Biotrauma during ultra-low tidal volume ventilation and venoarterial extracorporeal membrane oxygenation in cardiogenic shock: a randomized crossover clinical trial

Amado‑Rod ígueze al. Ann. In ensi e Ca e (2021) 11:132 h ps://doi.o g/10.1186/s13613‑021‑00919‑0 RESEARCH Bio auma du ingul a‑low idal olume en ila ion and enoa e ial ex aco po eal memb ane oxygena ion inca diogenic shock: a andomized c osso e clinical ial Lau a Amado‑Rod íguez1,2,3* , Cecilia Del Bus o1,2, Inés López‑Alonso2,3, Diego Pa a1,2, Juan Mayo domo‑Colunga2,3,4, Miguel A ias‑Guillén3,5, Rod igo Albillos‑Alma az1,2, Paula Ma ín‑Vicen e2,3,6, Cecilia López‑Ma ínez2,3, Co adonga Huidob o2,3, Luigi Campo o a7, A hu S. Slu sky8 and Guille mo M. Albaice a1,2,3,6 Abs ac Backg ound: Ca diogenic pulmona y oedema (CPE) may con ibu e o en ila o ‑associa ed lung inju y (VALI) in pa ien s wi h ca diogenic shock. The app op ia e en ila o y s a egy emains unclea . We aimed o e alua e he impac o ul a‑low idal olume en ila ion wi h idal olume o 3 ml/kg p edic ed body weigh (PBW) in pa ien s wi h CPE and eno–a e ial ex aco po eal memb ane oxygena ion (V–A ECMO) on lung in lamma ion compa ed o con en ional en ila ion. Me hods: A single‑cen e andomized c osso e ial was pe o med in he Ca diac In ensi e Ca e Uni (ICU) a a e ‑ ia y uni e si y hospi al. Se en een adul s equi ing V–A ECMO and mechanical en ila ion due o ca diogenic shock we e included om Feb ua y 2017 o Decembe 2018. Pa ien s we e en ila ed o wo consecu i e pe iods o 24 h wi h idal olumes o 6 and 3 ml/kg o PBW, espec i ely, applied in andom o de . P ima y ou come was he change in p oin lamma o y media o s in b onchoal eola la age luid (BALF) be ween bo h en ila o y s a egies. Resul s: Ven ila ion wi h 3 ml/kg PBW yielded lowe d i ing p essu es and end‑expi a o y lung olumes. O e all, he e we e no di e ences in BALF cy okines. Pos hoc analyses e ealed ha pa ien s wi h high baseline le els o IL‑6 showed s a is ically signi ican lowe le els o IL‑6 and IL‑8 du ing ul a‑low idal olume en ila ion. This educ ion was signi ican ly p opo ional o he dec ease in d i ing p essu e. In con as , hose wi h lowe IL‑6 baseline le els showed a signi ican inc ease in hese bioma ke s. Conclusions: Ul a‑low idal olume en ila ion in pa ien s wi h CPE and V–A ECMO may a enua e in lamma ion in selec ed cases. VALI may be d i en by an in e ac ion be ween he indi idual p oin lamma o y p o ile and he mechan‑ ical load o e imposed by he en ila o . T ial egis a ion The ial was egis e ed in ClinicalT ials.go (iden i ie NCT03041428, Regis a ion da e: 2nd Feb ua y 2017). © The Au ho (s) 2021. 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Open Access *Co espondence: la @c i ‑lab.o g 1 Unidad de Cuidados In ensi os Ca diológicos, Hospi al Uni e si a io Cen al de As u ias, A da de Roma s/n, 33011 O iedo, Spain Full lis o au ho in o ma ion is a ailable a he end o he a icle Page 2 o 10 Amado‑Rod ígueze al. Ann. In ensi e Ca e (2021) 11:132 Backg ound Dis ibu ion o idal olume (V ) wi hin lung pa en- chyma de e mines he egional dis ibu ion o o ces expe ienced by he issue. When end-inspi a o y s e ch is high o unc ional esidual capaci y is low, leading o ec ui men /de- ec ui men phenomena, excessi e mechanical loads may p omo e issue damage and in lamma ion [1]. In pa ien s wi h he acu e espi - a o y dis ess synd ome (ARDS), en ila o -associa ed lung inju y (VALI) con ibu es o lung in lamma ion and is one majo de e minan o ou comes [2]. Cal ee e  al. iden i ied wo ARDS subpheno ypes ha may bene i om di e en en ila o y app oaches, acco d- ing o hei p oin lamma o y p o ile [3]. In spi e o di e en pa hophysiological mechanisms, al eola looding caused by hyd os a ic mechanisms in pa ien s wi h ca diogenic pulmona y oedema (CPE) may p oduce simila espi a o y sys em mechanics o hose obse ed in pa ien s wi h ARDS [4, 5]. A ecen epo illus a es ha pa ien s wi h conges i e hea ailu e a e exposed o d i ing and pla eau p essu es simila o hose wi h ARDS [6]. Howe e , he e ec s o his mechanical load on egional in lamma ion in pa ien s wi h CPE, in which he in lamma o y esponse may no be so ac i a ed as in ARDS, ha e no been s udied. Reduced idal olume is he mains ay o he en ila- o y managemen o ARDS [7], whe e dec eases in d i - ing p essu es ha e been ela ed o lowe isk o dea h, wi h he lowe h eshold o his bene i s ill unclea . Low idal olumes may dec ease al eola en ila ion, inc easing CO2 le els, and p oduce a elec asis and pa ien - en ila o dyssynch onies [8]. Se e al au ho s ha e p oposed he use o ul a-low idal olume s a - egies wi h idal olumes o 3 ml/kg, p edic ed body weigh (PBW) [9, 10] and ex aco po eal gas exchange o emo e CO2 and possibly imp o e oxygena ion [11]. Veno- enous ex aco po eal memb ane oxygena ion [9] pe mi s his en ila o y s a egy and can lead o be e ou comes in pa ien s wi h e y se e e ARDS [10, 12]. Pa ien s wi h CPE due o se e e en icula dys unc- ion may equi e ex aco po eal ca diopulmona y sup- po wi h eno-a e ial ECMO (V–A ECMO) [13] and may also bene i om ul a-low idal olume s a egies, assuming a simila espi a o y mechanics and isk o VALI as ARDS pa ien s do, due o al eola looding. We conduc ed a p ospec i e s udy aimed o e alu- a e changes in lung in lamma ion in esponse o an ul a-low idal olume s a egy wi h idal olume o 3ml/kg PBW in pa ien s wi h CPE who we e on V–A ECMO. Ma e ials andme hods S udy design This single-cen e, p ospec i e, andomized, c oss- o e ial was egis e ed in Clinical ials.go (iden i ie NCT03041428) and pe o med acco ding o CONSORT s a emen (CONSORT checklis a ailable as Addi ional ile1). All p ocedu es pe o med we e in acco dance wi h he e hical s anda ds o he ins i u ional and/o na ional esea ch commi ee (Comi é de É ica de la In es igación del P incipado de As u ias, REF 22/17) and wi h he 1964 Helsinki Decla a ion and i s la e amendmen s. In o med consen was ob ained om each pa ien s’ nex o kin. Pa ien s F om Feb ua y 2017 o Decembe 2018, all mechanically en ila ed pa ien s ecei ing V–A ECMO in he Ca - diac In ensi e Ca e Uni a Hospi al Uni e si a io Cen- al de As u ias we e sc eened. Inclusion c i e ia, o he han mechanical en ila ion and V–A ECMO suppo , we e: ca diogenic shock (de ined as sys emic hypope - usion wi h sys olic blood p essu e below 90mmHg in spi e o luid esusci a ion and ino opes, e idence o dis an o gan ailu e—de ined as O gan-Speci ic SOFA sco e ≥ 2 [14]—and/o ca diac index < 2.2 l/min/m2, and co esponding o S ages C o D in he SCAI con- sensus de ini ion [15]) and CPE (de ined as impai ed gas exchange wi h a PaO2/FiO2 lowe han 300, bila e al in il a es in ches X- ay wi h pulmona y capilla y wedge p essu es (PCP) > 18 mmHg and/o echoca diog aphic signs o conges i e hea ailu e). Exclusion c i e ia we e age < 18-yea , immunosupp ession, his o y o ch onic espi a o y diseases, known o suspec ed acu e lung inju y om o he causes (pneumonia, a elec asis, mas- si e pleu al e usion), haemodynamic ins abili y e ac- o y o he apy, do-no esusci a e o de s o a e minal condi ion. In aao ic balloon pump was inse ed ia emo al a e y in all he cases [16]. Pa ien s we e ollowed up o hospi al discha ge. Ou comes The p ima y endpoin was he b onchoal eola la age luid (BALF) in e leukin (IL)-6 concen a ion a e each en ila o y s a egy. Addi ionally, a se o in lamma o y cy okines we e de e mined in he ob ained samples. Keywo ds: Ex aco po eal memb ane oxygena ion, Ven ila o ‑induced lung inju y, Mechanical en ila ion, Pulmona y oedema, Respi a o y mechanics Page 3 o 10 Amado‑Rod ígueze al. Ann. In ensi e Ca e (2021) 11:132 Seconda y ou comes we e he impac o he en ila o y s a egy on espi a o y mechanics and on haemodynamic a iables. Planned pos hoc analyses included com- pa isons o subg oups acco ding o d i ing o pla eau p essu es o IL-6 le els du ing con en ional p o ec i e en ila ion (6ml/kg PBW). In e en ion andmeasu emen s PBW was calcula ed as 45.5 + [0.91 (cen ime es o heigh − 152.4)] o emales; and 50 + [0.91 (cen ime es o heigh − 152.4)] o males. Be o e inclusion, pa ien s we e en ila ed wi h idal olumes o 6–8ml/kg PBW and pla eau p essu es below 28 cmH2O. A e inclusion, pa ien s we e en ila ed using a cons an - low, olume- con olled mode o 24h wi h a idal olume o 6 o 3ml/ kg PBW, applied in andom o de . A e he i s 24h in he ini ial s a egy, idal olume was modi ied by 1ml/kg PBW pe hou un il i achie ed he a ge o he consec- u i e en ila o y s a egy. Closed en elopes con aining he en ila ion sequence we e gene a ed be o e he s a o he en olmen pe iod, using a andom, compu e -gen- e a ed lis . All o he en ila o y and ECMO se ings we e selec ed by he physician in cha ge. No o he en ila o y s a egies (p one posi ion, ec ui men manoeu e s) o inhaled asodila o s we e allowed du ing he ial. Spon- aneous b ea hing du ing he s udy pe iod was a oided using muscle elaxan s o deep seda ion. P opo ol was used as seda i e in all he cases. A e 24h on each en ila o y s a egy, gas exchange and en ila o y and haemodynamic measu emen s we e collec ed. A e ial blood gases we e d awn om an a e- ial line placed in he uppe limb con ala e al o he ECMO a e ial inse ion. Respi a o y sys em compliance, end-expi a o y lung olume (EELV) and lung s ain (es i- ma ed as he a io be ween V and EELV) we e calcula ed as p e iously desc ibed [17]. In pa ien s wi h a Swan– Ganz ca he e , ca diac ou pu and pulmona y p essu es we e also measu ed. B onchoal eola la age was pe o med a e 24h on each s a egy as p e iously desc ibed [17]. A ca he e was inse ed in o he endo acheal ube beyond he dis al end o he ube and placed in wedge posi ion. The lung was la aged wi h up o h ee 20-ml aliquo s o s e ile saline. The olume collec ed was il e ed h ough s e ile gauze, cen i uged a 1500 pm o 15min o emo e cells, and he supe na an s we e il e ed h ough 70 μm s ain- e s and hen s o ed a − 80°C o subsequen analysis. Concen a ions o in e e on (IFN)-α2, IFN-γ, IL-1β, IL-6, monocy e chemoa ac an p o ein 1 (MCP-1), umou nec osis ac o (TNF)-α, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23 and IL-33 in BALF we e measu ed in all samples using a mul iplexed, low-cy ome y assay (LegendPLEX assay panel, BioLegend, USA), ollowing he manu ac u e ’s ins uc ions. Pa ien s we e classi ied as hype in lamed o non- hype in lamed based on IL-6 concen a ion on BALF du ing en ila ion wi h 6ml/kg PBW. Using da a om a p e ious s udy [17], an op imal cu -o poin o 680pg/ml o disc imina e be ween pa ien s wi h and wi hou en- ila ion- ela ed lung in lamma ion was iden i ied (Addi- ional ile2: Figu e S1A, B). Sample size calcula ion Based on he BALF IL-6 le els measu ed in a p e ious s udy in pa ien s wi h ARDS and low s ain [17], he s udy was designed o de ec a di e ence o 100pg/ml in he change o IL-6 le els (ma ched pai s), wi h a s anda d de ia ion o 100pg/ml. Wi h 95% powe and a 5% ype-I e o , he equi ed sample size was 17 pa ien s. S a is ical analysis All da a a e shown as median (in e qua ile ange). Da a ob ained du ing en ila ion wi h 6 and 3 ml/kg PBW we e compa ed using a Wilcoxon es o pai ed da a. Cy okine concen a ions we e log- ans o med o inde- penden compa isons. Di e ences in cy okines be ween subg oups we e s udied using an analysis o co a iance (ANCOVA) o a oid bias due o eg ession o he mean [18]. Co ela ions among cy okines we e calcula ed using Pea son’s co ela ion coe icien s. When app op i- a e, hese co ela ion coe icien s we e compa ed using he Fishe ’s - o-Z ans o ma ion. A hie a chical clus- e ing algo i hm was applied o he Euclidean dis ances be ween hese co ela ions o iden i y g oups o immune media o s wi h simila beha iou . All p alues we e epo ed, and hose below 0.05 conside ed signi ican . All he analyses we e pe o med in R ( e sion 3.5.1). Resul s Twen y pa ien s me inclusion c i e ia; 3 we e excluded, lea ing 17 pa ien s ec ui ed o analysis (Fig.1). Median age was 59 (53–65) yea s; 12 (70%) we e male. ECMO was implan ed on he i s 48h a e mee ing shock c i- e ia in all he pa ien s. Median ime om onse o V–A ECMO o s udy inclusion was 1 (0–1) day. Baseline and clinical cha ac e is ics o all pa ien s, including causes o ca diogenic shock, acco ding o ini ial en ila o y s a - egy a e shown in Addi ional ile2: TableS1. ECMO a e- ial inse ion was cen al in 11 cases and pe iphe al in he emaining 6. None o he included pa ien s had an open ches . Du ing he s udy, all pa ien s ecei ed asoac i e suppo wi h no ad enaline and dobu amine. Ten pa ien s we e andomized o ini ial en ila ion wi h V 6ml/kg PBW and he emaining 7 wi h 3ml/kg PBW. All pa ien s we e ecei ing neu omuscula blocking Page 4 o 10 Amado‑Rod ígueze al. Ann. In ensi e Ca e (2021) 11:132 agen s. Absence o spon aneous b ea hing was con i med by inspec ion o pa ien s’ ches and en ila o wa e o ms du ing he s udy pe iod. Two pa ien s equi ed enal eplacemen he apy du ing he s udy. The e we e no de ia ions om he en ila o y p o ocol, and c oss-o e was pe o med in all he pa ien s. Ex aco po eal sup- po was main ained o 8 (7–14) days, and mechanical en ila ion o 15 (8–25) days. ICU and hospi al mo ali y a es we e 35% and 41%, espec i ely. Respi a o y andci cula o y e ec s o ul a‑low idal olume en ila ion Ul a-low idal olume en ila ion was well ole a ed by all pa ien s. SOFA sco es we e no modi ied by he en- ila o y s a egy (7.5 [6–9] s. 7 [5–11] wi h V o 6 and 3ml/kg PBW, espec i ely, p = 0.56). Fluid balance, u ine ou pu , enal unc ion and haemoglobin alues we e no signi ican ly di e en be ween en ila o y s a egies (Table1). Ven ila ion wi h 3ml/kg PBW yielded lowe pla eau and d i ing p essu es (Table1). Respi a o y a e was no modi ied. The e was a small, bu signi ican , inc ease in posi i e end-expi a o y p essu e (PEEP) and a signi ican dec ease in compliance wi h ul a-low idal olume en i- la ion. Au o-PEEP was no de ec ed in any pa ien . EELV was measu ed wi h bo h en ila o y se ings in 9 pa ien s, dec easing wi h ul a-low idal olume en ila ion. Di - e ences in s ain be ween s a egies we e negligible. The e we e no signi ican di e ences in PaO2 o PaCO2 be ween s a egies, wi h a signi ican bu no clinically ele an dec ease in pH. Oxygen ac ion in en ila o and ECMO memb ane we e also simila be ween he en ila o y se ings. Sweep gas low was inc eased du - ing ul a-low idal olume en ila ion. The e we e no sig- ni ican e ec s o ul a-low idal olume en ila ion on haemodynamic pa ame e s (Addi ional ile2: TableS2). Lung in lamma ion du ingul a‑low idal olume en ila ion O e all, concen a ion o cy okines in BALF was no modi ied by he en ila o y se ings (Addi ional ile 2: Figu e S2). Figu e2 shows he box plo s and indi idual alues o IL6 and IL8 o each en ila o y s a egy. Clus- e analysis o he di e ences in cy okine le els be ween en ila ion wi h 6 and 3ml/kg PBW e ealed ou g oups Fig. 1 CONSORT low diag am o he s udy. COPD ch onic obs uc i e pulmona y disease, BAL b onchoal eola la age Table 1 Respi a o y mechanics and gas exchange du ing en ila ion wi h idal olumes o 6 and 3 ml/kg PBW Baseline kidney unc ion and haemoglobin alues a e also depic ed. Da a a e exp essed as median (in e qua ile ange) PEEP posi i e end‑expi a o y p essu e, RRT : enal eplacemen he apy, EELV: end‑expi a o y lung olume. EELV and s ain we e measu ed in only nine pa ien s 6ml/kg PBW 3ml/kg PBW p Tidal olume (ml) 400 (378–443) 215 (190–225) Respi a o y a e (min−1) 12 (10–13) 12 (10–14) 0.096 Pla eau p essu e (cmH2O) 18 (17–20) 15 (13–17) 0.003 PEEP (cmH2O) 6 (5–7) 8 (6–8) 0.034 D i ing p essu e (cmH2O) 12 (10–14) 7 (6–9) 0.003 Respi a o y sys em com‑ pliance (ml/cmH2O) 35 (29–40) 27 (23–32) 0.013 EELV (ml) 904 (664–1043) 538 (494–827) 0.024 S ain 0.50 (0.43–0.59) 0.38 (0.24–0.50) 0.529 PaO2 (mmHg) 100 (86–111) 97 (80–120) 0.782 PaCO2 (mmHg) 36 (32–37) 39 (36–44) 0.074 pH 7.45 (7.43–7.50) 7.40 (7.34–7.45) 0.027 FiO20.40 (0.35–0.50) 0.40 (0.35–0.50) 0.635 FECMOO20.65 (0.60–0.80) 0.70 (0.60–0.80) 0.283 ECMO blood low (l/min) 3.1 (2.9–3.7) 3.3 (2.9–3.5) 0.327 ECMO sweep low (l/min) 3.0 (2.38–5.00) 5.0 (3.5–6.5) 0.004 Fluid balance (l) 0.736 (‑0.19–2.34) 1.725 (508–3.165) 0.377 U ine ou pu (l) 1.57 (0.85–2.88) 1.18 (0.88–2.16) 0.206 C ea inine (mg/dl) 1.12 (0.80–1.41) 1.22 (0.79–2.11) 0.804 U ea (mg/dl) 58 (33.5–77.5) 57 (40.25–79.75) 0.974 Use o RRT (n) 2 2 1 Haemoglobin (g/dl) 9.1 (8.85–10.05) 8.8 (8.47–9.47) 0.083 Page 5 o 10 Amado‑Rod ígueze al. Ann. In ensi e Ca e (2021) 11:132 o media o s wi h simila beha iou (Addi ional ile2: Figu e S3). Se e al explo a o y analyses we e pe o med o be e cha ac e ize he in lamma o y esponse o en ila ion. Fi s , changes in in lamma o y media o s in pa ien s wi h high and low d i ing p essu es du ing 6 ml/kg PBW en ila ion (using a h eshold o 15 cmH2O) we e compa ed. No signi ican di e ences we e obse ed in any o he analysed media o s be ween bo h g oups (Addi ional ile2: Figu e S4). The use o median d i - ing p essu e (13 cmH2O) as h eshold did no yield any signi ican di e ences (da a no shown). Simila ly, he e we e no di e ences in hese analy es be ween pa ien s wi h high and low pla eau p essu es wi h he same en- ila o y s a egy (using he median alue, 19 cmH2O, as h eshold, Addi ional ile2: Figu e S5). Ele en ou o 17 pa ien s we e classi ied as hype in- lamed. The p opo ion o hype in lamed pa ien s was simila in hose who we e en ila ed i s wi h 6ml/kg and hose ecei ing a idal olume o 3ml/kg PBW (5 ou o 11 and 3 ou o 6, espec i ely, Fishe es p = 1). Plo ing BALF IL-6 concen a ion agains he s udy day a gued agains a educ ion o his media o o e ime, sugges ing ha he obse ed di e ences a e caused by he in lamma o y p o ile and en ila o y s a egy, bu no he cou se o he disease i sel (Addi ional ile2: Figu e S6). The e we e no di e ences in age, sex and se e - i y be ween hype in lamed and non-hype in lamed pa ien s (Table2). The e we e no di e ences in en i- la o y pa ame e s, espi a o y mechanics o haemo- dynamic pa ame e s be ween hype in lamed and non-hype in lamed pa ien s (Table2, Addi ional ile2: Fig. 2 Concen a ion o IL‑6 and IL‑8 in b onchoal eola la age luid du ing en ila ion wi h a idal olume o 6 ml/kg PBW o 3 ml/ kg PBW. Do s and dashed lines show he indi idual alues o each pa ien . Y‑axis is aced using a loga i hmic scale. The lowe and uppe hinges co espond o he i s and hi d qua iles ( he 25 h and 75 h pe cen iles). The uppe and lowe whiske s ex end om he hinge o he la ges o smalles alue no u he han 1.5 imes he in e qua ile ange om he hinge. Indi idual alues a e shown as poin s. Values o a gi en pa ien a e connec ed by dashed lines. P alues we e ob ained using a Wilcoxon es o pai ed da a. PBW p edic ed body weigh , IL in e leukin Table 2 Compa ison be ween pa ien s wi h and wi hou a hype in lamma o y sub ype (de ined as a IL‑6 le el in b onchoal eola la age luid abo e 680 pg/ml du ing en ila ion wi h a idal olume o 6 ml/kg) Da a a e exp essed as median (in e qua ile ange) SAPS3: Simpli ied Acu e Physiology Sco e III, DP: d i ing p essu e, PBW: p edic ed body weigh , RR: espi a o y a e, HR: hea a e, MAP: mean sys emic a e ial p essu e Hype in lamed Non‑hype in lamed P Age 58 (54–63) 62 (47–66) 0.840 Sex 7 male/4 emale 5 male/1 emale 0.768 SAPS3 58 (53–74) 57 (62–69) 0.725 Days on ECMO 9 (6–15) 8 (7–9) 0.880 Days o mechanical en ila ion 14 (8–29) 18 (10–20) 0.960 Mo ali y 6 (55%) 5 (83%) 0.333 DP (cmH2O) a 6 ml/ kg PBW 10 (10–11) 13 (12–14) 0.189 DP (cmH2O) a 3 ml/ kg PBW 7 (7–9) 7 (6–9) 1 RR (min−1) a 6 ml/kg PBW 12 (10–13) 12 (11–14) 0.473 RR (min−1) a 3 ml/kg PBW 11 (10–14) 13 (11–14) 0.444 PaO2 (mmHg) a 6 ml/ kg PBW 104 (90–117) 92 (75–101) 0.264 PaO2 (mmHg) a 3 ml/ kg PBW 105 (83–170) 83 (72–110) 0.350 pH a 6 ml/kg PBW 7.45 (7.43–7.50) 7.45 (7.43–7.48) 0.827 pH a 3 ml/kg PBW 7.40 (7.34–7.45) 7.40 (7.37–7.45) 0.879 HR (min−1) a 6 ml/kg PBW 87 (79–98) 86 (84–88) 0.664 HR (min−1) a 3 ml/kg PBW 88 (76–91) 93 (92–95) 0.664 PCP (mmHg) a 6 ml/ kg PBW 14 (12–19) 17 (16–18) 0.694 PCP (mmHg) a 3 ml/ kg PBW 18 (12–23) 14 (13–14) 0.793 MAP (mmHg) a 6 ml/ kg PBW 76 (71–84) 74 (66–83) 0.828 MAP (mmHg) a 3 ml/ kg PBW 74 (68–90) 70 (68–75) 0.545 Fluid balance a 6 ml/ kg (l) 1.50 (‑0.59–3.60) 0.46 (0.04–1.60) 0.660 Fluid balance a 3 ml/ kg (l) 2.08 (0.79–4.34) 1.14 (0.61–1.63) 0.462 Page 6 o 10 Amado‑Rod ígueze al. Ann. In ensi e Ca e (2021) 11:132 TableS3). Fluid balance was compa ed be ween in lam- ma o y p o iles and en ila o y s a egies, wi h no sig- ni ican di e ences being ound (Table2). Changes in d i ing p essu e a e dec easing idal olumes om 6 o 3ml/kg PBW we e 3 (3–4.5) and 6 (4–7) cmH2O in hype in lamed and non-hype in lamed pa ien s, espec i ely (p = 0.65 in he ANCOVA). The di e - ence in cy okine le els be ween en ila ion wi h 6 and 3 ml/kg PBW was compa ed be ween hype in- lamed and non-hype in lamed pa ien s. As shown in Fig.3, he e we e signi ican di e ences be ween hese g oups ega ding he change in IL-6 and IL-8, as hese media o s dec eased a e educing idal olume only in hype in lamed pa ien s, and inc eased in he non- hype in lamed g oup. The e was a end o simila di - e ences in IL-17A and MCP-1 (Addi ional ile2: Figu e S7). O e all, changes in he in lamma o y media o s we e no signi ican ly co ela ed wi h he change in d i - ing p essu e (Addi ional ile 2: Figu e S8). Howe e , when he baseline in lamma o y esponse was aken in o accoun , hype in lamed and non-hype in lamed pa ien s exhibi ed a signi ican ly di e en pa e n. In hype in lamed pa ien s, he educ ion in d i ing p es- su e achie ed by lowe ing idal olume was accom- panied by a linea dec ease in IL-6, IL-8 (Fig.4) and a g oup o media o s (IFN-γ, IL-1β, IL-12p70; Addi ional Fig. 3 Change in IL‑6 and IL‑8 om en ila ion wi h 6 ml/kg p edic ed body weigh (PBW) o 3 ml/kg PBW in hype in lamed and non‑hype in lamed pa ien s (de ined using a h eshold in IL‑6 le els du ing en ila ion wi h 6 ml/kg PBW o 680 pg/ml). The lowe and uppe hinges co espond o he i s and hi d qua iles ( he 25 h and 75 h pe cen iles). The uppe and lowe whiske s ex end om he hinge o he la ges o smalles alue no u he han 1.5 imes he in e qua ile ange om he hinge. Indi idual alues a e shown as poin s. P alues we e ob ained using an analysis o co a iance (ANCOVA) es . IL in e leukin Fig. 4 Co ela ion be ween he change in IL‑6 and IL‑8 BALF le els om en ila ion wi h 6 ml/kg p edic ed body weigh (PBW) o 3 ml/kg PBW and he co esponding change in d i ing p essu e in hype in lamed and non‑hype in lamed pa ien s (de ined using a h eshold in IL‑6 le els du ing en ila ion wi h 6 ml/kg PBW o 680 pg/ml). No e ha he x‑axis ep esen s he change in d i ing p essu e when idal olume is dec eased, which is mainly de ined by compliance o he espi a o y sys em. IL in e leukin. P alues co espond o he compa ison be ween he wo co ela ion coe icien s Page 7 o 10 Amado‑Rod ígueze al. Ann. In ensi e Ca e (2021) 11:132 ile 2: Figu e S9). Con e sely, in non-hype in lamed pa ien s, he educ ion in d i ing p essu e wi h V o 3ml/kg PBW was co ela ed wi h an inc ease in hese g oup o media o s. Discussion Ou esul s show ha ul a-low idal olume en ila ion wi h 3ml/kg PBW o 24h in pa ien s equi ing V–A ECMO due o ca diogenic shock was associa ed wi h a educ ion in lung mechanical load bu no wi h signi i- can changes in he local in lamma o y esponse. In pos hoc analyses, we ound ha pa ien s wi h a p oin lamma- o y esponse du ing con en ional en ila ion (V = 6ml/ kg, PBW) showed lowe cy okines le els, p opo ional o he dec ease in d i ing p essu e achie ed wi h ul a- low idal olume en ila ion. Con e sely, hose wi hou a p oin lamma o y p o ile, showed he opposi e beha iou (Fig.4, Addi ional ile2: Figu e S8). Low idal olume en ila ion is he mains ay o sup- po i e ea men in pa ien s wi h ARDS [19], and could minimize lung damage in o gan dono s [20], be o e lung ansplan a ion [21] o du ing majo su ge y [22]. Ul ap o ec i e en ila ion in his se ing, suppo ed by CO2 emo al o ECMO, may help o educe al eola in lamma ion [23]. Howe e , he ex ension o his ec- ommenda ion o o he diseases is no s aigh o wa d. A ecen ial demons a ed he sa e y o mode a e olumes in pa ien s wi h no mal lungs [24]. In he special case o CPE, idal olumes o 6–10ml/kg PBW ha e been ec- ommended [25], based on a e ospec i e epo showing an inc ease in mo ali y wi h idal olumes abo e 9.3ml/ kg PBW [26]. T adi ional unde s anding o he S a ling’s mecha- nisms in ol ed in he de elopmen o CPE a ional- ized his synd ome as non-in lamma o y [27]. Howe e , he e a e se e al mechanisms ha could p edispose lungs wi h CPE o inju y. Fi s , he e is inc easing e i- dence o p oin lamma o y esponses in hese pa ien s. Inc eased hyd os a ic p essu es may enhance in lam- ma ion [28], and pa ien s wi h ca diogenic pulmona y oedema show a p oin lamma o y monocy e p o ile [29]. Mo eo e , he e is e idence ha ca diogenic shock may be associa ed wi h al eolocapilla y ba ie dam- age and in lamma ion [30], wi h an inc ease in BALF cy okine concen a ions abo e he low le els epo ed in ca diogenic pulmona y oedema [31]. Second, he obse ed educ ion in EELV caused by al eola lood- ing may con ibu e o a he e ogeneous dis ibu ion o he en ila ion wi h a baby-lung e ec [32], simila o ha obse ed in pa ien s wi h ARDS. In his se ing, mechanical en ila ion wi h con en ional idal olumes inc eases lung s ain and egional o e dis ension in ae a ed a eas, acili a ing hede elopmen o VALI. In addi ion, changes in idal olume may a ec en icu- la p e and a e loads hus modi ying na i e ca diac ou pu [33]. Con e sely, educ ion o idal olumes leads o u he lung collapse, as shown by he low EELV du ing en ila ion wi h a idal olume o 3ml/kg PBW, po en ially leading o u he impai men s in es- pi a o y mechanics, gas exchange and haemodynamic [34]. ECMO may help o main ain no mal PaCO2 by adjus ing sweep gas low. O no e, PEEP le els (which we e le a clinicians’ disc e ion pe p o ocol) we e highe du ing en ila ion wi h ul alow idal olumes. Al hough he impac o his di e ence in PEEP on he obse ed esul s canno be isola ed, keeping PEEP con- s an could ha e led o e en lowe EELVs and an e en highe isk o inju y due o low olume en ila ion. ARDS subpheno ypes wi h di e en in lamma o y esponse and clinical ou comes [3] poin o he necessi y o indi idualized app oaches. The e we e no signi ican di e ences in clinical da a be ween hype in lamed and non-hype in lamed pa ien s, highligh ing he need o speci ic s a egies o bioma ke s in c i ically ill pa ien s ha could help o cha ac e ize hese sub ypes [35]. O he au ho s ha e sugges ed ha , in addi ion o compliance, dead space measu emen s could help o iden i y hose pa ien s in which ex aco po eal CO2 emo al could lead o signi ican dec eases in d i ing p essu es [36]. How- e e , bedside measu emen s o es ima ions o dead space in he p esence o an es ablished CO2 emo al de ice may be di icul o ob ain, and hei impac on hype in lamed o non-hype in lamed pa ien s has no been de e mined. We measu ed a se o immune media o s o gi e a b oad iew o he in lamma o y esponse in hese pa ien s. Howe e , we canno disca d o he speci ic bio- ma ke s would yield di e en esul s, as he lung bio- logical esponse o en ila ion includes a wide ange o cellula pa hways wi h speci ic ma ke s om epi he- lial/endo helial inju y o in lamma ion, apop osis o ma ix emodelling [37]. Ra he han iden i ying speci ic molecula mechanisms, ou esul s illus a e he di - e en ial esponse o en ila ion. CPE may equi e di - e en en ila o y adjus men s depending no only on espi a o y mechanics bu also on baseline biological s a e. In his s udy, hype in lamed pa ien s showed sig- ni ican ly lowe cy okine le els when placed on V 3ml/ kg PBW, compa ed o he cy okine le els ob ained on V 6ml/kg PBW, sugges ing a enua ed VALI when he ul a-low idal olume s a egy was applied. Con e sely, non-hype in lamed pa ien s exhibi ed highe p oin- lamma o y media o s’ le els du ing en ila ion wi h V 3 ml/kg PBW. These changes we e co ela ed wi h he magni ude o dec ease o anspulmona y p essu e, and could be explained by he p edominance o o e d- is ension o a elec auma. Howe e , i is unclea i hese Page 8 o 10 Amado‑Rod ígueze al. Ann. In ensi e Ca e (2021) 11:132 media o s play a pa hogene ic ole o a e bioma ke s o ongoing epai [38]. O no e, in bo h hype in lamed and non-hype in lamed pa ien s none o he haemodynamic pa ame e s we e signi ican ly modi ied by he change in idal olumes. Collec i ely, hese esul s sugges he exis ence o unde lying, in lamma ion-d i en sub ypes ha de e mine he esponse o en ila ion. The ansla ion o hese hypo hesis-gene a ing ind- ings may ha e a ele an clinical impac , o ei he apply o a oid ul a-low idal olume en ila ion depending on he in lamma o y p o ile. Howe e , u he s udies add essing his hypo hesis a e equi ed o op imize and s a i y clinical managemen . Ou s udy has se e al limi a ions. Fi s , he c osso e design is p one o ca y-o e e ec s. The ial was done wi hou a washou pe iod o minimize he impac o he e olu ion o he disease on ou measu emen s. Howe e , i has been shown ha wo o mo e hou s o en ila ion cause a change in he in lamma o y p o ile o he lung [39] and we did no ind a di e ence be ween pa ien s wi h di e en ini ial en ila o y s a egy. This c osso e design was chosen o achie e he a ge sample size in a easonable pe iod, as ec ui men o la ge samples o ECMO pa ien s may be a challenge [40], and he pu pose o his s udy was explo a o y. Second, no baseline meas- u emen s we e pe o med o a oid an addi ional in asi e p ocedu e such as he b onchoal eola la age. How- e e , hal o he pa ien s we e en ila ed i s wi h 6ml/ kg PBW (which could be conside ed baseline condi ions) and we obse ed no e ec caused by he o de o appli- ca ion o idal olumes. Thi d, he obse ed e ec size o idal olume in BALF IL-6 le els and i s a iabili y we e highe han he expec ed alues used o sample size calcula ion. The e o e, he s udy may be unde powe ed o de ec a ele an change in IL-6 (o o he media o s) in an unselec ed popula ion. Fou h, he he e ogenous beha iou o pa ien s wi h CPE equi es la ge sample sizes o achie e enough s a is ical powe o demons a e a di e ence in pa ien -cen ed ou comes such as mo - ali y. We did no obse e a signi ican change in SOFA sco es wi h en ila ion. Howe e , SOFA sco es ha e a poo pe o mance o p edic mo ali y in V–A ECMO pa ien s, unless da a on igh en icle unc ion a e added o he sco e [41]. Ra he , ou esul s may help o iden i y a subg oup o pa ien s which could bene i om a educ- ion o idal olume, hus acili a ing he inclusion o an en iched popula ion in clinical ials. Conclusion Collec i ely, ou indings sugges he exis ence o VALI in pa ien s wi h CPE e en hough ai way p essu es we e below he cu en ly accep ed sa e y h esholds. In hese se ings, ul a-low idal olume en ila ion is easible. Pos hoc analyses sugges ha a subg oup o pa ien s wi h hype in lamed lungs may bene i om an ul ap o ec i e app oach o en ila ion, acili a ed by ex aco po eal suppo . Ou indings highligh he need o app op ia e bioma ke s ha may allow clini- cians o an icipa e he esponse o a speci ic he apeu- ic app oach [42]. Abb e ia ions ANCOVA: Analysis o co a iance; ARDS: Acu e espi a o y dis ess synd ome; BALF: B onchoal eola la age luid; CPE: Ca diogenic pulmona y oedema; ECMO: Ex aco po eal memb ane oxygena ion; EELV: End‑expi a o y lung olume; FRC: Func ional esidual capaci y; ICU: In ensi e ca e uni ; IFN: In e ‑ e on; IL: In e leukin; MCP: Monocy e chemoa ac an p o ein; PEEP: Posi i e end‑expi a o y p essu e; TNF: Tumou nec osis ac o ; V–A ECMO: Venous–a e‑ ial ex aco po eal memb ane oxygena ion; VALI: Ven ila o ‑associa ed lung inju y; V : Tidal olume; ‑ECMO: Veno‑ enous ex aco po eal memb ane oxygena ion. Supplemen a y In o ma ion The online e sion con ains supplemen a y ma e ial a ailable a h ps:// doi. o g/ 10. 1186/ s13613‑ 021‑ 00919‑0. Addi ional ile1. Online supplemen a y ma e ial. Addi ional ile2: TableS1. Online supplemen a y esul s. Acknowledgemen s The au ho s hank all he s a o he Ca diac ICU a Hospi al Uni e si a io Cen al de As u ias o he suppo p o ided du ing his s udy. P io p esen a ion The p elimina y esul s o his s udy we e p esen ed a he 5 h In e na ional ARDS con e ence, Be lin, June 2019. Au ho s’ con ibu ions LAR, CBM and GMA designed he s udy. LAR, CBM, DPR, JMC and MAG col‑ lec ed pa ien da a and samples. LAR, ILA, RAA, PMV, CLM and CH quan i ied he in lamma o y media o s. LAR and GMA analysed he da a. LAR, GMA, LC and ASS discussed he esul s and pe o med addi ional analyses. The i s d a o he manusc ip was w i en by LAR and GMA, and all au ho s com‑ men ed on p e ious e sions o he manusc ip . LAR and GMA ake esponsi‑ bili y o he con en o he manusc ip and he accu acy o he epo ed da a. All au ho s ead and app o ed he inal manusc ip . Funding Suppo ed by Cen o de In es igación Biomédica en Red‑En e medades Respi a o ias (CB17/06/00021, and Imp o emen and mobili y P og amme, Mad id, Spain). LAR was he ecipien o a g an om Ins i u o de Salud Ca los III (P og ama Río Ho ega, CM16/00128). None o he unding sou ces had any ole in he design, analysis and epo o his s udy. A ailabili y o da a and ma e ials All da ase s unde lying he manusc ip esul s a e a ailable upon eques o he co esponding au ho (LAR). All o he indi idual pa icipan da a collec ed du ing he ial, in o med consen o ms, s udy p o ocol, s a is ical analysis plan, analy ic R code and aw da a, a e a ailable unde easonable eques , and a e de‑iden i ica ion. Page 9 o 10 Amado‑Rod ígueze al. Ann. In ensi e Ca e (2021) 11:132 Decla a ions E hics app o al and consen o pa icipa e The local Clinical Resea ch E hics Commi ee e iewed and app o ed he p o ocol ( e e ence 22/17). In o med consen was ob ained o each pa ien ’s nex o kin. Consen o publica ion No applicable. Compe ing in e es s ASS is a consul an o Bax e and Xenios. None o he emaining au ho s ha e con lic s o in e es o disclose. 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