Ventilation of Intact Lungs High lung volume VILI
Webb and Tierney were the first to demonstrate that mechanical ventilation could cause pulmonary edema in intact animals . They were able to show in rats subjected to positive airway pressure ventilation that pulmonary edema was more severe and occurred more rapidly when the animals were ventilated with 45 cmH2O than with 30 cmH2O peak airway pressure. Animals ventilated for 1 hour with 14 cmH2O peak airway pressure did not develop edema. It was later confirmed that ventilation with high airway pressure produces capillary permeability alterations, non-hydrostatic pulmonary edema and tissue damage resembling that observed during ARDS . Further studies demonstrated that VILI depended mainly on lung volume and especially on the end-inspiratory volume . The corresponding pressure is termed 'plateau' pressure and its clinical importance has been emphasized in a Consensus Conference on mechanical ventilation . The respective roles of increased airway pressure and increased lung volume on the development of VILI were clarified by showing that mechanical ventilation of intact rats with large or low tidal volume (VT),butwith identical peak airway pressures (45 cmH2O)  did not result in the same lung alterations. Pulmonary edema and cellular ultrastructural abnormalities were encountered only in rats subjected to high VT and not in those in which lung distention was limited by thoraco-abdominal strapping . Furthermore, animals ventilated with large Vt but negative airway pressure (by means of an iron lung) still developed pulmonary edema thus demonstrating that airway pressure is not a determinant for pulmonary edema . Consequently, it was suggested that the term 'volutrauma' would be more appropriate than barotrauma in this situation [12,13]. Other investigators have reached the same conclusions with different protocols and species. Hernandez and coworkers compared the capillary filtration coefficient (a measure of capillary permeability) of the lungs of rabbits ventilated with 15, 30 and 45 cmH2O peak airway pressures with that of animals ventilated with the same airway pressures but with limitation of thoraco-abdominal excursions by plaster casts placed around the chest and the abdomen . The capillary filtration coefficient of the lungs removed after ventilation was normal in animals ventilated at 15 cmH2O peak pressure, increased by 31% at 30 cmH2O peak pressure and by 430% at 45 cmH2O peak pressure in animals without restriction of lung distention. In striking contrast, limiting lung inflation prevented the increase of the capillary filtration coefficient . Carlton and coworkers confirmed this observation in lambs . Besides the lung distention that occurs during mechanical ventilation, the rate at which lung volume varies may also affect microvascular permeability. Peevy and coworkers  used isolated perfused rabbit lungs to determine the capillary filtration coefficient of lungs ventilated with various Vt and inspiratory flow rates. They found that small Vt with a high flow rate increased the filtration coefficient to the same extent (approximately 6 times baseline value) as ventilation with a markedly higher Vt but a lower inspiratory flow rate for the same peak airway pressure .
Unlike high volume lung injury (which can be observed in non-injured animals), low lung volume injury is not seen in healthy lungs, which can tolerate mechanical ventilation with physiologic Vt and low levels of positive end-expiratory pressure (PEEP) for prolonged periods of time without any apparent damage. Taskar and colleagues  have shown that the repetitive collapse and reopening of terminal units during 1 h does not seem to damage healthy lungs (although it does alter gas exchange and reduces compliance).
Ventilation of Damaged Lungs High-volume lung injury
Several investigators have evaluated the effect of mechanical ventilation with overdistension on damaged lungs. Results from these studies consistently stress the increased susceptibility of diseased lungs to the detrimental effects of mechanical ventilation.
The first studies were performed on isolated lungs. Bowton and Kong  showed that isolated perfused rabbit lungs injured by oleic acid gained significantly more weight when ventilated with 18 ml/kg bw than when ventilated with 6 ml/kg bw Vt. Hernandez and colleagues  compared the effects of oleic acid alone, mechanical ventilation alone, and a combination, on the capillary filtration coefficient and wet-to-dry weight ratio of isolated perfused lungs from young rabbits. These measurements were not significantly affected by low doses of oleic acid, or mechanical ventilation with a peak inspiratory pressure of 25 cmH2O for 15 min. However, the filtration coefficient increased significantly when oleic acid injury was followed by mechanical ventilation. The wet-to-dry weight ratio (a marker of edema severity) of these lungs was significantly higher than that of the lungs subjected to oleic acid injury or ventilation alone. The same workers also showed that the increased filtration coefficient produced by ventilating isolated blood-perfused rabbit lungs with 30-45 cmH2O peak pressure was greater when surfactant was inactivated by instilling dioctyl-succinate . Whereas light microscope examination showed only minor abnormalities (minimalhemorrhage and vascular congestion) in the lungs of animals subjected to ventilation alone, or surfactant inactivation alone, the combination of the two caused severe damage (edema and flooding, hyaline membranes and extensive alveolar hemorrhage).
These results on isolated lungs suggested that VILI might develop at lower airway pressure in abnormal isolated lungs. Whether this could also be the case in whole animals with 'pre-injured lungs' was investigated by comparing the effects of different degrees of lung distention during mechanical ventilation in rats whose lungs had been injured by a-naphtylthiourea (ANTU) . ANTU infusion alone caused moderate interstitial pulmonary edema of the permeability type. Mechanical ventilation of intact rats for 2 min resulted in a permeability edema whose severity depended on the VT amplitude. It was possible to calculate how much mechanical ventilation would theoretically injure lungs diseased by ANTU by summing up the separate effect of mechanical ventilation alone or ANTU alone on edema severity. The results showed that the lungs of the animals injured by ANTU ventilated at high volume (45 ml/kg bw) had more severe permeability edema than predicted, indicating synergism between the two insults rather than addition. Even minor alterations, such as those produced by spontaneous ventilation during prolonged anesthesia (which degrades surfactant activity and promotes focal atelectasis [22, 23]), are sufficient to synergistically increase the harmful effects of high volume ventilation . The extent to which lung mechanical properties have deteriorated prior to ventilation is a key factor in this synergy. The amount of edema produced by high volume mechanical ventilation in the lungs of animals given ANTU, or that had undergone prolonged anesthesia was inversely proportional to the respiratory system compliance measured at the very beginning of mechanical ventilation . Thus, the more severe the existing lung abnormalities before ventilation, the more severe the VILI. The reason for this synergy requires clarification. The presence of local alveolar flooding in animals given the most harmful ventilation protocol was the most evident difference from those ventilated with lower, less harmful, Vt. Itis conceivable that flooding reduced the number of alveoli that received the Vt, exposing them to overinflation and rendering them more susceptible to injury, further reducing the aerated lung volume and resulting in positive feed-back. The same reasoning applies to prolonged anesthesia, during which the aerated lung volume was probably gradually reduced by atelectasis . Both flooding and atelectasis decrease compliance, likely to an extent that is correlated with their spreading. It is thus not surprising that the lower the lung distensibility before ventilation (as inversely reflected by quasi-static compliance, an index of the amount of lung that remains open), the more severe the alterations induced by high volume ventilation . Thus, uneven distribution of ventilation that occurs during acute lung injury (ALI)  may render lungs more prone to regional overinflation and injury. To explore this possibility, alveolar flooding was produced by instilling 2 ml saline into the trachea. The rats were then immediately ventilated for 10 minutes with Vt of up to 33 ml/kg. Flooding with saline did not significantly affect microvascular permeability when Vt was low. As Vt was increased, capillary permeability alterations were larger in flooded than in intact animals, reflecting further impairment of their endothelial barrier. There was also a correlation between end-inspiratory airway pressure, the pressure at which was found the lower inflection point on the pressure-volume (PV) curve, and capillary permeability alterations in flooded animals ventilated with a high Vt . Thus, the less compliant and recruitable the lung was after saline flooding, the more severe were the changes in permeability caused by lung distention.
There maybe an increase in trapped gas volume during pulmonary edema and ALI, especially when surfactant properties are altered, because of terminal unit closure . Under such conditions, the slope ofthe inspiratory PV curve of the respiratory system often displays an abrupt increase at low lung volume. This change reflects the massive opening of previously closed units and has been termed the 'lower inflection point'. Most clinicians are aware of the importance of this phenomenon in terms of arterial oxygenation, since setting PEEP above this inflection point usually results in a very abrupt decrease in shunt and increase in PaO2 [27-30].
Attention has focused only relatively recently on the possibility that pulmonary lesions maybe aggravated if this inflection point lies within the Vt. Experimental evidence for this was initially provided by studies comparing conventional mechanical ventilation with high frequency oscillatory ventilation (HFOV) in premature or surfactant-depleted lungs. More recently, studies performed during conventional mechanical ventilation of surfactant-depleted lungs with various levels of PEEP also support the possibility that the repeated opening and closing of terminal units cause additional injury [31-33]. Sykes and coworkers [31, 32] studied this issue by ventilating rabbits whose lungs were depleted of surfactant by lavage. Peak inspiratory pressure was 15 mmHg at the beginning of the experiment and 25 mmHg at the end (5 hours later), because lung compliance decreased (Vt was set but not stated). PEEP was adjusted so that functional residual capacity (FRC) was either above or below the lower inflection point on the inspiratory limb ofthe PV curve. This resulted in PEEP levels of about 1-2 mmHg (below inflection) and 8-12 mmHg (above inflection). The mortality rates in the two groups were identical, but the arterial PaO2 was better preserved and there was less hyaline membrane formation in the high PEEP group [31,32]. This lessening of pathological alterations occurred even when the mean airway pressures in the low and high PEEP groups were kept at the same level by adjusting the inspiratory/expiratory time ratio . Muscedere and colleagues  recently reported similar results for isolated, unperfused, lavaged rabbit lungs ventilated with a low (5-6 ml/kg bw) Vt and with a PEEP set below or above the inflection point. However, Sohma and colleagues could not replicate these findings in rabbits with hydrochloric acid-injured lungs using the same ventilation settings . The reality of the repetitive opening and closure of terminal units and the significance of the lower inflection point on the PV curve have been recently challenged by Martynowicz and coworkers . They studied the regional expansion of oleic acid-injured lungs using the parenchymal marker technique. They found that the gravitational distribution of volume at the FRC was not affected by oleic acid injury and that the injury was not associated with decreased parenchymal volume of dependent regions. In addition, they found that the temporal inhomogeneity of regional tidal expansion did not increase with oleic acid injury. Their findings are, therefore, in contradiction with the hypothesis that a gravitational gradient in superimposed pressure during VILI produces compression atelectasis of dependent lung that in turn produces shear injury from cyclic recruitment and collapse . They propose a different explanation for the occurrence of a lower inflection point on the PV curve, namely the displacement of air-liquid interfaces along the tracheo-bronchial tree rather than alveolar recruitment and derecruitment and thus a different mechanism by which PEEP restores the regional tidal expansion of dependent regions and conclude that the knee in the P-V curve is the result ofthe mechanics ofparenchymawith constant surface tension and partially fluid-filled alveoli, not the result of abrupt opening of airways or atelectatic parenchyma . It, therefore, remains unsettled whether injury caused by the repetitive reopening of collapsed terminal units and the protective effect of PEEP is restricted to the peculiar situation of surfactant depletion. In the clinical field, the recent negative results of the ALVEOLI trial (http://hedwig.mgh.harvard.edu/ardsnet/ards04.html) cast doubt on the clinical existence of repetitive opening and closing lung injury .
Roles of VT, PEEP, and Overall Lung Distention
The influence of PEEP on ALI (and more specifically on ventilator-induced pulmonary edema) must be studied with respect to the level of Vt used. Indeed, PEEP increases FRC and opens the lung but also displaces end-inspiratory volume towards total lung capacity when VT is kept constant possibly thus favoring overinflation. PEEP may also affect hemodynamics and lung fluid balance. Therefore, close analysis of the numerous studies which have been done to clarify the relationships between PEEP, oxygenation, and the accumulation of extravascular lung water during hydrostatic or permeability type edema must take into account the experimental approach used, i.e., intact animals or isolated lungs (for which lung water content will differ) and whether or not VT is reduced (thus increasing or not end-inspiratory lung volume).
Application of PEEP may result in lung overinflation if it is followed by a significant change in FRC owing to the increase in end-inspiratory volume. Depending on the homogeneity of ventilation distribution, this overinflation will affect preferentially the more distensible areas, thus accounting for the usual lack of reduction or even the worsening of edema reported with PEEP during most experiments . In intact animals, application of PEEP does not counteract the accumulation of edema fluid during hydrostatic type edema  or permeability type edema [39, 40], though it improves oxygenation  because of the reopening of flooded alveoli. In isolated ventilated-perfused lung, PEEP aggravates edema fluid accumulation . Thus, for a given Vt, increasing FRC with PEEP has dissimilar effects on edema accumulation in isolated lungs and in intact animals. In the latter, the lack of effect of PEEP depends on the balance between PEEP-induced increase in end-inspiratory lung volume which decrease interstitial pressure and favors fluid filtration in extra-alveolar vessels and the hemodynamic depression due to elevated intrathoracic pressure that will decreases filtration pressure. In contrast, the preservation of perfusion-rate in isolated-perfused lungs favors the increase in edema .
Edema is less severe when Vt is decreased and end-inspiratory lung volume is kept constant by increasing FRC with PEEP during high-volume ventilation . Webb and Tierney showed that edema was lessened by 10 cmH2O PEEP application during ventilation with 45 cmH2O peak airway pressure . The authors attributed this beneficial effect of PEEP to the preservation of surfactant activity. It was shown later that although PEEP decreased the amount of edema, it did not change the severity of the permeability alterations as assessed by the increase in dry lung weight . However, no alveolar damage was observed in animals ventilated with PEEP in comparison with those ventilated in zero end-expiratory pressure (ZEEP). The only ultrastructural alterations observed with PEEP consisted of endothelial blebbing . This preservation ofthe epithelial layer has received no satisfactory explanation. It may be that PEEP prevented repetitive opening and closing of terminal units, thereby decreasing shear stress at this level. Similar observations have been made by other investigators in intact animals [42, 43] and in perfused canine lobes . The potential role of hemodynamic alterations induced by PEEP should be considered. For a given end-inspiratory airway pressure, application of PEEP produces an increase in intrathoracic pressure which adversely affects cardiac output [45, 46]. Indeed, rats submitted to high-peak airway pressure ventilation with 10 cmH2O PEEP had more severe edema when the hemodynamic alterations induced by PEEP were corrected with dopamine . The amount of edema was correlated with systemic blood pressure, suggesting that improvement in cardiac output and increased filtration were responsible for this aggravation. In conclusion, the reduction of edema and of the severity of cell damage by PEEP during ventilation-induced pulmonary edema may be linked to reduced tissue stress (by decreasing volume-pressure excursion) and capillary filtration, as well as to the preservation of surfactant activity.
Lung volume at the end of inspiration (i.e., the overall degree of lung distention) is probably the main determinant of VILI severity. Rats ventilated with a low Vt and 15 cmH2O PEEP developed pulmonary edema whereas rats ventilated with the same Vt but 10 cmH2O PEEP did not . Similarly, doubling Vt (which was not deleterious in animals ventilated in ZEEP) resulted in edema in the presence of 10 cmH2O PEEP. Thus the safety of a given Vt depends on how much FRC is increased.
In conclusion, VILI and edema occur when a certain degree of lung overinflation is reached. This situation is met when Vt is increased at a given end-inspiratory pressure. By contrast, when PEEP is added to reach the same end-inspiratory pressure, it seems to slow the development of edema and diminish the severity of tissue injury, although the occurrence of microvascular permeability alterations is not prevented [10,47]. Finally, when PEEP results in additional overinflation, there is greater edema .
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