressure and lungrecruitment selection strategies with mortality in acute respiratorydistress syndrome: a systematic review and network meta-analysis. AmJ Respir Crit Care Med 2022;205:1300–1310.5. Jonkman AH, Alcala GC, Pavlovsky B, Roca O, Spadaro S, Scaramuzzo G,et al.; Pleural Pleasure Working Group (PLUG). Lung RecruitmEntassessed by eleCtRical Impedance Tomography (RECRUIT):a multicenter study of COVID-19 ARDS. Am J Respir Crit Care Med2023;208:25–38.6. Frerichs I, Amato MBP, van Kaam AH, Tingay DG, Zhao Z, Grychtol B,et al.; TREND study group. Chest electrical impedance tomographyexamination, data analysis, terminology, clinical use andrecommendations: consensus statement of the TRanslational EITdevelopmeNt stuDy group. Thorax 2017;72:83–93.7. Costa ELV, Borges JB, Melo A, Suarez-Sipmann F, Toufen C Jr, BohmSH, et al. Bedside estimation of recruitable alveolar collapse andhyperdistension by electrical impedance tomography. Intensive CareMed 2009;35:1132–1137.8. Wrigge H, Zinserling J, Muders T, Varelmann D, G€unther U, von derGroeben C, et al. Electrical impedance tomography compared withthoracic computed tomography during a slow inflation maneuver inexperimental models of lung injury. Crit Care Med 2008;36:903–909.9. Muders T, Luepschen H, Zinserling J, Greschus S, Fimmers R, GuentherU, et al. Tidal recruitment assessed by electrical impedance tomographyand computed tomography in a porcine model of lung injury. Crit CareMed 2012;40:903–911.10. Patel BV, Arachchillage DJ, Ridge CA, Bianchi P, Doyle JF, Garfield B,et al. Pulmonary angiopathy in severe COVID-19: physiologic, imaging,and hematologic observations. Am J Respir Crit Care Med 2020;202:690–699.11. Chiumello D, Busana M, Coppola S, Romitti F, Formenti P, Bonifazi M,et al. Physiological and quantitative CT-scan characterization ofCOVID-19 and typical ARDS: a matched cohort study. Intensive CareMed 2020;46:2187–2196.12. Ball L, Robba C, Maiello L, Herrmann J, Gerard SE, Xin Y, et al.;GECOVID (GEnoa COVID-19) group. Computed tomographyassessment of PEEP-induced alveolar recruitment in patients withsevere COVID-19 pneumonia. Crit Care 2021;25:81.13. Goligher EC, Ranieri VM, Slutsky AS. Is severe COVID-19 pneumonia atypical or atypical form of ARDS? And does it matter? Intensive CareMed 2021;47:83–85.14. Muders T, Hentze B, Leonhardt S, Putensen C. Evaluation of differentcontrast agents for regional lung perfusion measurement usingelectrical impedance tomography: an experimental pilot study. J ClinMed 2023;12:2751.15. Hentze B, Muders T, Luepschen H, Maripuu E, Hedenstierna G,Putensen C, et al. Regional lung ventilation and perfusion by electricalimpedance tomography compared to single-photon emission computedtomography. Physiol Meas 2018;39:065004.16. Morais CCA, Safaee Fakhr B, De Santis Santiago RR, Di Fenza R,Marutani E, Gianni S, et al. Bedside electrical impedance tomographyunveils respiratory “chimera” in COVID-19. Am J Respir Crit Care Med2021;203:120–121.17. Perier F, Tuffet S, Maraffi T, Alcala G, Victor M, Haudebourg A-F, et al.Effect of positive end-expiratory pressure and proning on ventilationand perfusion in COVID-19 acute respiratory distress syndrome. Am JRespir Crit Care Med 2020;202:1713–1717.Copyright © 2023 by the American Thoracic SocietyEditorials 5EDITORIALS 

Electrical impedance tomography : the electrocardiogram for the lungs?

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Electrical impedance tomography : the electrocardiogram for the lungs?

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