Imperial College School of Medicine at the National Heart and Lung Institute, Royal Brompton Hospital, London, UK
*Corresponding author: Adult Intensive Care Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: m.griffiths@ic.ac.uk
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Abstract |
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Br J Anaesth 2004; 92: 26170
Keywords: complications, acute respiratory distress syndrome; complications, ventilator-associated lung injury; ventilation, mechanical
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Introduction |
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Following this, many clinicians began to adopt ventilatory strategies designed to minimize lung injury, although the clinical importance of ventilator-associated lung injury (VALI) induced by high tidal volumes has only recently been highlighted by the ARDS Network study.1 This paper establishes that low tidal volume ventilation should now be considered the gold standard ventilation strategy for patients with injured lungs. However, as with any research, this study raises a number of questions, such as the mechanisms underlying the decreased mortality and the appropriate level of positive end-expiratory pressure (PEEP) in patients with ARDS.
Protective ventilation trials in ARDS
In 1993, guidelines published from a consensus conference emphasized the importance of limiting airway pressures and alveolar distension in patients with ARDS.82 However, low tidal volume ventilation may be associated with severe hypercapnia and respiratory acidosis with potentially harmful neurological and cardiovascular sequelae.43 68 76 Previous strategies used to manage hypercapnia have included increasing tidal volume and airway pressure, or increasing carbon dioxide clearance with techniques such as tracheal gas insufflation or extracorporeal carbon dioxide removal. While carbon dioxide levels of two to three times normal seem to be well tolerated for prolonged periods, presently there are no data to confirm the degree of respiratory acidosis that is safe. Moreover, in a large survey of intensivists ventilation practices for patients with ARDS published in 1996, most respondents reported using tidal volumes equal to or greater than 10 ml kg1.17 Therefore, it was important to compare outcomes of patients randomized with either low tidal volume or traditional ventilation strategies. Five multicentre, randomized clinical trials were conducted recently to address this issue in patients with or at risk of acute lung injury or ARDS (Table 1).1 5 14 15 85
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The results from animal studies have suggested that hypercapnic acidosis may contribute to the benefits of lung-protective ventilation. In isolated perfused rabbit lungs, respiratory acidosis protected the lung from ischaemiareperfusion injury,80 whereas respiratory alkalosis potentiated the injury.49 This protective effect was associated with inhibition of xanthine oxidase and was prevented by buffering the acidosis, suggesting that the acidosis rather than the hypercapnia was protective.50 Furthermore, in isolated perfused rabbit lungs, hypercapnia was associated with substantially lower concentrations of protein and tumour necrosis factor (TNF)- in bronchoalveolar lavage fluid (BALF), less pulmonary oedema, better lung compliance, lower lung 8-isoprostane and nitrotyrosine concentrations (markers of reactions with reactive oxygen and nitrogen species respectively),69 and less apoptosis than the control group.51 Despite these experimental observations, we feel that there is no consensus currently concerning the management of respiratory acidosis induced by permissive hypercapnia. However, if bicarbonate is infused, it should be administered slowly to allow carbon dioxide excretion and avoid worsening of intracellular acidosis.
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Mechanisms of VALI |
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The main determinant of volutrauma seems to be the end-inspiratory volume (the overall lung distension) rather than the tidal volume or functional residual capacity (FRC), which depends on PEEP. Consequently, guidelines have emphasized the importance of monitoring and maintaining inspiratory plateau pressure (which most accurately reflects end-inspiratory volume) below 35 cm H2O in ARDS patients by reducing tidal volume to as low as 5 ml kg1.83 Peak airway pressure is not solely determined by alveolar pressure as it is influenced by respiratory resistance and the resistance of the ventilator circuit.
Atelectrauma: low-volume injury
Lung damage may also be caused by ventilation at low lung volume (meaning low absolute lung volume rather than low tidal volume). This has been well defined in animal models, but the relevance to humans is not firmly established.8 29 78 Oedema formation in intact rats was less severe when PEEP (10 cm H2O) was applied during ventilation with 45 cm H2O peak airway pressure.91 This beneficial effect of PEEP was attributable to reduced lung tissue stress (by decreasing tidal volume) and capillary filtration (at least in part because of haemodynamic depression), as well as the preservation of surfactant. Ventilation with a high tidal volume and low or zero PEEP therefore appears to be more damaging than low tidal volume and high PEEP, even though both strategies result in similar high levels of end-inspiratory pressure and alveolar distension.
Theoretically, small airways may become occluded by exudate or apposition of their walls, and the airway pressure required to restore patency greatly exceeds that in an unoccluded passage. Cyclic opening and closing (recruitmentderecruitment) of small airways or lung units may lead to increased local shear stress (so-called atelectrauma), particularly if the cycle is repeated with each breath (20 000 times per day). PEEP effectively works, therefore, by splinting open the distal airways, maintaining recruitment throughout the ventilatory cycle.
Ventilator-induced pulmonary oedema: hydrostatic forces or microvascular permeability?
It has been suggested that hydrostatic mechanisms are responsible for ventilator-induced pulmonary oedema.91 However, the oedema fluid is rich in protein, suggesting that either increased filtration by hydrostatic forces is very localized, or other mechanisms are involved, especially if one considers the extreme severity of the oedema that may be produced in small species such as rats.28 29 91 Theoretical considerations based on lung interdependence predict that considerable increases in regional microvascular transmural pressure may occur during the inflation of very heterogeneous lungs.57 However, increased microvascular permeability is the most likely cause of ventilator-induced pulmonary oedema, and there is probably no large increase in transmural pressure over the whole pulmonary vasculature during high airway pressure ventilation.
Major alterations in pulmonary epithelial and endothelial permeability occur in isolated lungs in animals subjected to high airway pressures. Discontinuities in alveolar type 1 cells have been reported in rabbits ventilated with moderate (20 cm H2O) peak airway pressure for 6 h,49 and widespread alterations of epithelial and endothelial barriers were seen when a higher peak airway pressure was used.28 29 If VALI was the result of changes in hydrostatic forces only, there should be no25 or little11 ultrastructural alteration. Ventilation for longer periods resulted in alveolar flooding, diffuse alveolar damage, profound alterations in the epithelial layer, and capillary lesions.28 The severity of the alterations was unevenly distributed; the epithelial lining appeared to be intact in some areas, whereas there were discontinuities and sometimes almost complete destruction of type 1 cells in many others. Furthermore, alveolar oedema and epithelial lesions were prevented by the application of PEEP (10 cm H2O).
Biotrauma
The clinical effects of VALI may extend beyond the lungs. The majority of patients with ARDS die not from hypoxaemia but from multi-organ failure (MOF).59 The mechanisms leading to MOF are probably multifactorial, but there is evidence that lung injury caused by mechanical ventilation can result in the release of several mediators, including proinflammatory cytokines.84 These mediators may enter the systemic circulation,19 60 61 88 causing organ dysfunction and ultimately MOF.84 The term biotrauma has been coined to describe this potentially injurious local and systemic inflammatory response to physical stress. Injurious ventilation of rats, using zero PEEP combined with very high end-inspiratory volumes, was associated with a fifty-fold increase in the recovery from BALF of proinflammatory cytokines, TNF-, interleukin (IL)-1ß, IL-6, macrophage inflammatory protein-2, and a significant increase in serum concentrations of these substances.86 Similarly, patients with ARDS subjected to lung-protective mechanical ventilation had significantly lower levels of plasma and BALF cytokines and significantly less organ failure.73 74 The ARDS Network study found that plasma levels of IL-6 were lower in the protective ventilation group.1 However, it is not clear what role underlying lung bacterial colonization or infection may have played.
In experimental models, bacteraemia is more likely to develop when lungs that have been inoculated with bacteria are ventilated with high tidal volume/zero PEEP, as opposed to less injurious strategies.73 74 86 The data suggest that overventilation may represent a stimulus for the immune system similar to that elicited by bacterial lipopolysaccharide.39 Furthermore, these findings suggest that a ventilatory strategy associated with overdistension of the lungs and repetitive opening and closing of alveoli is most likely to facilitate bacterial translocation from the alveoli to the bloodstream. This opens the possibility that inappropriate ventilation strategies may contribute to ventilator- associated pneumonia.
Biotrauma, therefore, may be the missing link between the pulmonary pathophysiology of ARDS and MOF. These concepts may lead to a paradigm shift in which novel therapy for VALI is based not only on minimizing the physical forces causing injury, but also on modulating biotrauma using anti-inflammatory interventions to help limit the consequences of ventilator-associated inflammation.22
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The injured lung: set up for VALI? |
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Pressurevolume curves
The static pressurevolume (PV) curve is often used to illustrate the pathophysiology of injured lung and, in particular, the balance between overdistension and recruitment (Fig. 3). Static PV curves can be obtained by inserting pauses during an inflationdeflation cycle of the respiratory system using a large syringe (super-syringe), or holding a ventilator at end-inspiration of varying tidal volumes. The lower inflection point (LIP) may represent the approximate pressure and volume at which lung units are recruited. The upper inflection point (UIP), at which lung compliance decreases at higher airway pressure, is thought to reflect the point at which alveoli become overdistended, and therefore potentially damaged.4 Based on these concepts, an ideal ventilation strategy would be one in which the tidal ventilation would take place on the steep, most compliant portion of the PV curve, between LIP and UIP.23 This may be achieved in part by the application of PEEP, at a level that exceeds the pressure indicated by the LIP, which should prevent the repeated opening and closing of lung units (cyclical atelectasis). This manoeuvre is central to a protective ventilation strategy called open lung ventilation.4
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Other factors
The surfactant obtained from patients with ARDS shows increased minimal surface tension and decreased hysteresis of the surface tensionsurface area relationship, two indicators of surfactant dysfunction.55 Surfactant dysfunction and deficiency amplify the injurious effects of mechanical ventilation, and mechanical ventilation itself can impair surfactant function. Surfactant dysfunction, in part caused by plasma proteins in the airspace, may contribute to the pathophysiology of ARDS and VALI via a number of mechanisms, including exacerbation of atelectasis, increased oedema formation, and impairment of the local host defence. Therefore it is logical to propose that increasing the pool of functioning surfactant might lessen lung injury.48 However, a role for surfactant supplementation in ARDS is not yet established, in part due to difficulties in delivering adequate amounts of active surfactant to damaged and collapsed lung regions.7
Current practice in ARDS is to manipulate the level of PEEP and use the lowest FIO2 to give an oxygen saturation of around 90%. Oxygen toxicity may exacerbate lung injury,81 probably through the increased generation of reactive oxygen species in lung tissue that has been overdistended.18 24 In humans, no detectable oxygen toxicity occurred in normal subjects when the FIO2 was less than 50%,20 but impaired gas exchange was apparent after breathing 100% oxygen for approximately 40 h.12 Although the relationship of FIO2 to oxygen-induced lung injury has not been clearly defined in patients with ARDS, an FIO2 less than 60% is usually considered to be safe.2
Finally, changes in the cellular constituents of injured lungs may make them susceptible to further mechanical damage.67 For example, soon after injury type 1 alveolar epithelial cells die and are replaced by hyperplastic type 2 cells that may respond differently to mechanical strain. Similarly, leucocyte activation and emigration from the pulmonary microvasculature occur almost immediately after lung injury and an influx of myofibroblasts occurs later in the clinical course. This high concentration of cells primed to take part in inflammation may underlie the production of mediators that spill over into the systemic circulation.
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Mechanical ventilation strategies in patients with ARDS |
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Optimizing PEEP
PEEP may improve arterial oxygenation by redistributing lung water from alveolar to interstitial spaces, or by recruiting atelectatic alveoli and thus increasing FRC.10 79 PEEP-induced improvement in arterial oxygenation in eight patients with ARDS correlated with the volume of lung recruited measured using static PV curves.72 However, the increase in mean intrathoracic pressure produced by applying PEEP and maintaining the same tidal volume may exacerbate overdistension, increase dead space by occluding pulmonary capillaries, or cause circulatory depression.
Selecting the right level of PEEP for a given patient with ARDS is difficult, because the severity of injury varies throughout the lungs.23 89 Moreover, there is very little information to guide clinicians on optimizing PEEP in patients with ARDS, and an international survey published in 1996 found wide variations in its use.17 In theory, setting PEEP above the LIP may prevent derecruitment and atelectrauma. However, in ARDS the linear portion of the PV curve may be very short, so that a tidal volume that would not be deleterious in normal lungs may lead to excessive end-inspiratory volume when the PEEP is set above the LIP. Therefore, tidal volume strongly influences the PEEP level at which optimal compliance is recorded.31
In a study involving six patients with ARDS, for example, the use of PEEP at 13 cm H2O resulted in the recruitment of non-aerated portions of lung, but in three patients overdistension of already aerated portions of lung occurred.90 Overinflation is probably the explanation for the usual lack of reduction or even the worsening of oedema reported with PEEP during most experiments.75 The only way to avoid both low- and high-volume lung injury therefore, seems to be to set the PEEP above the LIP and to markedly reduce the tidal volume to minimize overinflation.5
Presently, there is no consensus on the optimum level of PEEP in patients with ARDS. The ARDS Network ALVEOLI study, a prospective, randomized, multicentre trial of ARDS patients, comparing hospital or 60-day mortality, using higher PEEP/lower FIO2 vs lower PEEP/higher FIO2 ventilation, was recently discontinued prematurely after recruiting 550 patients, due to lack of efficacy.3
Prone ventilation
Prone positioning was first reported to improve oxygenation in patients with ARDS in 1976.66 There is little information to predict which patients will respond positively to prone ventilation. However, the improvements in some patients are quite striking. Recruitment of dorsal lung appears to be the predominant mechanism of improved oxygenation with prone ventilation. In patients with ARDS in the supine position, ventilation is diverted to the non-dependent part of the lung if the dependent region is consolidated or collapsed. In the prone position, ventilation is more evenly distributed because of changes in gravitational distribution of pleural pressure, and reduction of pleural pressure in the dorsal region of the lung.52 This suggests that prone ventilation could prevent VALI by promoting more uniform distribution of tidal volume and by recruiting dorsal lung regions, preventing repeated opening and closing of small airways or excessive stretch at margins between aerated and atelectatic dorsal lung units. Furthermore, it has recently been suggested that the addition of a recruitment manoeuvre, such as cyclical sighs during ventilation in the prone position, may provide optimal lung recruitment in the early stages of ARDS.64
Potential problems of prone positioning are dislodgement of tracheal tubes and intravascular catheters, increased intra-abdominal pressure, facial oedema, and eye damage. A multicentre randomized controlled trial of prone positioning for patients with acute respiratory failure has recently been completed.36 Patients randomized to prone positioning were assessed daily for the first 10 days and turned prone for at least 6 h each day if severity criteria were met. However, despite a significant improvement in oxygenation, no differences in clinical outcome were observed. Therefore, at present, prone positioning is a useful adjunct to ventilation that may help to improve oxygenation and pulmonary mechanics, but has not yet been shown to alter outcome in ARDS.
Recruitment manoeuvres
One means of minimizing the loss of lung volume from low tidal volume ventilation is by the use of sighs, involving the delivery of intermittent breaths of large tidal volume, administered either via the ventilator or by hand.63 In one study, increasing the plateau pressure by at least 10 cm H2O during sighs, applied three times a minute over a period of 1 h, caused a 26% decrease in shunting with a 50% increase in oxygenation.65 However, it is unknown whether sighs used at this frequency cause injury from alveolar overdistension. Furthermore, recruitment manoeuvres may improve oxygenation only in patients with early ARDS who do not have impairment of chest wall mechanics and who have a large potential for recruitment.38
Sustained inflation or continuous positive airway pressure (CPAP) is another form of recruitment manoeuvre. It is well recognized that even a single breath without PEEP results in derecruitment. Therefore, when a patient requiring lung-protective ventilation is disconnected from the ventilator, for suctioning for example, a recruitment manoeuvre utilizing a CPAP of 3540 cm H2O for 3040 s before reinstituting the previous level of PEEP has been suggested.53 However, at present there are no published data from randomized studies to indicate whether recruitment manoeuvres, of whatever form, influence outcome.
High-frequency ventilation (HFV)
HFV uses very small tidal volumes with very high respiratory rates (>60 per minute). HFV offers potentially all the goals of lung-protective ventilation, with minimum tidal volume (15 ml kg1) while maintaining maximal recruitment (the open lung), provided sufficient end-expiratory lung volume is maintained.34 There has been a resurgence of interest in HFV over the last few years. Initial enthusiasm had been tempered by practical difficulties and the lack of clinical outcome data showing any advantage over conventional ventilation. High-frequency jet ventilation (HFJV) and high-frequency oscillatory ventilation (HFOV) are the two most commonly used modes.
HFJV uses a high-pressure gas jet delivered into a tracheal tube at high frequency (100200 Hz). The tidal volume produced can be adjusted by altering the inspiratory time and/or driving pressure. During HFJV, expiration occurs passively. HFJV has been investigated in two large randomized studies. In one study of 309 patients, the use of HFJV resulted in no significant outcome differences.16 Similarly, a study of 113 patients at risk of ARDS demonstrated similar clinical outcomes in groups that were ventilated conventionally and in those in whom HFJV was used.47 However, these studies did not use recruitment manoeuvres that may be beneficial when used in conjunction with HFJV,41 and they were underpowered with respect to clinical outcomes such as mortality.
HFOV differs from HFJV in a number of important aspects. Tidal volume (13 ml kg1) is generated by the excursion of an oscillator within a ventilator circuit similar to that used for CPAP and is varied by altering the frequency, inspiratory time and oscillator amplitude. The use of an oscillator to generate tidal volume results in active expiration. HFOV is very frequently used in hyaline membrane disease of neonates to avoid end-inspiratory lung overstretching (by greatly reducing the tidal volume), although it has not been shown to be better than conventional mechanical ventilation in terms of morbidity and mortality.44
The first randomized controlled trial comparing HFOV with a conventional ventilation strategy in 148 adults with early ARDS has recently been completed.26 Although this study expands on two recent studies showing HFOV to be effective and safe,33 58 there was no significant difference in mortality between the groups.26 One of the limitations of this (and almost all other older studies of ventilation strategy) was that HFOV was not compared with the current gold standard, low tidal volume ventilation used in the ARDS Network trial.
Liquid ventilation
Filling the lung with liquid removes the airliquid interface and supports alveoli preferentially in the dependent lung regions that are most susceptible to collapse. Perfluorocarbons (PFCs) have been used because they have a low surface tension, and they dissolve both oxygen and carbon dioxide readily.
Total liquid ventilation involves filling the entire lung with liquid and uses a special ventilator to oxygenate the PFC, a technique that is both difficult and expensive. In partial liquid ventilation (PLV), the lung is filled to FRC with liquid and ventilated with a conventional ventilator. The appropriate dose of PFC during PLV remains to be determined. Concerns over air and PFC leaks have been reported with large doses of PFC.21 Moreover, improvement in lung mechanics using lower doses of PFC has been demonstrated, which also has financial implications.87 Although PLV has been shown to be practical and safe,45 a recent randomized, prospective study against conventional ventilation showed no difference in outcome.46 However, no attempt to control tidal volume was made in this study.
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Conclusions |
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Acknowledgement |
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References |
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2 Albert RK. Least PEEP: primum non nocere. Chest 1985; 87: 24[ISI][Medline]
3 ALVEOLI Study, ARDS Network http://hedwig.mgh.harvard.edu/ardsnet/ards04.html
4 Amato MB, Barbas CS, Medeiros DM, et al. Beneficial effects of the open lung approach with low distending pressures in acute respiratory distress syndrome. A prospective randomized study on mechanical ventilation. Am J Respir Crit Care Med 1995; 152: 183546[Abstract]
5 Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338: 34754
6 Amato MB, Marini JJ. Barotrauma, volutrauma, and ventilation of acute lung injury. In: Marini JJ Slutsky AS, eds. Physiological Basis of Ventilatory Support. New York: Marcel Dekker, 1998; 1187245
7 Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. N Engl J Med 1996; 334: 141721
8 Argiras EP, Blakeley CR, Dunnill MS, et al. High PEEP decreases hyaline membrane formation in surfactant deficient lungs. Br J Anaesth 1987; 59: 127885[Abstract]
9 Ashbaugh DG, Bigelkow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2: 31923[ISI][Medline]
10 Ashbaugh DG, Petty TL, Bigelow DB, Harris TM. Continuous positive-pressure breathing (CPPB) in adult respiratory distress syndrome. J Thorac Cardiovasc Surg 1969; 57: 3141[ISI][Medline]
11 Bachofen H, Schurch S, Weibel ER. Experimental hydrostatic pulmonary edema in rabbit lungs: morphology. Am Rev Respir Dis 1993; 147: 98996[ISI][Medline]
12 Barber RE, Hamilton WK. Oxygen toxicity in man. A prospective study in patients with irreversible brain damage. N Engl J Med 1970; 283: 147884[ISI][Medline]
13 Bowton DL, Kong DL. High tidal volume ventilation produces increased lung water in oleic acid-injured rabbit lungs. Crit Care Med 1989; 17: 90811[ISI][Medline]
14 Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 158: 18318
15 Brower RG, Shanholtz CB, Fessler HE, et al. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 1999; 27: 14928[ISI][Medline]
16 Carlon GC, Howland WS, Ray C, et al. High frequency jet ventilation: a prospective, randomized evaluation. Chest 1983; 84: 5519[Abstract]
17 Carmichael LC, Dorinskey PM, Higgins SB, et al. Diagnosis and therapy of acute respiratory distress syndrome in adults: an international survey. J Crit Care 1996; 11: 918[ISI][Medline]
18 Chabot F, Mitchell JA, Gutteridge JM, Evans TW. Reactive oxygen species in acute lung injury. Eur Respir J 1998; 11: 74557
19 Chiumello D, Pristine G, Slutsky AS. Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 160: 10916
20 Clark JM, Lambertsen CJ. Pulmonary oxygen toxicity: a review. Pharmacol Rev 1971; 23: 37133[ISI][Medline]
21 Cox PN, Frndova H, Tan PS, et al. Concealed air leak associated with large tidal volumes in partial liquid ventilation. Am J Respir Crit Care Med 1997; 156: 9927
22 Cranshaw JH, Griffiths MJ, Evans TW. The pulmonary physician in critical carepart 9: non-ventilatory strategies in ARDS. Thorax 2002; 57: 8239
23 Dambrosio M, Roupie E, Mollett JJ, et al. Effects of positive end-expiratory pressure and different tidal volumes on alveolar recruitment and hyperinflation. Anesthesiology 1997; 87: 495503[ISI][Medline]
24 Davis WB, Rennard SI, Bitterman PB, Crystal RG. Pulmonary oxygen toxicity. Early reversible changes in human alveolar structures induced by hyperoxia. N Engl J Med 1983; 309: 87883[Abstract]
25 DeFouw DO, Berendsen PB. Morphological changes in isolated perfused dog lungs after acute hydrostatic edema. Circ Res 1978; 43: 7282[Abstract]
26 Derdak S, Mehta S, Stewart TE, et al. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults. Am J Respir Crit Care Med 2002; 166: 8018
27 Desai SR, Wells AU, Rubens MB, et al. Acute respiratory distress syndrome: CT abnormalities at long-term follow-up. Radiology 1999; 210: 2935
28 Dreyfuss D, Basset G, Soler P, Saumon G. Intermittent positive pressure hyperventilation with high inflation pressures produces pulmonary microvascular injury in rats. Am Rev Respir Dis 1985; 132: 8804[ISI][Medline]
29 Dreyfuss D, Soler P, Basset G, et al. High inflation pressure pulmonary edema. Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am J Respir Crit Care Med 1988; 137: 115964
30 Dreyfuss D, Soler P, Saumon G. Mechanical ventilation-induced pulmonary edema. Interaction with previous lung alterations. Am J Respir Crit Care Med 1995; 151: 156875[Abstract]
31 Dries DJ, Marini JJ. Optimized positive end-expiratory pressurean elusive target. Crit Care Med 2002; 30: 115960[CrossRef][ISI][Medline]
32 Esteban A, Alia I, Gordo F, et al. Prospective, randomized trial comparing pressure-controlled ventilation and volume-controlled ventilation in ARDS. Spanish Lung Failure collaborative group. Chest 2000; 117: 16906
33 Fort P, Farmer C, Westerman J, et al. High-frequency oscillatory ventilation for adult respiratory distress syndrome. Crit Care Med 1997; 25: 93747[ISI][Medline]
34 Froese AB, McCullough PR, Siguira M, et al. Optimizing alveolar expansion prolongs the effectiveness of exogenous surfactant therapy in the adult rabbit. Am Rev Respir Dis 1993; 148: 56977[ISI][Medline]
35 Gattinoni L, Pesenti A, Avalli L, et al. Pressure-volume curve of total respiratory system in acute respiratory failure. Computed tomographic scan study. Am Rev Respir Dis 1987; 136: 7306[ISI][Medline]
36 Gattinoni L, Tognoni G, Pesenti A, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001; 345: 56873
37 Goldstein I, Bughalo MT, Marquette CH, Lenaour G, Lu Q, Rouby JJ. Mechanical ventilation induced air space enlargement during experimental pneumonia in piglets. Am J Respir Crit Care Med 2001; 163: 95864
38 Grasso S, Mascia L, Del Turco M, et al. Effects of recruitment maneuvers in patients with acute respiratory distress syndrome ventilated with protective ventilatory strategy. Anesthesiology 2002; 96: 795802[ISI][Medline]
39 Held HD, Boettcher S, Hamann L, Uhlig S. Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-ß and is blocked by steroids. Am J Respir Crit Care Med 2001; 163: 7116
40 Hernandez LA, Coker PJ, May S, et al. Mechanical ventilation increases microvascular permeability in oleic acid-injured lungs. J Appl Physiol 1990; 69: 205761
41 Herridge MS, Slutsky AS, Colditz GA. Has high-frequency ventilation been inappropriately discarded in adult acute respiratory distress syndrome? Crit Care Med 1998; 26: 20737[CrossRef][ISI][Medline]
42 Hickling KG. The pressure-volume curve is greatly modified by recruitment. A mathematical model of ARDS lungs. Am J Respir Crit Care Med 1998; 158: 194202[ISI][Medline]
43 Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med 1990; 16: 3727[ISI][Medline]
44 High-frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants: the HIFI Study Group. N Engl J Med 1989; 320: 8893[Abstract]
45 Hirschl RB, Conrad S, Kaiser R, et al. Partial liquid ventilation in adult patients with ARDS: a multicentre phase III trial. Ann Surg 1998; 228: 692700[CrossRef][ISI][Medline]
46 Hirschl RB, Croce M, Gore D, et al. Prospective, randomized, controlled pilot study of partial liquid ventilation in adult acute respiratory distress syndrome. Am J Respir Crit Care Med 2002; 165: 7817
47 Hurst JM, Branson RD, Davis K, et al. Comparison of conventional mechanical ventilation and high-frequency ventilation: a prospective randomized trial in patients with respiratory failure. Ann Surg 1990; 211: 48691[ISI][Medline]
48 Jobe AH. Pulmonary surfactant therapy. N Engl J Med 1993; 328: 8618
49 John E, McDevitt M, Wilborn W, Cassady G. Ultrastructure of the lung after ventilation. Br J Exp Pathol 1982; 63: 4017[ISI][Medline]
50 Laffey JG, Engelberts D, Kavanagh BP. Injurious effects of hypocapnic acidosis in the isolated lung. Am J Respir Crit Care Med 2000; 162: 399405
51 Laffey JG, Engelberts D, Kavanagh BP. Buffering hypercapnic acidosis worsens acute lung injury. Am J Respir Crit Care Med 2000; 161: 1416
52 Lamb WJ, Graham MM, Albert RK. Mechanism by which the prone position improves oxygenation in acute lung injury. Am J Respir Crit Care Med 1994; 150: 18493[Abstract]
53 Lapinsky SE, Aubin M, Mehta S, Boiteau P, Slutsky AS. Safety and efficacy of a sustained inflation for alveolar recruitment in adults with respiratory failure. Intensive Care Med 1999; 25: 1297301[CrossRef][ISI][Medline]
54 Lessard MR, Guerot E, Lorino H, et al. Effects of pressure-controlled ventilation on respiratory mechanics, gas exchange and haemodynamics in patients with adult respiratory distress syndrome. Anesthesiology 1994; 80: 98391[ISI][Medline]
55 Lewis JF, Jobe AH. Surfactant and the adult respiratory distress syndrome. Am Rev Respir Dis 1993; 147: 21833[ISI][Medline]
56 Martynowicz MA, Minor TA, Walters BJ, et al. Regional expansion of oleic acid-injured lungs. Am J Respir Crit Care Med 1999; 160: 2508
57 Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol 1970; 28: 596608
58 Mehta S, Lapinsky SE, Hallet DC, et al. A prospective trial of high-frequency oscillation in adults with acute respiratory distress syndrome. Crit Care Med 2001; 29: 13609[ISI][Medline]
59 Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132: 4859[ISI][Medline]
60 Murphy DB, Cregg N, Tremblay L, et al. Adverse ventilatory strategy causes pulmonary to systemic translocation of endotoxin. Am J Respir Crit Care Med 2000; 162: 2733
61 Nahum A, Hoyt J, Schmitz L, Moody J, Shapiro R, Marini JJ. Effect of mechanical ventilation strategy on dissemination of intratracheally instilled Escherichia coli in dogs. Crit Care Med 1997; 25: 173343[ISI][Medline]
62 Nash G, Bowen JA, Langlinais PC. Respirator lung: a misnomer. Arch Pathol 1971; 91: 23440[ISI][Medline]
63 Patroniti N, Foti G, Cortinovis B, et al. Sigh improves gas exchange and lung volume in patients with acute respiratory distress syndrome undergoing pressure support ventilation. Anesthesiology 2002; 96: 78894[ISI][Medline]
64 Pelosi P, Bottino N, Chiumello D, et al. Sigh in supine and prone position during acute respiratory distress syndrome. Am J Respir Crit Care Med 2003; 167: 5217
65 Pelosi P, Cadringher P, Bottino N, et al. Sigh in acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 159: 87280
66 Piehl MA, Brown RS. Use of extreme position changes in respiratory failure. Crit Care Med 1976; 4: 134[ISI][Medline]
67 Pinhu L, Whitehead T, Evans T, Griffiths M. Ventilator-associated lung injury. Lancet 2003; 361: 33240[CrossRef][ISI][Medline]
68 Puybasset L, Stewart T, Rouby JJ, et al. Inhaled nitric oxide reverses the increase in pulmonary vascular resistance induced by permissive hypercapnia in patients with acute respiratory distress syndrome. Anesthesiology 1994; 80: 125467[ISI][Medline]
69 Quinlan GJ, Upton RL. Oxidant/antioxidant balance in acute respiratory distress syndrome. In: Evans TW, Griffiths MJD, Keogh BF, eds. ARDS, 20th edn. Leeds: Maney Publishing, 2002; 3346
70 Radford PR. Static mechanical properties of mammalian lungs. In: Fenn WO, Rahn H, eds. Handbook of Physiology. Washington DC: American Physiological Society, 1964; 42949
71 Rappaport SH, Shpiner R, Yoshihara G, et al. Randomized, prospective trial of pressure-limited versus volume-controlled ventilation in severe respiratory failure. Crit Care Med 1994; 22: 2232[ISI][Medline]
72 Ranieri VM, Eissa NT, Corbeil C, et al. Effects of positive end-expiratory pressure on alveolar recruitment and gas exchange in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1991; 144: 54451[ISI][Medline]
73 Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999; 282: 5461
74 Ranieri VM, Giunta F, Suter PM, Slutsky AS. Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome. JAMA 2000; 284: 434
75 Rizk NW, Murray JF. PEEP and pulmonary edema. Am J Med 1982; 72: 3813[ISI][Medline]
76 Rodrigo C, Rodrigo G. Subarachnoid haemorrhage following permissive hypercapnia in a patient with severe acute asthma. Am J Emerg Med 1999; 17: 6979[CrossRef][ISI][Medline]
77 Rouby JJ, Lherm T, Martin de Lassale E, et al. Histologic aspects of pulmonary barotrauma in critically ill patients with acute respiratory failure. Intensive Care Med 1993; 19: 3839[ISI][Medline]
78 Sandhar BK, Niblett DJ, Argiras EP, et al. Effects of positive end-expiratory pressure on hyaline membrane formation in a rabbit model of the neonatal respiratory distress syndrome. Intensive Care Med 1988; 14: 53846[ISI][Medline]
79 Shapiro BA, Cane RD, Harrison RA. Positive end-expiratory pressure in adults with special reference to acute lung injury. Crit Care Med 1984; 12: 12741[ISI][Medline]
80 Shibata K, Cregg N, Engelberts D, Takeuchi A, Fedorko L, Kavanagh BP. Hypercapnic acidosis may attenuate acute lung injury by inhibition of endogenous xanthine oxidase. Am J Respir Crit Care Med 1998; 158: 157884
81 Singer MM, Wright F, Stanley LK, Roe BB, Hamilton WK. Oxygen toxicity in man. A prospective study in patients after open heart surgery. N Engl J Med 1970; 283: 14738[ISI][Medline]
82 Slutsky AS. Mechanical ventilation. American College of Chest Physicians Consensus Conference. Chest 1993; 104: 183359[ISI][Medline]
83 Slutsky AS. Consensus conference on mechanical ventilation. Intensive Care Med 1994; 20: 6479[ISI][Medline]
84 Slutsky AS, Tremblay LN. Multiple system organ failure: is mechanical ventilation a contributing factor? Am J Respir Crit Care Med 1998; 157: 17215[ISI][Medline]
85 Stewart TE, Meade MO, Cook DJ, et al. Evaluation of a ventilation strategy to prevent barotraumas in patients at high risk for acute respiratory distress syndrome. N Engl J Med 1998; 338: 35561
86 Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos mRNA expression in an isolated rat lung model. J Clin Invest 1997; 99: 94452
87 Tutuncu AS, Akpir K, Mulder P, Erdmann W, Lachmann B. Intratracheal perfluorocarbon administration as an aid in the ventilatory management of respiratory distress syndrome. Anesthesiology 1993; 79: 108393[ISI][Medline]
88 Verbrugge SJ, Sorm V, Veen A, et al. Lung overinflation without positive end expiratory pressure promotes bacteremia after experimental Klebsiella pneumoniae inoculation. Intensive Care Med 1998; 24: 1727[CrossRef][ISI][Medline]
89 Vieira SR, Puybasset L, Lu Q, et al. A scanographic assessment of pulmonary morphology in acute lung injury: significance of the lower inflection point detected on the lung pressurevolume curve. Am J Respir Crit Care Med 1999; 159: 161223
90 Vieira SR, Puybasset L, Richecoeur J, et al. A lung computed tomographic assessment of positive end-expiratory pressure induced lung overdistension. Am J Respir Crit Care Med 1998; 158: 15717
91 Webb HH, Tierney DF. Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection by positive pressures end-expiratory pressure. Am Rev Respir Dis 1974; 110: 55665[ISI][Medline]