INTRODUCTION

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Keywords: ARDS; mechanical ventilation; permissive hypercapnia; pulmonary gas exchange; ventilation-perfusion relationships

Experimental studies in animals (1, 2) and recent data in humans (3) suggest that mechanical stimuli generated by different ventilatory modalities may trigger signal-transduction processes leading to release of inflammatory mediators that can cause pulmonary and also systemic injury. The 1998 International Consensus Conference on Ventilator-Associated Lung Injury (VALI) defined this entity as lung damage with characteristic features of acute respiratory distress syndrome (ARDS) that can occur in patients receiving mechanical ventilation (4). Preexisting pulmonary disease such as ARDS itself (5) seems to constitute a risk factor for VALI. The two most important mechanical factors proposed as responsible for VALI (6) are: (1) the association of alveolar overdistension and high transpulmonary pressure; and, (2) repeated alveolar collapse and reopening owing to ventilation at inappropriate tidal ranges of transpulmonary pressure.

The prevention of alveolar overdistension by limiting tidal volume (VT) to approximately 6 to 7 ml · kg¹ body weight, but using standard positive end-expiratory pressure (PEEP) levels (8 to 11 cm H₂O), has been examined as a method of minimizing VALI in four controlled studies (9). Three of these investigations (9) did not show significant differences in mortality between the two branches: low and high VT. The latter National Institutes of Health study (12), however, clearly demonstrated a significant reduction in mortality from 40% to 30% associated with a low VT strategy. These positive results were conceivably explained by the wider difference in true delivered VT achieved in this study (12) compared with the former ones (9), thereby accentuating differences in outcome. However, reduction in VT alone, using standard levels of external PEEP, can deteriorate pulmonary gas exchange by three different mechanisms (13): reduction of alveolar ventilation (A); collapse of alveolar units and increase in intrapulmonary shunt; and increase in cardiac output (), which may further worsen intrapulmonary shunt in patients with ARDS (14).

A combined strategy of low VT and high levels of PEEP (to avoid alveolar overdistension and to prevent repeated collapse and reopening of alveolar units throughout the ventilatory cycle) has been also proposed as an alternative mode of ventilation to decrease VALI. Recently, Amato and colleagues (15) showed a substantial reduction of mortality in ARDS by tailoring the level of PEEP and the inflation volume, respectively, above and below the lower and the upper inflexion zones of the static volume-pressure curve of the respiratory system, accepting an increase in Pa_CO2. However, permissive hypercapnia (16) may provoke transient systemic vasodilatation with an increase in that results in a worsening of intrapulmonary shunt, hence jeopardizing arterial oxygenation (14).

The purpose of the present study was to investigate whether a combined protective ventilatory strategy (PVS) with low VT and high level of PEEP can induce pulmonary recruitment and facilitate a redistribution of pulmonary blood flow to properly ventilated alveolar units, hence preventing the deleterious effects of a decrease of VT alone on pulmonary gas exchange.

	METHODS

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Patient

We studied eight mechanically ventilated patients with ARDS at an early stage (< 48 h) (5). Prominent characteristics of the patients are described in Table 1. The protocol was approved by the ethics committee of the Hospital Clínic and informed consent was obtained from each patient's next of kin.

Measurements

Pulmonary and systemic hemodynamics were assessed in each ventilatory modality. The electrocardiogram was continuously monitored. was measured by thermodilution technique. Systemic vascular resistance (Rsv) and pulmonary vascular resistance (Rpv) were calculated according to standard formulae.

Respiratory mechanics. All patients were sedated and paralyzed to avoid muscular activity during the measurements. Airway pressure (Paw) and flow () were continuously measured. Peak airway (Ppeak), mean airway (), and plateau pressures (Pplat) during brief end-inspiratory airway occlusion (17, 18) were recorded. Direct assessment of intrinsic PEEP (PEEPi) was done. The static pressure- volume (P-V) loops of the respiratory system were evaluated as described by Jonson and coworkers (19) for the presence of inflexion zones at early (low P_FLEX) and late (high P_FLEX) inflation, as indicated in Figure 1. Recruited volume (Vrec) was assessed as described by Jonson and coworkers (19).

View larger version (16K): [in this window] [in a new window]   Figure 1.   P-V curve obtained at zero PEEP showed the curvilinear shape in early inflation before taking the linear slope; the pressure zone where this definite change in slope was observed was the low inflexion pressure (low PFLEX, see arrow).

Respiratory blood gases. Arterial (a) and mixed venous (v) blood was collected with heparinized syringes to measure arterial PO₂, PCO₂, and pH by standard electrode technique. Distribution of ventilation-perfusion ratios was obtained using the multiple inert gas elimination technique (MIGET) (20).

Study Design

First, the bedside P-V static curve of the respiratory system was obtained as previously described. Then, volume-controlled mechanically ventilated patients were studied under the following conditions: (1) baseline; (2) PVS; and (3) post-PVS, again at baseline conditions. The respiratory rate (f) and fraction of inspired oxygen (FI_O2) were kept unaltered throughout the study. The two ventilatory modalities compared in the study were set as follows: (1) Baseline: VT 10 to 12 ml · kg¹, PEEP 8 to 10 cm H₂O, f needed to keep Pa_CO2 between 35 and 45 mm Hg, and FI_O2 required to achieve an arterial oxygen saturation (Sa_O2) of approximately 95%. Pplat < 35 cm H₂O, always below the high P_FLEX identified in the P-V curve, was requested. (2) During PVS, PEEP was set 2 cm H₂O above the low P_FLEX in all instances and VT was progressively reduced to 5 to 7 ml · kg¹ to avoid a marked impact on arterial pH. In those patients in whom the high P_FLEX could not be clearly identified, VT was decreased by 25%. Patients were studied under steady-state conditions, which in all instances had been established after 30 min of ventilation with each condition, as judged by the monitoring of ventilatory and hemodynamic variables, as well as mixed expiratory respiratory gases. Measurements were made in the following order: MIGET and expired, and arterial and mixed venous blood gases; pulmonary and systemic hemodynamics; respiratory mechanics.

Statistical Analysis

Results are presented as mean ± SD. One-way analysis of variance (ANOVA) for repeated measurements and Student-Newman-Keuls analysis were used for comparison among the different ventilatory modes.

	RESULTS

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Baseline measurements were obtained during volume-controlled mechanical ventilation using conventional settings (VT, 9.5 ml · kg¹; PEEP, 9 cm H₂O; and FI_O2, 0.82) (Table 1). In all of the patients with ARDS the low P_FLEX (16 ± 3.4 cm H₂O) of the corresponding static P-V curve measured at zero PEEP (Figure 1) was clearly identified; however, the high P_FLEX could not be established in two of them. Respiratory mechanics and pulmonary and systemic hemodynamics are reported in Table 2. Inert gas measurements (Table 3) showed a substantial amount of increased intrapulmonary shunt (39% of ) which, as expected, was the main determinant for the hypoxemia in these patients. Ventilation-perfusion (A/) distributions were unimodal in all instances (Figure 2). The perfusion distribution was centered at a normal A/ ratio of 1.0, but showed a moderate to severe increase in its dispersion. In contrast, the ventilation distribution was centered at a high A/ ratio of 2.2 and its dispersion was only slightly above the reference limit (24). Both the percentage of perfusion to areas with low A/ ratio and the percentage of ventilation to areas with high A/ ratio were almost negligible. Inert gas dead space was within the normal limits.

View larger version (20K): [in this window] [in a new window]   Figure 2.   A/ distributions in a representative patient with ARDS at baseline (PaO2 96 mm Hg, PaCO2 37 mm Hg), during PVS (PaO2 334 mm Hg, PaCO2 75 mm Hg), and post-PVS (PaO2 54 mm Hg, PaCO2 65 mm Hg). Decrease in intrapulmonary shunt during PVS explained the improvement in arterial PO2. The increase in dead space due to both low VT and high PEEP values results from the permissive hypercapnia approach used in these patients.

Combined effects of high PEEP and low VT. During the PVS, mean PEEP was increased to approximately 18 cm H₂O and mean VT was decreased to approximately 5.9 ml · kg¹ (Table 2). By design, all patients were ventilated between the lower and the higher inflexion zones identified by the static P-V curve measured at zero PEEP (Figure 1). Compared with baseline, P_peak decreased and moderately increased, but no significant changes were shown in Pplat (Table 2). Respiratory system linear compliance significantly increased during PVS. Rsv fell and increased, likely because of the transient systemic vasodilator effect (16) caused by permissive hypercapnia (Table 3). The increase in mean pulmonary arterial pressure () without changes in Rpv was most likely a reflection of the increased . Despite the decrease in alveolar PO₂ due to permissive hypercapnia, a variable but substantial increase in both Pa_O2 and partial oxygen pressure in mixed venous blood (Pv_O2) was seen in all patients. Because of the simultaneous increase in PaO₂ and , systemic O₂ delivery also increased (from 1.05 ± 0.17 to 1.27 ± 0.25 L · min¹) (p < 0.004) during the protective ventilatory modality.

The inert gas measurements showed a marked decrease in intrapulmonary shunt (from 39% to 31% of ) (p < 0.04). Compared with baseline (Figure 2), both perfusion and ventilation distributions were left shifted owing to decrease in the overall A/ ratio which, in turn, can be explained by the simultaneous decrease in minute ventilation (E) and the increase in . Whereas the dispersion of the perfusion distribution decreased, no significant changes were observed in the alveolar ventilation distribution. Dead space, however, significantly increased during PVS.

Predicted Pa_O2 (MIGET) both at baseline (90 ± 29 mm Hg) and during PVS (157 ± 102 mm Hg) were close to Pa_O2 independently obtained from respiratory gas measurements (Table 3), hence indicating the adequacy of the model provided by MIGET to estimate Pa_O2 in the conditions of the present study.

A multiple forward stepwise regression analysis carried out to explore the relative contribution of the different factors determining the improvement in arterial oxygenation during PVS indicated that the combination of increased Pv_O2 (r² = 0.80) and the fall in intrapulmonary shunt (r² = 0.12) explained together 92% of the increase in Pa_O2. One of the most striking findings of the study was that the PEEP-induced volume recruitment (184 ± 141 ml) during PVS explained approximately 80% of the amelioration of pulmonary gas exchange observed during this ventilatory modality. Most interestingly, such a close correlation was observed between Vrec and two independently measured variables reflecting the same physiologic phenomenon: increase in Pa_O2 (r² = 77) (p < 0.005) and decrease in intrapulmonary shunt (r² = 0.79) (p < 0.005) during PVS (Figure 3). Except for a moderate residual fall in arterial pH, all measurements (respiratory mechanics, pulmonary and systemic hemodynamics, and respiratory blood gases) returned to baseline values when the conventional ventilatory settings were restored (Tables 2 and 3).

View larger version (15K): [in this window] [in a new window]   Figure 3.   Relationships between increase in PaO2 (top graph) (r2 = 0.77, p < 0.005) and decrease in intrapulmonary shunt (bottom graph) (r2 = 0.79, p < 0.005) with recruited Vrec during PVS in patients with ARDS. The solid lines are the regression lines; dots correspond to individual patients.

	DISCUSSION

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The results of the present study indicate that the combined low VT and high PEEP, set to provide a PVS for VALI, exhibited a marked efficacy to improve pulmonary gas exchange in mechanically ventilated patients with early ARDS. During PVS, Pa_O2 improved (from 93 ± 27 to 166 ± 77 mm Hg) whereas intrapulmonary shunt significantly decreased from 39% to 31%, on average. Recruitment of previously collapsed alveolar units was the key factor to explain the reduction in intrapulmonary shunt. The strong association (r² = 0.79) between the decrease in intrapulmonary shunt and the amount of PEEP-induced lung volume recruitment (Figure 3) is consistent with this notion. The beneficial effects of PVS on pulmonary gas exchange fully overcame the deleterious effect of permissive hypercapnia on arterial oxygenation (decline in alveolar PO₂). Moreover, the increase in (by 15%, on average) during PVS due to systemic vasodilatation (16) did not result in a proportional increase in intrapulmonary shunt as one would expect in patients with ARDS (14), likely because pulmonary blood flow was appropriately diverted to normal alveolar units owing to the concomitant efficient phenomenon of alveolar recruitment (Figure 2). The reduction in the dispersion of the blood flow distribution (logSD ) (from 1.1 ± 0.4 to 0.8 ± 0.3) (p < 0.01) during PVS was likely caused by the fall of the A/ ratio due to the concomitant effects of both decrease in A and increase in provoked by this ventilatory modality. However, a more efficient distribution of pulmonary blood flow toward areas with normal A/ ratio cannot be ruled out. Likewise, the marked increase in inert gas dead space observed during PVS (Table 3) can be explained by the combined effect of decrease in A and the increase in FRC provoked by high levels of PEEP.

Respiratory System Mechanics

The mean low inflexion point (low P_FLEX) (16 ± 3.4 cm H₂O; n = 8) was similar to that described by Amato and colleagues (15), but it was moderately higher than the figures (10 to 12 cm H₂O) reported by other researchers (25, 26). Factors such as severity and cause of ARDS, stage of the disease, and probably ventilatory setting used before the P-V curve maneuver may explain these results in our patients. Because an esophageal balloon was not in place and transpulmonary pressures could not be measured, we do not know to what extent the shape of the chest wall P-V curve may influence the low P_FLEX. However, the influence of the chest wall mechanics in the shape of the respiratory system P-V curve at the beginning of the inflation has been estimated as very low (27).

Despite the high levels of PEEP, all patients were ventilated within the safe zone, that is, below the high inflexion point (high P_FLEX) (32 ± 4.3 cm H₂O; n = 6), hence allowing a PVS. An interesting finding of the study was that the effects of the combined high PEEP/low VT strategy on respiratory mechanics and pulmonary gas exchange were obtained without significant changes in Pplat between ventilatory interventions (Table 2). The fact that in all our patients Pa_O2 improved with increasing PEEP from conventional settings to PVS, and that this improvement occurred without major changes in , strongly suggests that PEEP mainly induced alveolar recruitment. Indeed, the strong correlation between Vrec and gas exchange (Figure 3) supports this statement. The driving pressure (Pplat  total PEEP) was markedly lower during the PVS (20 and 9 cm H₂O, baseline and PVS, respectively), which may reflect less shear stress of the alveolar wall throughout the respiratory cycle, a pivotal factor for VALI (4).

Role of Mixed Venous PO₂

The stepwise multiple regression analysis explaining 92% of the increase in Pa_O2 during PVS suggested a pivotal role for the increase in Pv_O2 (r² = 0.80), but ascribed a relatively minor role for the fall in shunt (r² = 0.12). However, the physiologic interpretation of Pv_O2 during PVS can be rather complex. Mixed venous PO₂ (28) may be influenced by the various factors determining Pa_O2 and by the amount of tissue O₂ extraction, that is: intrapulmonary shunt and A/ mismatch, E, , FI_O2; and systemic O₂ uptake. In the present study, we hypothesized that the increase in Pv_O2 during PVS was mostly a reflection of the improvement of intrapulmonary factors determining arterial oxygenation (fall in shunt). In other words, it might be speculated that the apparently minor role of intrapulmonary shunt indicated by the multiple regression analysis alluded to was only a result of the high co-linearity between +Pv_O2 and shunt, even though the two variables were independently measured.

The potential of MIGET (22, 28) to predict the relative impact of the different factors influencing arterial oxygenation was used to analyze the effects of the aforementioned variables on the increase in Pa_O2 during PVS. Because FI_O2 and oxygen consumption (O₂) did not change between baseline and PVS, these two factors were not considered relevant for the analysis. Because E during PVS provoked permissive hypercapnia, changes in ventilation could have had a negative influence on arterial oxygenation only. Consequently, a first step was to evaluate the effects of the alone which explained approximately a 12% increase in predicted Pa_O2. The decrease in intrapulmonary shunt alone determined a 48% increase in predicted Pa_O2. However, the combined and shunt had a synergistic effect explaining an additional 19% improvement in predicted Pa_O2. The E had a negligible impact on estimated Pa_O2, such that the combined effects of and shunt during PVS fully accounted for the 79% increase in Pa_O2 (from 93 ± 27 to 166 ± 77 mm Hg).

Low VT Alone versus a Combined Low VT/High PEEP Strategy: Clinical Implications

Recently, four controlled studies (9) compared the effects of ventilation with low (6 to 7 ml · kg¹) versus high (10 to 12 ml · kg¹) VT. In all these trials, patients receiving lower VT exhibited permissive hypercapnia (50 to 60 mm Hg) and lower Pplat (22 to 26 cm H₂O) than those ventilated with higher VT. However, no differences were observed in PEEP levels (8 to 11 cm H₂O) between high and low tidal volume patients. Only the latter study (12) showed a significant decrease in mortality by 20% (from 39% to 31%) with PVS, likely because of a higher statistical power (861 patients, some of them with acute lung injury [ALI]) and a larger difference between low and high VT branches.

It is well accepted, however, that a reduction of VT (27, 31), even preserving reasonable PEEP levels (10 to 11 cm H₂O), may provoke significant alveolar derecruitment with a subsequent deterioration of pulmonary gas exchange that may generate higher FI_O2 requirements. Recently, Maggiore and coworkers (32) reported that alveolar derecruitment after a reduction of VT cannot be fully prevented even with PEEP levels equal to low P_FLEX values. A value of PEEP 4 cm H₂O above P_FLEX was shown to be effective to prevent atelectasis (32), but full prevention of alveolar derecruitment could only be obtained by reexpansion maneuvers, as suggested by other investigators (33). Amato and colleagues (15) have shown the efficacy of a combined PVS (encompassing a low VT, high PEEP set according to static P-V curves, plus intermittent reexpansion maneuver using high levels of continuous positive airway pressure [CPAP]) to significantly improve the survival at 28 d in patients with severe ARDS as compared with mechanical ventilation using conventional high VT and no limitation in pulmonary pressures generated by the ventilator.

In summary, the present study provides novel information on the mechanisms of pulmonary gas exchange improvement using a PVS set by measurement of static P-V curves of the respiratory system to ensure alveolar recruitment and to avoid overdistension of pulmonary parenchyma. The main results of the investigation are, first, the strong relationship between improvement of alveolar gas exchange and the amount of PEEP-induced alveolar recruitment; and second, the identification of decreased intrapulmonary shunt as key determinant of the enhanced arterial oxygenation induced by the PVS. Moreover, the increase in systemic O₂ delivery owing to the rise in during this ventilatory modality ameliorates tissue oxygenation. Overall, these findings strongly suggest that a PVS using combined low VT/high PEEP seems to be the most appropriate approach, based on pathophysiologic grounds, to combine prevention of VALI and enhanced pulmonary and peripheral gas exchange in patients with ALI/ARDS, at least at an early stage. Nevertheless, the issue of whether the results of this investigation can be extrapolated to later stages of ALI/ARDS remains unsettled. Further studies are warranted in this area to confirm the clinical outcomes of a combined ventilatory strategy in these patients, as suggested by Amato and colleagues (15). Because P-V curves are not usually obtained as part of routine clinical assessment in patients with ALI/ARDS, guidelines to define routine ventilator settings and associated monitoring are needed (34). Moreover, it has been recently suggested that therapeutic hypercapnia, independently of reduced lung stress, may prevent pulmonary and systemic damage in patients with ARDS (35, 36), which introduces additional complexities to the analysis.