INTRODUCTION

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Acute respiratory distress syndrome (ARDS) is a diffuse heterogeneous lung disease that produces progressive hypoxemia because of a marked ventilation/perfusion mismatching causing intrapulmonary shunt. Inhaled nitric oxide (NO) and prone position (PP) are two of the supportive strategies proposed for ARDS. One of the main goals of these strategies is to increase arterial oxygenation by reducing intrapulmonary shunting of blood and at the same time, reduce the potential oxygen toxicity while allowing a decrease in the inspired oxygen fraction (FI_O2).

Inhaled NO has been shown to be beneficial in patients with ARDS by increasing Pa_O2 and reducing pulmonary artery pressure (1, 2). Inhaled NO produces a dilation of pulmonary vessels supplying ventilated alveolar units, causing a redistribution of pulmonary blood flow from unventilated and perfused regions to ventilated but underperfused areas (3, 4). Moreover, some investigators have documented a more pronounced increase in Pa_O2 induced by NO inhalation in lungs ventilated with adequate positive end-expiratory pressure (PEEP), probably owing to the alveolar recruitment (5, 6).

Since 1974 when Bryan (7) proposed PP to improve oxygenation, many studies have demonstrated its striking effect on gas exchange (8). It is known that mechanical ventilation in PP produces a more homogeneous and enhanced ventilation () of dorsal lung (16, 17) by the reduction of the gravitational gradient of pleural pressure (18). On the other hand, no gravitational effects on perfusion () have been documented with PP (19). The result is a better matching in the / relationships due to a redistribution of ventilation (20).

Recently, some investigators have studied the hemodynamic and respiratory gas exchange effects of the combination of PP and NO inhalation in patients with ARDS (21). However, the magnitude of the improvement in Pa_O2 greatly varied in these studies. It has been described (26) that ARDS can be caused by a pulmonary insult to the lungs (pulmonary or primary ARDS) or associated with a nonpulmonary insult (extrapulmonary or secondary ARDS). At least two groups have reported that patients with pulmonary (Pu) ARDS exhibit a normal chest wall compliance (Ccw), whereas patients with extrapulmonary (Epu) ARDS show decreased Ccw (26, 27).

Moreover, interesting data with respect to the behavior of respiratory system mechanics when changing from supine position (SP) to PP have recently been reported by Pelosi and coworkers (28). This study was carried out in predominantly Pu ARDS patients, and the researchers documented that the higher the Ccw in SP, the greater its decrease when turned to prone, and this was associated with a greater improvement in arterial oxygenation. However, since Gattinoni and coworkers (26) reported that Ccw was higher in Pu ARDS compared with Epu ARDS, we speculated that patients with Pu or Epu ARDS could respond differently to the turn because of these previously reported differences. The aim of our study was to evaluate the effects on hemodynamics, respiratory system mechanics, and gas exchange induced by the combination of NO inhalation and PP in ARDS patients and to analyze the response of Pu and Epu ARDS patients to these treatments.

	METHODS

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Patients

Fifteen patients (10 men, 5 women) with ARDS of different origins admitted to our intensive care unit (ICU) were prospectively enrolled. ARDS was defined according to the criteria recommended by the American European Consensus Conference (29). Patients were included when despite FI_O2 1 and PEEP greater than 5 cm H₂O they had a Pa_O2 equal to or less than 200 mm Hg for at least 24 h. The protocol was approved by the hospital ethics committee, and informed consent was obtained from the patients' next of kin. Criteria to classify Pu and Epu ARDS were made on clinical grounds, as previously described (26).

Study Protocol

Measurements were first collected in supine, whereas NO inhalation was randomized in each position. There were, thus, four different conditions in the study: (1) supine position without NO inhalation (SP), (2) supine position with NO inhalation (SP + NO), (3) prone position without NO inhalation (PP), and (4) prone position with NO inhalation (PP + NO). This approach enabled a comparison of the response to position and to NO inhalation. Data collection was performed 30 min after stabilization in each condition.

External PEEP was titrated according to the lower inflection zone of the respiratory system's pressure-volume (PV) curve. If a lower inflection was not detected, a PEEP level of 10 cm H₂O was set. The applied PEEP level was kept constant throughout the study. Tidal volume (VT) and respiratory rate remained unchanged. FI_O2 was set at 1 throughout the study. In PP, the abdomen was unsupported.

NO was delivered into the inspiratory limb of the ventilator using a precision flowmeter (AGA S.A., Toulouse, France). The dose administered was 5 parts per million (ppm) of NO and was measured at the Y piece of the ventilator by the chemiluminescence method with a rapid response analyzer (NOX 4000 Sérès; Aix-en-Provence, France).

A patient was considered to be a responder either to NO or to PP when an increase in Pa_O2/FI_O2 of 20% or more with respect to baseline (SP) was observed. Nonresponders were those who exhibited changes less than the ± 20% threshold, and a deterioration was defined when Pa_O2/FI_O2 decreased by more than 20% with respect to the baseline.

Statistical Analysis

All results are reported as mean ± SD (unless otherwise specified). Data analysis was performed using the statistical software package SPSS 6.1 (Statistics Package for Social Sciences, Inc., Chicago, IL). An analysis of variance for repeated measures with two factors was performed: (1) position, with two levels (supine and prone), and (2) inhalation of NO, with two levels (yes and no). This statistical approach allowed us to compare the effects of SP and PP, the effects of NO in SP and PP, and the interactions between both treatments (position and NO inhalation). A p < 0.05 was considered significant. If significant differences were observed, comparisons between two conditions (SP versus PP, SP versus SP + NO, PP versus PP + NO) were performed by a two-tailed Student's t test for paired samples. Chi-square test was performed to compare qualitative variables.

	RESULTS

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Clinical Data

Relevant clinical data are shown in Table 1. No short-term complications attributable to PP, such as accidental extubations, withdrawal of indwelling catheters, cardiac arrhythmias, major hemodynamic instability, or need for immediate suction of airway secretions, were seen. Overall mortality was 80% (12 of 15).

Respiratory System Mechanics

Comparing SP to PP, no differences were found in peak airway pressure (42 ± 6 cm H₂O versus 41 ± 7 cm H₂O, respectively) and plateau airway pressure (Pplat) (28 ± 5 cm H₂O versus 29 ± 6 cm H₂O). No significant change in respiratory system compliance (Crs) was observed between the two positions (35 ± 14 ml/cm H₂O in supine versus 35 ± 18 ml/cm H₂O in prone).

Gas Exchange and Hemodynamics

These data are summarized in Table 2. PP, in comparison with SP, resulted in a significant increase in Pa_O2 (p < 0.001), and NO inhalation significantly increased Pa_O2 during both SP (p = 0.013) and PP (p = 0.005). The effect of PP on gas exchange was significantly greater than that observed in SP with NO inhalation. The inhalation of NO induced a slight but significant improvement in Pa_O2 in SP and PP, without statistical differences between the two situations. However, when patients were turned from SP to PP, the increase in Pa_O2 was significantly higher (p = 0.002) when compared with NO inhalation alone (Figure 1). Compared with SP, the combination of PP and NO inhalation induced an increase of Pa_O2/FI_O2 from 106 ± 58 to 225 ± 93 mm Hg (p < 0.001), without synergistic effects between the two treatments. In other words, the effects of inhaled NO were simply additive and did not achieve a greater effect when patients were turned prone.

View larger version (56K): [in this window] [in a new window]   Figure 1.   Comparison of the change in PaO2/FIO2 ratio induced by PP and NO inhalation for the whole population. SP + NO versus SP indicates the change in PaO2/FIO2 with the inhalation of NO in SP, PP versus SP indicates the change from SP to PP, and PP + NO versus PP indicates the change induced by the inhalation of NO in PP. Columns and bars depict mean ± SEM, respectively.

Inhalation of NO induced a decrease in shunt fraction (S/T) of 11 ± 16% in SP and 7 ± 16% in PP, without statistical differences between the two situations. S/T decreased by 28 ± 13% when patients were turned from SP to PP, a decrease which was significantly higher (p < 0.001) than that observed during SP with NO inhalation (Figure 2). Methemoglobin levels were, in all cases, below 2.5%, and the concentration of NO₂ measured at the Y piece of the ventilator was always below 0.01 ppm.

View larger version (53K): [in this window] [in a new window]   Figure 2.   Comparison of the change in S/ T induced by PP and NO inhalation for the whole population. Columns and bars depict mean ± SEM, respectively.

Differences between Pu and Epu ARDS

Total PEEP, as titrated according to the lower inflection point of the PV curve of the respiratory system, was slightly higher in Epu, 12 ± 3 cm H₂O, versus Pu ARDS, 8.7 ± 2 cm H₂O, (p = 0.04). The effects on gas exchange and hemodynamics induced by position changes and NO inhalation, according to the causes of ARDS are shown in Figure 3. Intrapulmonary shunt was significantly lower (p = 0.05) in Epu versus Pu ARDS in both SP (53 ± 14 versus 41 ± 7%) and PP (38 ± 10 versus 29 ± 6%). Interestingly, in PP, those patients with Epu ARDS had significantly higher Pa_O2/FI_O2 in comparison with those who had Pu ARDS (p = 0.01). In Pu ARDS, we observed a significant improvement in Pa_O2/FI_O2 when NO was inhaled in both SP and PP, and also when these patients were turned from SP to PP. In Epu ARDS, NO inhalation slightly improved Pa_O2/FI_O2, although the difference did not reach statistical significance either in SP or in PP, and only the turn from SP to PP markedly improved Pa_O2/FI_O2 (p = 0.005).

View larger version (16K): [in this window] [in a new window]   Figure 3.   Values of PaO2/FIO2 (mean ± SEM) in Pu (closed squares) and Epu (closed triangles) ARDS patients during each situation. SPNO = supine position and NO inhalation; PPNO = prone position and NO inhalation.

Individual Changes in Pa_O2 Induced by NO Inhalation and Turning from SP to PP

NO inhalation induced an improvement in Pa_O2 above 20% in 60% of patients (9 of 15) in SP and in 46.6% patients (7 of 15) in PP, whereas 80% of patients (12 of 15) were Pa_O2 responders when turned to PP. Changes in arterial oxygenation, on a patient by patient basis, are depicted in Figure 4. All patients who responded to NO inhalation in SP also responded to PP, and the 50% of patients who had responded to PP also responded to NO inhalation while prone. Two patients, Patients 13 and 15 (13%), did not respond to any intervention (NO inhalation in SP, NO inhalation in PP, and turning from SP to PP). No patient deteriorated their Pa_O2 at levels higher than 20% with respect to their basal value (SP) either after NO inhalation or after the turn. As can be seen in Figure 4, the decrease in Pa_O2 observed after NO inhalation (observed in four patients) or after the turn (observed in only one patient) ranged between 6 and 28 mm Hg; these figures correspond to percent changes in Pa_O2 between 3 and 18% of their respective basal values. We did not observe differences between Pu ARDS and Epu ARDS in terms of response, except in the number of patients who responded to NO in PP, which was significantly higher in Pu ARDS (6 of 8, 75%) in comparison with Epu ARDS (1 of 7, 14%), p = 0.02. Patients with Pu ARDS always responded either to NO or to PP or both, whereas two of seven patients with Epu ARDS (28.5%) responded neither to NO nor PP.

View larger version (22K): [in this window] [in a new window]   Figure 4.   Individual changes in PaO2/FIO2, between the different conditions. Patients with Epu ARDS are shown with dashed lines; patients with Pu ARDS, with continuous lines.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

General Clinical Characteristics and Critique of the Methods

The ARDS patients we studied had a profound gas exchange derangement (mean Pa_O2 106 mm Hg) despite mechanical ventilation with FI_O2 1 and average PEEP levels of 10 cm H₂O. Twelve of 15 had associated septic shock and were under vasoconstrictive drugs (norepinephrine, dopamine or a combination of both). In addition, five patients had malignancies, and another had acquired immunodeficiency syndrome. The combination of these factors probably explains the high mortality rate (80%), congruent with other reports dealing with patients with ARDS similar to ours (14, 30).

All our measurements were done 30 min after stabilization in each of the four conditions studied. Both the effects of inhaled NO and positioning are seen after a relatively short delay. In fact, physiologic changes induced by NO inhalation are almost immediate and achieve a rapid steady state (1). With respect to PP, Jolliet and coworkers (14) documented that no further changes in Pa_O2 were observed between 30 and 120 min after the turn and suggested that a 30-min trial in PP is sufficient to assess the response in terms of arterial oxygenation. Chatte and coworkers (9) reported that arterial blood gases were fairly constant between 1 h and 4 h after the turn, although these investigators did not measure arterial blood gases at 30 min. More recently, Nakos and coworkers (15) have reported that in patients with ARDS who responded to the turn, there were no significant changes in Pa_O2/FI_O2 from 30 min to 12 to 48 h after the turn. A very similar profile (no major changes in arterial oxygenation) is observed in those patients who are considered as nonresponders to the turn (14, 15). However, Pelosi and associates (28), in a study including almost exclusively Pu ARDS patients, observed significant increases in Pa_O2 2 h after the turn but not at 30 min. Their patients, however, were studied 4.3 d after ARDS onset, PEEP was titrated according to the clinical needs, the abdomen was supported, and the increase in Pa_O2 after the turn was relatively modest (from 106 to 129 mm Hg). In contrast, we studied our patients 3.1 d after ARDS onset, PEEP was titrated according to the PV curve, the abdomen was unsupported, and we observed major increases in Pa_O2 after the turn.

The criteria to classify Pu or Epu ARDS was made on clinical grounds, as with Gattinoni and coworkers (26). Unfortunately, this physiologically sound classification lacks validation and no sensitivity/specificity figures can be given. Data on different components of respiratory system mechanics seem to differ in Pu and Epu ARDS (26). These investigators reported high lung and normal chest wall elastances in Pu ARDS and the estimated recruitment up to 15 cm H₂O PEEP was nil, whereas in Epu ARDS, they reported normal lung and high chest wall elastances, and the estimated recruitment was 293 ml at PEEP 15 cm H₂O. Nevertheless, other researchers have documented significant PEEP-induced alveolar recruitment in patients who predominantly had bronchopneumonia as a cause of acute lung injury (ALI) (33). In addition, histologic data differentiating Pu and Epu ARDS are lacking. Finally, the presence of "mixed" ARDS cannot be ruled out, because ventilator-associated pneumonia often complicates the clinical course of ARDS, irrespective of whether it is Pu or Epu (34, 35). This is specially true for those patients in whom a full-blown ARDS is diagnosed after days or weeks under mechanical ventilation. From a clinical point of view, we believe that comprehensive definitions proposed by Murray and coworkers (36) (i.e., ARDS "caused by" or "associated with") are still very useful to communicate.

We titrated PEEP levels in as objective a way as possible, as other researchers did (15, 37, 38). Such a strategy does not necessarily maximize alveolar recruitment nor improve arterial oxygenation. There are indeed data indicating that alveolar recruitment still continues at pressures higher than the lower inflection point (33, 39). We used a PEEP level that is conceivably accompanied by a sudden increase in alveolar recruitment. Interestingly, we observed that with our method of PEEP titration (i.e., the lower inflection zone of the PV curve), this resulted in a higher external PEEP in Epu ARDS compared with Pu ARDS. Although we did not perform a partitioning between the two components of respiratory system mechanics (lungs and chest wall), it has been shown that in patients having an ALI (40), the PV curve of the chest wall exhibits a lower inflection point at 3 cm H₂O on average. This observation, together with that reported by Ranieri and coworkers (27), indicating a rightward shift of the chest wall PV relationships in patients with ARDS secondary to abdominal processes, may explain why our Epu ARDS patients (two of whom had peritonitis and another three pancreatitis) exhibited a lower inflection zone at higher pressures when compared with Pu ARDS patients.

Another factor that could influence our results is the implementation of PP. While in PP, our patients had their abdomen unsupported. Other investigators have employed PP with the abdomen supported (8, 12, 13, 28). Although supporting the abdomen can minimize restriction of abdominal movements and the effect of hydrostatic pressure transmission from the abdomen to the thorax, and thus help increase functional residual capacity, Pelosi and associates (28) failed to show significant changes in end-expiratory lung volume from supine to prone abdomen supported position in patients with ARDS ventilated with PEEP. Interestingly, Mure and coworkers (41) reported that in healthy pigs ventilated in PP, arterial oxygenation improved and / heterogeneity decreased in comparison with SP, only when the animals had abdominal distension. They speculated that in the presence of abdominal distension, the gravitational pleural pressure gradient is more uniform in the PP. This increases regional lung ventilation near the diaphragm and thus helps to decrease / heterogeneity. Whether or not these findings can be extrapolated to human ARDS lungs is not known.

Additionally, data provided by Puybasset and colleagues (42) suggest that in supine patients with ALI, factors implicated in the distribution of lung densities observed in the thoracic computed tomographic (CT) scans are not only the decrease in transpulmonary pressure caused by the increased abdominal pressure, but also the presence of anatomic factors. In line with this hypothesis, a recent study carried out in supine patients with ARDS (43) has shown that the cardiac mass and volume are significantly increased when compared with normal subjects, which together with the cephalic displacement of the diaphragm and the compression exerted by the edematous lungs, contributes to the marked loss of aeration of lower lung lobes in these patients. Furthermore, studies performed in spontaneously breathing patients (44) and in patients with cardiomegaly (45) have shown that the compressive force of the heart on dorsal lung regions is reversed when turning these individuals prone. Such a mechanism could then explain, at least in part, the improvement in oxygenation observed in patients with ARDS when turned from the SP to PP.

Gas Exchange and Hemodynamics

The current study confirms that PP and inhaled NO are useful therapeutic tools to improve gas exchange in patients with severe ARDS, without inducing hemodynamic derangements or other short-term adverse effects. More important, however, is the observation that gas exchange did not deteriorate more than 20% (with respect to the basal values obtained in SP) in any patient either with NO inhalation or PP. Variability in response to NO or PP has been reported by others (9, 11, 12, 14, 15, 21). This can be explained by different evolutive stages (11, 15), as well as different hemodynamic profiles among patients (15). Of course, other factors such as shape of the chest and abdominal wall (28, 46), ventilatory settings (6), and anatomic factors such as the compression of the heart directed to the sternum instead of the lungs when patients are prone (44) may all influence the effects on oxygenation. Nevertheless, in accordance with the current literature and our own data, we think it is important to point out that a harmful deterioration in gas exchange after the turn is extremely infrequent.

As previously described (21, 25), an additive relationship in the improvement of oxygenation with the two treatments was observed. Also, in accordance with these studies, we were unable to find any interaction between the effects of the two treatments as could have been expected according to the different mechanism accounting for the improvement of oxygenation induced by PP and NO inhalation. In fact, the number of patients and the magnitude of response to NO inhalation was essentially the same in both SP and PP. Other investigators (23), however, claimed that in patients with ARDS improvement in arterial oxygenation induced by NO inhalation happened to a lesser extent in SP (from 110 to 134 mm Hg) in comparison with PP (from 161 to 197 mm Hg). The differences between our study and that of Martinez and coworkers (23) could be explained by different mean FI_O2 employed (0.85), different doses of inhaled NO (10 ppm), a different way of titrating external PEEP (without using PV curves), and different evolutive ARDS stage (their patients were studied after an average of 6.5 d of ARDS onset).

Also of note is the finding that the magnitude of improvement in oxygenation was greater with PP than with NO inhalation (78 mm Hg versus 25 mm Hg, p < 0.002) as Gillart and coworkers (24) also observed. In contrast, some researchers (21, 22, 25) failed to detect differences between the improvement in arterial oxygenation induced by NO inhalation and that induced by changing position from SP to PP. This perhaps could be attributed to the causes of ARDS, differences in respiratory system mechanics, different ventilatory settings, different hemodynamic status, the extension and distribution of hypoxic pulmonary vasoconstriction, and the degree of / mismatch among the patients.

It is worth mentioning that the number of patients responding to PP (80%) was higher than the number of patients responding to inhaled NO (60%). These results are in accordance with other studies in which the percentage of patients responding to PP ranged from 57 to 78%, whereas the response to NO inhalation was observed in 36 to 57% of patients (21, 25). Our data clearly indicate that turning patients to PP is more beneficial in terms of improvement of oxygenation than the inhalation of NO. Also interesting is the fact that the beneficial response to inhaled NO is maintained during PP, and this effect is mainly observed in Pu ARDS patients.

Although the arterial oxygen saturation and oxygen content in arterial blood significantly improved with NO inhalation and with PP, the oxygen delivery did not. This was probably a result of the intraindividual changes in cardiac output, because some individuals tended to decrease their cardiac output when oxygenation improved. A decrease in S/T has been constantly associated with the improvement of oxygenation either with NO inhalation or PP (1, 3, 4, 8, 10, 11, 47). Again, the reduction of S/T induced by change of position was significantly greater than that observed with the inhalation of NO in SP (28 ± 13% versus 11 ± 16%, p < 0.0001).

A slight decrease in Pa_CO2 was detected with the inhalation of NO in both SP and PP. This trend has also been observed by others (21, 23). It can be interpreted as a reduction of dead space as a consequence of changes in / matching and also as an effect of dead space washout caused by a continuous flow of approximately 0.2 L/min at the Y piece coming from the NO tank.

Pu versus Epu ARDS

When the causes of ARDS were considered, a different response to treatment was observed (see Figures 3 and 4). Patients with Epu ARDS did not significantly improve oxygenation with the administration of inhaled NO in either SP or PP, but markedly improved gas exchange with PP. In fact, this group of subjects showed a slightly lower pulmonary vascular resistance index (PVRI) in comparison with Pu ARDS patients, and several investigators have documented a direct relationship between PVRI and the improvement in Pa_O2 (4, 21, 23). However, in our study, Pu ARDS patients improved oxygenation when turned from SP to PP, and also after inhaling NO, both in SP and PP. These findings can be attributed to the fact that there is a redistribution of ventilation toward dorsal (nondependent) zones in PP, and thus, it is conceivable that NO may reach lung regions with low / ratios.

Our Pu ARDS patients had a significantly higher intrapulmonary shunt compared with Epu ARDS, and values of cardiac output were virtually the same. This indirectly suggests that alveolar consolidation occurred to a greater extent in the former compared with the latter. In fact, in the presence of true shunt (zero / ratios), which conceivably exists in Pu ARDS because consolidation seems to predominate over alveolar edema collapse (26), the effects of inhaled NO are mainly related to shunt reduction through a "stealing" of blood from shunting to nonshunting regions, thus helping improve arterial oxygenation. However, we speculate that in Epu ARDS patients, arterial hypoxemia was due not only to true shunt but also to perfused low / regions. Recent data indicate that when FI_O2 1 is used in ALI, there is a slight increase in the perfusion going to low / areas (50). In this setting, NO might possibly have reached perfused but underventilated alveolar regions at end-inspiration, thus enhancing their perfusion. If this particular scenario were to occur, NO would be associated with a lack of improvement in arterial oxygenation, as demonstrated by Hopkins and coworkers in an experimental model (51).

It has been reported that ARDS patients (mainly Pu ARDS) with higher Ccw in SP show greater improvement in oxygenation when they are turned to PP (28). According to these findings, one could speculate that Pu ARDS patients might present a greater improvement in oxygenation when turned to prone in comparison with Epu ARDS patients because Ccw is higher in the former as compared with the latter (26). Our study, however, does not seem to confirm this contention because no different response to PP was found between Pu and Epu ARDS in terms of gas exchange. It is important, however, to point out that PEEP levels, titrated as in our investigation, gave as a result a higher external PEEP in Epu ARDS compared with Pu ARDS. Finally, we should stress that our study may have lacked power to detect small changes.

Conclusion

NO inhalation and PP are two easy-to-perform therapeutic measures that have proved to be efficacious and safe, at least in short-term clinical studies, and thus may be considered useful tools in the treatment of early ARDS patients. Additionally, PP is associated with a more consistent improvement in oxygenation compared with NO inhalation, in both magnitude of response and number of responders. An added advantage of PP is that it is cheaper than NO inhalation. Remarkably, PP was not associated with untoward effects on a short-term basis. Finally, and although our sample size may not be sufficiently large to draw definitive conclusions, we were unable to find differences between Pu and Epu ARDS with respect to the response to PP, whereas patients with Epu ARDS were poor NO responders in comparison with patients with Pu ARDS. These data taken together suggest that turning ARDS patients prone early, in comparison with NO inhalation, is more useful to improve gas exchange in both magnitude of response and number of responders.