How respiratory system mechanics may help in minimising ventilator-induced lung injury in ARDS patients

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1 Eur Respir J 2003; 22: Suppl. 42, 15s 21s DOI: / Prited i UK all rights reserved Copyright #ERS Jourals Ltd 2003 Europea Respiratory Joural ISSN How respiratory system mechaics may help i miimisig vetilator-iduced lug ijury i ARDS patiets P.P. Terragi, G.L. Rosboch, A. Lisi, A.G. Viale, V.M. Raieri How respiratory system mechaics may help i miimisig vetilator-iduced lug ijury i ARDS patiets. P.P. Terragi, G.L. Rosboch, A. Lisi, A.G. Viale, V.M. Raieri. #ERS Jourals Ltd ABSTRACT: The mai supportive therapy i acute respiratory distress sydrome patiets is mechaical vetilatio. As with ay therapy, mechaical vetilatio has sideeffects, ad may iduce lug ijury (vetilator-iduced lug ijury (VILI)/vetilatorassociated lug ijury). The mechaical factors resposible for VILI are thought to be related to tidal recruitmet/derecruitmet of previously collapsed alveoli ad/or pulmoary overdistesio. The volume/pressure (V/P) curve of the respiratory system i patiets as well as i aimal models of acute lug ijury (ALI) has a characteristic sigmoid shape, with a lower iflectio poit (LIP) correspodig to the pressure/ed-expiratory volume required to iitiate recruitmet of collapsed alveoli, ad a upper iflectio poit (UIP) correspodig to the pressure/ed ispiratory volume at which alveolar overdistesio occurs. "Protective" vetilatory approaches have therefore set out to miimise mechaical ijury by usig the V/P curve to idividualise positive ed-expiratory pressure (PEEP) (PEEP above the LIP) ad tidal volume (by settig ed-ispiratory V/P below the UIP) sice a large umber of experimetal studies correlate P/V curves to histological ad biological maifestatios of VILI ad two radomised trials showed that protective vetilatory strategy idividually tailored to the P/V curve miimised pulmoary ad systemic iflammatio ad decreased mortality i patiets with ALI. However, despite the fact that several studies have: 1) proposed ew techiques to perform pressure/volume curves at the bedside, 2) cofirmed that the lower iflectio poit ad upper iflectio poit correspod to computed tomography sca evidece of atelectasis ad overdistesio, ad 3) demostrated the ability of the pressure/volume curve to estimate alveolar recruitmet with positive ed-expiratory pressure, o large studies have assessed whether such measuremet ca be performed i all itesive care uits as a moitorig tool to oriet vetilator therapy. Prelimiary experimetal ad cliical studies show that the shape of the dyamic ispiratory pressure/time profile durig costat flow iflatio (stress idex), allows predictio of a vetilatory strategy that miimises the occurrece of vetilator-iduced lug ijury. Eur Respir J 2003; 22: Suppl. 42, 15s 21s. Uiversità di Torio, Dipartimeto di disciplie Medico-Chirurgiche, Sezioe di Aestesiologia e Riaimazioe, Ospedale S. Giovai Battista, Torio, Italy. Correspodece: V.M. Raieri Uiversità di Torio Dipartimeto di disciplie Medico-Chirurgiche Sezioe di Aestesiologia e Riaimazioe Ospedale S. Giovai Battista Corso Dogliotti Torio Italy Fax: marco.raieri@uito.it Keywords: Acute respiratory distress sydrome mechaical stress mechaical vetilatio respiratory mechaics stress idex vetilator-iduced lug ijury Supported by Cofiaziameto Miistero dell9istruzioe, dell9uiversità e della Ricerca. The acute respiratory distress sydrome (ARDS) is a commo disease with devastatig cliical effects. Mechaical vetilatio is the mai supportive therapy to re-establish sufficiet oxyge supply to peripheral orgas. As with ay therapy, mechaical vetilatio may expose patiets to sideeffects. Cliicias quickly recogised that mechaical vetilatio could cause alveolar rupture ad air leak, the so-called barotrauma [1]. I 1974, WEBB ad TIERNEY [2] showed that mechaical vetilatio could also be resposible of ultrastructural ijury, idepedetly of air leaks. The potetial cliical implicatio of these data was ot realised util a series of studies showed that, apart from the physical alveolar disruptio, mechaical vetilatio ca iduce further ijury to the lug by icreasig alveolar-capillary permeability through the overdistesio of the lug (volutrauma) [3] ad/ or worseig lug ijury through the tidal recruitmetderecruitmet of the collapsed alveoli (atelectrauma) [4, 5], ad lead to eve more subtle ijury maifested by the activatio of the iflammatory process (biotrauma) [6 8]. All these experimetal ad cliical data led to the cocept that all the pathophysiological mechaisms ivolved i ARDS (vetilatio-perfusio mismatch ad reduced compliace, lug oedema, atelectasis, pulmoary iflammatio) may be worseed by the mechaical stress caused by iappropriate vetilator settigs. I the early 1990s, a iteratioal cosesus coferece cocluded that both tidal overdistesio of ormal alveoli ad opeig-closig of collapsed alveoli, cotribute to a compoet of a progressive lug ijury that arises ot oly from the disease process itself, but also from the impact of the vetilator patters applied durig the course of the disease [9]. Vetilator-iduced lug ijury (VILI) was therefore defied as acute lug ijury directly iduced by mechaical vetilatio i aimal models whereas vetilatorassociated lug ijury (VALI) was defied as lug ijury that resembles ARDS ad that occurs i patiets receivig mechaical vetilatio [10, 11]. Although radomised cliical trials [8, 12, 13] have successfully demostrated that vetilatory strategy desiged to miimise overdistesio ad opeig-closig may reduce mortality i patiets with ARDS, iformatio regardig the

2 16s P.P. TERRAGNI ET AL. bio-mechaical characteristics of stress applied to the vetilated lugs are still missig. VALI is i fact determied by the dyamic ad cotiuous iteractio betwee 1) the mechaical characteristics of the lug ad 2) the vetilator settigs. The relatioship betwee these terms is coditioed by the dyamic variatios i respiratory mechaics as determied by the status ad evolutio of the pathological process ad by the cosequeces of vetilator parameters o the mechaical characteristics of the lug. Therefore cliicias have to choose tidal volume, positive ed-expiratory pressure (PEEP) ad recruitig maoeuvres assumig that the vetilator settigs are ot causig VALI but lackig a cliical tool able to idetify whether or ot the iteractio betwee the curretly used vetilator settigs ad the actual status of pulmoary mechaics is resultig i mechaical stress. The mechaical characteristics of aimal models [4, 6, 14] ad patiets [15, 16] with ARDS have bee ivestigated by the aalysis of the static pressure/volume (P/V) curve of the respiratory system. Besides this, aalysis of the P/V curve provided most of the physiological ratioale explaiig the pulmoary ijury due to VILI/VALI. The static P/V curve is i fact characterised by a lower (LIP) ad a upper (UIP) iflectio poit that are thought to represet the average critical opeig pressure above which alveolar uits start to re-ope ad the V/P values above which stretchig ad overdistesio start to occur, respectively [17]. Several studies demostrated that tidal iflatio startig below the LIP o the P/V curve leads to tidal recruitmet/derecruitmet of previously collapsed alveoli while tidal vetilatio occurrig above the UIP results i pulmoary overstretchig both leadig to a spectrum of pulmoary ad systemic lesios such as air leaks [18], alteratios i lug fluid balace [3], icreases i edothelial ad epithelial permeability [19, 20], severe tissue damage [4], ad pulmoary [6] ad systemic [11, 21] productio of iflammatory mediators. Because of this lik betwee VILI/VALI ad assessmet of the P/V curve, ad i a effort to make the measuremet of the P/V curve available at the bedside, a growig iterest i the developmet of ew techologies, ad o the cliical iterpretatio of the P/V curve has become evidet i the last few years [22 30]. However, although a large umber of experimetal studies correlated P/V curves to histological [4] ad biological [6, 21] maifestatios of VILI, oly two radomised trials showed that protective vetilatory strategy idividually tailored to the P/V curve miimised pulmoary ad systemic iflammatio [8] ad decreased mortality i patiets with ALI [12]. Furthermore, despite the fact that several studies have proposed ew techiques to perform P/V curves at the bedside [23, 24, 27], cofirmig that the LIP ad UIP correspod to computed tomography (CT) sca evidece of atelectasis ad overdistesio [26, 28, 29] ad demostratig the ability of the P/V curve to estimate alveolar recruitmet with PEEP [15, 16], o large cliical studies have assessed whether such measuremet ca be performed i all itesive care uits as a moitorig tool to oriet vetilator therapy. This chapter will: 1) review the basic priciples of mechaical stress, 2) discuss how to measure ad iterpret the static P/V curve to miimise VILI/VALI, 3) revise the potetial advatage of the use of the dyamic P/V curve to moitor, prevet ad miimise VILI/VALI. Biophysical characteristics of the lugs relative to mechaical stress MEAD et al. [31] examied the itrapulmoary distributio of pressure i a lug model that icluded ormal ad collapsed alveoli. I such a model tidal iflatio meat that: 1) part of the alveoli cotiuously accessible to vetilatio was overiflated; ad 2) part of the collapsed alveoli were cotiuously recruited ad derecruited. Uder these circumstaces whe tidal iflatio geerated a pressure of 30 cmh 2 O at the airway opeig, i the area ecompassed betwee the hyperiflated ad the ormal alveoli ad betwee the cotiuously recruited-derecruited alveoli ad the ormally expaded regios, the iterstitial pressure was amplified up to 140 cmh 2 O. This distributio of pressure may cause the geeratio of two sources of mechaical distortio [31 35]: shear stress ad stress failure. Shear stress Shear stress is a form of mechaical stress geerated whe blood or air move across a cell surface, thereby geeratig a force parallel to the plasma membrae that iduces a tagetial distortio of the cell. I damaged lugs the developmet of shear stress is related to the cyclic opeig ad closig of small airways iduced by recruitmet/derecruitmet of alveolar uits. Diseased lugs with a heterogeeous distributio of lesios may be subjected to a much greater regioal stress tha homogeeous lugs [4, 31]. The occlusio of small airways by exudate or appositio of their walls requires high airway pressure to restore patecy, resultig i shear stress ad damage of the airways, particularly if the cycle is cotiuously repeated [36]. Airway collapse ad the cosequet recruitmet-derecruitmet may ot occur i ormal lugs, beig favoured by surfactat deficiecy ad lug disease, modifyig the iterstitial support of the airways [35]. Stress failure Stress failure depeds o the developmet of excessive wall stress, defied as the ratio of alveolar wall tesio to thickess. The limited stregth of the alveolar-capillary barrier may explai such a mechaism of mechaical stress. It has bee kow that high airway pressure betwee the alveolus ad the vascular bed durig positive pressure vetilatio causes the passage of air across the epithelial surface, alog the brochovascular sheath ad the ito the iterstitial tissues [32, 33]. The edothelium, so close to the epithelial surface, is subject to stress failure determied by forces derived both from traspulmoary ad itravascular pressures [32]. FU et al. [33] showed that at a costat trasmural pressure, a icrease of traspulmoary pressure from 5 to 20 cmh 2 0 produced a sigificat icrease i the umber of epithelial ad edothelial breaks. There was a further icrease i umber of breaks at the same traspulmoary pressure whe capillary trasmural pressure was icreased. The local or regioal stress iduced by lug iflatio may icrease microvascular trasmural pressures with disruptio of capillaries ("capillary stress failure"), determiig chages i the alveolo-capillary barrier [34]. The forces geerated by mechaical vetilatio may therefore iteract with those due to pulmoary vascular perfusio to icrease lug ijury. The mechaical characteristics of the lugs are coditioed by the mechaics of its microstructure ad the relative cotet of elasti ad collage i the alveolar walls. The alveolar septum is composed of a skeleto of collage ad elasti fibres that are iterlaced with the capillary etwork. May models of lug parechyma have used various geometrical bodies to describe the volumetric structure of the alveolar regio. To ivestigate fibre orgaisatio ad the potetial distributio of mechaical deformatio ad stress, a twodimesioal model of the alveolar sac was proposed [37].

3 MINIMISING VILI IN ARDS PATIENTS 17s Two-dimesio electro microscope scaig showed that the tractio stresses (s) at differet lug volumes were detected with a aalysis of iteral stresses withi the septal walls. Characteristics of lug tissue were evaluated through measuremets of legth-tesio [37, 38]. The authors foud the followig relatioship: s~l 1 {l -2 ð1þ where s represets the stress, l the stretch ratio. This equatio therefore idetifies differet tractio stresses (s) at differet lug volumes ad alveolar pressures. Experimetal studies showed that at 60% total lug capacity, tesios are up to 6 times higher tha those at restig lug volume. I cotrast, the tesio stress withi iteral walls shared by adjacet alveoli, is early zero thus cofirmig that alveolar distortio is ot uiform. The use of the static pressure/volume curve to miimise vetilator-iduced lug ijury/vetilator-associated lug ijury Patiets with ARDS are characterised by a reductio of the rage of volume excursio, because of the reductio i the vetilatig uits, ad a smaller chage i volume for uit of chage i pressure. The iitial part of the P/V curve, at very low lug volume, is therefore cosiderably flatter tha the rest of the curve, showig the amout of pressure required to ope collapsed peripheral alveoli. This "lower iflectio poit", separates a tract of the curve with bad elastic properties from the tract characterised by optimal elastic properties. After this iitial tract, the curve presets a liear sectio i which the ope alveoli are vetilated. The the V/P curve flattes agai at values of tidal volume lower tha those observed i ormal subjects. This "upper iflectio poit" idicates that stretchig ad overdistesio of at least some alveolar structures is occurrig. Lower iflectio poit Iflatio of a excised lug requires a critical opeig pressure to be applied i order to re-expad the collapsed alveoli [39]. This critical pressure appears o the P/V curve as the pressure correspodig to the sudde chage i slope of the curve after the iitial iflatio. I ormal subjects, this critical opeig pressure amouts to y20 cmh 2 O. Similarly, i patiets with ARDS, the ispiratory P/V curve shows a LIP, that is the sudde chage i slope occurrig at the oset of tidal iflatio, whe the applied pressure varies betwee cmh 2 O. This shows that i ARDS the vast majority of the lug is collapsed at the begiig of ispiratio. The pressure correspodig to the LIP should therefore represet the miimal level of PEEP that should be applied i order to have tidal iflatio withi a ope lug. Cosiderig that ARDS ad ALI are coditios of ot homogeeous lug parechyma, desities, evaluated with CT are more cocetrated i depedet lug regios, where there is a more positive pleural pressure if compared with odepedet regios (0 cmh 2 O ad -3, -5 cmh 2 O respectively). The ifluece of this vertical gradiet i pleural pressure i the supie positio may be ehaced by the gravitatioal distributio of oedema. Upper iflectio poit The decrease of P/V curve slope idicates the ed of alveolar recruitmet, the begiig of alveolar overdistesio ad so the maximal alveolar pressure that should be applied to obtai the maximal amout of alveolar recruitmet. I ormal subjects, the UIP is reached at a lug volume that is 85 90% of total lug capacity (TLC); i patiets with ARDS UIP occurs at a much lower volume. A icrease i pressure above the UIP oly gives overdistesio without ay other icrease i volume, with a maximal stretch of lug aerated areas. Techique to assess the static pressure/volume curve The super-syrige techique. The super-syrige techique was the first techique used to assess the status of elastic properties of the respiratory system i mechaically vetilated ALI/ ARDS patiets i supie positio sedated ad paralysed, to permit the slow iflatio of the lug with predetermied gas volume of oxyge. The iflated volume is ml. The syrige stops for 2 3 s, the the respiratory system is iflated with itermittet pause util a volume of 25 ml?kg -1 or a airway pressure of 40 cmh 2 O are reached. With this techique it is easy to detect the LIP ad UIP but, o the other had, paralysis, sedatio ad discoectio of the patiet from the vetilator are required. Rapid airway occlusio techique. The rapid airway occlusio techique is based o a sigle-breath occlusio at differet iflatio durig mechaical vetilatio. With ispiratory costat flow differet volumes are achieved. Each occlusio is maitaied util a plateau i the ope airways pressure is obtaied thus represetig the static pressure of the total respiratory system. Usig differet volumes the static V/P curve ca be costructed. Advatages of this techique iclude o eed for patiet discoectio ad the ability to idetify the elastic properties of the respiratory system as determied by the actual volume. Besides, the measuremet does ot require special devices. However, patiets must be paralysed ad sedated ad curves are ot immediately available sice sigle data poits eed to be first collected ad recorded ad the plotted; idetificatio of LIP ad UIP is ot easy. Costat flow techique. The costat flow techique is based o the assumptio that whe ispiratory flow is costat durig passive iflatio the rate of chage i the airway opeig pressure is related to the elastace of the respiratory system ad the resistive compoets are il. There is o eed to discoect the patiet from the vetilator, special devices are ot required ad results are available at the bedside; LIP ad UIP are usually easily idetified. Yet, this method requires paralysis, sedatio ad oly a few vetilators are equipped with such a moitorig tool. I patiets with ARDS, the rapid airway occlusio techique (static V/P curve) provides the same iformatio as the costat flow techique (with a flow of 3 L?mi -1 ) regardig the elastic properties of the respiratory system, whereas the V/ P curve obtaied by the 9 L?mi -1 costat flow is slightly shifted to the right [27]. The slopes of the V/P curves ad the LIP are ot differet betwee all methods, idicatig that the resistive compoet iduced by admiisterig a costat flow f9 L?mi -1 is ot of cliical relevace. However all methods have a itrisic risk of adverse effects, icludig hypoxaemia at low lug volumes ad derecruitmet at low levels of PEEP [26 28]. Other problems iclude haemodyamic chages (decrease of veous retur) or complicatios related to sedatio or paralysis required to obtai the characteristics of passive mechaics of the respiratory system. For all these reasos, P/V curves are ot usually obtaied i the routie cliical assessmet [39]. A oliear model of respiratory mechaics i ARDS has recetly bee used to verify the physiological iterpretatio of

4 18s P.P. TERRAGNI ET AL. the LIP ad UIP ad to examie their potetial use i the cliical settig to set mechaical vetilatio [30, 40]. This aalysis showed that: 1) the iitial icrease i slope of the V/P curve idicates the miimal pressure at which alveolar recruitmet starts to occur rather tha the maximum level of PEEP able to provide maximum recruitmet. Uder these circumstaces, a PEEP level equal to the LIP uderestimates the optimal level of PEEP able to miimise ed-expiratory alveolar collapse; 2) the decrease i the slope of the V/P curve does ot idicate the begiig of alveolar overdistesio but the ed of alveolar recruitmet. Accordig to this mathematical model, the UIP is therefore urelated to alveolar overdistesio beig caused by the decrease i rate of alveolar recruitmet durig lug iflatio. Uder these circumstaces, the LIP will idicate the maximal alveolar pressure that should be applied to obtai the maximal amout of alveolar recruitmet. Aimal ad cliical experimets are cosistet with these data ad have show that recruitmet occurs throughout the etire lug iflatio from ed-expiratory lug volume to TLC rather tha beig a "all or oe" pheomeo [41, 42]. Aalysis of the dyamic pressure/time curve durig costat flow: a "stress idex" to miimise vetilatoriduced lug ijury/vetilator-associated lug ijury The curret authors recetly proposed that the use of the static P/V curve could be replaced by the aalysis of the dyamic airway opeig pressure/time (P/t) profile durig costat-flow iflatio [43]. I 19 patiets with ALI the preset authors previously foud that a dowward cocavity o the P/t profile durig costat flow iflatio correspoded to a static P/V curve with a distict LIP ad a cotiuous icrease i compliace (i.e. progressive recruitmet with iflatig volume) [15]. O the other had, a upward cocavity o the P/t profile durig costat flow iflatio correspoded to a static P/V curve with a distict UIP ad a cotiuous reductio i compliace (i.e. progressive overdistesio with iflatig volume) [15]. Based o these results the curret authors raised the hypothesis that aalysis of the shape of the P/t curve durig costat flow iflatio could idetify the presece of tidal recruitmet ad/or tidal overiflatio ad therefore allow a oivasive ad cotiuous assessmet of mechaical stress due to oappropriate vetilator settigs. Durig costat flow coditios ad if resistaces are costat, airway opeig pressure (Pao) chages liearly with time whe compliace does ot chage with icreasig lug volume. Whe compliace decreases, Pao is cocave upward ad whe compliace icreases Pao is cocave dowward with respect to the time axis [15, 44 46]. Such a aalysis of the P/t relatioship is based o the assumptio that durig volume cotrolled vetilatio with a costat flow iflatio, the rate of chage of pressure is related to the chages i pulmoary compliace [15, 44 46]. Uder these circumstaces, the Pao profile as fuctio of ispiratory time (t) ca be described by a power equatio (fig. 1): Pao~a : t b zc ð2þ The coefficiet a is a scalig factor, c is the pressure value at t=0. The coefficiet b is a dimesioless umber that describes the shape of the P/t curve ad that ca therefore idetify ad quatify mechaical stress (stress idex): a stress idex=1 meas that the P/t curve is liear ad compliace remais costat throughout tidal iflatio; a stress idexv1 idicates that the P/t curve has a dowward cocavity due to the tidal icrease i compliace therefore idetifyig stress due to tidal recruitmet; a stress idex w1 idicates that the P/t curve has a upward cocavity due to the tidal reductio i compliace therefore idetifyig stress due to tidal overiflatio. This aalysis requires several assumptios: 1) a stiff chest wall may ifluece estimatio of the upward/dowward cocavity o the dyamic P/t curve [44]. 2) I more complex coditios, the P/t curve may be characterised by a sigmoidal shape with a iitial dowward cocavity due to alveolar opeig, followed by a liear portio ad a fial dowward cocavity due to alveolar overdistesio. Uder these circumstaces, it would be best to fit the power equatio first to the iitial portio of the curve (to set PEEP) ad the to the secod portio of the curve (to set tidal volume (VT)). 3) O a theoretical basis, the time course of applied pressure durig costat flow iflatio should be characterised by a immediate step chage due to the resistive compoets, abruptly followed by the progressive icrease i pressure reflectig the chages i pulmoary compliace [45]. However, o- ad off flow trasiets may be due to pedelluft (i.e. the time required to achieve a steadystate flow to each alveolar uit with differet time costats) [47], viscoelasticity [30, 48] ad the time required by the vetilator to iitiate ad to stop delivery of costat flow [15]. The first part of the pressure evets must therefore be discarded, ad oly the portio o the P/t relatioship correspodig to costat flow remais valid. 4) A high samplig frequecy of the recorded sigals is required to achieve a adequate dyamic recordig of airway pressure with o phase lag at high frequecy. 5) Resistive ad viscoelastic cotributio to airway pressure are assumed costat over the rage of chages i lug volume. Some of these factors may explai the relative low specificity (i.e. a relevat umber of false positive) of the dyamic P/t profile to detect VILI. The "stress idex" approach was iitially tested i a isolated lavage model of ARDS [43]. A sigificat (pv0.0001) U-shaped relatioship betwee idividual values of stress idex ad pulmoary histological damage ad pulmoary cocetratio of pro-iflammatory cytokies was foud; the lowest values of histological ijury score ad cytokie cocetratio was systematically associated with a stress idex y1. The threshold value for the stress idex that discrimiated best betwee lugs with ad without histological ad iflammatory evideces of VILI raged betwee For such threshold values, the sesitivity of the stress idex to idetify oijurious vetilatory strategy was A secod study [49] examied the impact of differet vetilatory strategies o the developmet of ischemia-reperfusio ijury followig lug trasplatatio ad evaluated whether a vetilatory strategy aimed to maitai a stress idex of 1 would miimise pathophysiological idices of ARDS i the settig of lug trasplatatio. I a rat lug trasplat model, aimals were radomised ito two groups defied by the vetilatory strategy durig the early reperfusio period. I the covetioal mechaical vetilatio group the trasplated lug was vetilated with a VT equal to 50% of the ispiratory capacity of the left lug ad a low PEEP. I the miimal mechaical stress vetilatio group the trasplated lug was vetilated with a VT equal to 20% of the ispiratory capacity of the left lug ad PEEP adjusted accordig to the shape of the P/t curve to obtai a stress idex of 1. After 3 h of reperfusio, oxygeatio from the trasplated lug was sigificatly higher i aimals vetilated with a stress idex of 1 tha i aimals vetilated with covetioal vetilatio. I additio, elastace, cytokie levels, ad morphological sigs of ijury were sigificatly lower i the group vetilated with a stress idex of 1. This study demostrates that the mode of mechaical vetilatio used i the early phase of reperfusio of the trasplated lug ca ifluece ischemia-reperfusio ijury, ad a protective vetilatory strategy based o a stress idex of 1 ca lead to improved lug fuctio after lug trasplatatio. I a rabbit

5 MINIMISING VILI IN ARDS PATIENTS 19s a) DP cmh 2 O 30 5 b) c) Flow ml s Dt s Dt s Dt s Fig. 1. The coceptual illustratio of the dyamic pressure/time (P/t) curve used i the curret study. Based o the power equatio PL=a?t b zc (where PL=traspulmoary pressure; a=slope of the P/t relatioship at time=1 s; b=dimesioless umber that describes the shape of the P/t curve; c=pressure at time=0); a) b=0.7 (a stress idex v1) produces a covex P/t curve, idicatig cotiuig recruitmet; b) b=1.01 (a stress idex =1) produces a straight P/t lie, idicatig o alveolar cotiuig recruitmet or overdistesio; ad c) b=1.32 (a stress idexw1) produces a cocave P/t curve, idicatig alveolar overdistesio. The power equatio was applied to the PL sigal durig a costat ispiratory flow (vertical bars) [43]. ARDS model, NAKANE et al. [50] compared efficacy to miimise VILI of a vetilatory strategy aimed to maitai a stress idex of 1 to the Natioal Istitutes of Health (NIH) protective vetilatory strategy [13]. Aimals were radomly vetilated for 3 h usig oe of the followig vetilatory strategies: stress idex group: VT 6mL?kg -1, PEEP adjusted so that b=1; NIH group: VT 6mL?kg -1, PEEP set accordig to the table created by NIH ARDSNet; Ijurious group: VT ml?kg -1, PEEP 1 2, ispiratory oxyge fractio was adjusted so that arterial oxyge tesio was i all groups. Respiratory mechaics worseed with time oly i aimals vetilated with the NIH ad the ijurious vetilatory strategies while they were maitaied at the baselie levels oly i aimals vetilated with a stress idex of 1. After 3 h of mechaical vetilatio, lug homogeate cocetratio of iterleuki-8 i the depedet regio was sigificatly lower i aimals protected by VILI usig the stress idex strategy tha i aimals protected usig the NIH strategy; histological exams showed sigificatly lower icidece of VILI i the stress idex group compared to the other groups. I eight pigs lug ijury was iduced with lug lavage [51]. Each aimal was vetilated i radom order with three vetilator settigs aimed to obtai a stress idex =1 a stress idex w1 ad a stress idex v1. At the ed of each experimetal coditio the curret authors measured respiratory mechaics, gas exchage ad quatified tidal recruitmet ad tidal overiflatio with spiral CT sca ad multiple iert gas elimiatio techique (MIGET). As ca be see i table 1, CT evideces of itratidal alveolar collapse ad/or overdistesio are mirrored by the stress idex. Prelimiary data i patiets with ARDS [52, 53] show that the use of the stress idex is feasible also i the cliical sceario ad that, compared to the gold stadard protective vetilatory strategy (NIH protocol), patiets vetilated with a stress idex of 1 have lower elastace ad higher recruitmet of collapsed alveoli. Other groups have idepedetly cofirmed ad expaded these fidigs. I 20 paralysed childre with acute respiratory distress sydrome, NEVE et al. [54] showed that the aalysis of the profile of the dyamic pressure/time curve durig costat flow vetilatio permits detectio of hyperiflatio ad has a good agreemet with the results of the static pressure/volume curve. GAMA DE ABREU et al. [55] i a rabbit model of uilateral acute respiratory distress sydrome cofirmed that the aalysis of the pressure/time curve durig costat flow vetilatio allows detectio of optimal protective strategy also durig oe-lug vetilatio. These data therefore suggest that the shape of the dyamic ispiratory pressure/time profile durig costat flow iflatio (stress idex) allows predictio of a vetilatory strategy that miimises the occurrece of vetilator-iduced lug ijury. Moder vetilators are able to Table 1. Values of tidal recruitmet ad hyperiflatio (computed tomography sca techique) ad shut ad dead space (multiple iert gas elimiatio techique (MIGET)) i eight pigs with acute respiratory distress sydrome (ARDS) ad vetilated with a stress idex=1, w1 ad v1 [51] Stress idexv1 Stress idex=1 Stress idexw1 Coefficiet b *** *** VT ml?kg *** *** PEEPtot cmh 2 O *** *** Tidal recruitmet g *** 1 1.4*** Tidal hyperiflatio g *** Shut % Qt *** 1 1*** Alveolar dead space ml *** Qt: cardiac output; VT: tidal volume; PEEPtot: total positive ed-expiratory pressure. ***: pv0.001.

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