A recent study by the Acute Respiratory Distress Syndrome Network compared the traditional lower end-expiratory pressure strategy with a higher end-expiratory pressure strategy in patients with the acute respiratory distress syndrome ventilated with low tidal volumes. Clinical outcomes were similar whether lower or higher positive end-expiratory pressure (PEEP) levels were used. We applied both the lower (9 ± 2 cm H2O) and higher (16 ± 1 cm H2O) PEEP strategy in 19 patients. In nine recruiters, the higher end-expiratory pressure strategy resulted in significant alveolar recruitment (587 ± 158 ml), improvement in arterial oxygen partial pressure/inspired oxygen fraction ratio (from 150 ± 36 to 396 ± 138), and reduction in static lung elastance (from 23 ± 3 to 20 ± 2 cm H2O/L). In 10 nonrecruiters, alveolar recruitment was minimal, oxygenation did not improve, and static lung elastance significantly increased (from 26 ± 5 to 28 ± 6 cm H2O/L). The increase in oxygenation, the reduction in static lung elastance, and the shape of the volume–pressure curve during the lower PEEP strategy were independently associated with alveolar recruitment. In conclusion, the protocol proposed by the Acute Respiratory Distress Syndrome Network, lacking solid physiologic basis, frequently fails to induce alveolar recruitment and may increase the risk of alveolar overinflation.
The first lung-protective ventilatory strategy proposed by the Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, based on low Vt, resulted in a 22% mortality reduction in a prospective, multicenter, randomized study (2). Pivotal to that strategy were both prevention of tidal alveolar overstretch and limitation of tidal alveolar excursions. Positive end-expiratory pressure (PEEP) and inspired oxygen fraction (FiO2) were set according to traditional criteria, using a table of lower PEEP/higher FiO2 combinations, aiming at the lowest PEEP level compatible with an oxygenation target.
Besides tidal alveolar overstretch, tidal alveolar recruiting/derecruiting has also been implicated in ventilator-induced lung injury (3, 4). Higher-than-traditional PEEP levels together with lung recruiting maneuvers have been proposed to reduce the portion of nonaerated lung, thus avoiding cyclic alveolar recruiting/derecruiting during mechanical ventilation (5). Combining low Vts and high PEEP levels blunted the inflammatory response (6) and reduced mortality in patients with ARDS (7). The ARDS Network Assessment of Low Tidal Volume and Elevated End-Expiratory Lung Volume to Obviate Lung Injury (ALVEOLI) study was designed to validate these results in a larger clinical study (8). Study-arm patients were ventilated with low Vts and with a higher PEEP strategy aiming to decrease the amount of nonaerated lung at end-expiration, whereas control-arm patients were ventilated according to the former ARDS Network protective protocol (lower PEEP strategy) (2). Technically, the higher PEEP strategy was implemented through a higher PEEP/lower FiO2 combination table with the addition of lung recruiting maneuvers. The ALVEOLI study was stopped after the enrollment of 549 patients, having crossed a protocol-specified futility-stopping boundary (8).
For the effectiveness of lung protection, any higher PEEP approach should increase the end-expiratory lung volume through alveolar recruitment, avoiding lung overinflation (9). Furthermore, PEEP and lung recruiting maneuvers may increase the end-expiratory lung volume through two opposite mechanisms: (1) by increasing the proportion of aerated alveoli at end-expiration or (2) by further inflating already-ventilated lung regions (10, 11). The occurrence of one of these two mechanisms (or their combination) may depend on ARDS etiology (12), lung and chest wall mechanics (13), the stage of the disease (14), and lung morphology seen on the computed tomography scan (11). In addition, the optimal implementation protocol for higher PEEP and recruiting maneuver is still debated (15).
Because, in the ALVEOLI study, the higher PEEP strategy was table-based, matched on an oxygenation target, and applied regardless of any patient-related variable, we set up the hypothesis that the effectiveness of this strategy in generating alveolar recruitment could be unpredictable.
Nineteen patients with ARDS were studied. Inclusion and exclusion criteria were those of the ALVEOLI study (8). The institutional review board approved the protocol, and written, informed consent was obtained from the subjects or their next of kin.
Patients were ventilated according to the ARDS Network lower PEEP strategy before the study (2). After a brief (30–35 minutes) baseline ventilation period (PEEP, 0; Vt, 10 ml/kg predicted body weight; FiO2, 1; respiratory rate, 15 breaths/minute; inspiratory-to-expiratory ratio, 1:2), each patient was ventilated with the lower PEEP strategy for 12 hours and subsequently with the higher PEEP strategy for 12 hours (Table 1)
Common to both strategies
|Mode of ventilation: volume cycled assist/control|
|VT/Pao,plat goals: VT, 6 ml/kg PBW; Pao,plat < 30 cm H2O|
|Inspiratory flow: square; I/E = 1:2|
|Arterial oxygenation goal: SpO2 = 88–95%; PaO2 = 55–80 mm Hg|
|Lower PEEP strategy*|
|Higher PEEP strategy*|
Flow, volume, airway opening pressure, and esophageal pressure were measured (pneumotachograph and differential pressure transducers). Values of airway opening pressure at end-expiration of a regular breath (PEEPexternal) and 3 to 5 seconds after the onset of an end-expiratory occlusion (PEEPtotal) were also measured. Static intrinsic PEEP (PEEPi,st) was obtained as the difference between PEEPtotal and PEEPexternal. Static elastance of the respiratory system, chest wall, and lung were calculated through standard formulae (16).
Quasi-static pressure–volume curves of the respiratory system during low-flow inflation of the Vt (low-flow tidal inflation) were obtained during each experimental condition applying the same principles of the “low-flow technique” (17–19). Subsequently, the shape of each volume–pressure curve was quantitatively analyzed by fitting it to the following equation:
Volume–pressure curves obtained during each experimental condition were plotted on the same volume/pressure axis by referring them to the elastic equilibrium volume of the respiratory system. The recruited volume was measured as the difference in lung volume for the same static airway opening pressure read on the volume–pressure curves (20, 21). Patients were defined as recruiters if the higher PEEP strategy induced an alveolar recruitment of more than 150 ml and as nonrecruiters if alveolar recruitment was lower than 150 ml (22).
Invasive arterial pressure, heart rate, right atrial pressure, continuous cardiac output (transesophageal Doppler, Doptek ODM1; Deltex Medical, Chichester, UK), and arterial blood gases (Rapid Lab 865; Bayer Diagnostics, Dublin, Ireland) were recorded.
A preliminary power analysis, which considered an alveolar recruitment higher than 150 ml as clinically significant, was performed. Data are presented as mean ± SD. Data obtained in the same group of patients were compared by an analysis of variance for repeated measures and, if significant, a Student's t test for paired data was applied for comparisons between the different experimental conditions. Comparisons between the two groups of patients were made using the Student's t test for unpaired data. Differences were considered significant if p values were less than 0.05. Multivariate regression analysis followed by a stepwise regression with backward elimination was used to evaluate the relationship between alveolar recruitment and potentially relevant physiologic and clinical variables. Statistical analysis was performed using the software package StatView (Abacus, Inc., Berkeley, CA).
Moving from the lower to the higher PEEP strategy resulted in alveolar recruitment between 25 and 125 ml (mean, 70 ± 38 ml) in 10 nonrecruiters and between 425 and 850 ml (mean, 587 ± 158 ml; p < 0.01) in 9 recruiters. Compared with the baseline period, the lower PEEP strategy induced alveolar recruitment in both groups; however, the amount of alveolar recruitment induced by the lower PEEP strategy was significantly higher in recruiters than in nonrecruiters (Figure 1).
|Baseline||Lower PEEP||Higher PEEP||Baseline||Lower PEEP||Higher PEEP|
|VT, ml||650 ± 60||394 ± 28*||351 ± 58†,‡||660 ± 50||392 ± 35*||389 ± 39‡|
|RR, breaths/minute||15 ± 0||23 ± 5*||24 ± 4‡||15 ± 0||24 ± 3*||25 ± 4‡|
|PEEPexternal, cm H2O||0.9 ± 0.6||8.9 ± 1.7*||16.2 ± 1.7†,‡||0.6 ± 0.3||8.56 ± 1.7*||14.9 ± 1.4†,‡,‖|
|PEEPi,st, cm H2O||2.1 ± 1.4||0.6 ± 0.5||0.5 ± 0.5||1.9 ± 1.7||0.9 ± 0.5||1.1 ± 0.4|
|Pao,plat, cm H2O||25.5 ± 2.7||22.9 ± 2.3*||28.6 ± 2.1†,‡||23.5 ± 2.4§||21.6 ± 0.9*||26.5 ± 1†,‡,‖|
|FIO2||1 ± 0||0.49 ± 0.09*||0.47 ± 0.09‡||1 ± 0||0.48 ± 0.1*||0.39 ± 0.08†,‖|
|pH||7.462 ± 0.04||7.397 ± 0.05*||7.371 ± 0.09‡||7.474 ± 0.1||7.426 ± 0.09||7.435 ± 0.07|
|PaO2/FIO2||107 ± 34||149 ± 38*||142 ± 36‡||93 ± 23||150 ± 36*||396 ± 138†,‡,‖|
|PaCO2, mm Hg||37.7 ± 3.6||44.2 ± 6.9*||48.6 ± 8.2†,‡||35.7 ± 6.1|| 41.7 ± 6.5*||40.9 ± 5.9‖|
Demographic and clinical characteristics of the studied patients are shown in Table 3
|SD|| 17.1|| 17.3|
At baseline, static lung elastance was significantly higher in nonrecruiters than in recruiters (29.6 ± 5.8 vs. 25.3 ± 3.9 cm H2O/L), whereas static chest wall elastance was not significantly different between the two groups (6.8 ± 2.5 in nonrecruiters and 7.8 ± 2.3 cm H2O/L in recruiters) and remained unchanged during the different experimental conditions (Figure 2). Compared with baseline measurements, the lower PEEP strategy induced a significant reduction of static lung elastance in both groups. The higher PEEP strategy further reduced static lung elastance in recruiters (from 23.2 ± 3.1 to 20.2 ± 2.4 cm H2O/L, p < 0.05), whereas it increased it in nonrecruiters (from 26.8 ± 5.5 to 28.3 ± 6.4 cm H2O/L).
In a representative recruiter, the quasi-static volume–pressure curve obtained during the lower PEEP strategy showed a progressive decrease in elastance (i.e., an upward concavity; Figure 3), with coefficient b less than 1 (see Methods, Equation 1). In the same patient, the curve obtained during the higher PEEP strategy was shifted upward along the volume axis, suggesting alveolar recruitment. In a representative nonrecruiter, the quasi-static volume–pressure curve obtained during the lower PEEP strategy showed a progressive increase in elastance during low-flow tidal inflation (i.e., an upward convexity; Figure 3), with coefficient b higher than 1; the quasi-static volume–pressure curve obtained during the higher PEEP strategy was almost superimposed to the volume–pressure curve obtained during the lower PEEP strategy, suggesting an increase in end-expiratory lung volume without lung recruitment.
At baseline, the coefficient b was lower than 1 in both groups (mean, 0.967 ± 0.062 in nonrecruiters and 0.889 ± 0.098 in recruiters; p < 0.05). In recruiters, it remained lower than 1 during lower PEEP strategy (mean, 0.908 ± 0.081; p = not significant as compared with baseline), whereas in nonrecruiters, it increased significantly (1.050 ± 0.06). During the higher PEEP strategy, the mean coefficient b value significantly increased in both groups (1.133 ± 0.089 in nonrecruiters and 1.026 ± 0.050 in recruiters, p < 0.05 between the two groups).
The hemodynamic pattern remained unchanged in both groups during the different experimental conditions, except for a significant increase in stroke volume in recruiters during the higher PEEP strategy (Table 4)
|Baseline||Lower PEEP||Higher PEEP||Baseline||Lower PEEP||Higher PEEP|
|HR, beats/min||106 ± 17||116 ± 9||109 ± 4||103 ± 10||98 ± 19||93 ± 21|
|CO, L/min||6.9 ± 0.7||6.7 ± 1||7.1 ± 1.3||6.8 ± 1.7||6.1 ± 1.4||6.6 ± 0.9|
|SV, ml||61.6||58 ± 5||65 ± 12||66 ± 12||62 ± 16||72 ± 17*|
|MAP, mm Hg||79 ± 11||81 ± 7||78 ± 11||89 ± 16||88 ± 18||86 ± 7|
|RAP, mm Hg||14 ± 5||12 ± 2||15 ± 5||11 ± 2||11 ± 2||13 ± 2|
|Fluid balance, ml||—||−77 ± 1,520||1,344 ± 1,280*||—||255 ± 3,380||−194 ± 1,279†|
The relationship between alveolar recruitment induced by the higher PEEP strategy (dependent outcome variable) and four potentially relevant independent variables was examined by multivariate regression analysis followed by a stepwise regression with backward elimination. The independent variables entered in the model were ARDS underlying disease, coefficient b value during the lower PEEP strategy, and variations in static respiratory system elastance and in PaO2/FiO2 ratio induced by the higher PEEP strategy as compared with the lower PEEP strategy. We found that coefficient b value during the lower PEEP strategy and variations in static respiratory system elastance and in the PaO2/FiO2 ratio induced by the higher PEEP strategy were independently associated with alveolar recruitment. On the contrary, the ARDS underlying disease was not independently associated with alveolar recruitment (Table 5)
Variable Entered in Model
Stepwise Backward Analysis
|Underlying disease|| 6.266|| 54.91||0.911||—|
The implementation protocol for the higher PEEP strategy used in the ALVEOLI study resulted in alveolar recruitment only in 9 of 19 patients, confirming our hypothesis that such a protocol may have unpredictable effects on alveolar recruitment.
Some limitations of this study must be addressed:
A lower/higher PEEP strategy sequence was applied to every patient instead of randomizing the two strategies. Because the lower PEEP strategy applies low Vts and relatively low PEEP levels, it may result in lung derecruitment. Consequently, the efficacy of the higher PEEP strategy could have been reduced by its application after several hours of the lower PEEP strategy. However, a low PEEP “rescue” ventilatory strategy is a logical first-line treatment in patients with ARDS, and commonly it is only after the patient conditions are stable and the volemic state has been optimized that the “potential for lung recruitment” is checked (24). Because a lower/higher PEEP sequence is likely to be applied in the clinical context, we considered it useful to elucidate its physiologic effects. Furthermore, we deemed it appropriate to apply the sequential testing to standardize the “lung volume history” before applying the higher PEEP strategy.
In contrast to the ALVEOLI study, we performed a short and tightly controlled study on a relatively small number of patients. Because our study was physiologically focused, any extrapolation of our data to the clinical context should be conducted with caution (15).
Respiratory mechanics measurements were performed during a brief period of paralysis. In patients who are paralyzed, diaphragmatic muscular tone and active muscular contraction are lost, and this may contribute to the loss of aeration in dependent caudal lung regions (25). Therefore, paralysis, although applied only briefly, may have biased the results of our study toward nonrecruitment.
PEEP optimization may lead to lung protection via mechanisms other than alveolar recruitment—for example, by avoiding surfactant depletion and disruption occurring at low end-expiratory lung volumes (26). Corbridge and coworkers (27) showed that combining low PEEP and small Vt reduces edema accumulation in a ventilator-induced lung injury model by limiting alveolar tidal excursions, regardless of its effects on lung recruitment. We must therefore outline that alveolar recruitment is not the only reason why PEEP optimization is potentially important.
According to the ALVEOLI protocol (8), in our study the applied PEEP level was significantly different between the two strategies (9 ± 2 vs. 16 ± 1 cm H2O, p < 0.05). However, in nonrecruiters, PEEP had to be increased significantly more than in recruiters to match the oxygenation target (Table 2). These findings can be explained if it is considered that the higher PEEP/lower FiO2 combination table adopted in the ALVEOLI study favors the increase of PEEP against the increase of FiO2 (Table 1). In nonrecruiters lacking alveolar recruitment, the oxygenation was most likely dependent on the applied FiO2, and to reach a higher FiO2 level in the table, PEEP had to be increased to higher levels than in recruiters.
In a recent study, De Durante and coworkers (28) found significant intrinsic PEEP in patients ventilated according to the ARDS Network lower PEEP strategy, although we were not able to replicate these findings (Table 2). The difference in respiratory rate between ours (23 ± 5 breaths/minute) and De Durante's study (34 ± 1 breaths/minute) may explain these discrepancies. This hypothesis is confirmed by another study demonstrating that the use of high respiratory rates to compensate for Vt reduction, whereas maintaining a constant inspiratory-to-expiratory ratio may generate intrinsic PEEP (29). Furthermore, if the increase in respiratory frequency is associated with an increase in inspiratory-to-expiratory ratio (the inspiratory time remaining constant despite the shortening of duty cycle), the use of high respiratory rate further reduces the time for lung emptying, generating significant air trapping (30).
The physiologic effects of the lung recruiting maneuvers were not specifically assessed in our study. However, our data suggest that lung recruiting maneuvers were not effective in nonrecruiters. A possible explanation for this finding is that lung recruiting maneuvers were applied by following the protocol after the initial PEEP setting (Table 1). In fact, experimental data suggest that the effects of a lung recruiting maneuver on alveolar recruitment are transient if the preceding PEEP levels are maintained after the maneuver (22) and that, once the alveoli have been recruited, higher PEEP levels are required to keep them aerated (31). Confirming our explanation, an ancillary study performed during the ALVEOLI trial showed that the improvement in oxygenation induced by the lung recruiting maneuvers was only transient (32).
Gattinoni and coworkers (12) showed that PEEP improves lung mechanics and induces significant alveolar recruitment in patients with extrapulmonary ARDS, whereas it results in lung overinflation and worsening of lung mechanics in patients with pulmonary ARDS. Although in our study the number of patients with pulmonary ARDS was higher in nonrecruiters than in recruiters, the underlying disease was not independently associated with alveolar recruitment (Table 5). On the other hand, Rouby and coworkers (11) were not able to confirm the correlation between ARDS etiology and PEEP-induced alveolar recruitment, whereas they clearly demonstrated that the distribution pattern of the loss of lung aeration seen on the computed tomography scan may predict the potential for lung recruitment. The same group has recently shown that applying a PEEP level of 15 cm H2O results in maximal recruitment in patients with “diffuse” loss of lung aeration and in mild recruitment plus lung overinflation in patients with “lobar” loss of lung aeration (33). Although we have no data to show which was the distribution pattern of the loss of lung aeration in our patients, in nonrecruiters we found both lung recruitment at lower PEEP levels and an increase in end-expiratory lung volume without further lung recruitment at higher PEEP levels (Figure 4).
In recruiters, the shape of the static volume–pressure curve during the lower PEEP strategy showed a pattern of ongoing elastance reduction during low-flow tidal inflation, with a coefficient b lower than 1 in the power equation fitting. Because this finding suggests the occurrence of intratidal recruitment (20, 34), we can speculate that, in recruiters, the lower PEEP strategy was not able to completely meet the potential for lung recruitment. Confirming this hypothesis, we found that lower coefficient b values during the lower PEEP strategy were independently associated with alveolar recruitment induced by the higher PEEP strategy (Table 5). On the contrary, the pattern of an ongoing increase in elastance with tidal inflation in nonrecruiters suggests that tidal overinflation was already present during the lower PEEP strategy, thus predicting a very low potential for further alveolar recruitment with the higher PEEP strategy (20, 34).
In nonrecruiters, PaCO2 increased significantly during the higher PEEP strategy as compared with the lower PEEP strategy (Table 2). Because minute ventilation was not significantly different between the two conditions, the increase in PaCO2 suggests a PEEP-induced increase in alveolar dead space, which is an indirect sign of alveolar overinflation (35). However, we have compared PaCO2 levels recorded with a time interval of 12 hours and the effects of differences in metabolic CO2 production cannot be ruled out.
Although PEEP may critically affect venous return, particularly if it does not induce alveolar recruitment (36), we were not able to show systemic hemodynamic impairment in nonrecruiters. Because nonrecruiters received significantly more intravenous fluids during the higher PEEP strategy period as compared with recruiters (Table 4), we speculate that blood volume expansion could have compensated for the PEEP-induced systemic hemodynamic impairment (37). These results are strengthened by the standardization of the hemodynamic management throughout the study period (see online supplement). Higher PEEP levels may increase right ventricular afterload, which induces right ventricular impairment (37). However, right ventricular function was not directly assessed in this study, so we have no data to show if our patients developed right ventricular dysfunction.
In conclusion, our data suggest that the standardized higher PEEP and lower FiO2 implementation protocol proposed by the ARDS Network in the ALVEOLI study lacks a solid physiologic basis and therefore frequently fails to induce alveolar recruitment. In addition, this protocol may increase the risk of alveolar overinflation, favoring the use of higher PEEP levels whenever the lungs are not prone to be recruited. We found that some physiologic variables (the increase in oxygenation, the reduction in static lung elastance, and the shape of the volume–pressure curve) could be useful in predicting alveolar recruitment when applying higher-than-traditional PEEP levels. Further studies are needed to fully elucidate the role of higher-than-traditional PEEP levels in patients with ARDS.
The authors thank Lidia Dalfino, M.D., for her help in statistical analysis, and Caterina Brindicci, M.D., and Sarah Esselfie-Quaye, M.D., for their help in English-language editing.
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