Selecting the Right Level of Positive End-Expiratory Pressure in Patients with Acute Respiratory Distress Syndrome

JEAN JACQUES ROUBY, QIN LU, and IVAN GOLDSTEIN

Réanimation Chirurgicale Pierre Viars, Department of Anesthesiology, Hospital Pitié-Salpétrière, University of Paris VI, France

	INTRODUCTION

TOP INTRODUCTION RATIONALE FOR RE-EXPANDING THE... MECHANICAL FORCES OPPOSING PEEP-... FACTORS LIMITING PEEP-INDUCED... SELECTING THE RIGHT LEVEL... WHAT REMAINS TO BE... REFERENCES

The administration of positive end-expiratory pressure (PEEP) is aimed at preventing the end-expiratory collapse of diseased pulmonary areas in order to reverse severe hypoxemia resulting from pulmonary shunting, a hallmark of acute respiratory distress syndrome (ARDS). Despite its first introduction in the late sixties (1), and the publication of more than 9,000 articles, it is not easy to establish practical recommendations for setting the "right level of PEEP." The issue remains highly controversial. For 30 years, the pendulum has swung between minimal PEEP, providing maximum oxygen delivery at the lowest airway pressure (2, 3), and high PEEP, keeping the lung fully open at end-expiration (4). A reasonable approach to determining the "right level of PEEP" requires a comprehensive understanding of the rationale for providing alveolar recruitment, the mechanical forces opposing PEEP-induced reopening of atelectatic areas, and the determinants of PEEP-induced lung overinflation and ventilator-induced lung injury (VILI). Hemodynamic impairment that may be observed after PEEP implementation is basically the result of PEEP-induced lung overinflation and has been extensively described in recent reviews (5, 6).

	RATIONALE FOR RE-EXPANDING THE DISEASED LUNG

TOP INTRODUCTION RATIONALE FOR RE-EXPANDING THE... MECHANICAL FORCES OPPOSING PEEP-... FACTORS LIMITING PEEP-INDUCED... SELECTING THE RIGHT LEVEL... WHAT REMAINS TO BE... REFERENCES

Lung injuries provoke surfactant alterations, high permeability-type pulmonary edema, and massive loss of aeration. In patients with ARDS, dependent lung regions are less aerated than nondependent regions, and lower lobes are essentially nonaerated, whereas, often, upper lobes remain partially aerated (7). Because hypoxic pulmonary vasoconstriction is severely impaired (8), lung perfusion remains predominant in lower lobes, creating a pulmonary shunt. Severe hypoxemia results in the prescribed administration of high inspiratory concentrations of oxygen (FI_O2) that may worsen lung injury by causing resorption atelectasis and lung inflammation (9). Establishing safe levels of arterial oxygenation at nontoxic FI_O2 ( 0.6) is one of the rationales for using PEEP.

Experimentally, PEEP reduces the severity of high tidal volume, ventilation-induced permeability-type pulmonary edema (10). This protective effect is likely related to the preservation of surfactant function (11). Although large inflations stimulate the production of surfactant by alveolar cells, when lung regions collapse at end-expiration, surfactant molecules move away from the alveolar surface toward terminal bronchioles, and cannot be reused during the next inflation. Repetitive cycles of recruitment/derecruitment induce a progressive surfactant depletion that can be limited by PEEP, preventing end-expiratory collapse. In injured lungs, mechanical ventilation with large tidal volumes and no PEEP induces bronchiolar and alveolar distension. This peculiar form of VILI has been demonstrated in rabbit-excised lungs (12), piglets ventilated for three days for a bronchopneumonia (13), and patients with ARDS (14). In the absence of lung recruitment, ventilator- induced bronchial and alveolar distension is likely related to opening and closing of distal bronchioles during tidal ventilation. Whether experimental VILI induces the release of pro-inflammatory cytokines is still a matter of controversy (15, 16). In patients with ARDS, alveolar and systemic inflammatory responses can be attenuated by minimizing overinflation and cyclic recruitment/derecruitment of the lung, via a reduction of tidal volume and an increase in PEEP (17).

	MECHANICAL FORCES OPPOSING PEEP-INDUCED LUNG RE-AERATION

TOP INTRODUCTION RATIONALE FOR RE-EXPANDING THE... MECHANICAL FORCES OPPOSING PEEP-... FACTORS LIMITING PEEP-INDUCED... SELECTING THE RIGHT LEVEL... WHAT REMAINS TO BE... REFERENCES

Partial or complete inactivation of surfactant characterizes the early stages of ARDS. In the presence of a normal surfactant, transpulmonary pressures around 10 cm H₂O are enough to keep the lung open at end-expiration. If tensioactive properties of the surfactant are impaired, transpulmonary bronchioloalveolar opening pressures may increase to 25 cm H₂O (11), requiring airway pressures as high as 60 cm H₂O to keep open a surfactant-deficient lung. This "opening pressure" may be even higher in caudal lung regions where additional mechanical compression results from increased cardiac weight and increased abdominal pressure. The price to pay for keeping these lung regions open at end-expiration is the rapid onset of bronchoalveolar damage in other lung regions.

In ARDS, lung inflammation and high permeability-type pulmonary edema increase extravascular lung water, and the weight of upper and lower lobes increases proportionally, whereas aeration of the lobes may be lost or preserved (7). In the supine position, terminal bronchioles are subjected to a superimposed hydrostatic pressure that increases from sternal to vertebral regions, resulting in a progressive collapse of dependent bronchioles. The resulting sternovertebral gradient of aeration observed in the supine position is reversed in the prone position because parasternal lung regions are subjected to the highest superimposed pressure (18). It has been hypothesized that PEEP re-expands the lung by counteracting this superimposed pressure (19). The "sponge theory" postulates that the lung should be entirely reopened at a PEEP of 20 cm H₂O because the maximum sternovertebral dimension of the human thorax cannot exceed 20 cm H₂O. Because such a re-expansion is not observed in a majority of patients with ARDS, additional mechanical forces are likely involved in bronchiolar collapse. In fact, the "sponge theory" is seriously challenged by experimental data on regional expansion of oleic acid- injured lungs (20). In contrast to the theory of alveolar collapse, terminal bronchioles are likely obstructed by "liquid plugs" issued from alveolar flooding as the gas-liquid interface moves back and forth between conducting airways and alveoli during tidal ventilation.

Physiologically, in the supine position, the lung aeration of pulmonary areas located beneath the heart is reduced when compared with the rest of the lung (21). Patients with ventricular failure and dilated cardiac chambers lying supine are prone to develop atelectasis of lower lobes (22). Despite the lack of left ventricular failure, this is also true in many patients with ARDS whose heart is heavier than normal, compresses a greater portion of the lower lobes, and induces a dramatic loss of aeration in infracardiac lung regions (21). Right ventricle dilation secondary to pulmonary hypertension is one of the mechanisms by which the cardiac dimensions increase in ARDS. In some patients, the pressure exerted by the heart on dependent bronchioles may be at least as important as the pressure exerted by the lungs, and the prone position could promote the re-aeration of lower lobes, mainly by relieving this compression (23).

In ARDS, the overall lung volume (gas + tissue) decreases because the loss of aeration is greater than the excess of lung tissue (7, 24). Recent computed tomography (CT) findings have shown that although the end-expiratory lung volume of upper lobes is similar in patients with ARDS and in healthy volunteers, lower lobes of patients with ARDS are always characterized by a dramatic loss of volume with a quasi-complete disappearance of normal aeration (7). In fact, there is a reduction of the cephalocaudal dimension of the lungs related to an upward displacement of the diaphragm (7, 24). Very likely, the increased abdominal pressure resulting from abdominal surgical procedures and/or the acute lung injury itself, is transmitted to the thoracic cavity through the paralyzed diaphragm. In other words, lower lobes are literally sandwiched within the cardioabdominal "forceps."

In ventilated ARDS patients, bronchioloalveolar superinfection occurs rapidly. Microorganisms move from the pharyngeal reservoir toward distal airways due to gravity, and in the supine position, the dependent bronchioles can be obstructed by purulent secretions (25). As a consequence, disseminated bronchiolitis likely contributes to the loss of aeration of lower lobes even in the absence of true alveolar infection. When pulmonary edema is predominant, terminal bronchioles are obstructed by "liquid plugs" and not collapsed as predicted by the "sponge theory" (26). The presence of "liquid bridges" in alveolar ducts prevents the penetration of gas within alveolar structures that remain fluid-filled.

	FACTORS LIMITING PEEP-INDUCED ALVEOLAR RECRUITMENT AND PROMOTING LUNG OVERINFLATION

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Basically, PEEP provides alveolar recruitment by two mechanisms that may be associated in the same patient: it prevents end-expiratory bronchiolar collapse and translocates edema fluid from airways and alveoli to interstitial perivascular space (27, 28). In most patients with ARDS, the increase in functional residual capacity (FRC) resulting from PEEP is greater than alveolar recruitment (29, 30). As demonstrated by CT findings, alveolar recruitment and lung overinflation can be observed simultaneously in different parts of the lung parenchyma after PEEP administration (29, 31, 32). This finding was indirectly confirmed in surfactant-depleted piglets in which overinflation was observed together with alveolar recruitment for PEEP levels near the lower inflection point (33). Because the loss of aeration in ARDS has very frequently a focal distribution, regional compliances are unequal, creating a lobar interdependence (29). Thus, the price to pay for maintaining open atelectatic or fluid-filled lower lobes at end-expiration is an overinflation of compliant upper lobes (26, 34). Several factors limiting PEEP-induced alveolar recruitment and promoting lung overinflation have been identified. The overall lung volume (gas + tissue) of a given nonaerated lung region is a determinant factor of its response to PEEP. Lung areas characterized by "compression atelectasis" (nonaerated lung without excess of tissue resulting in a massive loss of overall lung volume) are less easily recruited than lung regions with "inflammatory atelectasis" (nonaerated lung with tissue in excess resulting in a relative preservation of overall lung volume), and at a given PEEP, there is an inverse relationship between alveolar recruitment and overall lung volume (29). Atelectatic lower lobes may require pressures as high as 50 cm H₂O to reopen, putting the aerated parts of the lung at risk of overinflation.

The lung morphology pattern also markedly influences PEEP-induced alveolar recruitment and overinflation. Patients with a loss of aeration predominating in lower lobes recruit less than patients with an equal loss of aeration to the upper and lower lobes (29, 32). As shown in Figure 1, at PEEP levels greater than 10 cm H₂O, overinflation of lung regions normally aerated at zero end-expiratory pressure (ZEEP) occurs in patients with lobar CT attenuations, a phenomenon not observed in patients with diffuse CT attenuations. The degree of lung aeration before PEEP administration also directly influences PEEP-induced overinflation. Lung regions that have greater than 80% aeration at ZEEP are at risk of overinflation for PEEP levels as low as 10 cm H₂O (29).

View larger version (59K): [in this window] [in a new window]   Figure 1.   Total respiratory system P-V curve (ZEEP conditions) and volumic distribution of lung aeration (CT attenuations in Hounsfield units [HU]) of the entire lung measured at ZEEP (open squares) and two PEEP levels (PEEP1 and PEEP2, solid and open circles) in two patients with ARDS characterized by different lung morphology patterns. The dashed areas indicate pleural effusion, which was not taken into consideration for the CT analysis. In the upper part of the figure, an illustrative CT section of a patient with diffuse CT attenuations and loss of aeration is represented at ZEEP, PEEP 12 cm H2O (PEEP1), and 17 cm H2O (PEEP2). In ZEEP conditions, there are no normally ventilated lung regions, defined as lung areas characterized by CT attenuations ranging from 500 to 900 HU. After increasing levels of PEEP, nonaerated lung regions progressively decrease, whereas a good part of the lung parenchyma becomes normally aerated, an indication of alveolar recruitment. The threshold of overdistension (900 HU) is never reached. In the lower part of the figure, an illustrative CT section of a patient with focal CT attenuations and loss of aeration is represented at ZEEP, PEEP 10 cm H2O (PEEP1), and 15 cm H2O (PEEP2). In ZEEP conditions, half of the lung is normally aerated (upper lobes), whereas the other half (lower lobes) is either poorly aerated (CT attenuations ranging from 500 to 100 HU) or nonaerated (CT attenuations greater than 100 HU). After increasing levels of PEEP, lower lobes are recruited, as evidenced by the decrease in nonaerated lung volume, whereas upper lobes are either distended or overdistended, as evidenced by the appearance of 250 ml of lung parenchyma characterized by CT attenuations less than -900 HU. Reproduced from Vieira and coworkers (32, 43) with permission.

Although recently suggested (35), the hypothesis that PEEP-induced alveolar recruitment is less in primary than in secondary ARDS has not been confirmed by further studies (29, 36). As recently demonstrated in a large series of ARDS patients (29, 32), PEEP-induced alveolar recruitment is maximum in patients with diffuse loss of lung aeration, a lung morphology pattern that is predominantly caused by a primary insult to the lungs (29).

	SELECTING THE RIGHT LEVEL OF PEEP

TOP INTRODUCTION RATIONALE FOR RE-EXPANDING THE... MECHANICAL FORCES OPPOSING PEEP-... FACTORS LIMITING PEEP-INDUCED... SELECTING THE RIGHT LEVEL... WHAT REMAINS TO BE... REFERENCES

A pragmatic rather than a dogmatic approach for selecting the "right level of PEEP," based on a realistic assessment of the risk of overdistension and overinflation, can be proposed for each patient with ARDS. The potential benefit of keeping the diseased lung fully open during tidal ventilation (an hypothetical reduction of the so-called mechanical ventilation-induced "biotrauma" [16]) has to be balanced against the well-established risk resulting from lung overinflation (13, 14). At the bedside, the physician should make his or her decision after confronting three elements: the lung morphology pattern, the shape of the pressure-volume (P-V) curve, and the changes in gas exchange resulting from different PEEP levels.

A majority of patients with ARDS have normally aerated lung regions coexisting with edematous and atelectatic areas at ZEEP (7). The extension of nonaerated territories and the regional distribution of the loss of aeration have a major influence on the P-V curve. Patients with atelectatic lower lobes coexisting with aerated upper lobes have a P-V curve characterized by a moderate decrease in the slope of the P-V curve and a low or nonexistent lower inflection point (8, 32). In patients whose loss of aeration has a focal distribution, the P-V curve has two components: one related to the mechanical properties of the normally aerated lung regions; and the other resulting from the recruitment of the nonaerated lung areas. Very often, high PEEP levels result in overinflation of aerated parts of the lungs, whereas lower lobes are only partially recruited (32). In other words, the concept of "keeping the lung fully open during tidal ventilation" cannot be applied to patients with a focal loss of aeration without reintroducing a risk of VILI. As a consequence, PEEP should be limited to relatively low levels (around 10 cm H₂O) and be combined with the prone position and the administration of nitric oxide and/or almitrine, both of which improve arterial oxygenation by redistributing pulmonary blood flow toward ventilated lung areas. The prone position reduces lobar interdependence and promotes the recruitment of juxtadiaphragmatic lung regions by decreasing the chest wall compliance through a limitation of the expansion of the cephalic parts of the thorax (37).

In the minority of patients with ARDS without any normally aerated lung regions at ZEEP (7, 8), optimizing PEEP should follow a different rationale. As predicted by a mathematical model of ARDS in which the entire lung is collapsed at end-expiration (38), the P-V curve of patients with a diffuse and nonfocal loss of aeration can be considered as a lung recruitment curve. On this curve, lower and upper inflection points indicate the pressures at which lung recruitment begins and ends, whereas the slope of the P-V curve represents the potential for alveolar recruitment. Because the risk of overinflation appears minimum even for high PEEP (29, 32), the highest PEEP consistent with the administration of a tidal volume providing enough CO₂ elimination without reaching a plateau pressure greater than the upper inflection point (39) should be administered. In other words, the concept of "keeping the lung fully open during tidal ventilation" can be applied to these patients without introducing a risk of VILI.

Finally, at the bedside the physician should try to evaluate the lung morphology pattern by considering chest radiographs in combination with the shape of the P-V curve. As recently demonstrated, frontside chest radiographs can be misleading (8) and the obtention of a thoracic CT scan at the early phase of ARDS appears to be the reference method to characterize lung morphology. Using a technique that does not require any special equipment, P-V curves in ZEEP and PEEP can be obtained with most ICU ventilators (40). The last generation of ICU ventilators is equipped with systems that provide the possibility of measuring P-V curves without disconnecting the patient from the ventilator. Because one of the goals of PEEP is the obtention of an arterial saturation above 90% at the lowest FI_O2, the monitoring of arterial oxygen saturation and blood gas is a well-established clinical practice. However, since arterial oxygenation is dependent on parameters other than alveolar recruitment, such as cardiac output, mixed venous oxygen saturation, and hypoxic pulmonary vasoconstriction, it would be dangerous to consider Pa_O2 as the unique gold standard for optimizing PEEP. In particular, because alveolar recruitment and lung overinflation can be simultaneously observed in different parts of the lung, changes in Pa_O2 cannot be considered sensitive enough to detect the risk of VILI. In Figure 2 we propose a logical sequence of steps that the clinician could follow at the bedside for selecting the "right level of PEEP," defined as the PEEP optimizing arterial oxygenation without introducing a risk of oxygen toxicity and VILI.

View larger version (47K): [in this window] [in a new window]   Figure 2.   Sequence of steps for selecting the "right level of PEEP," defined as the PEEP allowing an optimization of arterial oxygenation without introducing a risk of oxygen toxicity and ventilator-induced lung injury.

	WHAT REMAINS TO BE DETERMINED

TOP INTRODUCTION RATIONALE FOR RE-EXPANDING THE... MECHANICAL FORCES OPPOSING PEEP-... FACTORS LIMITING PEEP-INDUCED... SELECTING THE RIGHT LEVEL... WHAT REMAINS TO BE... REFERENCES

A vital condition of the safe determination of the "right level of PEEP" is the identification of clinical tools allowing the early detection of lung overinflation. Whether changes in Pa_CO2 and alveolar dead space could be predictive of lung overinflation remains to be determined. An alternative option could be to assess the predictive value of the ratio between PEEP-induced increase in FRC and PEEP-induced alveolar recruitment derived from the P-V curves. Another important issue concerns the role of lung recruitment maneuvers for optimizing PEEP. Although recently evaluated in experimental animals (41) and in a small number of patients with ARDS (42), the question as to whether or not periodic sighs could increase alveolar recruitment for a given PEEP level requires additional study in larger series of patients. Along these lines, differences in opening and closing pressures of injured lungs may have direct clinical implications. Clinical studies are required to determine if setting the right level of PEEP should be performed according to inflation or deflation P-V curves; in other words, should PEEP be systematically implemented after a recruitment maneuver. Last but not least, a multicenter randomized study assessing the impact of PEEP optimization on mortality rate and duration of mechanical ventilation is warranted. For such a study to have a chance of success, it should include a treatment group where "high" PEEP levels are adjusted according to the individual lung morphology and not systematically and indiscriminately administered.

	Footnotes

Correspondence and requests for reprints should be addressed to Pr. J. J. Rouby, Réanimation Chirurgicale Pierre Viars, Department of Anesthesiology, La Pitié- Salpétrière Hospital, 47-83 boulevard de l'hopital, 75013 Paris, France. E-mail: jjrouby.pitie{at}invivo.edu

(Received in original form May 24, 2001 and accepted in revised form December 21, 2001).

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