Application of dead space fraction to titrate optimal positive end-expiratory pressure in an ARDS swine model

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1 1572 EXPERIMENTAL AND THERAPEUTIC MEDICINE 13: , 2017 Appliction of ded spce frction to titrte optiml positive end-expirtory pressure in n ARDS swine model WEISHUAI BIAN 1, WEI CHEN 1, YANGONG CHAO 2, LAN WANG 3, LIMING LI 2, JIAN GUAN 2, XUEFENG ZANG 1, JIE ZHEN 1, BO SHENG 1 nd XI ZHU 4 1 Deprtment of Criticl Cre Medicine, Beijing Shijitn Hospitl, Cpitl Medicl University, Beijing ; 2 Deprtment of Criticl Cre Medicine, The First Affilited Hospitl, Tsing Hu University, Beijing ; 3 Deprtment of Criticl Cre Medicine, Dongzhimen Chinese Medicl Hospitl, Beijing Chinese Medicl University, Beijing ; 4 Deprtment of Criticl Cre Medicine, Third Hospitl, Peking University, Beijing , P.R. Chin Received August 6, 2015; Accepted October 5, 2016 DOI: /etm Abstrct. This study imed to pply the ded spce frction [rtio of ded spce to tidl volume (VD/VT)] to titrte the optiml positive end expirtory pressure (PEEP) in swine model of cute respirtory distress syndrome (ARDS). Twelve swine models of ARDS were constructed. A lung recruitment mneuver ws then conducted nd the PEEP ws set t 20 cm H 2 O. The PEEP ws reduced by 2 cm H 2 O every 10 min until 0 cm H 2 O ws reched, nd VD/VT ws mesured fter ech decrement step. VD/VT ws mesured using single breth nlysis of CO 2, nd clculted from rteril CO 2 prtil pressure (PCO 2 ) nd mixed expired CO 2 (PeCO 2 ) using the following formul: VD/VT = (PCO 2 PeCO 2 )/PCO 2. The optiml PEEP ws identified by the lowest VD/VT method. Respirtion nd hemodynmic prmeters were recorded during the periods of pre injury nd injury, nd t 4 nd 2 cm H 2 O below nd bove the optiml PEEP (Po). The optiml PEEP in this study ws found to be 13.25±1.36 cm H 2 O. During the Po period, VD/VT decresed to lower vlue (0.44±0.08) compred with tht during the injury period (0.68±0.10) (P<0.05), while the intrpulmonry shunt frction reched its lowest vlue. In ddition, significnt chnge of dynmic tidl respirtory complince nd oxygention index ws induced by PEEP titrtion. These results indicte tht miniml VD/VT cn be used for PEEP titrtion in ARDS. Introduction Acute respirtory distress syndrome (ARDS) is severe nd life thretening medicl condition tht is common in criticlly Correspondence to: Dr Wei Chen, Deprtment of Criticl Cre Medicine, Beijing Shijitn Hospitl, Cpitl Medicl University, 10 Tieyi Rod, Yngfngdin, Hidin, Beijing , P.R. Chin E mil: weichendr@163.com Key words: cute respirtory distress syndrome, ded spce frction, positive end expirtory pressure, recruitment mneuver ill ptients nd hs high mortlity rte (1). It is min reson for cute respirtory filure, nd is chrcterized by widespred inflmmtion in the lungs (1,2). ARDS cn induce pthophysiologicl mechnisms of lveolr collpse, hyoxemi, vsculr dysfunction nd elevted ded spce frction [the rtio of ded spce volume to tidl volume (VD/VT)] (3,4). Currently, the lung protection strtegy for ventiltion involves the use of high positive end expirtory pressure (PEEP) levels combined with low tidl volumes to prevent end expirtory lveolr collpse, increse functionl residul cpcity, reduce VD/VT nd ttenute hypoxemi (5,6). However, the ppliction of higher levels of PEEP my not be necessrily beneficil, since it increses the infltion of lung regions. Additionlly, it will lso increse the risk of hemodynmic bnormlities s well s the lung injury induced by ventiltion (7,8). Numerous studies hve ttempted to define the optiml PEEP level on the bsis of vriety of methods during recruitment mneuver (RM) with decresing PEEP (9 11). A number of studies hve pplied the VD/VT method to ssess the effects of lung recruitment nd PEEP titrtion in ptients with severe ARDS (9 11). VD/VT is specific vlue bsed on the reltively high diffusibility of CO 2 cross tissue membrnes (12), nd the exchnge of CO 2 depends strictly on lveolr ventiltion volume (13). However, some studies did not find similr effect on VD/VT during PEEP titrtion (14,15). Therefore, the ppliction of the lowest VD/VT method to titrte the optiml PEEP in ptients with ARDS remins to be investigted. In the present study, n oleic cid lung injury model in swine ws used to evlute the effect of vrying the PEEP level on ded spce frction. The im ws to relize the chnges in VD/VT induced by different PEEP levels in the ARDS swine model nd to explore the fesibility of using the VD/VT rtio to guide the optiml PEEP titrtion. Mterils nd methods Animls nd nesthesi. The study ws prospective, shm controlled nd in vivo niml study, nd ws pproved by the niml ethics committee of Beijing Shijitn Hospitl, ffilited to Cpitl Medicl University (Beijing, Chin).

2 BIAN et l: VD/VT TITRATED OPTIMAL PEEP 1573 Twelve helthy mle swine (ge, months) with n verge weight of 39.13±3.27 kg were provided by the niml center of Pinggu Hospitl of Cpitl Medicl University [licence: SYXK (B) ]. The nimls were housed t C with humidity of 45 55%, with free ccess to food nd wter. Swine were fsted for 24 h nd then were orotrchelly intubted in the supine position during deep intrmusculr nesthesi with ketmine (35 mg/kg; Jingsu Hengrui Medicine Co. Ltd., Linyungng, Chin), 3% pentobrbitl sodium (30 mg/kg; Sigm Aldrich; Merck KGA, Drmstdt, Germny) nd dizepm (1.5 mg/kg; Sigm Aldrich). A double cvity centrl venous ctheter ws inserted into the right internl jugulr vein using the Seldinger technique (16) nd connected to the monitoring system. Following line plcement, the nesthetic ws switched to totl intrvenous nesthesi with continuous infusion of pentobrbitl sodium (2 mg/kg/h), ketmine (3 mg/kg/h) nd pipecurium bromide (0.03 mg/kg/h; Gedeon Richter Plc., Budpest, Hungry). In ll swine, 4 French guge rteril thermodilution ctheter ws inserted vi the left femorl rtery. The rteril ctheter ws connected to computer for pulse contour nlysis (Pulsion Medicl Systems, Munich, Germny) for the clinicl monitoring of hemodynmic mesurements. Monitoring. The respirtion prmeters of lveolr prtil pressure of O 2 (PAO 2 )/frction of inspirtion O 2 (FiO 2 ) rtio (P/F), rteril CO 2 prtil pressure (PCO 2 ) nd rteril O 2 sturtion (SO 2 ) were directly mesured through rteril blood gs nlysis using the (GEM Premier 3000; Instrumenttion Lbortory, Inc., Lexington MA, USA) (17). Lung mximum dynmic tidl respirtory complince (Cdyn) ws monitored using SERVI i ventiltor (Siemens Mquet Criticl Cre AB, Slon, Sweden). The VD/VT rtio ws mesured vi the single breth nlysis of CO 2 (18) (NICO Crdiopulmonry Mngement System; Novmetrix; Philips Respironics, Murrysville, PA, USA). With this method, the prtil pressure of mixed expired CO 2 ws clculted followed by the Enghoff modifiction of the Bohr eqution s follows: VD/VT=(PCO 2 PeCO 2 )/PCO 2, where PeCO 2 represents mixed expired CO 2 (19). An rteril blood gs smple ws obtined when the PeCO 2 vribility on the NICO monitor ws 1 mmhg within 5 min. The NICO sensor fitted between the Y piece nd the endotrchel tube. The intrpulmonry shunt frction (Qs/Qt) ws clculted ccording to the stndrd formule: Qs/Qt = (CcO 2 CO 2 )/(CcO 2 CvO 2 ) CO 2 = Hb x SO 2 x PAO 2 x CvO 2 = Hb x SvO 2 x PvO 2 x CcO 2 = Hb x ScO 2 x PcO 2 x ScO 2 100% PcO 2 PAO 2 PAO 2 = PiO 2 PCO 2 /R PiO 2 = (PB PH 2 O) x FiO 2 where Qs represents shunted pulmonry blood flow; Qt represents totl pulmonry blood flow; CcO 2 represents pulmonry cpillry O 2 content; PvO2 represents mixed venous O2 prtil pressure; CO 2 represents rteril O 2 content; CvO 2 represents mixed venous O 2 content; Hb represents hemoglobin; PiO 2 represents prtil pressure of inspired O 2 ; R represents respirtory quotient (0.8); PB represents brometric pressure (~100 kp on se level); PH 2 O represents sturtion vpor pressure (6.3 kp t 37 C). The hemodynmic prmeters of crdic output index (CI), globl end distolic volume index (GEDI), extrvsculr lung wter index (ELWI), intr thorcic blood volume index (ITBI) nd systemic vsculr resistnce index (SVRI) were directly mesured by the thermodilution method (20) using the PICCO system (Pulsion Medicl Systems). The centrl venous pressure (CVP) ws monitored with the centrl venous ctheter in the right internl jugulr vein. Protocol. Following intubtion, lungs were ventilted in volume controlled ventiltion mode, with the following initil prmeters: VT of 8 ml/kg, FiO 2 of 1.0, PEEP of 5 cm H 2 O, respirtory rte of 40 breths/min, nd inspirtory to expirtory time rtio (I:E) of 1:2. These settings were mintined for 30 min to chieve stbiliztion. ARDS induction. After recording pre injury hemodynmic, gs exchnge, respirtory mechnics mesurements nd oxygen metbolism, 0.2 ml/kg oleic cid (Sigm Aldrich) in 40 ml sline ws slowly (within 15 min) injected in the right trium vi the centrl venous ctheter. After 90 min injury stbiliztion period, the experimentl protocol ws initited. A successful model of ARDS ws defined by P/F <200 mmhg for 90 min following oleic cid infusion (21). Ech swine ws infused continuously with intrvenous sline t rte of 100 ml/h. Lung recruitment mneuver. The swine were stbilized for 15 min on the following ventiltor settings nd followed by dt gthering: Pressure control ventiltion (PCV) pek pressure, 35 cm H 2 O; PEEP, 20 cm H 2 O; inspirtory time, 0.6 sec; rte, 40/min nd FiO The PEEP ws then set to 20 cm H 2 O nd pressure control set to pek irwy pressure of 40 cm H 2 O. These settings were mintined for 2 min, followed by 15 min stbiliztion period with pek pressure 35 cm H 2 O. Dt were gthered if PAO 2 + PCO 2 ws >400 mmhg. If PAO 2 + PCO 2 ws <400 mmhg, the PEEP setting remined unchnged nd pressure control ws incresed to obtin pek irwy pressure of 45 cm H 2 O. This pttern ws sustined for 2 min, followed by 15 min stbiliztion period with pek pressure 35 cm H 2 O. If PAO 2 + PCO 2 ws >400 mmhg, the lung recruitment ws considered complete (22,23). PEEP titrtion. When the sum of PAO 2 nd PCO 2 ws >400 mmhg, ll swine underwent decrementl PEEP titrtion in volume control mode. PEEP ws decresed in 2 cm H 2 O steps (from 20 to 0 cm H 2 O) nd ws mintined t ech level for 10 min. Cdyn ws mesured t ech step using VT of 8 ml/kg nd frequency of 40/min. Additionlly, the physiologicl dt including Cdyn, VD/VT nd P/F were gthered following ech step. The optiml open lung PEEP ws identified by the lowest VD/VT method, which ws chieved s determined by reduction in VD/VT nd then rise with ech PEEP step. The study consisted of the following seven experimentl periods: i) Pre injury period, which involved introduction of ctheters nd mechnicl ventiltion using the initil prmeters; ii) injury period, when ARDS ws induced by the

3 1574 EXPERIMENTAL AND THERAPEUTIC MEDICINE 13: , 2017 intrvenous dministrtion of oleic cid; iii) PEEP period 1 (Po 4), 4 cm H 2 O below the optiml PEEP; iv) PEEP period 2 (Po 2), 2 cm H 2 O below the optiml PEEP; v) PEEP period 3 (Po), optiml PEEP; vi) PEEP period 4 (Po+2), 2 cm H 2 O bove the optiml PEEP; vii) PEEP period 5 (Po+4). 4 cm H 2 O bove the optiml PEEP. Sttisticl nlysis. All dt were nlyzed using IBM SPSS version 19.0 sttistics softwre (IBM SPSS, Armonk, NY, USA) nd were expressed s men ± stndrd devition. Anlysis of non prmetric repeted mesures ANOVA test ws used for comprison of ll vribles collected during the seven ssessment periods. P<0.05 ws considered to indicte sttisticlly significnt difference. Results Optiml PEEP. The optiml PEEP identified by the lowest VD/VT method ws 13.25±1.36 cm H 2 O. VD/VT chnges induced by different PEEP levels. There ws significnt (P<0.05) increse in VD/VT from the pre injury period (0.35±0.11) to the injury period (0.68±0.10). Following the RM, VD/VT decresed to the lowest vlue of 0.44±0.08 (vs. injury, P<0.05) t the optiml PEEP. When PEEP decresed to Po 4 cm H 2 O, VD/VT significntly incresed to 0.60±0.07 (P<0.05). However, t the Po+4 cm H 2 O, VD/VT ws higher (0.64±0.10; Fig. 1 nd Tble I). Figure 1. VD/VT of the cute respirtory distress syndrome swine model under different conditions. * P<0.05 vs. pre injury; P<0.05 vs. injury. VD/VT, rtio of ded spce volume to tidl volume (ded spce frction); PEEP, positive end expirtory pressure; Po, optiml PEEP; n, n cm Hg below Po; +n; n cm Hg bove Po. Chnges of P/F during PEEP decrement. There ws sttisticlly significnt (P<0.05) reduction in P/F from the pre injury period (562±162 mmhg) to the injury period (75±21 mmhg). Following the RM, P/F vlues significntly incresed from 166±109 to 365±133 mmhg when the PEEP incresed from the Po 4 cm H 2 O to Po+2 cm H 2 O. However, P/F decresed gin t Po+4 cm H 2 O (Fig. 2 nd Tble I). Chnges of Cdyn nd Qs/Qt during PEEP decrement. At ll periods fter injury, the Cdyn vlues were decresed compred with the pre injury vlue (P<0.05), but the highest post RM vlues were observed t the pressure level of optiml PEEP. However, Qs/Qt vlues were significntly (P<0.05) lower t the pressure level of optiml PEEP compred with the levels t the injury period (Figs. 3 nd 4 nd Tble I). Hemodynmic chnges induced by different PEEP levels. The CI, ITBI, GEDI nd SVRI did not chnge significntly during the pre injury, injury nd vrible PEEP periods, lthough downtrend ws observed in CI with the increse of PEEP. For CVP, significnt (P<0.05) increment ws observed during the vrible PEEP period reltive to the pre injury nd injury period. In ddition, CVP incresed mrkedly s PEEP incresed. In comprison with the pre injury period, EVLWI vlues were significntly higher during the injury nd vrible PEEP periods (P<0.05; Tble II). Discussion Currently, mny methods exist in the literture for identifying the PEEP to set in ptients with ARDS following lung RM. Figure 2. P/F rtio of the cute respirtory distress syndrome swine model under different conditions. * P<0.05 vs. pre injury; P<0.05 vs. injury. P/F, lveolr prtil pressure of oxygen/frction of inspirtion oxygen (oxygention index); PEEP, positive end expirtory pressure; Po, optiml PEEP; n, n cm Hg below Po; +n; n cm Hg bove Po. The detection prmeters include Cdyn, PAO 2, mximum PAO 2 + PCO 2, s well s the infltion lower inflection point (Pflex) nd defltion upper Pflex on the pressure volume curve (22). However, controversy over the pproch for setting PEEP hs existed since 1967 when Ashbugh et l (24) first used PEEP to mnge ARDS. A previous study hs reported tht n incresed VD/VT rtio is one of the mrkers of erly ARDS, nd furthermore, n elevted VD/VT rtio is ssocited with n incresed risk of mortlity (10). In the present study, decrementl PEEP procedure ws performed following n RM in swine with ARDS. It ws observed tht PEEP cused significnt chnges of VD/VT, Qs/Qt, Cdyn nd P/F. The results indicted tht in cses of recruitment mneuver nd

4 BIAN et l: VD/VT TITRATED OPTIMAL PEEP 1575 Tble I. Respirtion prmeters of the cute respirtory distress syndrome swine model under different conditions (men ± stndrd devition). Prmeter Pre injury Injury Po 4 Po 2 Po Po+2 Po+4 VD/VT 0.35± ± ±0.07,b 0.52±0.11,b 0.44±0.08,b 0.61± ±0.10 PCO 2 (mmhg) 34.80± ± ± ± ± ± ±12.89 SO 2 (%) 99.86± ± ±1.52b 98.58±0.48b 98.75±2.55b 97.78±0.96b 96.34±2.50b Qs/Qt (%) 1.88± ± ±4.14,b 5.01±1.53b 2.77±2.53b 6.68±2.86b 9.55±5.85,b P/F (mmhg) 562±162 75±21 166± ±62,b 342±144,b 365±133,b 294±170,b Cdyn (ml/cm H 2 O) 38.17± ± ± ± ±5.58,b 19.33±4.44,b 17.50±3.34 P<0.05 vs. pre injury; b P<0.05 vs. injury. VD/VT, ded spce volume/tidl volume (ded spce frction); PCO2, lveolr prtil pressure of crbon dioxide; SO 2, rteril oxygen sturtion; Qs/Qt, intrpulmonry shunt frction; P/F, lveolr prtil pressure of oxygen/frction of inspirtion oxygen (oxygention index); Cdyn, dynmic tidl respirtory complince; Po, optiml positive end expirtory pressure; n, n cm Hg below Po; +n; n cm Hg bove Po. Tble II. Hemodynmics prmeters of the cute respirtory distress syndrome swine model under different conditions (men ± stndrd devition). Prmeter Pre injury Injury Po 4 Po 2 Po Po+2 Po+4 CVP (mmhg) 6.58± ± ±1.72,b 10.83±2.67,b 10.75±2.83,b 11.33±2.06,b 11.83±1.90,b CI (l/min/m 2 ) 4.84± ± ± ± ± ± ±1.22 ITBI (ml/m 2 ) 694± ± ± ± ± ± ±130 GEDI (ml/m 2 ) 555± ± ± ± ± ± ±104 EVLWI (ml/kg) 10.69± ± ± ± ± ± ±4.81 SVRI (dyn.sec.cm 5.m 2 ) 1,430±590 2,113±1,012 2,469±948 2,541±1,366 2,179±1,439 2,152±1,532 1,970±1,237 P<0.05 vs. pre injury; b P<0.05 vs. injury. CVP, centrl venous pressure; CI, crdic output index; ITBI, intr thorcic blood volume index; GEDI, globl end distolic volume index; ELWI, extrvsculr lung wter index; SVRI, systemic vsculr resistnce index; Po, optiml positive end expirtory pressure; n, n cm Hg below Po; +n; n cm Hg bove Po.

5 1576 EXPERIMENTAL AND THERAPEUTIC MEDICINE 13: , 2017 Figure 3. Cdyn of the cute respirtory distress syndrome swine model under different conditions. * P<0.05 vs. pre injury; P<0.05 vs. injury. Cdyn, dynmic tidl respirtory complince; PEEP, positive end expirtory pressure; Po, optiml PEEP; n, n cm Hg below Po; +n; n cm Hg bove Po. Figure 4. Qs/Qt of the cute respirtory distress syndrome swine model under different conditions. * P<0.05 vs. pre injury; P<0.05 vs. injury. Qs/Qt, intrpulmonry shunt rtio; PEEP, positive end expirtory pressure; Po, optiml PEEP; n, n cm Hg below Po; +n; n cm Hg bove Po. PEEP titrtion procedure, VD/VT might become cliniclly useful tool for ssessing collpsed lveolr opening nd titrting the optiml PEEP in ARDS. A mrkedly elevted VD/VT my be detected in erly ARDS, which is suggested to be due to the obstruction of pulmonry blood flow in the extr lveolr pulmonry circultion (25), nd incresing res with low ventiltion (26). Importntly, injury of pulmonry cpillries by inflmmtion nd thrombus cn lso result in incresed VD/VT (27,28). As shown in Fig. 1, VD/VT ws significntly higher during the injury period thn during the pre injury period, which ws in ccordnce with results from previous studies (29,30). In ddition, the results showed tht different PEEP levels following RM cused significnt chnges in VD/VT, which ws in greement with the findings of Misch et l (31), who showed tht different PEEP levels fter RM cused significnt chnges in VD/VT nd P/F, s well s complince in ptients with ARDS. With the increse of PEEP, VD/VT showed trend of decline. However, higher PEEP my led to n increse of the VD/VT rtio, which might be cused by the regionl over distention of well ventilted lveoli (26) or by reduction in crdic output (32). As cn be seen from the formul used to clculte VD/VT, VD/VT is inversely relted to CO 2 elimintion. The elimintion of CO 2 by the lung is influenced by effective lveolr surfce re, lveolr ventiltion nd crdic output (33,34). Following the RM nd optiml PEEP, the CO 2 elimintion cpcity of the lung is incresed, becuse lveolr ventiltion is mrkedly incresed. The present study lso showed tht in the PEEP levels rnging from Po 4 to Po, VD/VT ws grdully reduced. However, when the PEEP levels rnged from Po+2 to Po+4 cm H 2 O, VD/VT incresed gin. A previous study demonstrted tht VD ws significntly incresed in piglets with higher PEEP (20 cm H 2 O), which ws induced by hyperinfltion of the lung region (35). In ARDS, the lveolr collpse cuses deficiency of lveolr ventiltion while the blood flow does not significntly decrese nd VD/VT increses, which leds to decline of the ventiltion nd blood flow nd increse of Qs/Qt. In the present study, the Qs/Qt rtio chieved its mximum vlue with the increse of VD/VT in ARDS conditions. Under the ppliction of PEEP, the Qs/Qt rtio showed trend of decline to pproch the bse vlue with the reduction of VD/VT. Furthermore, Qs/Qt reched its minimum under the optiml PEEP stte. Higher PEEP increses VD/VT vi reduction in crdic output (32,36). In the present study, following the ppliction of PEEP, CVP incresed s the PEEP incresed, indicting tht PEEP significntly ffected the loding conditions of the right trium to reduce the volume of returned blood. The increse of CVP might be due to the ugmenttion of intrpleurl pressure nd ven cv reflux resistnce tht were induced by the high PEEP levels. Moreover, the reduction of returned blood volume gives rise to reduction of left trium crdic output, which is in ccordnce with the present study's findings tht the CI grdully declined with the increse of PEEP. Notbly, CI hd no evident significnt difference mong PEEP sttes, becuse the PEEP rnge in this study ws <20 cm H 2 O. In conclusion, mesurement of VD/VT is vluble in ssessing the effects of lung recruitment. The miniml VD/VT cn be used s one of mny options for the ssessment of PEEP titrtion in ARDS. In the context of RM nd PEEP titrtion procedure, reduction in VD/VT nd Qs/Qt, nd n increse in Cdyn nd P/F indicte mximum mount of effectively expnded lveoli. The VD/VT my be prospectively used in future clinicl trils, prticulrly when the gol is to evlute the benefit of n open lung protective ventiltion strtegy in ptients with ARDS. However, there re certin limittions to the present study. In the context of RM nd PEEP, lveolr ventiltion volume could not be ssessed by direct computed tomogrphy methods. In ddition, PEEP ws not evluted t >20 cm H 2 O fter RM in the ARDS model, so it is impossible to comment on the effect of higher PEEP on VD/VT nd Qs/Qt under those circumstnces. Finlly, the smple size of 12 swine

6 BIAN et l: VD/VT TITRATED OPTIMAL PEEP 1577 is reltively smll, nd rgubly underpowered to detect n importnt effect. Acknowledgements This study ws supported by grnt from the Ntionl Nturl Science Foundtion of Chin (grnt no ). References 1. Phu J, Bdi JR, Adhikri NK, Friedrich JO, Fowler RA, Singh JM, Scles DC, Stther DR, Li A, Jones A, et l: Hs mortlity from cute respirtory distress syndrome decresed over time? A systemtic review. Am J Respir Crit Cre Med 179: , Petty TL: Acute respirtory distress syndrome (ARDS). Dis Mon 36: 1 58, Villr J, Blnco J, Añón JM, Sntos Bouz A, Blnch L, Ambrós A, Gndí F, Crriedo D, Mosteiro F, Bsldú S, et l: The ALIEN study: Incidence nd outcome of cute respirtory distress syndrome in the er of lung protective ventiltion. Intensive Cre Med 37: , Bull TM, Clrk B, McFnn K nd Moss M; Ntionl Institutes of Helth/Ntionl Hert, Lung, nd Blood Institute ARDS Network: Pulmonry vsculr dysfunction is ssocited with poor outcomes in ptients with cute lung injury. 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