INTRODUCTION

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Keywords: ARDS; static pressure-volume curve; expiratory flow limitation

It has long been suggested that information from the inspiratory pressure-volume (PV) curve of the respiratory system could be used in clinical practice (1). In addition to reduced compliance of the respiratory system, loss of lung volume in acute respiratory distress syndrome (ARDS) results in an inflation PV curve with an initial segment of minimal compliance, an intermediate segment of maximal compliance, and a final segment, where compliance is reduced again (2). These segments are separated by two inflexion points (IP), lower (L) and upper (U), which delineate a lung volume range over which the respiratory system compliance is maximal. The clinical use of the PV curve has been updated by the sophisticated software of modern respirators that plot the curve at the bedside (3). In particular, the presence of a lower segment with a low compliance indicates that some lung compartments still do not receive insufflated gas because distal airway closure and/or alveolar collapse prevent their inflation.

An uneven distribution of distal airway resistance in ARDS, produced by localized airway narrowing, may result in the association of a "fast compartment," characterized by a relatively short time constant, with a "slow compartment," characterized by a relatively long time constant (4, 5). In the present clinical study, we hypothesized that the presence of this slow compartment was responsible for the change in respiratory system compliance observed on the PV curve between the initial and the intermediate segments. We also hypothesized that this slow compartment was excluded from tidal ventilation at the usual supportive respiratory rate, producing gas trapping. Finally, we tested the hypothesis that this squeeze of a substantial alveolar volume could be almost completely relieved by applying a relatively low external positive end-expiratory pressure (PEEP).

Patients

Over a 12-month period (June 2000-May 2001) we studied 16 successive patients (13 males, 3 females, mean age 57 ± 16 years) who required mechanical ventilation for an episode of acute respiratory failure. All these patients met the North American-European Consensus Committee criteria for ARDS, with an acute onset of respiratory failure, bilateral chest infiltrates, an arterial oxygen pressure to fraction of inspired oxygen (Pa_O2/FI_O2) ratio of less than 200 mm Hg, and no evidence of left atrial hypertension by trans-thoracic echocardiographic examination. No patient had a previous history of chronic obstructive pulmonary disease. The clinical characteristics of the 16 patients are provided in Table 1.

All patients were sedated with midazolam and sufentanyl, paralyzed with cisatracurium during the time required to determine adequate ventilator settings, and ventilated in volume-controlled mode. Continuous monitoring of all patients included heart rate, arterial systolic pressure by an indwelling radial artery catheter, and oxygen saturation by a pulse oxymeter. Initial ventilator settings included a constant inspiratory flow of 40-60 L/minute, a tidal volume (V_T) of 8 ml/kg, a respiratory rate (RR) of 15 breaths/minute, an I:E ratio of 1:2, and an end-inspiratory pause of 0.6 seconds. Average FI_O2 at the time of the study was 0.67 ± 0.12. The PEEP selected was that producing oxygenation improvement without requiring additional hemodynamic support, resulting in an average PEEP for the whole group of 7 ± 2 cm H₂O.

Respiratory measurements were included in a routine strategy to determine adequate ventilation on the first day of respiratory support. The study was accepted by the Ethics Committee of the Société de Réanimation de Langue Française (SRLF, Paris, France), and waived informed consent was authorized.

	METHODS

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Airway pressure (P), flow, and volumes (V) were measured with the pressure transducers and pneumotachographs incorporated into the ventilator used in the study (Puritan-Bennet 7200). In-built software was used to monitor these variables, and online records of the time-course of Paw and V, as well as plots of flow-volume and pressure-volume (PV) loops, were recorded by connecting an Epson LX-300 printer to the respirator.

A complete PV loop of the total respiratory system was recorded during a single inspiration of an 8 ml/kg volume at a constant inspiratory flow of 10 L/min, followed by a low-flow exhalation, as described previously (6). The coordinates on the volume and pressure axes of the final point of the inspiratory curve/initial point of the expiratory curve were V_MAX and P_MAX, respectively (Figure 1). From the recording obtained, we determined manually the lower inflexion point (LIP) of the inspiratory curve by tracing two straight lines tangentially to the two initial portions of this curve (Figure 1) (3). The coordinates on the volume and pressure axes of this point were V_LIP and P_LIP, respectively (Figure 1). The chord compliances of the whole inspiratory curve (C_chordT), of the first segment (C_chord1) and of the second segment (C_chord2), were calculated as V_MAX/P_MAX, V_LIP/P_LIP and (V_MAX  V_LIP)/(P_MAX  P_LIP), respectively.

View larger version (14K): [in this window] [in a new window]   Figure 1.   (A) An example of the PV loop obtained at low flow in a patient of Group 1 (patient no. 3). The LIP was determined manually by tracing two straight lines tangentially to the two initial portions of the inspiratory curve, and was defined as the intersection between these lines. The coordinates of the final point of the inflation curve/initial point of the deflation curve, on the volume and pressure axes, were VMAX and PMAX, respectively. Two PEEPs were also projected on the deflation curve, PEEPe and PLIP + 2 cm H2O, and we predicted changes in functional residual capacity (FRCpredicted) by their coordinates on the volume axis. (B) An example of the PV loop obtained in a patient of Group 2 (patient no.10). In this case, the inspiratory limb was close to linear.

After restoring the supportive respiratory frequency (15 breaths/ min) and maintaining zero end-expiratory pressure (ZEEP), intrinsic PEEP (PEEPi) was assessed by occluding the airway at the end of tidal expiration by use of the end-expiratory hold button of the ventilator. This measurement was first obtained with a brief expiratory pause (0.5 seconds) to obtain an initial value of PEEPi (PEEPi_0.5), and was repeated after a prolonged expiratory pause (4 seconds) to obtain a final value of PEEPi (PEEPi₄). This procedure detected a slow compartment responsible for a substantial PEEPi, unnoticed with the supportive respiratory rate and a brief expiratory pause. The volume of this slow compartment (V_slow) was then measured after a 5-minute sequence of supportive ventilation with ZEEP, during a prolonged expiration (> 6 seconds) obtained by reducing the respiratory frequency from 15 to 6 breaths/minute (7). The same procedure was used to assess the increase in functional residual capacity (FRC_measured) produced by PEEP, after simultaneously removing PEEP. The ratio of V_slow over total exhaled volume during a prolonged expiration (V_slow ratio) was calculated as V_slow / (V_T + V_slow).

Measurements were repeated with two successive PEEPs: a level that reopens the slow compartment (PEEPe), determined by applying progressive PEEP increments of 1 cm of water, until PEEPi₄ disappeared, and a level determined by P_LIP + 2 cm H₂O (3). This latter level required a tidal volume reduction to maintain an identical plateau pressure, and temporary removal of the heat and moisture exchanger to avoid excessive hypercapnia.

By noting PEEP on the expiratory limb of the PV curve, we measured the volume coordinate of this point, as predicted increase in functional residual capacity (FRC_predicted) caused by PEEP (Figure 1).

Using the end-inspiratory pause and the end-expiratory occlusion, we obtained the total compliance (C_rs) and resistance (R_rs) of the respiratory system (4, 5), and the time constant was calculated as C_rs · R_rs.

Statistical Analysis

Statistical calculations were performed using the Statgraphics plus package (Manugistics, Rockville, MD). Data are expressed as mean ± 1 standard deviation. Respiratory measurements were compared using a Wilcoxon signed rank test. Least square linear regression analysis was also used when appropriate. A one-way analysis of variance (ANOVA), followed by a Bonferroni's multiple comparison procedure, was used to compare C_rs measured at the three end-expiratory pressures. A p value less than 0.05 excluded the null hypothesis.

	RESULTS

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Among the 16 patients studied, 11 exhibited a clear LIP on the inspiratory limb of their PV curve, and were individualized as Group 1. Conversely, no LIP was discernible in five patients, who were individualized as Group 2. Individual examples are shown in Figure 1, illustrating the main measurements obtained from this curve.

Group 1

As stated previously, all Group 1 patients (11 cases) exhibited a clear LIP on their inspiratory curve, whose coordinates were 9 ± 4 cm H₂O for P_LIP (range: 3-18 cm H₂O) and 63 ± 30 ml for V_LIP (range: 34-114 ml).

With the supportive respiratory rate and ZEEP, PEEPi_0.5 was negligible (< 0.5 cm H₂O), whereas a substantial PEEPi₄ (3 ± 2 cm H₂O) was observed in Group 1. Illustrative examples of the influence of the duration of the end-expiratory pause on PEEPi measurements are shown in Figure 2. This PEEPi₄ was produced by the elastic recoil of a substantial V_slow (172 ± 83 ml). An example of V_slow determination in a Group 1 patient is shown in Figure 3.

View larger version (15K): [in this window] [in a new window]   Figure 2.   Two examples of PEEPi determination, after pressing the hold button of the respirator (large vertical arrows). (A) Airway pressure recording in patient no. 4 (Group 1 patient) demonstrated a slow and regular rise in PEEPi, which after a prolonged end-expiratory pause reached a plateau at PEEPi4. (B) A first end-expiratory pause of 0.5 seconds in patient no. 8 (Group 1 patient) revealed a quite negligible PEEPi0.5. However, when a prolonged end-expiratory pause of 4 seconds was performed, a PEEPi of 2 cm H2O was unmasked, also characterized by a slow rise to plateau (PEEPi4).

View larger version (13K): [in this window] [in a new window]   Figure 3.   (A) An example of measurement of the slow compartment (Vslow) in a Group 1 patient (patient no. 2). During supportive ventilation with ZEEP, a sufficiently long expiratory period (> 6 seconds) was obtained by abruptly reducing the respiratory rate from 15 to 6 breaths/ minute, permitting exhalation of tidal volume (VT) to be followed by complete exhalation of Vslow. The same method was used to measure the increase in FRC produced by PEEP, by simultaneously removing PEEP and reducing respiratory rate. (B) An example of measurement of the slow compartment in a Group 2 patient (patient no. 16).

Application of an average PEEPe of 6 ± 2 cm H₂O reduced PEEPi₄ to a negligible level (< 0.5 cm H₂O). This PEEPe (6 ± 2 cm H₂O) was significantly higher than PEEPi₄ (3 ± 2 cm H₂O), and significantly lower than P_LIP (9 ± 4 cm H₂O).

Flow-volume loops were also obtained at supportive respiratory rate in five patients. They already exhibited expiratory flow limitation (EFL) at supportive respiratory rate with ZEEP, which was more or less marked and was relieved by application of PEEPe (Figure 4).

View larger version (16K): [in this window] [in a new window]   Figure 4.   Individual flow-volume loops (only the expiratory limb is shown) obtained at supportive respiratory rate and ZEEP in Group 1 (A) and Group 2 (C ). Expiratory flow limitation (EFL, arrows) was only present at ZEEP in Group 1, and was suppressed by PEEPe (B).

Three end-expiratory pressures (ZEEP, PEEPe, and PEEP equal to P_LIP + 2 cm H₂O) were applied in Group 1 patients. Respiratory measurements obtained with these three pressures are presented in Table 2. Application of PEEPe produced a significant improvement in C_rs, suppressed LIP on the inspiratory curve as illustrated in Figure 5, and generated a FRC_measured significantly greater than V_slow. These mechanical changes were accompanied by a significant increase in Pa_O2, without change in arterial carbon dioxide pressure (Pa_CO2). Application of an external PEEP equal to P_LIP + 2 cm H₂O produced a significantly greater FRC_measured. To maintain an identical plateau pressure, application of this higher external PEEP required a major reduction in V_T. Application of this higher PEEP also produced a significant decrease in C_rs when compared with PEEPe. These mechanical changes were accompanied by a significant additional increase in Pa_O2, whereas Pa_CO2 significantly deteriorated.

View larger version (18K): [in this window] [in a new window]   Figure 5.   An example of the simultaneous effect of PEEPe application on PEEPi4 and on LIP. A: the PV loop recorded in a Group 1 patient (patient no. 13) exhibited a clear LIP. B: pressing the hold button of the respirator (arrow) permitted a progressive increase in PEEPi during a 4-second occluded end-expiratory pause. C: the inspiratory limb of the PV loop after applying PEEPe (5 cm H2O in this patient) became almost linear. D: the disappearance of PEEPi was observed with PEEPe application.

A diagram summarizing our data in Group 1 is presented in Figure 6. The lower panels of this diagram was constructed with end-expiratory and end-inspiratory volume and pressure measurements obtained during supportive ventilation with ZEEP (left panel), PEEPe (middle panel), and an end-expiratory pressure set at P_LIP + 2 cm H₂O (right panel). In the upper panels, we have added a diagrammatic representation of different alveolar zones, showing a possible explanation of our mechanical findings.

View larger version (25K): [in this window] [in a new window]   Figure 6.   A diagrammatic summary of our data. A: the presence of a slow compartment (Vslow) with ZEEP reduced the distribution of tidal volume to the fast compartment (Vfast) (upper panel), and thus affected Crs, which was constructed in the lower panel as a line between end- expiratory and end-inspiratory values of pressure and volume measured at supportive respiratory rate (values are mean ± SD). B: the squeezed alveolar volume is re-introduced in tidal ventilation by using PEEPe (upper panel), also producing an additional increase in FRC (dotted alveolar zone). The net result is an improvement in Crs, as evidenced in the lower panel. C: use of PLIP + 2 cm H2O as external PEEP led to a reduction in tidal volume to prevent an increase in airway pressure produced by an increased end-expiratory volume (the dotted alveolar zone in the upper panel illustrates the major increase in FRC). As a result, the lung is "open" but underventilated (upper panel ). The net result is a reduced Crs (lower panel ).

Group 2

As stated previously, not all Group 2 patients (five cases) exhibited a discernible LIP, the inspiratory PV curve being linear (Figure 1).

With the supportive respiratory rate and ZEEP, both PEEPi_0.5 (< 0.5 cm H₂O) and PEEPi₄ (< 0.5 cm H₂O) remained negligible, reflecting the negligible elastic recoil of a negligible, but nevertheless measurable, V_slow (28 ± 10 ml). An example of V_slow determination in a Group 2 patient is also shown in Figure 3.

Flow-volume loops were also obtained at supportive respiratory rate in four patients. All were free of EFL at ZEEP (Figure 4).

Time Constant and Chord Compliances for the Whole Group

Average value for the time constant at ZEEP was 3.8 ± 1.8 seconds. A strong and significant linear correlation was found between the individual time constant at ZEEP and the size of the slow compartment (Figure 7). Application of PEEPe significantly reduced time constant to 2.4 ± 1.5 seconds.

View larger version (10K): [in this window] [in a new window]   Figure 7.   Individual values of the time constant are plotted against individual measurements of the slow compartment, evidencing a strong linear correlation.

In Group 1, the average values were 29 ± 8 ml/cm H₂O for C_chordT, 8 ± 4 ml/cm H₂O for C_chord1, and 45 ± 12 ml/cm H₂O for C_chord2. In Group 2, C_chordT = C_chord1 = C_chord2 = 31 ± 4 ml/cm H₂O.

Individual values of C_rs calculated with ZEEP were significantly correlated with C_chordT (Figure 8A). Individual values of V_slow ratio were significantly and inversely correlated with C_chord1 (Figure 8B). Finally, individual values of C_rs with PEEPe were significantly correlated with C_chord2 (Figure 8C).

View larger version (26K): [in this window] [in a new window]   Figure 8.   This figure summarizes the relations between individual mechanical data obtained by the PV curve and the individual mechanical data obtained during supportive ventilation. A: the total compliance of the respiratory system (Crs), measured with zero end-expiratory pressure (ZEEP), was significantly correlated with the chord compliance of the total PV curve (CchordT). B: the ratio of the slow compartment volume over the theoretical volume potentially concerned by tidal ventilation (Vslow ratio) was significantly, but inversely, correlated with the chord compliance of the initial segment of the PV curve (Cchord1). C: the total compliance of the respiratory system (Crs), measured with PEEPe, was significantly correlated with the chord compliance of the intermediate segment of the PV curve (Cchord2).

	DISCUSSION

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PEEP titration in patients with ARDS has long been associated with the concept of "recruitment." However, this association appears debatable, because recruitment is an inspiratory phenomenon, and PEEP an expiratory procedure. Thus, observing recruitment on the inspiratory limb of a PV curve appears perfectly logical (8), whereas the use of the same inspiratory curve to set an adequate PEEP appears questionable. Because PEEP is an expiratory procedure, it appears more advisable to examine the expiratory curve for PEEP titration (2).

We observed in the present study that a majority of patients with ARDS (73%) ventilated with ZEEP, and a relatively low respiratory frequency (15 breaths/minute), exhibited airflow limitation producing intrinsic PEEP. However, this limitation appeared somewhat different than airflow limitation observed in patients with chronic obstructive pulmonary disease submitted to mechanical ventilation, or in patients ventilated with a high respiratory rate, as in the original description of Pepe and Marini (9). In the present study, airflow limitation required a prolonged end-expiratory pause to be unmasked. These results, which are concordant with a previous report (10), suggested that airflow limitation was not diffuse, but limited to an alveolar zone constituting a slow compartment, which was actually excluded from tidal ventilation at supportive respiratory rate and ZEEP. The relative importance of this slow compartment, expressed in the present study as V_slow ratio, was inversely related to the slope of the first segment of the PV curve. This finding suggested that initial lung compliance on the PV curve was progressively decreased by an increasing proportion of the slow compartment, and corroborated the hypothesis that the LIP might represent the opening pressure of the slow compartment. This observation might have a greater clinical impact when using lower FI_O2, because the relatively high FI_O2 used in the present study is expected to reduce the size of the slow compartment by gas absorption (11).

An original finding, leading to re-evaluation of the usual calculation and interpretation of C_rs changes produced by application of an external PEEP, and possible correction for PEEPi (12), was the demonstration of an extremely slow rise in PEEPi during airway occlusion. To our knowledge, this particularity was only noted previously by Bilen and Cohen (10). These authors described a discrepancy between airway opening pressure, reflecting dynamic PEEPi, and expiratory occlusion pressure, reflecting static PEEPi, and called this discrepancy "pseudo auto-PEEP" (10). In fact, this discrepancy is well known (13, 14), but in our opinion, the original finding of Bilen and Cohen was the illustration of the slow rate of rise in expiratory occlusion pressure before reaching a plateau. Similar findings are reported here. Bilen and Cohen suggested as an explanation that subcutaneous or mediastinal emphysema might produce retrograde flow across the site of airway leak during expiration (10). More likely, this particular auto-PEEP might result from a progressive emptying of the slow compartment in the other alveolar compartments (the pendelluft effect) before producing a substantial PEEPi. When the size of this slow compartment was negligible (< 50 ml), as in our Group 2 patients, it did not produce discernible PEEPi. We suggested that calculation of C_rs at a given supportive respiratory rate should be corrected for the dynamic value of PEEPi, but not for the static value, obtained after a prolonged end-expiratory pause, which presumably represented the elastic recoil of an excluded compartment. Correction for the dynamic value of PEEPi was suggested previously by Maltais and coworkers, but these authors introduced a distinction between expiratory and inspiratory compliance (14). In our opinion, this distinction is difficult to accept for a "two-point" compliance calculation. Because technical requirements for an adequate measurement were particularly restrictive (14), we did not assess the dynamic value of PEEPi in the present study. However, in all instances, it could not be greater than PEEPi_0.5, which was negligible. Our results are somewhat at variance with those of Maltais and coworkers, who observed only a minor discrepancy between dynamic and static values of PEEPi in patients without chronic obstructive pulmonary disease, like those studied here (14). But in the study by Maltais and colleagues, a high respiratory rate (33 breaths/minute) was used to produce PEEPi, obviously resulting in a diffuse airflow limitation (14). Conversely, our results, obtained at a lower respiratory rate (15 breaths/minute), reflected a localized airflow limitation in Group 1 patients, whereas negligible airflow limitation was present in Group 2 patients.

Another interesting finding was the observation that a relatively low PEEPe (6 ± 2 cm H₂O) was sufficient to suppress almost completely the slow compartment, reducing PEEPi₄ in all Group 1 patients to a negligible level (< 0.5 cm H₂O). But, even if low, PEEPe was significantly higher than PEEPi₄ measured at ZEEP. A possible explanation for this discrepancy might be found in the measurement of PEEPi at the tracheal level, and not at the level of the slow compartment, as the pendelluft effect is expected to result in an underestimation of the actual PEEPi. Suppression of the slow compartment by PEEPe was associated with restoration of an almost linear inspiratory PV curve, without discernible LIP. Moreover, expiratory flow-volume loops obtained in five patients of Group 1 exhibiting EFL, and their modification by PEEPe application, were concordant with the recent work by Koutsoukou and associates (15). They permitted to illustrate a clear relation between an expiratory phenomenon, EFL, and an inspiratory phenomenon, LIP. We concluded that the alveolar zone previously constituting the slow compartment was re-integrated be PEEPe in the functional alveolar zone receiving tidal ventilation. As a result, application of PEEPe produced in Group 1 patients a marked increase in C_rs, accompanied by a significant improvement in Pa_O2, a finding very similar to that made 25 years ago by Suter and coworkers (16). We interpreted this improvement as resulting from the distribution of the same tidal volume in an increased alveolar space (Figure 6). Accordingly, we found a strong correlation in our patients between C_rs with PEEPe and the slope of the second segment of the PV curve. It should also be noted that application of PEEPe in Group 1 produced an increase in FRC significantly greater than the size of the slow compartment, suggesting that reopening the slow compartment might also prevent de- recruitment in other areas. Recently, a computed tomographic study by Crotti and coworkers has emphasized the fact that the "threshold closing pressure" in ARDS may be a low alveolar pressure, in the same range as the PEEPe used in the present study (17).

Also noteworthy is the fact that the PEEPe required to re-open the "slow compartment" in Group 1 was significantly lower than the pressure of the LIP. When a higher external PEEP was applied in this group, using P_LIP + 2 cm H₂O, as recommended by Amato and colleagues (3), we observed a major increase in FRC, requiring a marked reduction in tidal volume to avoid a sharp increase in plateau pressure (Figure 6). Application of the latter PEEP was associated with a significant decrease in C_rs compared with PEEPe, suggesting an increased alveolar distension. In fact, interpretation of this change appeared difficult, because tidal volume reduction per se may reduce C_rs (8, 17). Moreover, a decrease in C_rs has recently been considered as indicating recruitment (8, 18). Nevertheless, we suggested that the respiratory strategy recommended by Amato and colleagues (3) might result in an unnecessary tidal volume reduction. Its detrimental effect on Pa_CO2 was also demonstrated here, despite instrumental dead space reduction associated with application of this specific PEEP.

In conclusion, we have proposed in the present study an alternative for clinical interpretation of the PV curve at the bedside in patients with ARDS. In a majority of ARDS patients, examination of the shape of the PV curve revealed an LIP. This LIP is currently interpreted as indicating the onset of recruitment. We demonstrated that it was, in fact, related to the presence of a slow compartment. Measurement of PEEPi after a prolonged end-expiratory pause suggested that this compartment, unable to empty at the supportive respiratory rate, was thus excluded from tidal ventilation. Low PEEP, regularly set below the LIP, was able to re-integrate the slow compartment as a functional respiratory zone.