Does high PEEP prevent alveolar cycling?
Acute respiratory distress syndrome (ARDS) patients need mechanical ventilation to sustain gas exchange. Animal experiments showed that mechanical ventilation with high volume/plateau pressure and no positive end-expiratory pressure (PEEP) damages healthy lungs, while low tidal volumes and the application of higher PEEP levels are protective. PEEP makes the lung homogeneous, reducing the pressure multiplication at the interface between lung units with different inflation statuses and keeps the lung open through the whole respiratory cycle, avoiding intratidal opening and closing. Four randomized clinical trials tested a higher PEEP strategy compared to a lower PEEP strategy but failed to show any survival benefit. These results, which apparently contradict preclinical data, may be explained by CT scanning, which investigates the behaviour of ARDS lung upon inflation and deflation demonstrating that: (1) 15 cmH2O PEEP is insufficient to overcome the closing pressures of the lung and keep it open through the whole respiratory cycle; (2) lung recruitment is continuous along the volume-pressure curve. The application of a PEEP level around 15 cmH2O does not abolish opening and closing, but the lung region undergoing opening and closing is simply shifted downward, i. e. becomes more vertebral in the supine patient. (3) Recruited lung tissue becomes poorly inflated and not well inflated; poorly inflated tissue is inhomogeneous: while increasing PEEP the reduction in lung inhomogeneity is small or non-existent.
KeywordsAcute respiratory distress syndrome Respiration, artificial Ventilator-induced lung injury Collapse and decollapse Opening and closing
Verhindert ein hoher PEEP den zyklischen Kollaps der Alveolen?
Patienten mit akutem Lungenversagen („acute respiratory distress syndrome“ [ARDS]) müssen beatmet werden, um den Gasaustausch aufrechtzuerhalten. Tierversuche belegen, dass eine Beatmung mit hohen Atemzugvolumina bzw. hohem Plateaudruck und ohne positiven endexspiratorischen Druck (PEEP) die gesunde Lunge schädigt, während niedrige Atemzugvolumina und die Anwendung eines hohen PEEP protektiv wirken. Der PEEP sorgt für einen homogenen Zustand der Lunge, indem er die starke Druckerhöhung an Grenzflächen zwischen Lungenabschnitten mit unterschiedlich starker Belüftung verringert. Zudem hält er die Lunge über den gesamten Atemzyklus hinweg offen und vermeidet ein intratidales Öffnen und Schließen. In vier randomisierten klinischen Studien wurden Beatmungsstrategien mit hohem und niedrigem PEEP verglichen. Ein Überlebensvorteil konnte aber nicht belegt werden. Diese Ergebnisse widersprechen offensichtlich präklinischen Daten und könnten mithilfe computertomographischer Untersuchungen zum Verhalten der ARDS-Lunge bei Be- und Entlüftung erklärt werden. Hier zeigt sich: 1. Ein PEEP von 15 cmH2O reicht nicht aus, um die Verschlussdrücke der Lunge zu überwinden und die Lunge über den gesamten Atemzyklus offen zu halten; 2. Die Lungenrekrutierung nimmt entlang der Volumen-Druck-Kurve einen kontinuierlichen Verlauf. Mit einem PEEP von etwa 15 cmH2O lässt sich das Öffnen und Schließen nicht unterbinden. Der sich öffnende und schließende Lungenabschnitt wird schlicht nach unten verschoben, das heißt, er wird bei einem Patienten in Rückenlage vertebraler. 3. Rekrutiertes Lungengewebe wird nicht etwa gut, sondern schlecht belüftet. Schlecht belüftetes Gewebe ist inhomogen; bei Erhöhung des PEEP nimmt die Lungeninhomogenität nur geringfügig oder gar nicht ab.
SchlüsselwörterAkutes Lungenversagen Beatmung Beatmungsinduzierter Lungenschaden Kollaps und Wiedereröffnung Öffnen und Schließen
Acute respiratory distress syndrome (ARDS) is characterized by widespread lung inflammation with permeability alteration of the lung microvasculature and edema involving the whole lung parenchyma [2, 31, 38]. No etiologic treatment is available and supportive treatment with mechanical ventilation is associated with a mortality rate of up to 43% in severe ARDS . The causes of mortality in ARDS patients are still debated, but hypoxemia is the leading cause of death in a minority of cases . In most patients with unfavorable outcome the lung does not heal, but the persistence of the inflammatory process leads to widespread lung fibrosis  and the patient cannot be weaned from the ventilator. Some authors have shown that the inflamed lung releases cytokines into the blood stream, possibly leading to multi-organ failure [7, 34]. There is extensive experimental evidence that mechanical ventilation itself can damage healthy lungs [15, 19, 26]. Several theories to explain the possible mechanisms of lung damage in healthy and diseased lungs have been proposed over the years [17, 19]. Most of the literature accepts that excessive stress and strain (barotrauma and volutrauma) in healthy lungs  lead to mechanical rupture of lung parenchyma and activation of inflammatory cascade . In contrast, a diseased lung is non-homogeneous on the small scale, presenting lung regions with different inflation statuses. Consequently, in the ARDS lung, two additional disease mechanisms apply: pressure multiplication at the interface between lung regions with different inflation statuses [13, 15, 27] and intratidal collapse/decollapse . Mead showed that the applied pressure is regionally multiplied at the interface between lung regions with different inflation statuses [7, 13]. A second possible mechanism of ventilator-induced lung injury (VILI) in a diseased lung is intratidal collapse and decollapse of lung units (atelecrauma) [32, 38], which may be seen both as an extension of the Mead model or a different disease mechanism. Lung damage may occur at the small airway level where the applied pressure acts on the fluid meniscus, accelerating it towards the alveoli and damaging the epithelium . A series of rat experiments showed that when the lungs were allowed to cyclically collapse and re-inflate, serious histological lung damage occurred , associated with cytokine release .
High PEEP mechanisms
Intratidal collapse and decollapse is almost unavoidable in ARDS, as it is related to the pathophysiology of the disease and, in particular, to the mechanism of lung collapse. The edematous lung becomes heavy and collapses under its own weight [14, 33]. The dependent (vertebral) lung regions become gasless, while the non-dependent ones (sternal), even if they are edematous, remain inflated . If the patient is positioned prone, the verterbral lung regions become non-dependent and re-inflate, while the sternal ones become dependent and collapse . PEEP (positive end-expiratory pressure) works by overcoming the superimposed pressure and keeping open whatever lung region had been opened during the previous inspiration .
The open lung theory and the lung protective strategy
PEEP levels used in randomized clinical trials at day 1. Table 1 summarizes the PEEP levels (cmH2O) applied in randomized clinical trials at day 1. Data represent mean and standard deviation except for the ART trial, where they are reported as mean and 95% confidence interval
Bedside implementation of PEEP setting strategy
Bedside variables in lower and higher tidal volume groups of the ARDS Network study. Table 2 summarizes data of PaO2/FiO2, PaCO2, and compliance of the respiratory system in the ARDS network trial (New England Journal of Medicine, 2000 ). Compliance of the respiratory system is computed from the averages presented in Table 3 of the original manuscript as: (minute ventilation/respiratory rate)/(plateau pressure—PEEP)
Low tidal volume group
High tidal volume group
158 ± 73
176 ± 76
PaCO2 (mm Hg)
40 ± 10
35 ± 8
Respiratory system compliance (ml/cmH2O)
Is opening and closing real and what is the “real” effect of PEEP?
As clinical trials failed to show any clear survival benefit, one may wonder whether the “opening and closing” theory is real or if it is a mechanism occurring only in some experimental models, mainly rats . Direct proof of VILI is nearly impossible to obtain in “real” ARDS patients, but a recent PET study  showed that the non-homogeneous lung regions at the interface between collapsed and inflated lung tissue, where putatively intra-tidal collapse and decollapse occur, are always inflamed.
The second assumption beyond the use of higher PEEP is that the lung would become more homogeneous upon recruitment. This would happen in a pure atelectasis model where all recruited lung units would re-gain normal gas/tissue status and normal mechanical properties; in ARDS, this does not happen, as the recruited lung units mainly become poorly inflated . Upon recruitment, especially in the more severe patients, one may see an increase in poorly inflated tissue, , which is strongly related to the lung inhomogeneity . The lung inhomogeneity itself is not completely abolished, but is slightly reduced or may paradoxically increase .
In conclusion, the application of 15 cmH2O PEEP does not reduce intra-tidal collapse and decollapse and lung inhomogeneity . In consequence, the “open lung strategy” has never been tested as a whole in the published randomized clinical trials. One may wonder how a mechanical ventilation protocol aimed at the “open lung strategy” should be designed and if it would reduce mortality, as the effect on lung inhomogeneity is limited/non-existent [10, 13, 18]. To really apply the “open lung” strategy, a PEEP level sufficient to overcome the lung superimposed pressure [14, 21, 33], to keep the lung parenchyma open thorough the whole respiratory cycle, and to lift the chest wall is needed [9, 14]. This PEEP level would be around 20 cmH2O,  greater than the one applied in clinical trials and higher than the one selected by the absolute esophageal pressure . A recruitment maneuver performed at 45 cmH2O should completely open up the lung and a PEEP around 20 cmH2O should keep it open. Afterwards, one should set a tidal volume, perhaps keeping a plateau pressure limit of 30 cmH2O (i. e., allowing for a driving pressure up to 10 cmH2O). Two questions remain unsolved: first, what would happen to the lung units with opening pressure between 30 and 45 cmH2O: would they stay open as PEEP overcomes their closing pressure or collapse again in the next few breaths? Second, would the tidal volume be sufficient to allow carbon dioxide removal?
Compliance with Ethical Guidelines
Conflict of interest
M. Cressoni and L. Gattinoni hold an Italian patent (0001409041) and US patent (14/364,551) for the determination of lung inhomogeneities. C. Chiurazzi and D. Chiumello declare that they have no competing interests.
This article does not contain any studies with human participants or animals performed by any of the authors.
The supplement containing this article is not sponsored by industry.
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