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  Individualized PEEP Setting in Subjects With ARDS:A Randomized Controlled Pilot Study María-Consuelo Pintado MD PhD, Rau´l de Pablo MD PhD, María Trascasa,Jose´-María Milicua, Santiago Rogero, Martín Daguerre, Jose´-Andre´s Cambronero,Ignacio Arribas MD PhD, and Miguel Sa´nchez-García MD PhD BACKGROUND: Low-tidal-volume ventilation may be associated with repetitive opening andclosing of terminal airways. The use of PEEP is intended to keep the alveoli open. No method of adjusting the optimal PEEP has shown to be superior or to improve clinical outcomes. We con-ducted a pilot study to evaluate the effect of setting an individualized level of PEEP at the highestcompliance on oxygenation, multiple-organ-dysfunction, and survival in subjects with ARDS.METHODS: Subjects with ARDS ventilated with low tidal volumes and limitation of airway pres-sure to 30 cm H 2 O were randomized to either a compliance-guided PEEP group or an F IO 2 -guidedgroup. RESULTS: Of the 159 patients with ARDS admitted during the study period, 70 met theinclusion criteria. Subjects in the compliance-guided group showed nonsignificant improvements inP aO 2  /F IO 2 during the first 14 days, and in 28-day mortality (20.6% vs. 38.9%,  P    .12). Multiple-organ-dysfunction-free days (median 6 vs 20.5 d,  P  .02), respiratory-failure-free days (median 7.5vs 14.5 d,  P  .03), and hemodynamic-failure-free days (median 16 vs 22 d,  P  .04) at 28 days weresignificantly lower in subjects with compliance-guided setting of PEEP. CONCLUSIONS: In ARDSsubjects, protective mechanical ventilation with PEEP application according to the highest com-pliance was associated with less organ dysfunction and a strong nonsignificant trend toward lowermortality. ClinicalTrials.gov Number NCT01119872.  Key words: ARDS; mechanical ventilation; tidalvolume; multiple organ dysfunction.  [Respir Care 2013;58(9):1416–1423. © 2013 Daedalus Enterprises] Introduction ARDS is characterized by the acute onset of hypoxemiaand bilateral infiltrates that are consistent with pulmonaryedema, without evidence of left heart failure. 1 Mechanicalventilation is potentially lifesaving in patients with ARDS,but may cause ventilator-associated lung injury. Lung-protective ventilation strategies seek to prevent ventilator-associated lung injury by using low tidal volume (V T ) toavoid overdistention, and PEEP to prevent repetitive alve-olar collapse and reopening. 2-4 S EE THE  R ELATED  E DITORIAL ON  P AGE  1552 The application of PEEP improves gas exchange andlung function. The main effect of increasing PEEP is tomaintain the recruitment of alveolar units that were pre-viously collapsed. Thus, since the V T  is distributed to morealveoli, peak airway pressure is reduced and compliance isincreased. 5 However, the pressure needed to open and re-cruit some alveoli may overdistend others, which maydirect blood perfusion away from these areas, thereby in-creasing dead space, pulmonary vascular resistance, and Dr Pintado, Dr de Pablo, Ms Trascasa, Mr Milicua, Mr Rogero,Mr Daguerre, Dr Cambronero, and Dr Sa´nchez-García are affiliated withthe Intensive Care Unit; and Dr Arribas is affiliated with the Foundationfor Biomedical Research, Hospital Universitario Príncipe de Asturias,Alcala´ de Henares, Madrid, Spain.Drs Pintado and de Pablo are co-first authors.Supplementary material related to this paper is available at http:// www.rcjournal.com.Correspondence: María-Consuelo Pintado MD PhD, Intensive Care Unit,Hospital Universitario Príncipe de Asturias, Carretera Alcala´-Meco,SN E-28805, Alcala´ de Henares, Madrid, Spain. E-mail: consuelopintado@yahoo.es.DOI: 10.4187/respcare.02068 1416 R ESPIRATORY  C ARE  ã  S EPTEMBER  2013 V OL  58 N O  9  mean hydrostatic pressure, and thus increase lung dam-age. 6 The preferred method of adjusting the PEEP is stillcontroversial. 7,8 The amount of potentially recruitable lungtissue has best been evaluated using computed tomogra-phy, 9 but this approach is usually not readily available inICUs for routine assessment of ventilator settings.Some have suggested that lung mechanics are a bettersurrogate than gas exchange for bedside assessment of lung recruitment, 10 and that the PEEP should be chosenindividually. 10-12 In fact, several studies have shown im-proved survival when PEEP is set above the lower in-flection point on the pressure-volume curve, the steepestportion of the curve, a sign of increase of functional re-sidual capacity. 12-15 Unfortunately, all these studies alsocompared low versus high V T  ventilation, which hindersevaluation of the effect directly attributable to PEEP. Re-cently, 2 studies compared different methods of PEEPsetting. One study, based on individual maximum alveolarrecruitment, failed to demonstrate a reduction in mortality,although they observed significant improvements in oxy-genation 16 and lung function. 17 Weconductedanopen,randomizedcontrolledpilotstudyto test the hypothesis that individualized PEEP set basedon highest compliance would improve oxygenation, com-pared to setting PEEP based on F IO 2 . 18 Methods This study was conducted in a 14-bed mixed medical-surgical ICU in Spain, over a time period of 60 months.The study protocol was approved by our institution’sEthics and Clinical Trials Committee, and registered athttp://clinicaltrials.gov (NCT01119872). Written informedconsent was required for inclusion, and obtained from thenearest relatives. No commercial entities had any role inany aspect of this study.We screened all patients with ARDS according to theAmerican-Europeanconsensusconferencedefinition, 1 whomaintained ARDS criteria after 24 hours of mechanicalventilation, in order to confirm ARDS and exclude othercauses of hypoxemia and pulmonary infiltrates, since me-chanical ventilation parameters can affect oxygenation andwhether the patient meets the ARDS definition. 19 We ex-cluded patients who were younger than 18 years, pregnant,or had neuromuscular disease, intracranial hypertension,head trauma, left ventricular dysfunction (on echocardiog-raphy),    72 hours of mechanical ventilation, or baro-trauma. Patients with end-stage conditions (death expectedwithin 90 days) were also excluded. We defined baro-trauma as the presence of air outside the tracheobronchialtree, resulting from presumed alveolar rupture, and man-ifested as interstitial emphysema, pneumothorax, pneumo-mediastinum,pneumoperitoneum,orsubcutaneousemphy-sema. 20 Patients who developed barotrauma during thefirst 24 hours of observation prior to randomization werealso excluded, because it was not feasible to measure pla-teau pressure. In subjects excluded after randomization,the respiratory protocol was not applied, although protec-tive lung ventilation was maintained, and they were kept intheir assigned study groups for outcome analysis. Study Design All patients who met ARDS criteria were ventilatedduring 24 hours with low V T  (6–8 mL/kg predicted bodyweight [PBW]), an inspiratory plateau pressure    30 cmH 2 O, a breathing frequency of 30 breaths/min, adjusted tomaintain a pH between 7.30 and 7.45, and limited to amaximum of 35 breaths/min, F IO 2 that kept arterial oxygensaturation at 88–95% or P aO 2 at 55–80 mm Hg, and PEEPadjusted to achieve the best oxygenation with the lowestF IO 2 while avoiding adverse hemodynamic effects. If theplateau pressure was    30 cm H 2 O with a V T  of 6 mL/ kg PBW, a stepwise V T  reduction of 1 mL/kg PBW to aslow as 4 mL/kg/PBW was allowed, in which case theplateau pressure limit was set at 35 cm H 2 O.After 24 hours, subjects who met the inclusion criteriawere randomized to either F IO 2 -guided PEEP (controlgroup) or compliance-guided PEEP. Randomization wasperformed in blocks of 10, using sealed envelopes.In the control group, PEEP was set based on the sub- ject’s F IO 2 , as applied in the ARDS Network study. 18 In thecompliance-guided group, PEEP was set daily, accordingto the method described by Suter et al. 12 Static compliancewas measured at increasing levels of PEEP and at constantPEEP. Static compliance was calculated as V T  divided bythe pressure difference at end of inflation hold (2 s), andPEEP was increased in steps of 2 cm H 2 O, beginning at5 cm H 2 O, without an upper PEEP titration limit. Thehighest static compliance was considered to be the bestPEEP. If at 2 different PEEPs the static compliance was QUICK LOOKCurrent knowledge Lung-protective ventilation (low tidal volume and lim-ited plateau pressure) improves outcomes in ARDS, butthe best method of selecting the PEEP is controversial,and clinical trials have had conflicting results. What this paper contributes to our knowledge In ARDS patients, low-tidal-volume ventilation cou-pled with PEEP set according to the highest pul-monary compliance was associated with more organ-dysfunction-free days and a trend toward lower mortality. I NDIVIDUALIZED  PEEP S ETTING IN  S UBJECTS  W ITH  ARDSR ESPIRATORY  C ARE  ã  S EPTEMBER  2013 V OL  58 N O  9 1417  identical, we chose the one with the lower plateau pressure(see the respiratory protocol in the supplementary materi-als at http://www.rcjournal.com). All subjects receivedsedatives and opioids at the time of PEEP setting. Neuro-muscularblockingagentswereusedasrequiredforlow-V T ventilation, although not for the measurement of intrinsicPEEP or plateau pressure.According to the study group, PEEP was adjusted oncedaily during the morning shift, until the weaning phasestarted. Intrinsic PEEP was measured before and after ev-ery change of applied PEEP, and the inspiratory/expiratoryratio was changed accordingly to prevent intrinsic PEEP.All other ventilator parameters were set in the same wayin both study groups, following the protocol applied for24 hours before randomization. 18 The weaning protocol was identical for both groups.Weaning was begun if the cause of respiratory failure hadresolved, P aO 2 was    60 mm Hg, F IO 2 was    0.4, andPEEP was below 6 cm H 2 O. In the compliance-guidedgroup, PEEP was lowered by steps of 2 cm H 2 O. In thecontrol group we applied the protocol described in theARDS Network study 18 (see the supplementary materialsat http://www.rcjournal.com).Subjects were monitored with a pulmonary artery cath-eter for at least the first 72 hours after randomization, tostudy the hemodynamic effects of PEEP. Therapy otherthan mechanical ventilation was prescribed at the discre-tion of the attending physicians not involved in the study.Our local protocols were applied to guide sedation, hemo-dynamic support, and other standard interventions.End points were assessed at 28 days. The primaryend point was P aO 2  /F IO 2 . Secondary end points were mor-tality, ventilator-free days, ICU and hospital stay, multiple-organ-dysfunction (MOD) free days, and respiratory andhemodynamic parameters. Measurements Data collected from each subject included demograph-ics, risk factors for ARDS, routine laboratory measure-ments, Acute Physiology and Chronic Health Evaluation IIscore 21 at ICU admission, daily Lung Injury Score, 22 Sepsis-Related Organ Failure Assessment score, 23 MODscore, 24 days on mechanical ventilation, ICU and hospitaloutcomes and stay, 28-day mortality, pulmonary mea-surements, physiologic measurements, ventilatory mea-surements, cardiovascular measurements, adverse events,extrapulmonary organ failures, sedation, and daily chestx-ray. All measurements and data were recorded at studyinclusion, at 6 hours after inclusion, and between 6:00  AM and 8:00  AM  on days 1, 2, 3, 4, 7, 14, 21, and 28.Organ failure was defined as a Sepsis-Related OrganFailure Assessment score 23   2, and MOD requires    2organ failures. Organ-dysfunction-free days were de-fined as days alive and free of any organ dysfunction, 15,17 and ventilator-free days were defined as days of unassistedbreathing, both calculated at 28 days (all deaths oc-curring prior to day 28 were considered as zero organ-dysfunction-free or ventilator-free days). 18 Subjects werefollowed until hospital discharge or death. Statistical Analysis Normality of data distribution was assessed using theKolmogorov-Smirnovtest.Quantitativevariableswithnor-mal distribution are expressed as mean    SD, and werecompared using the Student  t   test. Non-normal distributionvariables are shown as medians and interquartile ranges,and were compared using the Mann-Whitney test. Quali-tative variables are shown as percentages, and were com-pared with the chi-square test. Kaplan-Meier analysis withlog-rank test was applied to compare survival at 28 daysbetween groups. Statistical significance was set at  P  .05,and results are expressed with their 95% confidence inter-vals.Statisticalanalysiswasperformedusingstatisticssoft-ware (SPSS 15.0, SPSS, Chicago, Illinois). Results A total of 159 patients met the criteria for ARDS duringthe study period, 70 of whom were randomized to either Fig. 1. Screening and enrollment. I NDIVIDUALIZED  PEEP S ETTING IN  S UBJECTS  W ITH  ARDS1418 R ESPIRATORY  C ARE  ã  S EPTEMBER  2013 V OL  58 N O  9  compliance-guided ( n  34) or F IO 2 -guided PEEP adjust-ment ( n    36) (Fig. 1). No patients were excluded afterrandomization or discharged from hospital earlier than28 days.The main cause of ARDS was infection ( n  50, 71.4%)(detailed causes of ARDS per study group are shown inthe supplementary materials at http://www.rcjournal.com).There were no significant differences in subject character-istics between study groups at randomization, except forthehighincidenceofMODinthecompliance-guidedgroup(Table 1). Physiological Measurements There was no difference in median PEEP at study entry(Fig. 2). Figure 3 shows the ventilatory parameters overthe 28-day study period. There was no significant differ-ence in P aO 2  /F IO 2 . There was a trend toward better oxy-genation in the compliance-guided group over the first2 weeks of study (see Fig. 3 and the supplementary ma-terials at http://www.rcjournal.com). In the compliance-guided group there was also a nonsignificantly higher pul-monary compliance and lower airway pressure (see Fig. 3and the supplementary materials at http://www.rcjournal.com). There were no differences in pH, V T , intrinsic PEEP,or breathing frequency (see the supplementary materials athttp://www.rcjournal.com).In a post-hoc analysis we found that 80% of the subjectsin the compliance-guided group would have had a differ-ent PEEP if set according to the F IO 2  /PEEP table. Therewere no limitations in daily PEEP changes, rather than themeasurement frequency of PEEP. Clinical Outcomes The compliance-guided group had significantly moreMOD-free days at day 28 (Table 2), in spite of a higherbaseline incidence (see Table 1), as well as more ventila-tor-free days and hemodynamic failure-free days.Twelve subjects developed barotrauma after randomiza-tion: 6 per study group (see Table 2). A total of 9 episodes Table 1. Baseline Characteristics of Subjects at Study InclusionF IO 2 -Guided PEEP( n  36)Compliance-Guided PEEP( n  34)Male, no. (%) 29 (80.55) 20 (58.82)Age, y 54.1  2.9 55.6  3.1APACHE II score 20.53  1.33 18.71  1.02SOFA score 8.86  0.61 9.38  0.66Multiple-organ-dysfunction score 8.36  0.52 8.50  0.57Lung Injury Score, median (IQR) 3 (2.5–3.25) 3 (2.5–3.25)Percentage of patients with multiple-organ-dysfunction syndrome* 77.8 97.1P aO 2  /F IO 2 , mm Hg 133.15  5.88 146.33  6.19PEEP pre-randomization, median (IQR) cm H 2 O 10 (8–14) 10 (8–12)Tidal volume, mL/kg predicted body weight 6.61  0.87 6.66  1.01Peak pressure, cm H 2 O 38.10  1.11 38.22  1.33Plateau pressure, cm H 2 O 31.87  1.56 28.24  1.22Breathing frequency, breaths/min 23  1 25  1Minute ventilation, L/min 12.1  0.4 12.9  0.4pH 7.34  0.01 7.33  0.01P aCO 2 , mm Hg 43.28  1.27 42.11  1.01 Values are mean   SD unless otherwise indicated.* There were no significant differences between the groups at study randomization, except percentage of patients with multiple-organ-dysfunction syndrome:  P  .02.APACHE  Acute Physiology and Chronic Health EvaluationSOFA  sepsis-related organ failure assessment Fig. 2. PEEP in the first 28 days. I NDIVIDUALIZED  PEEP S ETTING IN  S UBJECTS  W ITH  ARDSR ESPIRATORY  C ARE  ã  S EPTEMBER  2013 V OL  58 N O  9 1419
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