ARDSnet Ventilatory Protocol and Alveolar Hyperinflation: Role of Positive End-Expiratory Pressure

By Grasso, Salvatore Stripoli, Tania; De Michele, Michele; Bruno, Francesco; Moschetta, Marco; Angelelli, Giuseppe; Munno, Irene; Ruggiero, Vincenzo; Anaclerio, Roberto; Cafarelli, Aldo; Driessen, Bernd; Fiore, Tommaso

Rationale: In patients with acute respiratory distress syndrome (ARDS), a focal distribution of loss of aeration in lung computed tomography predicts low potential for alveolar recruitment and susceptibility to alveolar hyperinflation with high levels of positive end-expiratory pressure (PEEP). Objectives:We tested the hypothesis that, in this cohort of patients, the table-based PEEP setting criteria of the National Heart, Lung, and Blood Institute’s ARDS Network (ARDSnet) low tidal volume ventilatory protocol could induce tidal alveolar hyperinflation.

Methods: In 15 patients, physiologic parameters and plasma inflammatory mediators were measured during two ventilatory strategies, applied randomly: the ARDSnet and the stress index strategy. The latter used the same ARDSnet ventilatory pattern except for the PEEP level, which was adjusted based on the stress index, a monitoring tool intended to quantify tidal alveolar hyperinflation and/or recruiting/derecruiting that occurs during constant-flow ventilation, on a breath-by-breath basis.

Measurements and Main Results: In all patients, the stress index revealed alveolar hyperinflation during application of the ARDSnet strategy, and consequently, PEEP was significantly decreased (P

Conclusions: Alveolar hyperinflation in patients with focal ARDS ventilated with the ARDSnet protocol is attenuated by a physiologic approach to PEEP setting based on the stress index measurement.

Keywords: acute lung injury; inflammatory response; mechanical ventilation; ventilator-induced lung injury

Mechanical ventilation can exacerbate the inflammatory response in patients with acute respiratory distress syndrome (ARDS) by inducing cyclic tidal alveolar hyperinflation and/or recruiting/ derecruiting (1). Several protective ventilatory strategies have been proposed to minimize these forms of ventilator-induced micromechanical stress. A randomized multicenter study by the National Heart, Lung, and Blood Institute’s ARDS Network (ARDSnet) comparing tidal volumes of 6 versus 12 ml/kg predicted body weight showed a significantly better survival in those individuals allocated to the low tidal volume arm (2). However, because the same positive end-expiratory pressure (PEEP) setting criteria (protocolized alternating increases of PEEP and inspired oxygen fraction [FIO^sub 2^]) were applied in both arms of the ARDSnet study, their impact in terms of lung protection remains unclear (3). Moreover, a more recent ARDSnet investigation (Assessment of Low Tidal Volume and Elevated End Expiratory volume to Obviate Lung Injury [ALVEOLI] trial) (4), testing the effects on mortality of a “higher” PEEP titration table, did not show any improvement when compared with the original trial. A study by our group suggests, as a possible explanation of this result, that the table-based approach to the higher PEEP setting of the ALVEOLI study may have failed to induce a physiologic response in terms of alveolar recruitment in a significant group of patients (5).

Using computed tomography (CT), Gattinoni and coworkers have recently shown that the potential for alveolar recruitment is quite variable among patients with ARDS (6). Previously, the CT Scan ARDS study group classified ARDS into focal (36% of patients), diffuse (23%), and patchy (41%), based on the pattern of distribution of loss of aeration (7, 8), and showed that the chances of producing alveolar recruitment with PEEP can be predicted a priori using this classification (9). Accordingly, in patients with a focal distribution of loss of aeration (i.e., with atelectatic dependent lobes coexisting with aerated nondependent lobes), the use of high PEEP levels (15-20 cm H2O) resulted in minimal alveolar recruitment in the dependent lobes but significant hyperinflation in the nondependent lung lobes (10).

In the present study, we tested the hypothesis that ventilation using the standardized ARDSnet PEEP-FIO[sub]2[/sub] protocol would induce alveolar hyperinflation in patients with focal ARDS. Therefore, we compared in these patients the ARDSnet ventilatory strategy with an alternative strategy characterized by a more “physiologic” titration of PEEP, aimed at minimizing ventilator- induced tidal hyperinflation. To do so, we adjusted PEEP based on stress index monitoring, as recently proposed by De Perrot and colleagues and Ranieri and coworkers (11-13). The stress index is determined on a breath-by-breath basis during constant-flow ventilation by analyzing the shape of the in-spiratory airway opening pressure curve. This approach assumes that, during constant- flow tidal inflation, the rate of change in airway opening pressure over time reflects the rate of change in elastance of the respiratory system (14). A recent CT study suggested that the stress index may accurately quantify the degree of tidal alveolar hyperinflation (15).

Parts of this study have previously been reported in abstract format (16).

METHODS

Additional details provided in the online supplement.

Patients with early ARDS (17), fulfilling the inclusion criteria of the ARDSnet protocol (2), were included in the study provided they had undergone a thoracic CT scan for clinical purposes in the preceding 24 hours that revealed a pattern of focal loss of aeration according to the CT Scan ARDS study group criteria (7, 9). The qualitative CT analysis was performed by two independent radiologists (G.A. and M.M.). The institutional review board for clinical studies approved the protocol, and written, informed consent was obtained from each patient or his or her next of kin before enrollment into the study.

Measurements

Static elastance (partitioned for respiratory system, chest wall, and lung), quasi-static pressure-volume curves of the respiratory system (low-flow technique), and PEEP-induced alveolar recruitment were measured as previously described (5).

The stress index was measured during constant-flow assist- control mechanical ventilation without changing the baseline ventilatory pattern, as previously described (11-13, 15) (further details are provided in the online supplement). Briefly, a computer program (ICU-LAB; KleisTEK, Bari, Italy) aided in identifying the steady part of the inspiratory flow and the corresponding portion of the airway opening pressure curve, and in fitting to the latter the following power equation:

airway pressure=a . inspiratory time^sup b^+c,

where the coefficient b (“stress index”) describes the shape of the curve. For stress index values of less than 1, the curve presents a downward concavity suggesting a continuous decrease in elastance. For stress index values of higher than 1, the curve presents an upward concavity suggesting a continuous increase in elastance. Finally, for a stress index value equal to 1, the curve is straight, suggesting the absence of tidal variations in elastance (Figure 1). To suppress eventual spontaneous inspiratory efforts during the measurement, the baseline sedation level (Ramsay score 3- 4) (18) could be briefly (10-15 min) increased to a Ramsay score of 5 during stress index measurements. No further increase in sedation or neuromuscular blockade was allowed to facilitate the stress measurement.

Invasive arterial pressure, heart rate, right atrial pressure, continuous cardiac output (via transesophageal Doppler, Cardio Q; Deltex Medical, Chichester, UK), and arterial blood gases (Rapid Lab 865; Bayer Diagnostics, Dublin, Ireland) were determined under each experimental condition.

Plasma concentrations of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-a, and soluble TNF-alpha receptors I and II (sTNF- alpha RI and II) were measured with commercially available kits for solid-phase ELISAs (IL-6, IL-8, TNF-alpha; Bender Medical Systems, Vienna, Austria; sTNF-alpha RI and II; HyCult Biotechnology, Uden, The Netherlands).

Study Protocol

From the moment the diagnosis of ARDS was made all patients were ventilated following the ARDSnet protocol. During the study period of 24 hours, each patient was initially ventilated for 12 hours following the ARDSnet strategy (2) and for the subsequent 12 hours following the stress index strategy, or vice versa. The sequence of application of the two strategies was randomly assigned to patients using a concealed allocation approach by choosing between sealed envelopes that contained the individual procedure sequence. The stress index strategy used the same ARDSnet ventilatory pattern, except for the PEEP level, which was titrated to effect-that is, targeting a stress index between 0.9 and 1.1, a normal range identified according to previous investigations (12, 15). If, during the ARDSnet strategy application, the stress index was higher than 1.1, PEEP was decreased to achieve a value between 0.9 and 1.1; if stress index values between 0.9 and 1.1 were measured, no change was made; and if the stress index was lower than 0.9, PEEP was increased. Adjustment of PEEP was suspended if any one of the following conditions ensued: plateau pressure >30 cm H2O, SaO^sub 2^

Statistical Analysis

Data are presented as mean +- SD. Because plasma cytokine determinations were not normally distributed, values were expressed as median and 25th-75th interquartile range. Comparisons between the two ventilatory strategies were performed using analysis of variance for repeated measures followed by a Student t test for paired samples, or a Wilcoxon signed-rank test, where appropriate. A P value of less than 0.05 indicated significant differences between values. Statistical analysis was performed using the software package StatView (Abacus, Inc., Berkeley, CA).

RESULTS

The study was conducted in from January 2004 to February 2006. In this period, 964 patients were admitted to our 16-bed intensive care unit. ARDS was diagnosed in 114 (11.8%) of patients. Of those, 92 (80.7%) patients underwent thoracic CT scan within the first 3 days of diagnosis of ARDS, and the qualitative analysis of CT scans according to the CT Scan ARDS study group criteria revealed a focal, patchy, and diffuse pattern of loss of aeration in 30 (32.6%), 44 (47.8%), and 18 (19.6%) of patients, respectively. Hence, only 30 patients with early focal ARDS were considered eligible for inclusion in the study. Of those, 15 were excluded (10 because they did not meet the inclusion criteria of the ARDSnet protocol, 5 because they refused informed consent). All the 15 patients admitted completed the study; of those, 7 were randomized to the sequence ARDSnet strategy-stress index strategy and 8 to the stress index- ARDSnet strategy. Baseline ventilatory settings and demographic and clinical data of the 15 patients enrolled in the study are shown in Table 1. In seven patients, ARDS was of pulmonary origin.

In all patients, the stress index value during ARDSnet strategy ventilation was higher than 1.1 (1.154 +- 0.054). To implement the stress index strategy, in all patients PEEP was reduced accordingly. The target stress index range (0.90-1.1) was reached in all patients (1.008 +- 0.054, P

Figure 2 and Table 2 show the ventilatory, respiratory mechanics, and gas exchange parameters at the end of each study period. By protocol, FIO[sub]2[/sub] and VT were left unchanged. The PEEP value was significantly lower during the period the stress index strategy was used as compared with the period the ARDSnet strategy was used (6.8 +- 2.2 vs. 13.2 +- 2.4 cm H2 O, P

Figure 4 shows the quasi-static volume-pressure curves obtained in three representative patients under the two experimental conditions. Of note, the volume-pressure curves recorded during the ARDSnet strategy application were almost superimposed to those measured during the period the stress index strategy was applied, indicating minimal differences in alveolar derecruitment between the two strategies, despite a significant PEEP reduction. Overall, the alveolar derecruitment was between 25 and 145 ml (mean, 70 +- 39 ml).

Cardiac output was significantly lower (6 +- 0.8 vs. 7.1 +- 1.4 L/ min, P = 0.0163) and systemic vascular resistances higher (1,190 +- 200 vs. 974 +- 297 dyne . s . cm^sup -5^, P = 0.0491) when the ARDSnet strategy was applied. Mean arterial pressure and heart rate were not different.

Plasma levels of IL-6, IL-8, and sTNF-alpha RI were significantly higher during the phase of ARDSnet ventilation than during the period of stress index-guided ventilation, whereas the levels of TNF- alpha and sTNF-alpha RII were not significantly affected by the two strategies (Figure 5).

DISCUSSION

Our data support the hypothesis that application of the ARDSnet protocol may generate tidal alveolar hyperinflation in patients with ARDS with a focal pattern of loss of aeration. Furthermore, they show that the observed hyperinflation is likely due to the PEEP setting criteria of this specific protocol (table based, alternating PEEP and FIO[sub]2[/sub] increases to achieve an oxygenation target). We demonstrated that adjusting PEEP based on the respiratory system mechanics of an individual patient allows reduced risk of alveolar hyperinflation.

In the present study, the application of the stress index analysis revealed the occurrence of tidal alveolar hyperinflation in patients with focal ARDS who were ventilated using the ARDSnet protocol. Previous studies have documented the ability of the stress index to qualitatively detect alveolar hyperinflation in humans, both in adults (13) and children (19), as compared with static pressure-volume curves. However, human studies comparing the stress index method against the reference CT scan method are not available. A recent experimental CT study demonstrated that the amount of lung tissue subject to tidal alveolar hyperinflation grows exponentially for stress index values higher than 1.1, whereas it is negligible for stress index vales in the 0.9-1.1 range (15), but we must point out that this study was conducted in a surfactant-depleted ARDS model and under a wide range of stress indices. Therefore, the ability of the stress index to exactly quantify the amount of lung tissue undergoing tidal alveolar hyperinflation in the clinical context needs further validation. Moreover, PaCO^sub 2^ was significantly higher during the ARDSnet strategy period, whereas minute ventilation was not significantly different between the two modalities (Table 2). This provides further indirect evidence for alveolar overinflation during ARDSnet strategy-guided ventilation (20), but because we have compared PaCO^sub 2^ values recorded at the end of each study period (i.e., at a time interval of 12 h), effects of differences in metabolic CO2 production therefore cannot be ruled out. Finally, despite the PEEP level being significantly lower during the stress index strategy period as compared with the phase when the ARDSnet strategy was applied, static lung elastance improved and a slight, albeit significant, alveolar derecruitment occurred without worsening of arterial oxygenation. These data indirectly suggest that alveolar hyperinflation had developed during the ARDSnet ventilation period.

The rationale of the ARDSnet protective ventilatory strategy (2) is to minimize tidal alveolar hyperinflation, a well-known cause of ventilator-induced lung injury (1). The practical and standardized approach chosen by the ARDSnet investigators was deemed appropriate for a multicenter clinical study, involving hundreds of patients (21). However, ARDS is a complex condition, characterized by differences in etiology (22), severity, derangement of respiratory mechanics, and potential for alveolar recruitment (6). In patients with focal ARDS, lacking alveolar recruitment, oxygenation is likely more influenced by the applied FIO^sub 2^ than by PEEP (23), and we may speculate (as recently suggested [24]) that applying the ARDS- net PEEP-FIO^sub 2^ table (which mandates simultaneous PEEP and FIO^sub 2^ increases) may lead to the selection of higher PEEP levels merely to arrive at the higher FIO^sub 2^ levels predicted in the table, which unfortunately provokes tidal alveolar hyperinflation. Our data suggest that, in patients with focal ARDS, titrating PEEP to a lower level than the one prescribed by the ARDSnet protocol allows reducing the risk of hyperinflation and elevated plasma levels of inflammatory mediators. However, this implies that the development of dependent atelectasis is to some extent “tolerated.” Another possible approach would be use of aggressive recruitment maneuvers (in which airway pressures would be raised to values as high as 60 cm H2O) with subsequent use of high PEEP levels. Such a strategy has recently been shown to drastically reduce atelectasis, hyperinflation, and lung inflammation (25). Further studies are warranted to determine whether one of those two opposite approaches would be more beneficial in terms of clinical outcome parameters (3, 24, 26).

In our patients, plateau pressure was lower than 30 cm H2O during the period when the ARDSnet strategy was applied. Although several studies have suggested that this is a relatively safe threshold, we found a significant decrease in circulating inflammatory mediators by further lowering plateau pressures during the stress index strategy. Our data seem to accord with a recent review by Hager and coworkers (27) suggesting that reducing the “safe threshold” for plateau pressure below 30 cm H2 O could further limit ventilator- induced lung injury. In a recent study (28), Terragni and coworkers identified two groups among patients ventilated with the ARDSnet protocol: one “more” and one “less” protected against lung mechanical stress. Interestingly, less protected patients were characterized by significantly higher plateau pressures when compared with more protected patients. The authors speculated that the VT limitation prescribed by the ARDSnet protocol could be insufficient in the group of less protected patients. Our data seem to emphasize the role of PEEP in inducing lung hyperinflation in patients with focal ARDS. Of note, the less protected patients in the Terragni study were ventilated with significantly higher PEEP and FIO[sub]2[/sub] levels than those classified as being more protected, and the authors reported that less protected patients were characterized by a larger, dependent, nonaerated compartment, suggesting that they were affected by focal ARDS. We have tested a protective ventilatory protocol different from that of the ARDSnet because the PEEP level was chosen on the basis of stress index monitoring. The main advantage of the stress index monitoring is the potential for breath-by-breath determination of ventilator-induced lung mechanical stress, accomplished without the need for disconnecting the patient from the ventilator or changing ventilatory settings. In addition, if lung parenchyma is not homogeneously diseased, it could theoretically happen that regions where resistances and/or compliance are lower are dynamically hyperinflated during tidal inflation (29). None of the pressure- volume curves measured under static or quasi-static conditions or CT scans obtained during an end-inspiratory pause may detect such additional amount of alveolar hyperinflation, whereas the stress index may potentially be suitable to do it (14). However, this assumption has not been demonstrated and deserves further investigation. Although several theoretical assumptions are made when interpreting the stress index determination as a valid parameter (11, 12, 15) (see the online supplement for further discussion), the stress index has been shown to provide the same information as the static volume-pressure curve regarding the elastic properties of the respiratory system in both adults (13) and children (19). In a rat model, it predicted a noninjurious ventilatory strategy with a high positive power (12), whereas a stress index- guided ventilatory protocol was successfully applied in a mouse lung transplant model to protect the transplanted lung from ventilator-induced lung injury (11). In our study, for the clinical implementation of the stress index, one important point was to rule out the possible influence of spontaneous inspiratory efforts on the shape of the airway pressure-time curve (30). Although we report that 80% of the measurements were possible at a sedation level of Ramsay score 3-4 and that a transient increase to a level 5 allowed the measurement in the remaining 20% of the measurements, in a recent study even a sedation level of Ramsay 5 allowed obtaining a reliable measurement of a quasi-static volume- pressure curve in only 10 of 19 patients with ARDS (31). A possible explanation for the difference between the two studies could be the different time window (

Mechanical ventilation may be an important factor in determining systemic cytokine levels in patients with ARDS. Several human and experimental studies have documented that tidal alveolar hyperinflation and/or opening and collapse may increase plasma levels of cytokines, due to the disruption of the alveolar epithelial-endothelial barrier (32-36). This has been considered a mechanism underlying the development of multiple-system organ dysfunction syndrome in these patients (1, 34). Stuber and coworkers documented a sharp increase in plasma levels of TNF-alpha, IL-6, IL- 10, and IL-1beta within 1 hour after switching from a protective to an injurious ventilatory strategy, which was reversed as soon as the protective strategy was resumed (35). These data support our study. During the stress index strategy period, we found a significant decrease in plasma levels of IL-6 and IL-8, two key mediators of ventilator-induced lung injury (32). However, in contrast to the former study, we did not find significant variation in plasma levels of TNF-alpha. We may speculate that these differences may be explained by the fact that, different from the work of Stuber and colleagues, we compared two protective ventilatory strategies. The significant reduction in plasma levels of sTNF-alpha RI during the stress index strategy application is of particular interest because this receptor (differently than the type II) is directly released from alveolar epithelial cells and has been shown to be a sensitive marker of ventilator-induced lung injury (37). Furthermore, the plasma levels of this receptor are associated with morbidity and mortality in patients with acute lung injury (37).

Some limitations of this study must addressed:

1. The inclusion of patients with “diffuse” or “patchy” patterns of loss of aeration would have potentially broadened the impact of our investigation, and this issue deserves further investigation.

2. The stress index calculation is presently feasible only during constant-flow ventilation, whereas a decelerating ramp in-spiratory flow is frequently applied. In the online supplement, we present a theoretical approach to the application of the stress index software in this condition.

3. We report a slight (albeit significant) alveolar derecruitment, without significant changes in arterial oxygenation, even though PEEP was markedly decreased moving from the ARDSnet to the stress index strategy. This finding, which is quite unusual for patients with earlyARDS,may be explained by considering that we studied a particular subgroup of patients with ARDS, characterized by a low potential for alveolar recruitment. This significantly limits the possible implications of our study, which must always refer to this cohort of patients.

4. Our data indicate a greater physiologic benefit of the stress index over the ARDSnet approach, but they do not provide direct evidence regarding its superiority over other possible approaches, such as using a different PEEP-FIO^sub 2^ scale or setting PEEP at the same low level (5-7 cm H2O) in all patients with focal ARDS, as suggested by Rouby and coworkers (23).

5. A logical implication of the stress index approach-that is, setting VT based on its impact on the airway opening pressure profile-was not addressed in our study.

In conclusion, our data emphasize the importance of considering both the distribution of loss of aeration and the physiologic effects of PEEP when ventilating patients with ARDS. We have applied for the first time in the clinical setting the stress index strategy, and our results suggest that it could be a better physiologic approach for setting PEEP than the PEEP-FIO^sub 2^ table. We must emphasize, however, that our short and tightly controlled physiologic study, conducted on a relatively small number of patients, was not designed to evaluate the impact of the two ventilation strategies on clinically meaningful outcome parameters, and therefore any extrapolation of our results to the clinical situation must be conducted with caution.

Conflict of Interest Statement: S.G. received V4,800 in speaker fees in scientific courses organized and financed by Tyco and Maqnet. T.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.D.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. V.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

Mechanical ventilation may exacerbate lung injury in patients with acute respiratory distress syndrome (ARDS) causing tidal alveolar hyperinflation. The ARDSnet protective ventilatory protocol was intended to minimize hyperinflation by applying low tidal volumes.

What This Study Adds to the Field

We found evidence of alveolar hyperinflation in patients with focal ARDS ventilated with the ARDSnet protocol. Individual positive end-expiratory pressure titration based on the “stress index” monitoring reduced the risk of alveolar hyperinflation.

References

1. Slutsky AS. Ventilator-induced lung injury: from barotrauma to bio-trauma. Respir Care 2005;50:646-659.

2. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308. 3. Slutsky AS, Hudson LD. PEEP or no PEEP: lung recruitment may be the solution. N Engl J Med 2006;354:1839-1841.

4. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327-336.

5. Grasso S, Fanelli V, Cafarelli A, Anaclerio R, Amabile M, Ancona G, Fiore T. Effects of high versus low positive end- expiratory pressures in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005;171:1002-1008.

6. Gattinoni L, Caironi P, Cressoni M, Chiumello D, Ranieri VM, Quintel M, Russo S, Patroniti N, Cornejo R, Bugedo G. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006;354:1775-1786.

7. Puybasset L, Cluzel P, Gusman P, Grenier P, Preteux F, Rouby JJ. Regional distribution of gas and tissue in acute respiratory distress syndrome. I. Consequences for lung morphology. CT Scan ARDS Study Group. Intensive Care Med 2000;26:857-869.

8. Rouby JJ, Puybasset L, Cluzel P, Richecoeur J, Lu Q, Grenier P. Regional distribution of gas and tissue in acute respiratory distress syndrome. II. Physiological correlations and definition of an ARDS Severity Score. CT Scan ARDS Study Group. Intensive Care Med 2000;26:1046-1056.

9. Puybasset L, Gusman P,Muller JC,Cluzel P, Coriat P, Rouby JJ. Regional distribution of gas and tissue in acute respiratory distress syndrome. III. Consequences for the effects of positive end- expiratory pressure. CT Scan ARDS Study Group. Intensive Care Med 2000;26:1215-1227.

10. Nieszkowska A, Lu Q, Vieira S, Elman M, Fetita C, Rouby JJ. Incidence and regional distribution of lung overinflation during mechanical ventilation with positive end-expiratory pressure. Crit Care Med 2004; 32:1496-1503.

11. De Perrot M, Imai Y, Volgyesi GA, Waddell TK, Liu M, Mullen JB, McRae K, Zhang H, Slutsky AS, Ranieri VM, et al. Effect of ventilator-induced lung injury on the development of reperfusion injury in a rat lung transplant model. J Thorac Cardiovasc Surg 2002;124:1137-1144.

12. Ranieri VM, Zhang H, Mascia L, Aubin M, Lin CY, Mullen JB, Grasso S, Binnie M, Volgyesi GA, Eng P, et al. Pressure-time curve predicts minimally injurious ventilatory strategy in an isolated rat lung model. Anesthesiology 2000;93:1320-1328.

13. Ranieri VM, Giuliani R, Fiore T, Dambrosio M, Milic-Emili J. Volume- pressure curve of the respiratory system predicts effects of PEEP in ARDS: “occlusion” versus “constant flow” technique. Am J Respir Crit Care Med 1994;149:19-27.

14. Suratt PM, Owens DH, Kilgore WT, Harry RR, Hsiao HS. A pulse method of measuring respiratory system compliance. J Appl Physiol 1980;49:1116-1121.

15. Grasso S, Terragni P, Mascia L, Fanelli V, Quintel M, Herrmann P, Hedenstierna G, Slutsky AS, Ranieri VM. Airway pressure- time curve profile (stress index) detects tidal recruitment/ hyperinflation in experimental acute lung injury. Crit Care Med 2004;32:1018-1027.

16. De Michele M, Munno I, Stripoli T, Garofalo D, Anaclerio R, Cafarelli A, Ancona G, Bruno F, Fiore T, Grasso, S. Effects of a physiologically oriented PEEP setting strategy on inflammatory mediators in patients with “focal” ARDS. Intensive Care Med 2006;32:s112.

17. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R. Report of the American European Consensus Conference on acute respiratory distress syn- drome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee. J Crit Care 1994;9:72-81.

18. Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. BMJ 1974;2:656-659.

19. Neve V, de la Roque ED, Leclerc F, Leteurtre S, Dorkenoo A, Sadik A, Cremer R, Logier R. Ventilator-induced overdistension in children: dynamic versus low-flow inflation volume-pressure curves. Am J Respir Crit Care Med 2000;162:139-147.

20. Gattinoni L, Vagginelli F, Carlesso E, Taccone P, Conte V, Chiumello D, Valenza F, Caironi P, Pesenti A. Decrease in PaCO2 with prone position is predictive of improved outcome in acute respiratory distress syndrome. Crit Care Med 2003;31:2727-2733.

21. Slutsky AS, Ranieri VM. Mechanical ventilation: lessons from the ARDSNet trial. Respir Res 2000;1:73-77.

22. Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A. Acute respiratory distress syndrome caused by pulmonary and extrapulmo-nary disease: different syndromes? Am J Respir Crit Care Med 1998; 158:3-11.

23. Rouby JJ, Lu Q, Goldstein I. Selecting the right level of positive end-expiratory pressure in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;165:1182-1186.

24. Rouby JJ, Brochard L. Tidal recruitment and overinflation in acute respiratory distress syndrome: yin and yang. Am J Respir Crit Care Med 2007;175:104-106.

25. Borges JB, Okamoto VN, Matos GF, Caramez MP, Arantes PR, Barros F, Souza CE, Victorino JA, Kacmarek RM, Barbas CS, et al. Reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome. Am J Respir Crit Care Med 2006;174:268-278.

26. Pesenti A, Fumagalli R. PEEP: blood gas cosmetics or a therapy for ARDS? Crit Care Med 1999;27:253-254.

27. Hager DN, Krishnan JA, Hayden DL, Brower RG. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 2005;172:1241-1245.

28. Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, Gandini G, Herrmann P, Mascia L, Quintel M, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2007;175:160-166.

29. Otis AB, McKerrow CB, Bartlett RA, Mead J, McIlroy MB, Selver Stone NJ, Radford EP Jr. Mechanical factors in distribution of pulmonary ventilation. J Appl Physiol 1956;8:427-443.

30. Marini JJ, Smith TC, Lamb VJ. External work output and force generation during synchronized intermittent mechanical ventilation: effect of machine assistance on breathing effort. Am Rev Respir Dis 1988;138:1169-1179.

31. Decailliot F, Demoule A, Maggiore SM, Jonson B, Duvaldestin P, Brochard L. Pressure-volume curves with and without muscle paralysis in acute respiratory distress syndrome. Intensive Care Med 2006; 32:1322-1328.

32. Parsons PE, Eisner MD, Thompson BT, Matthay MA, Ancukiewicz M, Bernard GR, Wheeler AP. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005;33:1-6.

33. Ranieri VM, Suter PM, Tortorella C, De TR, Dayer JM, Brienza A, Bruno F, Slutsky AS. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999;282:54-61.

34. Ranieri VM, Giunta F, Suter PM, Slutsky AS. Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome. JAMA 2000;284:43-44.

35. Stuber F, Wrigge H, Schroeder S, Wetegrove S, Zinserling J, Hoeft A, Putensen C. Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury. Intensive Care Med 2002;28:834- 841.

36. Chiumello D, Pristine G, Slutsky AS. Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med 1999;160:109-116.

37. Parsons PE, Matthay MA, Ware LB, Eisner MD. Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol 2005;288:L426-L431.

Salvatore Grasso1, Tania Stripoli1, Michele De Michele1, Francesco Bruno1, Marco Moschetta2, Giuseppe Angelelli2, Irene Munno3, Vincenzo Ruggiero3, Roberto Anaclerio4, Aldo Cafarelli4, Bernd Driessen 5,6, and Tommaso Fiore1

1 Dipartimento dell’Emergenza e Trapianti d’Organo (DETO), Sezione di Anestesiologia e Rianimazione; 2 Dipartimento di Medicina interna e Medicina Pubblica (DiMIMP), Sezione di Diagnostica per Immagini; and 3 Dipartimento di Medicina Clinica Immunologia e Malattie Infettive, Universita degli Studi di Bari, Bari, Italy; 4 Azienda Sanitaria Locale Bari-4, Ospedale Di Venere, Servizio di Anestesia e Rianimazione, Bari, Italy; 5 Department of Clinical Studies-NBC, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania; and 6 Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California

(Received in original form February 5, 2007; accepted in final form July 20, 2007 )

Correspondence and requests for reprints should be addressed to S. Grasso, M.D., Universita di Bari, Dipartimento dell’Emergenza e Trapianti d’Organo (DETO), Sezione di Anestesiologia e Rianimazione, Ospedale Policlinico, Piazza Giulio Cesare 11, Bari 70124, Italy. E- mail: [email protected]

This article has an online supplement, which is accessible from this issue’s table of contents online at www.atsjournals.org

Am J Respir Crit Care Med Vol 176. pp 761-767, 2007

Originally Published in Press as DOI: 10.1164/rccm.200702-193OC on July 26, 2007

Internet address: www.atsjournals.org

Copyright American Thoracic Society Oct 15, 2007

(c) 2007 American Journal of Respiratory and Critical Care Medicine. Provided by ProQuest Information and Learning. All rights Reserved.