INTRODUCTION

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Keywords: recruitment maneuvers; acute respiratory distress syndrome; ventilator-associated lung injury; mechanical ventilation; overdistension

Mechanical ventilation can cause and perpetuate lung injury if alveolar overdistension, cyclic collapse, and reopening of alveolar units occur with each tidal breath. Consequently, ventilator-induced lung injury is indistinguishable from the pulmonary alterations attributable to acute respiratory distress syndrome (ARDS). To minimize the damage that mechanical ventilation can inflict on the lungs, lung protective strategies have been successfully used in patients with ARDS. Amato and coworkers (1) and the ARDS network trial (2) have demonstrated an improvement in the survival rate of patients with ARDS receiving a ventilator approach that included the use of low tidal volumes and limited airway pressure to avoid overdistension, together with high or moderate positive end-expiratory pressure (PEEP) to prevent alveolar collapse.

Recruitment maneuvers (RM) have been proposed as an adjunct to mechanical ventilation in anesthesia and ARDS. Several authors (3) have demonstrated that RM during general anesthesia in healthy patients reexpand collapsed lung tissue. In patients with ARDS, the application of periodic sighs (8) or transient elevations in airway pressure (9) produced an increase in oxygenation likely related to alveolar recruitment. Although sustained inflations aimed to produce lung recruitment may be an important component of mechanical ventilation, it is not known whether RM are beneficial when patients with ARDS are ventilated with high PEEP, or what physiologic alterations exist in patients with ARDS who are nonresponders to RM. Moreover, recent clinical and experimental studies suggested that the response to RM in patients with ARDS may depend on the previous respiratory system mechanics, the nature of the lung insult, and the type of ventilatory setting. Richard and coworkers (12) performed RM in patients with ARDS already ventilated with high PEEP and observed a modest improvement in oxygenation and minimal effects on requirements for oxygenation support. Moreover, Van der Kloot and coworkers (13) demonstrated no effect of RM when experimental animals with acute lung injury were ventilated with a PEEP level higher than the lower inflection point (LIP) of the static pressure-volume (P-V) curve of the respiratory system.

The objective of this investigation was to study the effect of RM as an adjunct of mechanical ventilation in patients with ARDS ventilated with a lung protective strategy: tidal volume lower than 8 ml/kg and PEEP 3-4 cm H₂O higher than the LIP observed in the P-V curve of the respiratory system. Specific objectives were to determine the effect of RM on oxygenation, venous admixture (VA/T), and lung mechanics during and after RM and to study the physiologic effects of RM in patients with early and late ARDS.

	METHODS

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The study was performed in the General Intensive Care Service (Critical Care Center) in a University Hospital in Sabadell (Spain) with the approval of the hospital's ethics committee. Written informed consent was obtained from the patient's next of kin.

Patients

We studied 17 patients, aged between 33 and 78 yr (mean, 56 yr). All were mechanically ventilated and ARDS was diagnosed according to the criteria proposed by the American-European Consensus Conference on ARDS (14). Patient's demographic and clinical characteristics are listed in Table 1.

Early ARDS was considered when patients diagnosed of ARDS received mechanical ventilation for less than 72 h. Late ARDS was defined as patients with ARDS requiring mechanical ventilation for more than 7 d. All 17 patients were studied in the early phase and 8 were also studied in the late phase of ARDS.

Responders (R) were defined as patients studied in the early phase who demonstrated an improvement in Pa_O2/fraction of inspired oxygen (FI_O2) of over 20% during RM. Nonresponders (non-R) were defined as patients in the early phase whose Pa_O2/FI_O2 worsened or improved less than 20% during RM.

Protocol

Patients were ventilated in volume control mode (VCV) with a constant inspiratory flow. Lung mechanics, gas exchange, hemodynamics, and static inflation P-V curve were obtained at zero end-expiratory pressure (ZEEP) (15). Subsequently we analyzed the static P-V curve, and LIP and upper inflection point (UIP) were identified. Patients were then ventilated in volume control mode according to the recommended "lung protective approach" (tidal volume [VT] < 8 ml/kg and PEEP 3-4 cm H₂O higher than the LIP). After a 30-min stabilization period, gas exchange, hemodynamic data, lung mechanics, and end-expiratory lung volume (EELV) were recorded. EELV was obtained after PEEP removal until no airflow was observed. Because PEEP removal can induce significant lung derecruitment, previous PEEP was resumed and an additional 30-min stabilization period was allowed before RM was performed. Recruited volume (VREC) induced by PEEP before the RM was obtained for each individual patient (see METHODS in the online data supplement).

RM was performed in pressure control ventilation (PCV). After the period of stable lung protective approach ventilation, a peak pressure of 50 cm H₂O and a PEEP level 3 cm H₂O higher than the UIP observed in the static P-V curve were applied for 2 min. Peak pressure and PEEP were then gradually decreased to 35 cm H₂O and 20 cm H₂O, respectively. At this point, the ventilatory mode was switched from PCV to VCV and PEEP was decreased in 2 cm H₂O steps to match the PEEP level set before RM. After RM, respiratory rate and tidal volume were equal to the values set in the ventilator before RM. Hemodynamic data, gas exchange, and lung mechanics were measured at the very end of RM and again 15 min later when EELV was also measured. Criteria to stop RM and return to basal ventilation were a ± 20% variation in heart rate or a decrease greater than 20% in mean arterial pressure. A chest X-ray was performed to detect extraalveolar air within 24 h after RM in all patients.

	RESULTS

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No differences were observed before RM on the study day regarding the ventilatory pattern and hemodynamics in patients with early stage ARDS as compared with patients with late ARDS (Table 2). Chest X-rays performed 24 h after RM did not reveal extraalveolar air in any patient.

Effect of RM on Hemodynamics

In no case was it necessary to interrupt the procedure due to the variations in hemodynamic parameters (Table 3). During RM in the early ARDS group a significant increase in mean pulmonary artery pressure () from 30 ± 10 mm Hg to 37 ± 10 mm Hg was observed (p < 0.001), with a rapid decline to the preRM level.

Effects of RM on Respiratory System Mechanics

All patients showed lower and upper inflection points in the static respiratory system P-V curves. Mean LIP values for LIP were 12.9 ± 2.0 cm H₂O for early ARDS and 11.4 ± 2.7 cm H₂O for patients with late ARDS. The mean values for UIP were 26.4 ± 2.5 cm H₂O for early ARDS and 25.6 ± 7.0 cm H₂O for patients with late ARDS. Table 4 summarizes the respiratory system mechanics before, during, and after RM. Plateau pressure (Pplat) decreased from 32.2 ± 5.4 cm H₂O to 31 ± 5.2 cm H₂O (p < 0.05), and respiratory system compliance (Crs) increased from 35.6 ± 15.4 ml/cm H₂O to 38.6 ± 17.2 ml/cm H₂O (p < 0.05) after RM in the early ARDS group. Changes after RM did not achieve significance in the late ARDS group.

Effect of RM on Gas Exchange

As depicted in Table 1, 17 patients were studied in the early stage of ARDS and eight of these patients were also studied in the late stage. The oxygenation responses to RM in both groups are depicted in Table 4 and Figure 1. Oxygenation tended to increase during RM in both groups but this was not statistically significant. The improvement in oxygenation was transient during the RM but was not sustained 15 min later. In both groups, Pa_CO2 increased and pH decreased significantly during RM (Table 4). Values returned to baseline 15 min after RM in the early ARDS group but remained altered (p < 0.05) in the late ARDS group.

View larger version (25K): [in this window] [in a new window]   Figure 1.   Individual PaO2/FIO2 values before, during, and after the RM in different ARDS stages. Solid lines: responders (improvement in PaO2/ FIO2 of greater than 20% during the RM). Dashed lines: nonresponders. Early ARDS = ARDS patients in the early stage. Late ARDS = ARDS patients in the late stage; pre-RM = before the RM; RM = during the RM; post-RM = 15 min after the RM. In two patients with late ARDS, arterial blood gases during the RM were not obtained.

Effect of RM on ·QVA/ ·QT and Cardiac Output in Responders and Nonresponders

Assessing the RM effect in VA/T and cardiac output was possible only in patients with early ARDS with a pulmonary artery catheter in place. Responders to RM (n = 5) (increase > 20% in Pa_O2/FI_O2) showed a significant decrease in VA/T during RM (from 0.35 ± 0.15 to 0.24 ± 0.1, p < 0.05), whereas in nonresponders (n = 7) (less than 20% increase in Pa_O2/FI_O2), VA/T showed a tendency to increase (from 0.33 ± 0.13 to 0.37 ± 0.18, p = 0.5) (Figure 2). Oxygenation and VA/T values after RM were similar to those observed before the procedure. Cardiac output remained unaltered before, during, and after RM in responders and in nonresponders.

View larger version (20K): [in this window] [in a new window]   Figure 2.   Individual VA/ T values before, during, and after the RM in responders and nonresponders based on PaO2/FIO2 changes (see text for definitions). In one patient, VA/ T during the RM was not obtained. *p < 0.05 compared with pre-RM in the responders group.

Effect of RM on End-Expiratory Lung Volume

In the early ARDS group, RM induced a slight increase in EELV from 630 ± 276 ml before RM to 697 ± 320 ml after RM (p < 0.05). In patients with late ARDS, the effect of RM on EELV was not significant (from 868 ± 520 ml before RM to 902 ± 487 ml after RM).

Factors Influencing the Effect of RM

We analyzed the relationship between recruited volume (Vrec) induced by PEEP before RM and RM-induced changes in Pa_O2, Crs, and VA/T. A significant negative correlation (r = 0.68, p < 0.05) was found only between Vrec induced by PEEP before RM and RM-induced changes in Pa_O2/FI_O2 at 15 min. A significant correlation was found between RM-induced changes in Pa_O2/FI_O2 during the RM and changes in Crs at 15 min (r = 0.66, p < 0.01) (Figure 3A) and RM-induced changes in VA/T (r = 0.85, p < 0.01) (Figure 3B). As can be observed in Figure 3 (A and B), the lower increase in oxygenation after RM was accompanied by a decrease in Crs and an increase in VA/T. RM-induced changes in VA/T were correlated with RM-induced changes in Crs at 15 min (r = 0.71, p < 0.01) (Figure 4). As shown in Figure 5, gas composition influenced the RM response on Pa_O2/FI_O2. A significant correlation was found between RM-induced changes in Pa_O2/ FI_O2 in responders and the inspired oxygen fraction at the time of RM (r = 0.77, p < 0.05).

View larger version (16K): [in this window] [in a new window]   Figure 3.   (A) Relation-ship between RM-induced changes in PaO2/FIO2 and RM-induced changes in Crs after 15 min in early ARDS. A significant positive correlation between these two parameters was observed (r = 0.66, p < 0.01). Responders: solid circles; nonresponders: solid triangles (see text for definitions). (B) Relationship between RM-induced changes in PaO2/FIO2 and RM-induced changes in VA/ T in early ARDS. There was a significant negative correlation between these two parameters (r = 0.85, p < 0.01) considering the complete group of early ARDS. Responders: solid circles; non- responders: solid triangles (see text for definitions).

View larger version (12K): [in this window] [in a new window]   Figure 4.   Correlation between RM-induced changes in VA/ T and RM-induced changes in Crs at 15 min in early ARDS. A significant negative correlation between these two parameters was found (r = 0.71, p < 0.01). Responders: solid circles; nonresponders: solid triangles (see text for definitions).

View larger version (11K): [in this window] [in a new window]   Figure 5.   Relationship between RM-induced changes in PaO2/FIO2 and gas composition in responders. A significant correlation between these two parameters was found (r = 0.77, p < 0.05).

	DISCUSSION

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The main findings in this study were (1) RM superimposed on the current recommended "lung protective approach" in ARDS patients receiving mechanical ventilation did not improve oxygenation in the majority of patients; (2) changes in oxygenation induced by RM were correlated with variations in both VA/T and Crs; (3) VA/T increased during RM in nonresponders; and (4) the effects of RM were independent of the stage of ARDS.

Rationale of RM

In an effort to reduce the degree of lung collapse, high-pressure RM have been proposed as adjuncts to mechanical ventilation (1, 10, 11, 16). However, the timing, optimal pressure, duration, and method to perform RM have not yet been determined. In animal and human research, some investigators have used single or sustained inflations applying airway pressures of 30 to 60 cm H₂O for 15 to 40 seconds (3, 5, 13, 17) with an associated reduction in atelectasis and/or increases in oxygenation. In patients with ARDS, periodic increases in peak airway pressure were followed by improvements in oxygenation, intrapulmonary shunt, and lung mechanics (8, 9). However, the increase in oxygenation observed after the RM might be short lived if PEEP is insufficient (10), and periodic sustained high-pressure recruitment maneuvers may be necessary to improve oxygenation (20).

We selected a ventilatory strategy according to current recommendations in order to prevent further development of ventilator-associated lung injury in patients with ARDS (1, 2, 16). Accordingly, we applied a PEEP level 3-4 cm H₂O above the LIP of the static inflation P-V curve and adjusted VT to a plateau pressure below 35 cm H₂O. Subsequently, the rationale to perform RM was based on the data obtained from the P-V curve as the pressure required to obtain lung recruitment is probably not the same in all patients or at different stages of ARDS within the same patient. Based on mathematical models and studies performed in patients with acute lung injury, Hickling (21) and Jonson and coworkers (22) proposed that recruitment continues on the linear portion of the P-V curve and ends or diminishes at the upper inflection point without significant lung overdistension. Therefore, for RM, we used a PEEP level 3 cm H₂O above the measured UIP in the P-V curve. The duration of RM was 2 min, assuming this would be the necessary yet sufficient time to recruit the lung, and that hypoventilation and hemodynamic derangement would be clinically insignificant.

Effects of RM Superimposed on the "Lung Protective Approach"

The lack of a marked improvement in oxygenation and lung volume after superimposing RM on the lung protective approach might suggest that an almost maximal alveolar recruitment can be obtained over a long period of ventilation with optimal PEEP and VT. In fact, these results are supported by the findings of Van der Kloot and coworkers (13) who observed a lack of response to RM in three different experimental models of acute lung injury when high PEEP was used. A recent study by Richard and coworkers (12) demonstrated that a ventilatory strategy based on limited VT and PEEP at or above the lower inflection point of the respiratory system P-V curve leads to alveolar instability and lung collapse. In the study by Richard and coworkers (12), increasing PEEP or performing RM appeared to be the two strategies to counteract low VT and moderate PEEP-induced derecruitment. When RM was performed in patients already ventilated with high PEEP, oxygenation modestly improved and there was a minimal effect on oxygenation support requirements. We also found a significant negative correlation between Vrec induced by PEEP before the RM and RM-induced changes in Pa_O2/ FI_O2 at 15 min. These results suggest no additional benefit of RM when the lungs have been near-optimally recruited by PEEP and tidal volume.

Relationship between Lung Volume and Gas Exchange

The improvement in EELV after RM was significant but rather modest and was not related with oxygenation changes at 15 min after the RM. This lack of correlation was also seen in the study of Van der Kloot and coworkers (13). In patients with ARDS with diffuse lung hyperdensities, PEEP induced significant alveolar recruitment but when densities were predominantly distributed in the lower lobes, PEEP was accompanied by lung overdistension (23). One explanation for the lack of relationship between lung volume and oxygenation may be that the RM increased lung volume by overdistending the more compliant already-opened and aerated alveolar units, rather than recruiting collapsed units. This overdistension would favor capillary collapse in the healthy areas and diversion of blood flow into the collapsed areas. Modifications of EELV might therefore be independent of variations in oxygenation. In our patients with ARDS, when oxygenation improved after RM, VA/T decreased and Crs increased; however, when oxygenation did not change or was impaired, VA/T increased and Crs decreased (Figures 3 and 4). Because hemodynamics and cardiac output were not affected by RM, changes in VA/ T should be attributed only to the pathophysiologic consequences of alveolar recruitment or alveolar overdistension induced by RM (i.e., ventilation/perfusion relationships).

Gas composition may influence the effect of RM on oxygenation. Breathing pure oxygen in patients with ARDS deteriorates intrapulmonary shunt owing to the collapse of unstable alveolar units with very low ventilation/perfusion ratios (27). After general anesthesia in humans, Rothen and coworkers (6) found that the amount of atelectasis and shunt was reduced by the recruitment maneuver, but the amount of lung units with low / increased at the same time. Interestingly, we found a significant correlation (Figure 5) between RM-induced changes in Pa_O2/FI_O2 and the inspired oxygen fraction at the time of the RM, suggesting that in patients ventilated with modest FI_O2, RM might result in a minimal increase in Pa_O2.

Comparison of ARDS Stages

There were no differences among the ARDS stages with respect to gas exchange, lung mechanics, or hemodynamic parameters before RM. Although oxygenation improvement during RM did not reach significance in any group, oxygenation in the late ARDS group was less responsive to RM than in the early ARDS group. Recent data in human ARDS (28) suggest that inflammation and repair occur in parallel rather than in series as fibroproliferation was already documented within 24 h of diagnosis. Consequently, intensivists might reconsider the optimal timing of RM, as ARDS within 72 h of diagnosis is perhaps already a late stage of the disease. Finally, differences between pulmonary and extrapulmonary ARDS need to be considered. In the majority of our patients with ARDS, the cause of acute respiratory failure had a pulmonary origin that was maybe less responsive to the RM (29).

Clinical Implications of the Study

Our data suggest that RM applied to patients with ARDS ventilated with a lung protective strategy (small VT and high PEEP) are not effective in improving oxygenation in the majority of patients at any stage of the disease. RM may result in no benefit if the lung has already been nearly optimally recruited by PEEP and VT. Nevertheless, in 5 of 17 patients studied in the early phase, Pa_O2 markedly improved and VA/T decreased during and after RM, whereas in the rest, oxygenation remained unchanged or worsened with a deterioration of VA/T. In such latter cases, RM may be detrimental, leading to stretch injury of more compliant lung units, with redistribution of blood flow to injured or atelectatic areas. When oxygenation increases during RM but the improvement is not sustained over time, it is likely that PEEP should be optimized after RM. Recent data from patients with ARDS (30) have shown that after a lung recruitment maneuver of 45 cm H₂O, derecruitment and an increase of nonaerated lung tissue substantially occur at airway pressures below 20 cm H₂O. This finding supports the contention that some patients need very high PEEP levels to keep the lung open. RM have been reported to be applied following disconnection from the ventilator and after aspiration of secretions (31). Nevertheless, it is not known whether restoring the lung protective strategy with high PEEP will also restore lung volume to its previous value.

An adverse effect of RM is the hypoventilation associated with the period of ventilation in pressure control mode using lower driving pressures. Because acute moderate hypercapnia can provoke a reduction in systemic vascular resistance with an increase in cardiac output (32), the reduction in cardiac preload induced by the elevated intrathoracic pressure might be counterbalanced by the systemic effects induced by hypercarbia.

In conclusion, in patients with ARDS ventilated with the lung protective approach we observed that a superimposed RM was ineffective in improving oxygenation in the majority of patients. Moreover, alveolar overdistension capable of redistributing blood flow and increasing intrapulmonary shunt can occur during RM. In such cases, RM may be detrimental, leading to stretch injury of more compliant lung units. The proposal of RM as an adjunct to mechanical ventilation requires further studies to elucidate the optimal time, optimal pressure, duration, and frequency before RM can be recommended to be widely used in critically ill patients with ARDS.