The Profile and Management of Acute Respiratory Distress Syndrome

Introduction

Since its fi rst description almost 40 years ago [1], the acute respiratory distress syndrome (ARDS) has been intrinsically linked with its management. In fact, the appearance of ARDS, in its most severe form, is possible only when artifi cial ventilatory support is available to keep the patient alive. Thus, the ‘natural his- tory’ of ARDS is the natural history of ARDS plus its ventilatory management.

Therefore, we need to keep in mind that the profi le and the management of this syndrome are interwoven. Nonetheless, in an attempt for clarity, we will try to discuss these two topics separately, considering the past, the present and, per- haps, the future.

Pathophysiological Profi le Gas Exchange

The past

The hypoxemia associated with ARDS was initially called ‘refractory hypox- emia’, as a normal value of arterial partial pressure of oxygen (PO

) could not be reached even when delivering an inspiratory oxygen fraction (FiO

equal to 1.0. The mechanism of this hypoxemia has been the object of several investiga- tions. An initial problem was to understand whether hypoxemia is caused by true right-to-left intrapulmonary shunt, i.e., blood fl ow perfusing non-ventilat- ed (atelectatic and/or consolidated) lung regions, or by venous admixture, i.e., a combination of true intrapulmonary shunt and lung regions with low ventila- tion/perfusion (V/Q) ratios. The theoretical framework of the shunt equation still in use to compute intrapulmonary shunt is based on the three-compartment lung model of Riley and Cournand [2]: an ideal compartment with a V/Q equal to the mean average V/Q of the lung, another compartment with a V/Q equal to zero (shunt), and a third one with a V/Q equal to infi nity (anatomical plus alveolar dead space). Unfortunately, this model does not allow discrimination between true intrapulmonary shunt and low V/Q lung compartments. In Riley’s model, low V/Q lung compartments are split between both the ideal and the true intrapulmonary shunt compartment.

of Acute Respiratory Distress Syndrome

L. Gattinoni, P. Caironi, and E. Carlesso

In the early 1980s, Wagner and colleagues [3] proposed a method based on the administration of six inert gases to the lungs to estimate V/Q distributions from 0 to infi nity. By applying this procedure in 16 patients affected by ARDS, Dantzker and colleagues [4] found that arterial hypoxemia was primarily due to the true intrapulmonary shunt; the contribution of low V/Q areas to the de- velopment of hypoxemia was negligible. Moreover, it was recognized early that shunt fraction is strictly dependent on hemodynamics; a reduction in cardiac output decreases shunt fraction and vice versa [5, 6]. This phenomenon has been observed not only in patients with ARDS but also during cardiogenic pulmonary edema [7]. However, up to now, the underlying mechanism has not been fully elucidated [8]. The main role of true shunt in determining hypoxemia in ARDS patients, although derived from a very small population, has become a universal and well-accepted dogma. However, it is conceivable that, in some patients, low V/Q lung compartments substantially contribute to the observed hypoxemia, depending on the FiO

used. Measuring the true intrapulmonary right-to-left shunt using sulfur hexafl uoride (SF

), we found that a signifi cant portion of the hypoxemia observed during acute respiratory failure was related to low V/Q lung regions rather than to true shunt, particularly among patients receiving FiO

be- tween 0.4 and 0.6 [9]. Unfortunately, the assessment of V/Q distribution, which is diffi cult in the routine clinical setting, does not tell us anything about the regional anatomical distribution of lung areas with different V/Q ratios.

It is important to note that, up to the early 1990s, the main focus of all the investigations dealing with gas exchange during acute respiratory failure was oxygenation, while the other side of the gas exchange, i.e., the clearance of car- bon dioxide (CO

), was neglected.

The present

During the 1980s, in patients with ARDS, the arterial partial pressure of CO

(PCO

) was targeted to values within normal range (35–45 mmHg). The price paid for achieving this target was the use of mechanical ventilation at high pres- sures and volumes. Recently, there has been increasing attention to the impor- tance of CO

in ARDS under different perspectives. It has been known for a long time that, for the same minute ventilation, the PCO

increases with increasing duration of the syndrome, from early (1 week) to intermediate (2 weeks) and late ARDS (3 weeks or more) [10]. This progression is likely to refl ect, more than what oxygenation does, the structural changes of the lung parenchyma, with ap- pearance of fi brosis, bubbles and pseudocysts [10–12].

Alteration of CO

elimination, inferred from an increase in dead space, is not

only associated with the time course of ARDS, but is considered a marker of

the severity and a prognostic index in early ARDS, as shown by Nuckton and

colleagues [13]. Moreover, we observed that when arterial PCO

(at the same

minute ventilation) decreases in ARDS patients after a change from supine po-

sition to prone position, survival is longer than when PCO

increases after the

same maneuver [14]. Also from this investigation, the arterial PCO

response

seems to be a marker of the underlying condition of the lung. In the Nuckton et

al. study [13], higher dead space was associated with higher mortality, suggest-

ing severe structural changes of the lung, both considering ventilation (alveolar disruption) and perfusion (microthrombosis). The response of arterial PCO

to the prone position likely refl ects the potential for recruitment, although the hy- pothesis needs to be proved.

Indeed, it is well established that high dead space is a marker of ‘severity’.

However, is high PCO

per se harmful? In the 1970s we did not have an answer to this question, as the arterial PCO

was maintained within the normal range with mechanical ventilator settings now considered harmful. The merit of the study by Hickling and colleagues, in the early 1990s, was the introduction of the concept of ‘permissive hypercapnia’, a procedure aimed to put the lung at rest by using mechanical ventilation with low pressures and volumes [15]. ‘Lung rest’

was fi rst obtained by avoiding mechanical ventilation and clearing CO

with ex- tracorporeal tools [16, 17]. Hickling et al. pursued a similar target, paying, as a price, a remarkable degree of hypercapnia. Nonetheless, despite theoretical dis- cussions about their relative importance, hypercapnia and acidosis have never been shown to be harmful. Setting arterial PCO

at a higher level [18] and de- creasing the ‘price’ of mechanical ventilation is nowadays the common strategy for mechanical ventilation.

Furthermore, it has been suggested that hypercapnia may be not only harm- less, but even benefi cial as ‘therapeutic hypercapnia’ [19]. The possible mecha- nisms of these effects are still speculative and we lack proof of similar fi ndings in patients. However, there is increasing evidence of possible benefi cial effects of hypercapnia in cell culture studies and experimental animal models [20]. Al- though we cannot recommend, at present, hypercapnia as a target, we may ac- cept it as a side effect.

The future

We believe that, in the future, new techniques will allow a better understanding of CO

clearance and oxygenation in ARDS. For this purpose, the knowledge of the real anatomical relationships between ventilation and perfusion in the ARDS lung is necessary. Without this knowledge, in our opinion, a full elucida- tion of gas exchange rules and their alteration while modifying the conditions of the system is impossible. Combinations of different imaging techniques such as computed tomography (CT), positron emission tomography (PET) and nuclear magnetic resonance [21, 22], will be essential in achieving this goal.

Lung Mechanics The past

Since the fi rst description of ARDS, the lungs in this condition were considered

to be ‘stiff’. This term suggests that the pulmonary structure is stiffer than nor-

mal. Only in the middle 1980s, was it recognized that the lungs in ARDS are

small rather than stiff; this is the ‘the baby lung’ concept. In ARDS, the elasticity

of the ventilated lung structure is nearly normal, as measured by the specifi c

compliance (the ratio of measured lung compliance and the measured end-ex- piratory gas volume) [23–25].

Lung mechanics during ARDS have been extensively studied in order to fi nd a physiological rationale for the selection of positive end-expiratory pressure (PEEP). For this purpose, the pressure volume (PV) curve of the respiratory sys- tem has been considered the ideal tool. The initial model of the relationship be- tween pressure and volume in ARDS was both simple and appealing. The initial part of the PV curve, up to the lower infl ection point, indicates the pressure at which the lung is open. Accordingly, it has been suggested that the PEEP should be set at a level 2 cmH

O higher than the lower infl ection point, in order to main- tain the lung open (minimal PEEP) [26–28]. This approach reached the height of its glory as part of the protocol of the ‘lung protective strategy’ proposed by Amato and colleagues in 1998 [29]. Second, the linear part of the PV curve (the infl ation compliance) was thought to include the range of pressures in which the alveolar units normally infl ate. Finally, the last part of the PV curve (above the upper infl ection point) was thought to indicate the high pressures at which over- stretching of the lung structures occurs. Although we doubt that the PV curve was largely used in clinical practice for PEEP selection, this approach has been widely accepted by the scientifi c community.

The present

Despite its simplicity and appeal, the physiological model underlying the ap- proach mentioned above is inadequate. Mathematical models [25, 30] applied to pressure and volume data from patients [31] and observations obtained with CT in experimental animals [32] and ARDS patients [24, 33, 34] indicate that alveo- lar recruitment occurs along the entire PV curve, including points well above the upper infl ection point. Indeed, the PV curve of the respiratory system, when expressed as a fraction of the inspiratory capacity, is indistinguishable from the pressure-recruitment curve, which represents alveolar recruitment, as a fraction of the maximal potential for recruitment, at the airway pressure applied (Fig. 1).

Unfortunately, the pressure-recruitment curve and the PV curve do not tell us anything about the absolute potential for recruitment, which may be relevant for a proper setting of mechanical ventilation. From what we have discussed above, the ‘2 cmH

O above lower infl ection point’ approach for setting the PEEP seems questionable, as the lower infl ection point does not correspond to a condition when the lung is open. Moreover, most of the studies referred to the infl ation limb of the PV curve, while PEEP should be referred to the expiratory limb [24].

Although not yet clinically applied, this new approach is now under investiga- tion regarding its physiological framework [34, 35].

For many years, PV curve parameters were identifi ed by eye. Recently, a

more rigorous and promising approach has been proposed by Venegas and col-

leagues [30, 36]. The new analysis consists of fi tting the PV curve data points

(or pressure-recruitment points) with a sigmoidal function. The advantage of

this approach is a more objective assessment of the data. The disadvantage is

the modifi cation of the traditional nomenclature. Thus, what Venegas defi nes

as the infl ection point is not the lower ‘knee’ of the curve, but, rather, the pres-

sure at which the maximal change of the curvature of the sigmoidal function occurs (i.e., the point of maximal compliance or the pressure at which the lung is infl ated to 50% of its maximal capacity). A summary of the traditional and new nomenclature is presented in Table 1.

Until the middle 1990s, a change in the compliance of the respiratory system was believed to be caused mostly by changes in lung compliance, while the chest wall compliance was always considered normal. Nowadays, the importance of the chest wall in affecting the respiratory system mechanics is increasingly rec- ognized [37, 38]. It has been found by our group and by other investigators that in ARDS patients with abdominal diseases, chest wall compliance is markedly reduced, due to increased intra-abdominal pressure [39, 40]. Intra-abdominal hypertension appears to be a common problem in critically ill patients, and it always is associated with decreased chest wall compliance [41]. Although it is extremely important to recognize decreased chest wall compliance in order to properly tailor ventilator settings, this observation has not yet affected routine practice.

Although respiratory mechanics in patients with ALI or ARDS are still widely investigated, a clear and defi nite relationship between lung mechanics assess- ment and clinical practice has not been found yet. What we believed in the past – mechanical ventilation should be tailored based on the inspiratory limb of the PV curve – does not have any rational physiological basis.

Fig. 1. Lung recruitment as a fraction of the applied airway pressure along the pressure volume curve of the respiratory system in an animal model of ARDS (oleic acid-induced lung injury in pigs – unpublished data from Quintel and Pelosi groups). As shown, alveolar recruitment oc- curs along the entire pressure volume curve, even above the lower and upper infl ection point.

Lung recruitment is expressed as a fraction of the maximal potential for recruitment, and is shown as CT scan images taken at the lung base at the corresponding airway pressure. Solid line represents pressure volume curve of the respiratory system, where volume is expressed as a percentage of the maximal inspiratory capacity. The data were fi tted with a sigmoid func- tion, according to Venegas and colleagues [30].

The future

Fortunately, we cannot predict and describe the future, but we can express our wishes. In our opinion, in order to tailor the mechanical ventilation on a more physiological basis, we should know the main determinants of its damage to the lung. There are consistent data indicating that the fi rst physical trigger of ven- tilator-induced lung injury (VILI) is excessive global and/or regional alveolar stress and strain [42]. Although monitoring the regional distribution of these parameters is beyond our actual technical possibilities, global alveolar stress and strain values may be estimated with rough surrogates. Alveolar stress, i.e., the tension developed onto the lung fi ber skeleton when a pressure is applied, is quantitatively equal to the distending force of the lung (transpulmonary pres- sure). The continuous monitoring of transpulmonary pressure requires an es- ophageal balloon, which should be incorporated into the nasogastric tube. The rough equivalent of alveolar strain, i.e., the increase in lung volume relative to its resting position, requires the monitoring of end-expiratory lung volume (EELV).

Adequate techniques (SF

, oxygen/nitrogen analysis, helium dilution) have been available for many years for this purpose, but unfortunately they have never reached the market, likely because of a lack of interest by ICU physicians. We hope that the relationship between alveolar stress and strain will be monitored in the future. Probably, it will be suffi cient to monitor either alveolar stress or

Table 1. Pressure volume curve nomenclature

Old nomenclature

Starting compliance [23] Cstart Computed as the ratio between the fi rst 100 ml on the infl ation limb and the

corresponding pressure

Infl ation compliance [23] Cinf Slope of the most linear segment on the

infl ation limb of the pressure-volume curve

Lower infl ection point [23] Pfl ex, LIP Intersection between Cstart and Cinf lines Upper infl ection point [71, 77] UIP Static end-inspiratory pressure after which

compliance decreases more than 20% or 10%

from the best compliance obtained New nomenclature

Infl ection point [30, 78] c, Pinf Point of maximal compliance

Lower infl ection point [30, 36] Pcl Lower corner point on infl ation/defl ation limb, calculated as c-2d or c-1.317d (d=linear portion of the curve/4) Lower infl ection point [79] Pmci Point of maximal compliance increase Upper infl ection point [30, 36] Pcu Upper corner point on infl ation/defl ation

limb, calculated as c+2d or c+1.317d Upper infl ection point [79] Pmcd Point of maximal compliance decrease

alveolar strain alone, as the specifi c elastance (which links the two parameters) is nearly normal in lungs affl icted with ARDS [23, 24]. In our opinion, the fol- lowing equation should be kept in mind for safe mechanical ventilation:

dP

= El,spec * V

/ EELV

where dP

is the variation of transpulmonary pressure, El,spec is the lung spe- cifi c elastance, and V

is the tidal volume.

Based on its physiological characteristics, the lung architecture receives ex- cessive tension when the ratio between tidal volume and EELV is above 0.8, a level at which lung collagen fi bers are fully distended [42]. It is conceivable that tailoring mechanical ventilation according to this physiological principle will make it safer.

Management and Side Effects

Mechanical Ventilation and Its Side Effects The past

In the 1970s, the goal of mechanical ventilation was to maintain arterial PO

and PCO

within the normal ranges for these parameters. As previously discussed, these targets were reached by using high tidal volumes (12–15 ml/kg), and by set- ting PEEP between 5–10 cm H

O. This approach was the ‘state of the art’ as stated by Pontoppidan, Geffi n, and Lowenstein in the New England Journal of Medi- cine [43]. The recognized side effect of using such high values of tidal volume was hypocapnia, which was corrected by adding artifi cial dead space in order to achieve a normal arterial PCO

. The main concern was oxygen toxicity, and the accepted dogma was to maintain FiO

below 0.6. In the same period, a new way of thinking had started, after the report by Hill and colleagues about the successful treatment of a young trauma patient with extracorporeal membrane oxygenation (ECMO) [44]. This new perspective led the National Institutes of Health to sponsor the fi rst randomized clinical trial on ARDS. In this study, patients were randomized to receive standard therapy or long-term venous-arte- rial membrane lung oxygenation. The only modifi cation of the ventilator setting in the treated group was reduction of FiO

aimed to decrease the oxygen toxicity, while the high tidal volumes and pressures were similar in treated and control patients. The mortality rate also was similar, being 90% in both groups [45].

The greatest debate, however, from about 1975 until about 1985 was the proper setting of PEEP. Suter and colleagues, in one of their famous papers [46], pro- posed that the best PEEP was that associated with the best oxygen transport, and this value was also associated with the best compliance. In France, Lemaire and colleagues [26] were the fi rst to propose the concept of ‘minimal PEEP’ as the pressure 2 cmH

O higher than the lower infl ection point on the PV curve.

On the other side of the Atlantic Ocean, in Florida, Kirby and colleagues [47]

promoted the use of ‘super-PEEP’ as that at which the shunt fraction was reduced

down to an average of 20%. It is impossible to quote all the contributions on this

issue. The conclusion, however, is clear – we still do not know what level of PEEP should be applied. What we do know is that most ICU physicians treat ARDS patients with PEEP levels between 5 and 10 cmH

O [48].

Another ‘hot’ topic in the 1980s was the hemodynamic profi le during ARDS.

The group from the Massachusetts General Hospital provided the best insights, carefully describing the development of pulmonary hypertension during ARDS and providing data about its physiological and pathological basis [49–53]. It is important to note that, as far as hemodynamics and gas exchange relationship is concerned, the oxygenation improvement mediated by hemodynamic changes caused by PEEP was well recognized in the 1980s but has been neglected in re- cent years.

The side effects of mechanical ventilation with high volumes and pressures have been recognized since the 1970s [54], and have been collectively named as

‘barotrauma’. Several years later, an apparently different view of the problem was provided by the extensive work of Dreyfuss and colleagues, which focused the attention of the scientifi c community on lung distension (volume/strain) rather then lung tension (pressure/stress) [55]. As a result, the term ‘volutrauma’

gained popularity. In this context, the concept of lung rest evolved progressively.

We fi rst provided true lung rest [17] by removing CO

through extracorporeal membranes and ventilating the lung with 3–5 breaths per minute. When this technique was proposed, the ‘baby lung’ concept [56] and the ‘sponge lung’ con- cept [57] were ignored. Afterwards, with further advances in our knowledge about the pathophysiology of ARDS, lung rest became an accepted target and, along the same line of thinking, Hickling and colleagues proposed the idea of using low tidal volumes for ventilation (permissive hypercapnia) [15] for the

‘gentle treatment’ of the ARDS lung.

In the 1990s, physiological reasoning and experimental data led to the general concept of the ‘lung protective strategy’. The theoretical basis of this approach was provided by Lachmann [58]. The biological effects of intratidal collapse and de-collapse were recognized in ex-vivo and in-vivo experimental models. Links between mechanical forces and infl ammatory reactions were found in hundreds of papers (with some exceptions [59]) in cell cultures [60], in ex vivo [61] and in vivo experimental models [62], as well as in humans [63]. The infl ammatory reaction consequent to mechanical forces was collectively named ‘biotrauma’.

By the late 1990s, the pathophysiological background for the present practice of mechanical ventilation was solid. Two concepts were clear: fi rst, mechanical ventilation can injure the lung; second, avoiding intratidal collapse and de-col- lapse of alveolar units is benefi cial.

The present

In this scenario, it is not easy to defi ne the chronological beginning of ‘the

present’. In our opinion, we may date ‘the present’ from the paper by Amato and

colleagues published in the New England Journal of Medicine, which represents

the fi rst clinical proof of the possible benefi ts of the lung protective strategy

[29]. This paper had striking effects on the scientifi c community and stimulated

further work. Indeed, we are living in the era of the lung protective strategy.

However, it is important to note that only the Amato study (on outcome) and the Ranieri study (on biotrauma) [63] really tested the lung protective strategy, which includes the control of both end-inspiratory and end-expiratory pressures (i.e., tidal volume or plateau pressure and PEEP). The following clinical trials separately investigated the effects of tidal volume and PEEP. The clinical trial conducted by the ARDS network clearly showed the advantages of gentle venti- lation (6 ml/kg tidal volume) versus mechanical ventilation with high volumes (12 ml/kg tidal volume) [64]. This trial, however, compared two extreme tidal volumes. Other clinical trials comparing intermediate tidal volumes (7 versus 10–10.5 ml/kg) failed to show any differences [65–67].

Now, we have clinical and experimental evidence indicating that high tidal volume ventilation (12 ml/kg) is unsafe. Different questions and debatable an- swers may arise when discussing the ideal tidal volume: is it really 6 ml/kg? In our opinion, 6 ml/kg should not become a dogma for several reasons. First, what puts the lung at risk for injury is alveolar strain, i.e., the ratio of tidal volume and end-expiratory lung volume, and this ratio, in ARDS patients, is unrelated to body weight. As an example, the end expiratory lung volume in a hypotheti- cal ARDS patient with an ideal body weight of 70 kg could be 500, 1000, 1500 ml, according to the severity of the disease. The alveolar strain resulting from 6 ml/kg tidal volume (420 ml) would be 0.84, 0.42, or 0.28, respectively. This is likely to be important for the development of VILI, but at the moment is not considered in standard care. Furthermore, it is not clear to us why we should use 6 ml/kg tidal volume in an ARDS patient with an intermediate lung compli- ance (which is an indirect estimate of the residual open lung [68]), and conse- quently a plateau pressure of about 25 cmH

O at the tidal volume used. The use of low tidal volumes could induce unnecessary hypercapnia and force us to use heavy sedation, which may be clinically more harmful than a plateau pressure below 25 cmH

O. These, of course, are only opinions, as we lack, at the moment, any direct proof that 6 is better than 8 or 10 ml/kg when the plateau pressure is limited. Moreover, it is important to highlight that the use of 6 ml/kg has not been widely implemented [69, 70], suggesting that in daily practice the problems caused by 6 ml/kg tidal volume ventilation are thought to be greater than the expected benefi ts [71–74]. Of note, the current recommendations for mechanical ventilation (published in the New England Journal of Medicine) [64] represent a complete reversal compared to the recommendations for mechanical ventila- tion advocated by experts in the 1970s (published in the New England Journal of Medicine) [43].

While the scientifi c community has reached a general consensus to avoid

mechanical ventilation with high tidal volumes, the clinical approach to select-

ing PEEP is still in the fog. The recent ALVEOLI trial conducted by the ARDS

network [75] failed to demonstrate any differences in outcome between ARDS

patients treated with low PEEP (8.3 ±3.2 cm H

O) or high PEEP (13.2 ±3.5 cm

H

O). In the era of the lung protective strategy, this result, possible methodo-

logical problems of the study notwithstanding [76], is disturbing. We may argue

that the PEEP interval explored was too low, that the PEEP/FiO

scale was asym-

metrical in the two arms of the study, and that the experimental design changed

during the study. The real problem, in our opinion, is different. Most ICU scien-

tists, at the moment, believe that the lung protective strategy is benefi cial, and consequently all results contrary to this view are rejected. Indeed, there are only two alternatives: either the ALVEOLI study has been erroneously designed or the PEEP level, at least in the range explored, is really irrelevant for the outcome.

We believe that we should be open to both possibilities. Certainly, the ALVEOLI study lacks a physiological rationale. We know that ARDS patients may have high or low potential for recruitment. It is possible that high PEEP will be benefi - cial in patients with high potential for recruitment and harmful in patients with low potential for recruitment. According to our knowledge of the pathophysiol- ogy of ARDS, the answer for PEEP benefi t should be found in a study in which patients with high and low potential for recruitment are randomized separately to high and low PEEP levels. But again, we should also be prepared for the pos- sibility that the level of PEEP is irrelevant for the outcome.

The future

The target for the future will be to make mechanical ventilation less harmful than it is today. This goal, however, implies an answer to a basic question: under this perspective, is opening the lung and keeping it open really the best strategy?

In this case, high PEEP and low tidal volume would be the best ventilator setting, with possible re-evaluation of techniques, such as high frequency jet ventilation or high frequency oscillation. On the other hand, if we keep a portion of the lung always closed, low PEEP and low tidal volume strategies should be acceptable, as they would decrease the global alveolar stress and strain. In our opinion, only physiological studies can solve the dilemma between opening the lung and keep- ing it open or accepting some lung closure and keeping it closed.

Conclusion

Acute lung injury and ARDS are still a therapeutic challenge in intensive care, but great advances have been made in the last twenty years. However, if we have to summarize all the improvements in a single sentence, we can say that what we have learnt is that more gentle treatment of the infl amed lung improves out- come.

References

1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE (1967) Acute respiratory distress in adults.

Lancet 2:319–323

2. Riley RL, Cournand A (1951) Analysis of factors affecting partial pressures of oxygen and carbon dioxide in gas and blood of lungs; theory. J Appl Physiol 4:77–101

3. Wagner PD, Saltzman HA, West JB (1974) Measurement of continuous distributions of ventilation-perfusion ratios: theory. J Appl Physiol 36:588–599

4. Dantzker DR, Brook CJ, Dehart P, Lynch JP, Weg JG (1979) Ventilation-perfusion distribu- tions in the adult respiratory distress syndrome. Am Rev Respir Dis 120:1039–1052

5. Hedley-Whyte J, Pontoppidan H, Morris MJ (1966) The response of patients with respira- tory failure and cardiopulmonary disease to different levels of constant volume ventila- tion. J Clin Invest 45:1543–1554

6. Lemaire F, Gastine H, Regner B, Teisseire B, Rapin M (1978) Perfusion changes modify intrapulmonary shunting (Qs/Qt) in patients with adult respiratory distress syndrome (ARDS). Am Rev Respir Dis 117:144 (abst)

7. Scheinman MM, Evans GT (1972) Right to left shunt in patients with acute myocardial infarction. A proposed mechanism. Am J Cardiol 29:757–766

8. Freden F, Cigarini I, Mannting F, Hagberg A, Lemaire F, Hedenstierna G (1993) Depen- dence of shunt on cardiac output in unilobar oleic acid edema. Distribution of ventilation and perfusion. Intensive Care Med 19:185–190

9. Pesenti A, Riboni A, Marcolin R, Gattinoni L (1983) Venous admixture (Qva/Q) and true shunt (Qs/Qt) in ARF patients: effects of PEEP at constant FIO2. Intensive Care Med 9:307–311

10. Gattinoni L, Bombino M, Pelosi P, et al (1994) Lung structure and function in different stages of severe adult respiratory distress syndrome. JAMA 271:1772–1779

11. Goodman LR (1996) Congestive heart failure and adult respiratory distress syndrome.

New insights using computed tomography. Radiol Clin North Am 34:33–46

12. Rouby JJ, Lherm T, Martin DL, et al (1993) Histologic aspects of pulmonary barotrauma in critically ill patients with acute respiratory failure. Intensive Care Med 19:383–389 13. Nuckton TJ, Alonso JA, Kallet RH, et al (2002) Pulmonary dead-space fraction as a risk

factor for death in the acute respiratory distress syndrome. N Engl J Med 346:1281–1286 14. Gattinoni L, Vagginelli F, Carlesso E, et al (2003) Decrease in PaCO2 with prone position

is predictive of improved outcome in acute respiratory distress syndrome. Crit Care Med 31:2727–2733

15. Hickling KG, Henderson SJ, Jackson R (1990) Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory dis- tress syndrome. Intensive Care Med 16:372–377

16. Gattinoni L, Agostoni A, Pesenti A, et al (1980) Treatment of acute respiratory failure with low-frequency positive-pressure ventilation and extracorporeal removal of CO2. Lancet 2:292–294

17. Gattinoni L, Pesenti A, Mascheroni D, et al (1986) Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure. JAMA 256:881–886

18. Pesenti A (1990) Target blood gases during ARDS ventilatory management. Intensive Care Med 16:349–351

19. Laffey JG, Kavanagh BP (1999) Carbon dioxide and the critically ill–too little of a good thing? Lancet 354:1283–1286

20. Laffey JG, O’Croinin D, McLoughlin P, Kavanagh BP (2004) Permissive hypercapnia–role in protective lung ventilatory strategies. Intensive Care Med 30:347–356

21. Gattinoni L, Caironi P, Pelosi P, Goodman LR (2001) What has computed tomography taught us about the acute respiratory distress syndrome? Am J Respir Crit Care Med 164:1701–1711

22. Schuster DP, Kovacs A, Garbow J, Piwnica-Worms D (2004) Recent advances in imaging the lungs of intact small animals. Am J Respir Cell Mol Biol 30:129–138

23. Gattinoni L, Pesenti A, Avalli L, Rossi F, Bombino M (1987) Pressure-volume curve of total respiratory system in acute respiratory failure. Computed tomographic scan study. Am Rev Respir Dis 136:730–736

24. Gattinoni L, D’Andrea L, Pelosi P, Vitale G, Pesenti A, Fumagalli R (1993) Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome. JAMA 269:2122–2127

25. Hickling KG (1998) The pressure-volume curve is greatly modifi ed by recruitment. A mathematical model of ARDS lungs. Am J Respir Crit Care Med 158:194–202

26. Lemaire F, Harf A, Simonneau G, Matamis D, Rivara D, Atlan G (1981) [Gas exchange, static pressure-volume curve and positive-pressure ventilation at the end of expiration.

Study of 16 cases of acute respiratory insuffi ciency in adults]. Ann Anesthesiol Fr 22:435–

441

27. Matamis D, Lemaire F, Harf A, Brun-Buisson C, Ansquer JC, Atlan G (1984) Total respira- tory pressure-volume curves in the adult respiratory distress syndrome. Chest 86:58–66 28. Pesenti A, Marcolin R, Prato P, Borelli M, Riboni A, Gattinoni L (1985) Mean airway pres-

sure vs. positive end-expiratory pressure during mechanical ventilation. Crit Care Med 13:34–37

29. Amato MB, Barbas CS, Medeiros DM, et al (1998) Effect of a protective-ventilation strat- egy on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347–354 30. Venegas JG, Harris RS, Simon BA (1998) A comprehensive equation for the pulmonary

pressure-volume curve. J Appl Physiol 84:389–395

31. Jonson B, Richard JC, Straus C, Mancebo J, Lemaire F, Brochard L (1999) Pressure-volume curves and compliance in acute lung injury: evidence of recruitment above the lower in- fl ection point. Am J Respir Crit Care Med 159:1172–1178

32. Pelosi P, Goldner M, McKibben A, et al (2001) Recruitment and derecruitment during acute respiratory failure: an experimental study. Am J Respir Crit Care Med 164:122–130 33. Crotti S, Mascheroni D, Caironi P, et al (2001) Recruitment and derecruitment during

acute respiratory failure: a clinical study. Am J Respir Crit Care Med 164:131–140 34. Albaiceta GM, Taboada F, Parra D, et al (2004) Tomographic study of the infl ection points

of the pressure-volume curve in acute lung injury. Am J Respir Crit Care Med 170:1066–

1072

35. Albaiceta GM, Taboada F, Parra D, Blanco A, Escudero D, Otero J (2003) Differences in the defl ation limb of the pressure-volume curves in acute respiratory distress syndrome from pulmonary and extrapulmonary origin. Intensive Care Med 29:1943–1949

36. Harris RS, Hess DR, Venegas JG (2000) An objective analysis of the pressure-volume curve in the acute respiratory distress syndrome. Am J Respir Crit Care Med 161:432–439 37. Pelosi P, Cereda M, Foti G, Giacomini M, Pesenti A (1995) Alterations of lung and chest

wall mechanics in patients with acute lung injury: effects of positive end-expiratory pres- sure. Am J Respir Crit Care Med 152:531–537

38. Mergoni M, Martelli A, Volpi A, Primavera S, Zuccoli P, Rossi A (1997) Impact of positive end-expiratory pressure on chest wall and lung pressure-volume curve in acute respira- tory failure. Am J Respir Crit Care Med 156:846–854

39. Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A (1998) Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease. Different syn- dromes? Am J Respir Crit Care Med 158:3–11

40. Ranieri VM, Brienza N, Santostasi S, et al (1997) Impairment of lung and chest wall me- chanics in patients with acute respiratory distress syndrome: role of abdominal disten- sion. Am J Respir Crit Care Med 156:1082–1091

41. Malbrain ML, Chiumello D, Pelosi P, et al (2004) Prevalence of intra-abdominal hyper- tension in critically ill patients: a multicentre epidemiological study. Intensive Care Med 30:822–829

42. Gattinoni L, Carlesso E, Cadringher P, Valenza F, Vagginelli F, Chiumello D (2003) Physi- cal and biological triggers of ventilator-induced lung injury and its prevention. Eur Respir J Suppl 47:15s–25s

43. Pontoppidan H, Geffi n B, Lowenstein E (1972) Acute respiratory failure in the adult. 3. N Engl J Med 287:799–806

44. Hill JD, O’Brien TG, Murray JJ, et al (1972) Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med 286:629–634

45. Zapol WM, Snider MT, Hill JD, et al (1979) Extracorporeal membrane oxygenation in se- vere acute respiratory failure. A randomized prospective study. JAMA 242:2193–2196

46. Suter PM, Fairley B, Isenberg MD (1975) Optimum end-expiratory airway pressure in pa- tients with acute pulmonary failure. N Engl J Med 292:284–289

47. Kirby RR, Downs JB, Civetta JM, et al (1975) High level positive end expiratory pressure (PEEP) in acute respiratory insuffi ciency. Chest 67:156–163

48. Esteban A, Anzueto A, Alia I, et al (2000) How is mechanical ventilation employed in the intensive care unit? An international utilization review. Am J Respir Crit Care Med 161:1450–1458

49. Zapol WM, Snider MT (1977) Pulmonary hypertension in severe acute respiratory failure.

N Engl J Med 296:476–480

50. Zapol WM, Kobayashi K, Snider MT, Greene R, Laver MB (1977) Vascular obstruction causes pulmonary hypertension in severe acute respiratory failure. Chest 71:306–307 51. Tomashefski JF Jr, Davies P, Boggis C, Greene R, Zapol WM, Reid LM (1983) The pulmo-

nary vascular lesions of the adult respiratory distress syndrome. Am J Pathol 112:112–

126

52. Jones R, Zapol WM, Reid L (1983) Pulmonary arterial wall injury and remodelling by hyperoxia. Chest 83:40S–42S

53. Zapol WM, Jones R (1987) Vascular components of ARDS. Clinical pulmonary hemody- namics and morphology. Am Rev Respir Dis 136:471–474

54. Kumar A, Pontoppidan H, Falke KJ, Wilson RS, Laver MB (1973) Pulmonary barotrauma during mechanical ventilation. Crit Care Med 1:181–186

55. Dreyfuss D, Soler P, Basset G, Saumon G (1988) High infl ation pressure pulmonary edema.

Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am Rev Respir Dis 137:1159–1164

56. Gattinoni L, Pesenti A (1987) ARDS: the non-homogeneous lung; facts and hypothesis.

Intensive Crit Care Digest 6:1–4

57. Bone RC (1993) The ARDS lung. New insights from computed tomography. JAMA 269:2134–2135

58. Lachmann B (1992) Open up the lung and keep the lung open. Intensive Care Med. 18:319–

321

59. Dreyfuss D, Ricard JD, Saumon G (2003) On the physiologic and clinical relevance of lung-borne cytokines during ventilator-induced lung injury. Am J Respir Crit Care Med 167:1467–1471

60. Pugin J, Dunn I, Jolliet P, et al (1998) Activation of human macrophages by mechanical ventilation in vitro. Am J Physiol 275:L1040–L1050

61. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS (1997) Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin In- vest 99:944–952

62. Chiumello D, Pristine G, Slutsky AS (1999) Mechanical ventilation affects local and sys- temic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med 160:109–116

63. Ranieri VM, Suter PM, Tortorella C, et al (1999) Effect of mechanical ventilation on in- fl ammatory mediators in patients with acute respiratory distress syndrome: a random- ized controlled trial. JAMA 282:54–61

64. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308

65. Brochard L, Roudot-Thoraval F, Roupie E, et al (1998) Tidal volume reduction for preven- tion of ventilator-induced lung injury in acute respiratory distress syndrome. The Mul- ticenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 158:1831–1838

66. Brower RG, Shanholtz CB, Fessler HE, et al (1999) Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute re- spiratory distress syndrome patients. Crit Care Med 27:1492–1498

67. Stewart TE, Meade MO, Cook DJ, et al (1998) Evaluation of a ventilation strategy to pre- vent barotrauma in patients at high risk for acute respiratory distress syndrome. Pres- sure- and Volume-Limited Ventilation Strategy Group. N Engl J Med 338:355–361 68. Gattinoni L, Pesenti A, Baglioni S, Vitale G, Rivolta M, Pelosi P (1988) Infl ammatory pul-

monary edema and positive end-expiratory pressure: correlations between imaging and physiologic studies. J Thorac Imaging 3:59–64

69. Weinert CR, Gross CR, Marinelli WA (2003) Impact of randomized trial results on acute lung injury ventilator therapy in teaching hospitals. Am J Respir Crit Care Med 167:1304–

1309

70. Young MP, Manning HL, Wilson DL, et al (2004) Ventilation of patients with acute lung injury and acute respiratory distress syndrome: has new evidence changed clinical prac- tice? Crit Care Med 32:1260–1265

71. Roupie E, Dambrosio M, Servillo G, et al (1995) Titration of tidal volume and induced hypercapnia in acute respiratory distress syndrome. Am J Respir Crit Care Med 152:121–

128

72. Feihl F, Perret C (1994) Permissive hypercapnia. How permissive should we be? Am J Respir Crit Care Med 150:1722–1737

73. Eichacker PQ, Gerstenberger EP, Banks SM, Cui X, Natanson C (2002) Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes.

Am J Respir Crit Care Med 166:1510–1514

74. Petrucci N, Iacovelli W (2004) Ventilation with smaller tidal volumes: a quantitative sys- tematic review of randomized controlled trials. Anesth Analg 99:193–200

75. Brower RG, Lanken PN, MacIntyre N, et al (2004) Higher versus lower positive end-expi- ratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 351:327–336

76. Levy MM (2004) PEEP in ARDS–how much is enough? N Engl J Med 351:389–391 77. Nunes S, Uusaro A, Takala J (2004) Pressure-volume relationships in acute lung injury:

methodological and clinical implications. Acta Anaesthesiol Scand 48:278–286

78. Markhorst DG, van Genderingen HR, van Vught AJ (2004) Static pressure-volume curve characteristics are moderate estimators of optimal airway pressures in a mathematical model of (primary/pulmonary) acute respiratory distress syndrome. Intensive Care Med 30:2086–2093

79. Pereira C, Bohe J, Rosselli S, et al (2003) Sigmoidal equation for lung and chest wall vol- ume-pressure curves in acute respiratory failure. J Appl Physiol 95:2064–2071