How large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography

Severe ARDS still has a very high mortality rate despite all advances in critical care [1]. Ventilator Induced Lung Injury (VILI) plays a major role in the poor prognosis of such patients, as demonstrated by extensive experimental and clinical evidence [2‐10]. But there is no consensus yet on the least harmful mechanical ventilation to be individually applied at bedside [11‐18]. Although most studies indicate that reducing inspiratory pressures and tidal volumes is generally beneficial, many uncertainties remain about the actual impact of the PEEP selection. Abundant physiological data suggest that the combination of recruitment maneuvers and individual PEEP titration is essential to optimize the effects of PEEP, but the proof of such benefits in humans is not yet conclusive [11, 12, 19‐22].

Recently, three large clinical trials [13‐15], including Acute Lung injury/ARDS patients ventilated with low tidal-volume, have compared different PEEP strategies (high vs. low), but none of them could show a significant difference in mortality. A recent meta-analysis has pooled those trials [23], revealing some combined benefit of the high PEEP strategy; still, the survival benefit was modest and limited to the subgroup of ARDS patients. Conceptually, one could argue that none of the "high-PEEP" strategies was designed to test the "open-lung hypothesis" postulated by Lachmann [24‐27], that is, the hypothesis that most of the collapsed lung tissue observed in early ARDS can be reversed at an acceptable clinical cost, potentially resulting in better lung protection. According to a recent study by Borges and colleagues [22, 28], a straight test of the "open-lung hypothesis" would certainly require more aggressive recruiting maneuvers in association with individualized, decremental PEEP titration. Thus, one can speculate that the limited results reported above were related to sub-optimal ventilatory strategy.

Although the study by Borges and colleagues [22] provided a good description of the physiological principles of the Maximum Recruitment Strategy (MRS), there is still a lack of information regarding the long term management, side effects, and generality of such findings in a non-selected population. In fact, a recent study by Gattinoni and colleagues [29] with 68 ALI/ARDS patients submitted to recruitment strategies, all under close monitoring by computed tomography (CT), has cast doubts about the feasibility of the "open-lung" strategy, since the recruitability of the lungs reported in this study varied too much among patients, amounting to less than 15% in most patients.

Thus, the objective of this study was to describe the feasibility and long term impact of the MRS applied in a case-series of non-selected patients with severe ARDS. All patients were closely monitored by multi-slice CT during the implemented strategy. Since the maneuver was individualized and applied in a more intensive fashion than in previous studies, we tried also to provide a more precise, bedside estimation of lung recruitability in a general population of patients with early ARDS.

Demographic and clinical characteristics of the study population are shown in Table 1. Gas exchange and mechanical ventilation data are shown in Table 2 and hemodynamic data in Table 3

Eighteen patients were excluded because of the following reasons: hemodynamic instability judged to represent high risk for transportation (six patients), absence of informed consent (three patients), barotrauma detected before transportation (one case due to thoracic trauma and one case due to mechanical ventilation - before MRS), morbid obesity in no condition for transportation (two patients), more than 72 h of ARDS onset (two patients), do-not-resuscitate orders (one patient), age above 80 years (one patient) and pregnancy (one patient).

Fifty-one severe ARDS patients were included and followed, of whom 84% had primary ARDS. Community-acquired and nosocomial pneumonia represented 57% of the causes. Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 20 ± 6, and Day-1 Sequential Organ Failure Assessment (SOFA) score was 10 ± 3. Non-pulmonary organ failure (NPOF) was 2 (IQR: 1 to 4) and 57% of patients required continuous renal replacement therapy. Seventy-one percent of the patients fulfilled sepsis criteria (89% of whom fulfilled septic shock criteria). Eighty-two percent of the patients required norepinephrine.

The main findings of this study can be summarized as follows. MRS was a safe strategy to reduce the amount of non-aerated tissue in our non-selected population of severe ARDS patients. In order to obtain and sustain expressive recruitment, opening pressures above 45 cmH₂O uninterruptedly followed by high PEEP were necessary, according to individual titration. By using MRS as a referential maneuver, the median percentage of potentially recruitable lung was 45%, a considerable number when compared to previous studies [29], but a higher amount of non-aerated tissue at baseline did not predict a worse response. All CT-scans were analyzed after MRS and no signs of minor or major barotrauma were observed in any patient. No significant clinical complications associated with MRS were noted either.

Recently, Gattinoni and colleagues [29] found that ALI/ARDS patients with a higher mass of non-aerated tissue and a higher potentially recruitable lung had increased mortality. They also demonstrated that the potentially recruitable lung varied widely in their population with a mean value of 13 ± 11% (considering the total lung mass). We believe that the main reason for the differences in relation to our study was the design of the recruitment maneuver per se: in Gattinoni's study [29], plateau inspiratory pressure was limited to 45 cmH₂O and the associated PEEP was 5 cmH₂O. Besides, there may be important differences in the studied population, since the patients in Gattinoni' s study had a mean duration of invasive mechanical ventilation of 5 ± 6 days when they were submitted to their recruitment protocol, while all our patients had less than 72 hours of ARDS onset. As demonstrated by Borges and colleagues [22], the maintenance of appropriate PEEP during the recruitment phase, above closing pressures (commonly above 15 cmH₂O), is an essential component of recruitment maneuver, enhancing the recruitment effects of high plateau inspiratory pressures. Thus, the use of a low PEEP by Gattinoni and colleagues (5 cmH₂O) interposed during their "recruitment phase" probably counteracted the net efficacy of the maneuver, promoting cyclic de-recruitment during this critical phase. Additionally, previous studies and the present one suggest that a maximum recruiting pressure of 45 cmH₂O was not enough to substantially re-aerate collapsed areas in severe ARDS [22, 28, 34]. In a preliminary CT analysis performed in 12 of our 51 patients, we observed the persistence of 22% of non-aerated tissue at airway pressures around 40 cmH₂O (accompanied by appropriate PEEP), in patients who later achieved less than 5% of lung collapse after MRS [33].

Our CT analysis revealed a four-fold reduction in the amount of non-aerated tissue after MRS (Figure 2), which means that the size of potentially recruitable lung in severe ARDS may be much higher (3.5 times) than previously reported [29, 35] (Figure 4). Thus, the assumption that just a minority of patients with ARDS can be recruited [29, 36] must be reconsidered. It is worthy of note that every single patient presented some radiological response to MRS, and the relative response to the maneuver could not be predicted by the baseline CT evaluation. Although there was some correlation between the amount of non-aerated tissue at baseline and the potential for lung recruitment (P < 0.001, r² = 0.54), the relative response to MRS was not correlated with the initial amount of non-aerated tissue (P = 0.24, r² = 0.03). Whereas the former, significant correlation likely reflects some mathematical coupling, that is, sicker patients have more room to improve, the latter, non-significant, correlation implies an important message: the initial CT quantification, even when showing impressive amounts of collapse, cannot rule out the chances of near-complete collapse reversal after MRS.

This interesting observation may explain why we did not find a correlation between mortality and the potential for lung recruitment in our patients, as previously reported by Gattinoni and Caironi [29, 35]. If many of our patients with the highest potential for lung recruitment had near-complete reversal of collapse, the deleterious effects of lung collapse might have been especially counteracted in this subgroup.

Although the present study was designed to be a prospective case-series testing the MRS as described by Borges and colleagues [22], the two protocols were not identical. Some slight differences may explain the apparent higher recruitability of their patients, although the exact numbers are not provided in their publication. First, this case series had more strict inclusion criteria, but a less strict exclusion one. Thus, the present study included sicker patients, better representing the daily activities of a general ICU center. Secondly, the recruitment strategy in Borges' study had one additional recruitment step (CPAP of 40 cmH₂0 for 40 seconds), with a longer duration of the intensive recruitment protocol: the total duration of their maneuver was 20 minutes (five steps of high inspiratory pressures, alternated with five steps of 25 cmH₂0 PEEP resting periods - each step with 2 minutes), as compared with a total duration of 8 minutes in the present study (four steps of progressive, high recruitment pressures, with 2 minutes at each step, and without resting periods in between).

The immediate response in terms of oxygenation revealed a large increment in PaO₂/FIO₂ (Figure 5), especially in the first few hours after MRS. The overall improvement in the PaO₂/FIO₂ ratio was higher than previously reported in recent trials [13‐15, 37] (Figure 6). As a counterpoint to some reports in the literature suggesting that the effects of a recruitment maneuver in ARDS are transitory [38, 39], our study showed that if PEEP is carefully selected after recruitment, the PaO₂/FIO₂ ratio can be maintained at high levels (> 300) during the first few days (or weeks) of mechanical ventilation. This finding suggests the possibility of long term maintenance of an open lung status, throughout the course of invasive mechanical ventilation, at an acceptable clinical cost [22].

By following the CT guided strategy and trying to select the minimum PEEP to keep the lungs open, we were forced to apply high levels of plateau-inspiratory pressures to our patients (between 30 and 40 cmH₂O), in spite of using relatively low-tidal volume ventilation (6 to 8 mL/kg). Such levels are higher than the ones recommended by some protective protocols [13, 14, 40], and are certainly a matter of concern. We believe, however, that some of the findings in the present study, as well as in the recent literature, provide compelling arguments to counterbalance such concern. First of all, we did not find an important correlation between mortality and plateau-pressures in our study. This finding is in alignment with the results of some recent trials about PEEP selection, in which higher-PEEP arms consistently presented higher levels of plateau-inspiratory pressure [23] (especially in the Lung Open Ventilation Strategy (LOVS) study [15]), and yet, they resulted in similar or better outcome. Thus, the concerns about tidal hyperinflation or of excessive stress/strain [41, 42] have always to be counterbalanced by the possibility of minimization of lung collapse with possible reduction of tidal-recruitment [35, 43, 44]. Secondly, overall mortality or barotrauma incidence in this study was comparable to the results of the best protective strategies reported in the literature [12‐15, 23, 40, 45], despite the higher severity of disease in our case-series. And finally, we kept our focus on minimizing the delta inspiratory-pressures in our patients and, in fact, this variable was found to be the most important predictor of survival (besides age) in our population. In most patients, we could keep it below 15 cmH₂O, a relatively safe value according to preliminary evidences [46, 47].

In retrospect, (maybe we could do better in terms of lung protection), trying to minimize further the delta-inspiratory pressures and plateau-pressures after the MRS could have done better in terms of lung protection. Nevertheless, except for some few cases in which we could have accepted more permissive values of hypercapnia, or could have optimized CO2 removal [48], the main constraints found during the realization of this protocol were related to PaCO₂ levels, which averaged 56 (± 16 mmHg) during the first 24 hours after mechanical ventilation (resulting in a pH around approximately 7.20), and also related to the need of high PEEP levels, sustained along days after the MRS. In practice, we did not reduce PEEP before the first 48 hours, otherwise we would have had to increase the FIO₂ (to > 40%), a procedure that we tried to avoid by protocol design.

Recently, Terragni and colleagues [41] showed that ventilation with tidal volumes around 6 ml/kg and "protective" plateau pressure (less than 30 cmH₂O) were not enough to prevent what the authors defined as "tidal hyperinflation" in ARDS patients, especially in those patients with large amounts of non-aerated tissue at the dependent lung zones. The authors' conclusion was that collapse was an unavoidable phenomenon during ARDS, promoting the heterogeneity of tidal ventilation and hyperinflation of the baby lung, despite low tidal-volume ventilation. The authors suggested that the only possible strategy to prevent harm was the further decrease of airway pressures, even at the expense of deterioration in blood gases. Since this strategy is unfeasible in many patients, especially in those with severe hypoxemia, our study suggests that an alternative strategy is conceivable. MRS was particularly effective in those patients presenting larger amounts of collapse at baseline. Although not specifically tested in this study, the subsequent reversal of collapse might promote a more homogeneous distribution of tidal ventilation, making use of the previously collapsed parenchyma to "share" the tidal volume, and possibly relieving nondependent lung hyperinflation described by Terragni and colleagues [41]. This hypothesis was already suggested by others [22, 34, 49]. It is worthy of mention that in a detailed CT analysis performed in the first 12 ARDS patients of our protocol, the overall amount of tidal hyperinflated tissue increased by only 1% (± 1%) after MRS, despite a large increase in PEEP from baseline (approximately 10 cmH₂O) to the titrated PEEP (approximately 25 cmH₂O) [33].

Recently, Talmor and colleagues [37] monitored esophageal pressure in ARDS patients and observed that even with PEEP levels around 18 cmH₂O and plateau pressures above 30 cmH₂O, transpulmonary inspiratory pressures were kept below reasonable levels (< 12 cmH₂O). They also showed that in order to keep the lung open, with transpulmonary expiratory pressures above zero, PEEP had to be kept above 15 cmH₂O. Similarly, many of our patients were ventilated with plateau pressures above 30 cmH₂O and PEEP levels above 15 cmH₂O during the first days of ARDS, but with driving pressures less than 15 cmH₂O, as in Talmor's study [37].

In our severe ARDS patients with multiple organ failure, MRS was a safe strategy to reverse non-aerated lung parenchyma and hypoxemia in most of them, for extended periods of time. In this particular study, CT was instrumental to individualize the strategy, in order to achieve almost full recruitment and to titrate PEEP, keeping the lungs open. Our results indicate that the general principles of the MRS are a valid alternative to conventional ventilation, worth being tested in future randomized trials.