The main findings of our study were that: (1) pendelluft was detected in 31% of 200 ARF patients ventilated in the ICU; (2) higher GI index and the existence of spontaneous breathing were the independent factors associated with pendelluft; (3) pendelluft was associated with longer 14-day ventilation duration among patients with PaO2/FiO2 ratio below 200 mmHg.
Definition and prevalence of pendelluft
Since the first report of “occult pendelluft” phenomenon in anesthetized pigs with acute lung injury and a patient with acute respiratory distress syndrome (ARDS) in 2013 [3], EIT has been increasingly used to detect the pendelluft in critically ill patients [14,15,16,17]. At least two studies tried to quantitatively assess the gas volume subjected to pendelluft and moving within the lungs through EIT-based algorithms. Coppadoro et al. [8] defined the increased regional impedance from four quadrant ROIs during the global expiratory phase and vice versa as pendelluft. They reported a median pendelluft volume of 3.3 (2.1, 8.8) mL in 20 patients who had just failed a spontaneous breathing test. Sang et al. [9] introduced a method to detect the amplitude of pendelluft by comparing the sum of all pixel TIV with the global TIV, and expressed it as percent, where 1% of pendelluft amplitude was equal to 1 mL pendelluft volume per 100 mL tidal volume. The latter algorithm was closer to the original theory of pendelluft proposed by Otis et al. [11] and was adopted in our study. According to Otis et al., pendelluft could occur where heterogeneity of respiratory time constants (compliance * resistance) existed between adjacent alveoli. The time shift due to heterogeneity of time constants within the lungs could be assessed by the present pendelluft evaluation. On the other hand, heterogeneous time constants may also result in a so-called “regional ventilation delay”: heterogeneous regional inflation as compared to the global due to collapse of alveoli and/or airways without time shift at the end of inspiration. Such regional ventilation delay was not captured by our calculation. Although the definition of pendelluft was relatively clear, the problem was, the EIT-based algorithm was so sensitive to detect a small amount of pendelluft, possibly without pathological significance, in healthy adults without underlying lung diseases. Therefore, we investigated the pendelluft amplitude in 30 healthy volunteers and then set the 95th percentile, i.e., 2.5% as a threshold, only above which the occurrence of clinically significant pendelluft was considered. Based on that definition, we were able to report the incidence of pendelluft for the first time among ventilated ICU patients with ARF.
Risk factors for pendelluft
Respiratory time constants inequality, also interpreted as alveolar heterogeneity, is the basis of respiratory pendelluft. In the present study, we used two easily accessible parameters to describe the lung heterogeneity. One was the ventilation defect score [12], a semi-quantitative parameter to describe the severity of uneven gas distribution to four quadrant ROIs, ranging from 0 to 6. Higher scores, reflecting higher heterogeneity in gas distribution, were associated with larger amplitudes of pendelluft. The other was the GI index [13], widely used in the evaluation of lung recruitment, PEEP titration and weaning process. The calculation of the GI index was based on the deviation of each pixel tidal impedance variation. Higher GI values denoted higher degree of lung heterogeneity. Our study recognized GI index as an independent factor associated with pendelluft.
Spontaneous breathing effort during mechanical ventilation might improve gas exchange and lung aeration, but excessive effort could also cause uneven distribution of intrathoracic pressure in already injured lung, which was proposed as another mechanism eliciting respiratory pendelluft [3]. Previous studies noticed the disappearance of pendelluft in ARDS patients when neuromuscular blockers were applied [3, 18], supporting the association between spontaneous effort and pendelluft. In our study population, pendelluft was more likely to occur in patients with spontaneous breathing, but there was no direct evaluation of breathing effort. Respiratory rate was an indirect indicator reflecting the breathing effort [19, 20]. It was higher in patients with pendelluft but without statistical significance after multivariable regression. Relatively low respiratory frequency (below 21 cycles/minute in 75% of spontaneously breathing patients) might obscure its effect. Careful monitoring of spontaneous breathing effort (e.g., P0.1, pressure muscle index, negative deflection of pressure during end-expiratory occlusion, etc.) and its association with pendelluft amplitude is needed. It should be also noted that zero spontaneous effort did not exclude the possibility of pendelluft, as was seen in around 21% of ARF patients without presence of spontaneous breathing and was proven by dynamic computed tomography in an experimental study conducted on a swine model of mild acute respiratory distress syndrome [18].
Some studies found that applying higher PEEP could alleviate pendelluft in ARDS [4, 5]. As pendelluft was mainly associated with lung heterogeneity and dynamic pleural pressure variations, higher PEEP may reduce the magnitude of pendelluft by lowering the level of spontaneous effort via neuromechanical uncoupling and by reducing atelectasis. Both mechanisms promote a more homogeneous lung expansion [21]. Opposite evidence also existed showing PEEP had no effect on pendelluft [22], but the ventilation mode, baseline P/F ratio and calculation of pendelluft in the study were all different from previous ones. Hence, we made subgroup analysis and found a week but significant negative correlation between PEEP and pendelluft amplitude in the more hypoxemic population and patients with spontaneous breathing. The different results among studies could be partly explained by the disease severity and whether spontaneous breathing was present.
Clinical implication and prognosis of pendelluft
Pendelluft has the potential to cause lung injury as it could increase local lung stress and cause regional overdistension even under protective ventilator settings. Previous animal experiments suggested that pendelluft was associated with tidal recruitment, and that effort-dependent lung injury occurred in the same region where pendelluft appeared [4,5,6]. Our study revealed for the first time that pendelluft was associated with longer duration of mechanical ventilation among ICU patients with PaO2/FiO2 ratio below 200 mmHg, after APACHE II score and PaO2/FiO2 ratio was adjusted. The effect of pendelluft on ventilation duration was dependent on the severity of ARF as similar effect was not seen in mild impaired oxygenation. Results from subgroup analysis according to whether spontaneous breathing was present might suggest different clinical impact of pendelluft in active or passive condition (Additional file 1: Fig. S4). We supposed that pendelluft associated with spontaneous effort in patients with moderate-to-severe impaired oxygenation could be an injurious ventilation pattern that possibly lengthen ventilation duration, while pendelluft in passive condition might only imply lung inhomogeneity but no direct evidence to lung injury.
Results from analysis of restricted cubic spline suggested that pendelluft amplitude below the reference of 2.5% had an unclear influence on the probability of successful discontinuation from mechanical ventilation, while higher amplitude of pendelluft above the threshold was associated with prolonged ventilation duration. The optimal threshold of pendelluft amplitude or volume for predicting clinical outcome warrants further investigation.
We also explored the relationship between pendelluft amplitude and ventilatory ratio, a variable reflecting ventilation efficiency of the lung [10]. A positive correlation was hypothesized because the pendelluft gas moving within the lung was not expected to contribute to gas exchange, possibly resulting in reduction of ventilation efficiency. However, our results did not support the hypothesis. The effect of pendelluft on ventilation efficiency might have been too weak or masked by confounders.