INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Partial liquid ventilation (PLV) has been successfully used to improve gas exchange and pulmonary mechanics during ventilatory support in animal models of acute respiratory distress syndrome (ARDS) (1) and in patients with ARDS (4) and infant respiratory distress syndrome (IRDS) (5). In each of these applications PLV was provided by filling the lung with perflubron (PFB) (LiquiVent; Alliance Pharmaceutical Corp., San Diego, CA and Hoechst Marion Roussel Inc., Bridgewater, NJ) and providing conventional ventilation on top of the PFB. Perflubron is an 8 carbon perfluorocarbon with a high gas solubility (53 ml O₂/dl PFB; 210 ml CO₂/dl PFB), a relatively high density (1.9 g/ml), and low surface tension (18 dynes/cm). However, little is known about how approaches to ventilation during PLV affect gas exchange, pulmonary mechanics, and hemodynamics.

Hernan and coworkers have shown that gas exchange during PLV is dependent upon tidal volume (VT) and that low levels of positive end-expiratory pressure (PEEP) ( 5 cm H₂O) are needed (6). They also noted no improvement in oxygenation or ventilation as PEEP increased in healthy animals. Recently, we observed a shifting of the lower inflection point (LIP) on the pressure-volume (P-V) curve of the lung with PFB in a dose-dependent manner (7). With PFB at moderate to total fill levels (10 to 30 ml/kg), a LIP of approximately 12 cm H₂O was observed. We, as well as others, have observed improved oxygenation when PEEP was set above the LIP during PLV (7, 8).

In most large animal studies volume-controlled ventilation (VCV) has been used during PLV (1, 9, 10); however, pressure-controlled ventilation (PCV) is used increasingly in the intensive care unit (ICU) to manage ARDS. During conventional gas ventilation, inspiratory time has not been shown to be a significant factor influencing oxygenation provided PEEP is set above the LIP and mean airway pressure is constant (11). However, with PLV the inertia of the high-density PFB may require longer inspiratory time to maximize gas distribution and gas exchange.

In this study we compare the effects of high and low levels of PEEP during both PCV and VCV at various inspiratory to expiratory time (I:E) ratios. We hypothesized that gas exchange and pulmonary mechanics would be best with PEEP set at the LIP regardless of mode of ventilation or I:E ratio and that because of the high inertia of the PFB the efficiency of ventilation would be improved with VCV compared with PCV because of the greater driving pressure with VCV and with long inspiratory time as opposed to short inspiratory time.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The following protocol was approved by the Subcommittee on Research Animal Care of the Massachusetts General Hospital

Preparation

Fourteen fasted Hampshire sheep (25.6 ± 4.0 kg body weight) were anesthetized with halothane and orally intubated using a 9-mm inner diameter endotracheal tube (Hi-Lo Tube; Mallinckrodt Medical, Inc., St. Louis, MO). To ensure gastric drainage an orogastric tube with esophageal balloon (151-14,14 Fr; Mallinckrodt Laboratories Ltd., Athlone, Ireland) was also inserted. After cannulating the right jugular vein and a loading dose of fentanyl (0.3 mg) and diazepam (10 mg), anesthesia was maintained using fentanyl (3 µg/kg/h) and sodium pentobarbital (5 mg/kg/h), and paralysis was established with pancuronium bromide (2 mg/h). Mechanical ventilation was provided with a PB 7200ae ventilator (Nellcor-Puritan-Bennett, Carlton, CA). Ventilatory settings were VCV, VT 12 ml/kg, respiratory rate 15 breaths/ min, I:E ratio 1:2, inspiratory plateau time 0.6 s, and PEEP 5 cm H₂O. The fraction of inspired oxygen (FI_O2) was 0.5 throughout the experiment except when it was set to 1.0 during lung lavage and filling of PFB. The right femoral artery was cannulated and a pulmonary artery catheter (Edwards Swan Ganzcontinuous cardiac output/mixed venous saturation [CCO/Sv_O2] 8.0 Fr; Baxter Healthcare Corp., Irvine, CA) was placed into the pulmonary artery via the right jugular vein and connected to a continuous cardiac monitor (Vigilance; Baxter Healthcare Corp.). Lactated Ringer's solution was administered intravenously to maintain adequate intravenous volume.

Lung Injury

Bilateral lung lavage was performed by instillation and passive drainage with the foot of the surgical table elevated using isotonic saline (30 ml/kg body weight) warmed to 39° C (11, 12). Residual saline was suctioned from the airway following drainage. The lavage was repeated every 15 min until the Pa_O2 fell below 100 mm Hg with an FI_O2 of 0.5. After lung lavage, the sheep were allowed to stabilize for at least 60 min, while the core temperature was maintained at 39° C using an electric heater and blankets.

Experimental Protocol

After the surgical procedure and a stabilization period of 30 min, baseline parameters (preinjury) were obtained as described in the measurement section. After inducing lung injury and a second stabilization period (60 min) the measurements were repeated (injury). Following the second stabilization period, each animal was administered up to 30 ml/kg of PFB. A meniscus was observed in the endotracheal tube at the level of the teeth. Thirty minutes after filling with PFB a P-V curve of the lung/thorax system was obtained using stepwise 50-ml inflations with a calibrated 500-ml syringe while recording the corresponding airway pressure (13). Each 50-ml inflation was held until a static pressure was observed on the recorded airway pressure tracing (2 to 3 s). The injured lung filled with PFB demonstrated a nonlinear pressure-volume relationship. The pressure associated with the intersection of two tangents applied to the changing slopes of the P-V curve identified the LIP (Figure 1).

View larger version (11K): [in this window] [in a new window]   Figure 1.   P-V curve of the total respiratory system identifying method used to determine the LIP. Tangents were drawn to the lower and upper part of the curve corresponding to the different slopes of the curve. The point of intersection of the tangents identified the LIP. The LIP was 11.4 ± 0.4 cm H2O (range, 11.1 to 12.1 cm H2O).

We assigned each sheep to one of two groups: high PEEP (Group H) and low PEEP (Group L) prior to the development of lung injury. In Group H applied PEEP was set at the LIP. In Group L applied PEEP was set at 5 cm H₂O. We compared six different ventilatory modes in each group in a randomized order: VCV and PCV with I:E ratios of 1:2, 1:1, and 2:1. Baseline data (Baseline 1 and 2) was obtained during VCV with an I:E ratio of 1:2 before (Baseline 1) and after (Baseline 2) the random application of the six modes at either 5 cm H₂O PEEP or PEEP at the LIP. VT in VCV and peak airway pressure in PCV were set in order to keep plateau pressure (Pplat) constant at approximately 26 cm H₂O during Baseline 1. A target Pplat of 26 cm H₂O was established based on pilot data using this model and a VT of 12 ml/kg. The upper deflection point on the P-V curve was always greater than 26 cm H₂O. Total PEEP (PEEPtot) was maintained constant by decreasing the level of applied PEEP by the amount of measured self-controlled positive end-expiratory pressure (auto-PEEP). In VCV we used a constant flow pattern and set inspiratory flow rate to ensure an active inspiratory time of 0.7 s with an end-inspiratory plateau time to 0.6, 1.3, and 1.9 s to achieve I:E ratios of 1:2, 1:1, and 2:1, respectively. In PCV we set the inspiratory time to 1.3, 2, and 2.6 s, respectively, which resulted in a 0.3 to 1.4 s end-inspiratory hold. In both PCV and VCV total inspiratory times equaled 1:3 s (I:E 1:2), 2.0 s (I:E 1:1), and 2.6 s (I:E 2:1). During the experiment we added 1 ml/kg/h of PFB to replace the volume evaporating but did not reassess the presence of a meniscus. Throughout the entire study sheep were maintained in the supine position without any positional change.

Measurements

Hemodynamics, gas exchange, and pulmonary mechanics were measured before lung injury, after lung injury, after filling with PFB, and 30 min after each ventilatory mode in both groups. Mean arterial, mean pulmonary artery, and central venous pressure (CVP) were monitored using pressure transducers (049924-507A, Argon; Maxxim Medical, Athens, TX) calibrated at 50 mm Hg, with the zero level at midthorax in the supine position. Pulmonary artery occlusion pressure (PAOP) and CVP were measured at end-expiration. Cardiac output was continuously monitored (Vigilance; Baxter Healthcare Corp.). Arterial and mixed venous blood samples were drawn at each measurement period and PO₂, PCO₂, pH, and hemoglobin content assessed by a blood gas analyzer (model 238; Ciba Corning Diagnostics Corp., Norwood, MA) and co-oximeter (model 282; Instrumentation Laboratory, Lexington, MA). To calculate dead space/tidal volume ratio (VD/VT) expired gas was collected for 3 min in a Douglas bag (Vacu-Med 25-L balloon; Vacumedics Inc., Ventura, CA). The mean expired CO₂ concentration in this bag was measured using a capnometer (model 2200; Traverse Medical Monitors, Saline, MI) and VD/VT calculated according to Enghoff's modification of the Bohr equation (14). Gas flow was monitored at the airway opening using a pneumotachometer (3700A; Hans-Rudolph Inc., Kansas City, MO) with differential pressure transducer (model 45-14-871 ± 2; Validyne, Northridge, CA). Airway and esophageal pressures were monitored using pressure transducers (model 45-32-871 ± 100; Validyne). Pplat was targeted by use of the ventilator monitor but actual measurement determined by independent assessment at the airway. This led to minor differences in Pplat among modes in each group. VT was integrated using the flow signal and reconfirmed with a 500-ml calibrated syringe. At each setting we also measured total PEEP with an end-expiratory hold maneuver for 5 s using the auto-PEEP function of the 7200 ventilator. Quasi-static compliance (Cst) was calculated with the following equation: Cst = VT/(Pplat  PEEPtot). During volume ventilation an end-inspiratory hold (plateau) of 0.6 to 1.9 s (dependent on I:E ratio) was set to establish static pressure measurements. With pressure control at all I:E ratios flow returned to zero before the end of the inspiratory phase, ensuring an end-inspiratory hold of 0.3 to 1.4 s across I:E ratios. All signals were amplified (model 8805C; Hewlett Packard, Waltham, MA) and recorded at 100 Hz using an analog to digital conversion system (WINDAQ/200 v1.36; Dataq Instruments, Hartfield, PA) and a personal computer. All devices were calibrated at the beginning of the experiment.

Statistical Analysis

All data are expressed as mean ± SD. A two-way analysis of variance (ANOVA) for repeated measures with mode as the repeated measure, was used to compare data at preinjury versus injury, Baseline 1 versus Baseline 2, and the six modes of ventilation evaluated. When statistical significance was reached, it was followed by a post hoc analysis (Tukey honest significant difference [HSD] test). A statistics software package (STATISTICA 5.1; StatSoft Inc., Tulsa, OK) was used, considering p < 0.05 as statistically significant.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Data from 10 of the 14 sheep were analyzed. Three sheep died of hypoxemia after lung lavage and one sheep died of sudden cardiac arrest during the stabilization period following lung lavage. A total of five sheep in each group were studied and analyzed. After the filling with PFB, PEEP was set at the LIP equaling 11.4 ± 0.4 cm H₂O (range, 11 to 12 cm H₂O) in Group H based on P-V curve analysis and at 5.4 ± 0.4 cm H₂O in Group L.

Gas Exchange

Pa_O2 fell significantly from 203 ± 29 to 81 ± 4 mm Hg in Group L and from 194 ± 37 to 80 ± 7 mm Hg in Group H at FI_O2 of 0.5 after lung lavage (p < 0.001; Table 1). There was no significant difference in oxygenation between groups before and after injury. Pa_CO2 and VD/VT did not change significantly with lung lavage in either group (Table 1). With 30 ml/kg of PFB, Pa_O2 increased significantly from 138 ± 30 mm Hg to 303 ± 41 in Group L and from 130 ± 30 mm Hg to 204 ± 59 in Group H with both groups at an FI_O2 of 1.0 and PEEP of 5 cm H₂O (p < 0.05) before and after filling. The Pa_O2 after filling of Group L was higher than that of Group H (p < 0.05) (Figure 2A).

View larger version (16K): [in this window] [in a new window]   Figure 2.   (A) PaO2 (mean = SD) before and after filling of PFB in low-PEEP (Group L) and high-PEEP (Group H) groups. Both groups were ventilated with the same PEEP (5 cm H2O) and FIO2 (1.0) before and after filling. Oxygenation significantly increased with 30 ml/kg of PFB (*p < 0.05). The improvement of Group L was greater than that of Group H (*p < 0.05). (B) PaO2 (mean ± SD) at Baseline 1 (post-PFB fill) and Baseline 2 (following ventilatory modes), FIO2 0.5: PaO2 of Group H did not change between baselines. In Group L PaO2 deteriorated significantly at Baseline 2 compared with Baseline 1 (#p < 0.05). Baselines in Group L were determined at a mean of 5.4 cm H2O PEEP and in Group H at a mean of 11.4 cm H2O PEEP.

As shown in Figure 3A, there was no significant difference in oxygenation between each mode in the high-PEEP group. With low PEEP, VCV I:E ratio 2:1 (VCV 2:1) showed a significantly lower Pa_O2 (p < 0.05 versus VCV 1:2 and 1:1) and PCV at I:E 1:2, 1:1, and 2:1 also showed significantly lower Pa_O2 than VCV 1:1 (p < 0.05). Although the experiment was performed in a randomized order, during low PEEP the Pa_O2 always deteriorated with VCV 2:1 (pre-VCV 2:1 Pa_O2 86 ± 24.3 mm Hg versus VCV 2:1 Pa_O2 60.8 ± 13.9 mm Hg, p < 0.01) and did not recover with the next randomized mode (post-VCV 2:1 Pa_O2 57 ± 11.9 mm Hg versus pre-VCV 2:1 86 ± 24.3 mm Hg, p < 0.01) (Figure 4). The Pa_O2 of the first and second baseline was not different in the high-PEEP group, but that in the low-PEEP group showed a significantly lower value than at the first baseline (Figure 2B). VD/VT with low PEEP was not significantly different from that with high PEEP. However VD/VT did differ significantly among modes with VD/VT higher at low PEEP and PCV 1:2 (Figure 3B). Pa_CO2 also differed among modes (p < 0.01) but not between PEEP levels (Table 2).

View larger version (26K): [in this window] [in a new window]   Figure 3.   (A) PaO2 (mean ± SD) during each ventilatory mode: VCV 2:1 of the low-PEEP group (Group L) showed significantly lower PaO2 than VCV 1:2 (p < 0.05) and VCV 1:1 (p < 0.05) in the low-PEEP group. PCV 1:2, 1:1, and 2:1 of Group L showed lower PaO2 than VCV 1:1 of Group L (p < 0.05). No significant differences in PaO2 between PEEP levels were identified. (B) VD/VT (mean ± SD) at each ventilatory mode: PCV 1:2 of Group L was higher than the VD/VT in VCV 1:1 of Group L (p < 0.05).

View larger version (16K): [in this window] [in a new window]   Figure 4.   Effect of VCV 2:1 on oxygenation of each animal in the low-PEEP group (Group L): PaO2 always decreased at VCV 2:1 regardless of the previous mode and did not recover regardless of the mode after VCV 2:1. Pre-VCV 2:1 PaO2 86 ± 24.3 mm Hg versus VCV 2:1 PaO2 60.8 ± 13.9 mm Hg, p < 0.01. Post-VCV 2:1 PaO2 57 ± 11.9 mm Hg versus pre-VCV 2:1 PaO2 86 ± 24.3 mm Hg, p < 0.01).

Lung Mechanics

With lung injury, Pplat increased from 19.3 ± 4.3 to 27.7 ± 4.4 cm H₂O in the low-PEEP group (p < 0.001) and from 19.5 ± 1.8 to 24.8 ± 3.2 cm H₂O in the high-PEEP group (p < 0.001) (Table 2). Cst decreased from 23.9 ± 4.0 to 15.0 ± 1.7 ml/cm H₂O in the low-PEEP group and from 24.3 ± 1.7 to 18.0 ± 2.9 ml/cm H₂O in the high-PEEP group (p < 0.001). There were no significant differences in Pplat and Cst between groups at both preinjury and injury. Total PEEP did not significantly differ among modes in each PEEP group but did vary by a mean of 0.45 cm H₂O in the low-PEEP group and by 0.42 cm H₂O in the high-PEEP group as a result of the development of auto-PEEP and the difference between measured PEEP at the airway and set PEEP on the ventilator. With 30 ml/kg of PFB, Cst increased significantly with high PEEP (injury versus Baseline 1, p < 0.001), but did not change with low PEEP (injury versus Baseline 1, p = 0.721, Table 1). There was no significant difference between and among group Pplat as various modes and PEEP were applied. VT differed among modes (p < 0.05) but not between PEEP levels. Cst with high PEEP was higher than that with low PEEP during each mode (p < 0.001, Figure 5). Mean airway pressure () with high PEEP was not significantly different from that with low PEEP. At high and low PEEP, differed among modes (p < 0.001).

View larger version (22K): [in this window] [in a new window]   Figure 5.   Quasi-static lung compliance (Cst) (mean ± SD) at different ventilatory modes of both groups: Cst of Group H was significantly higher than that of Group L (*p < 0.05).

Hemodynamics

Heart rate and mean arterial pressure () did not vary among modes but did vary between PEEP levels (p < 0.05) (Table 3). Both heart rate and were lower with low PEEP than with high PEEP. Mean pulmonary artery pressure (Ppaw) did not differ significantly (p = 0.058) between PEEP levels but did differ among mode (p < 0.05). Pulmonary vascular resistance (PVR) did not differ significantly between PEEP levels (p = 0.054). Cardiac output, PAOP, and systemic vascular resistance did not differ significantly between PEEP levels or among modes. There were significant hemodynamic differences between preinjury and injury and between Baseline 1 and Baseline 2. Cardiac output and PVR differed between PEEP levels (p < 0.05) preinjury and injury and Ppaw and PVR differed between preinjury and injury, whereas heart rate (p < 0.01) and Ppaw (p < 0.05) differed between PEEP levels, Baseline 1, and Baseline 2. 

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The most important findings of this study can be summarized as follows: (1) With PEEP set at the LIP, adequate gas exchange and improved lung mechanics could be obtained in all modes assessed. (2) Oxygenation was enhanced during VCV 1:1 when compared with VCV at longer I:E ratios or PCV at any I:E ratio.

We hypothesized that gas exchange and pulmonary mechanics would be best with PEEP set at the LIP regardless of mode of ventilation or I:E ratio and that because of the high inertia of PFB the efficiency of ventilation would be improved with VCV compared with PCV and with long inspiratory times as opposed to short inspiratory times. This hypothesis proved to be only partially correct. Setting PEEP at the LIP proved to result in better gas exchange and pulmonary mechanics than 5 cm H₂O PEEP. This was consistent with our and others' previously published data (7, 8, 15). However, lengthening the inspiratory time beyond a 1:1 I:E ratio resulted in poorer oxygenation at low PEEP, whereas I:E ratio had no effect on any of these variables at PEEP equal to the LIP. VCV and PCV essentially performed equivalently at high PEEP, however, at low PEEP VCV 1:1 did outperform PCV at all ratios. This is consistent with data previously published regarding gas ventilation (11, 16). When PEEP is set above the LIP no benefit in oxygenation, pulmonary mechanics, or hemodynamics has been shown by altering I:E ratio or changing ventilation target during gas ventilation.

Oxygenation

Oxygenation varied considerably among modes in the low-PEEP group but did not differ between PEEP levels. This is in conflict with our previously published data (15), which clearly showed improvement in oxygenation at PEEP above the LIP with 30 ml/kg PFB filling during VCV 1:2. There are a number of potential reasons for this difference. Primarily, the condition of the sheep postfilling in the low- and high-PEEP groups was different. Postfilling with PFB at the same FI_O2 (1.0) and PEEP (5 cm H₂O) the Pa_O2 of the high-PEEP group (204 ± 59 mm Hg) was significantly lower (p < 0.05, Figure 1A) than the Pa_O2 of the low-PEEP group (303 ± 41 mm Hg). Thus, although the Pa_O2 with the application of high or low PEEP were almost identical, there was a decrease in Pa_O2/FI_O2 observed in the low-PEEP group (postfill 303 mm Hg, Baseline 1 196 mm Hg) which did not occur in the high-PEEP group (postfill 204 mm Hg, Baseline 1 184 mm Hg). In our earlier study differences in level of injury between animals in various groups were avoided by the use of the same animals randomized to different treatments sequences. In the present study different animals were randomized to each PEEP group.

The setting of PEEP at or above the lower inflection point enhances oxygenation during PLV by two potential mechanisms (7, 15). The LIP during PLV identifies the minimal PEEP necessary to completely clear the large conducting airways of PFB at end exhalation and may be reflective of recruitment of nondependent lung units minimally affected by the PFB.

Ventilation

There were no statistically significant differences in Pa_CO2, VD/ VT, or VT between PEEP levels. However, significant differences did exist in Pa_CO2 (p < 0.01), VD/VT (p < 0.001), and VT (p < 0.05) among modes of ventilation. The greatest differences were observed with PCV 1:2 and low PEEP. PCV ventilation especially at low PEEP can be problematic with PLV because of the lower driving pressures than those observed with VCV. Because of the high impedance to gas movement especially at low PEEP, a higher peak inspiratory pressure is necessary to overcome both resistance and compliance. This can be better accomplished with VCV because peak pressure is not targeted. Even when end-inspiratory Pplat are the same, the driving pressure (actual peak pressure) is much greater with VCV than with PCV. The higher driving pressure available with VCV than with PCV along with the lower compliance noted in the PEEP equal to 5 cm H₂O group (Figure 5) made PCV I:E 1:2 less efficient than VCV I:E 1:1 in respect to dead space ventilation (Figure 3B) and oxygenation (Figure 3A) at low PEEP levels. The use of PEEP at LIP with PLV would appear to eliminate some of the heterogeneity in ventilation-perfusion (/) observed by Mates and coworkers (19) when a PEEP of 5 cm H₂O was used.

Extended Inspiratory Time

Although it did not reach statistical significance in all post hoc comparisons, VCV with an I:E ratio of 2:1 during low PEEP resulted in the worst oxygenation of all modes evaluated. In addition, oxygenation did not recover with the application of the next randomized mode (Figure 4). As a result, the final baseline Pa_O2 in the low-PEEP group was lower than the initial baseline in Group L and lower than the final baseline Pa_O2 during high PEEP (Figure 2B). The reason for this is unclear. During high PEEP no such deterioration was observed. The active gas delivery time during VCV was constant at 0.7 s regardless of I:E ratio or PEEP; in all comparisons the end- inspiratory pause time was increased to establish the I:E ratio. We believe that the change in pulmonary status after VCV 2:1 may have been a result of air trapping. Fuhrman and coworkers (10) reported increased expiratory resistance during PLV compared with gas ventilation with 5 cm H₂O PEEP. The high impedance to exhalation along with the short expiratory time during VCV 2:1 may have resulted in air trapping and auto-PEEP. With high PEEP, because the end-expiratory pressure maintains the central airways clear of PFB, impedance to expiratory flow is less than with low PEEP. The use of high PEEP may have altered the expiratory flow dynamics of the system sufficient to prevent air trapping. However, we did not measure a marked increase in auto-PEEP during any mode ( 2.5 cm H₂O). This may be a result of an inadequate end-expiratory hold time (5 s) and the trapping of air behind fluid, especially during low PEEP. With a partially liquid-filled lung much longer times may be needed to accurately measure auto-PEEP. Similar problems did not occur during PCV 2:1 at low set PEEP. Although our study design did not allow us to specifically determine the cause of the deterioration observed during VCV 2:1 and 5 cm H₂O PEEP, we believe that our findings are consistent with the development of unidentified auto-PEEP.

Lung Mechanics

Quasi-static compliance was affected by PEEP level but little affected by mode or I:E ratio. In all modes and baseline evaluations, the setting of PEEP at the lower inflection point improved the compliance. This was not observed in the low-PEEP group. The lack of change in compliance at low PEEP after filling with PFB is consistent with data from previous reports using the same sheep model (20, 21). The use of PEEP at the LIP, we believe, results in improved Cst by forcing fluid out of central airways, reducing impedance and recruiting nondependent lung units (7, 8, 15).

Lung Protection

It can be argued that the application of PEEP at the LIP afforded protection to the PFB-filled lung as compared with PEEP at 5 cm H₂O. Deterioration of pulmonary status over the course of the study in the low-PEEP group is evidenced by the change in oxygenation state and the difference in compliance of the two groups. As previously discussed, after filling with PFB the high-PEEP group had a lower Pa_O2 at an FI_O2 of 1.0 and 5 cm H₂O PEEP than the low-PEEP group (204 ± 59 versus 303 ± 41 mm Hg). However, at Baseline 1 Pa_O2 were equivalent 98 ± 19 mm Hg low PEEP and 92 ± 12 mm Hg high PEEP when measured at 5 cm H₂O and 12 cm H₂O PEEP respectively after initial filling. However, at Baseline 2 the Pa_O2 of the low-PEEP group was significantly lower than the high-PEEP group (63 ± 16 versus 94 ± 9 mm Hg). Because Pplat in both groups were kept below the upper deflection point, the application of PEEP at the LIP is the only variable that could account for these differences. However, lung protection was not the focus of this study and further research is required before the protective effects of PEEP in this setting can be established.

Hemodynamics

It is unclear how pulmonary hemodynamics should be interpreted in the PFB-filled lung. Significant differences in Ppaw between PEEP levels were observed with pressures being higher with low PEEP (p < 0.05). However, no statistically significant differences were observed for PAOP, CVP, PVR, or CO but there were differences in between PEEP levels (p < 0.05) with lowest with low PEEP. In addition, the cardiac output was lower in the low-PEEP group and PVR was lower in the high-PEEP group at preinjury and injury (p < 0.05) but these variables were not significantly different at Baseline 1 and 2. Fluid was liberally administered in both groups to maintain cardiac output at preinjury level. Tooker and coworkers have shown that the PAOP measurement using a pulmonary artery catheter is only reliable for estimations of left atrial pressure when the tip of the catheter is in zone 3 of the lung (22). It is not clear that our PAOP data when the lung is filled with PFB accurately reflect left atrial pressure. Conflicting data regarding pulmonary blood flow during PLV and PVR exist in the literature (23, 24). Lowe and Shaffer showed that PVR in the isolated lung increased linearly as a function of increasing alveolar pressure, independent of total liquid or gas ventilation (24), and Venegas and colleagues found that blood flow to gravity-dependent regions increased during PLV (23). We did not observe a PVR change from Baseline 1 in either group. We have observed that pressure readings of the pulmonary artery catheter during PLV do not necessarily reflect transesophageal echocardiography measurements (25). Hemodynamic measurements using a pulmonary artery catheter during PLV may not reflect the same changes in pulmonary circulation observed with gas ventilation.

Clinical Implications

Our data have potentially important implications for the clinical use of PFB during PLV. It is clear that the approach used to ventilate can have a large impact on gas exchange, pulmonary mechanics, and pulmonary hemodynamics. Of primary importance when ventilating a PFB-filled lung is the setting of PEEP at or above the lower inflection point on the inspiratory P-V curve (7, 15). There appears to be no benefit in extending inspiratory time during PLV. In fact air trapping and auto-PEEP may develop more rapidly than during gas ventilation (10). Our data would indicate that I:E ratio be kept  1:1. VCV provides more efficient gas exchange and more consistent volume delivery during PLV than PCV if low PEEP is set. Although our data would point strongly to a particular approach to ventilatory support during PLV, more research is required before a definitive approach can be defined.

Limitations

A number of limitations to this study exist. First, this study was performed on a sheep model of ARDS, not on humans. As a result it is inappropriate to directly apply this data to humans without further study. The lung model used was a lung lavage, surfactant washout model; as such, results may be different in other models of lung injury (oleic acid, sepsis). Also, because of the small sample size in each group (n = 5) a large beta error may have existed; that is, some of the comparisons that did not reach significance may have done so with a larger number in each group. An additional, potential limitation is the lack of a control group with gas ventilation only. We did not include a gas-ventilation-only group because of the body of literature currently available comparing gas ventilation with PLV in similar laboratory models showing the benefit of PLV with low PEEP over gas ventilation (1, 2, 9, 10). All of the controlled trials comparing gas ventilation with PCV versus VCV at various I:E ratios have failed to show any difference in lung mechanics, oxygenation, and hemodynamics provided total PEEP was held constant (11, 16). Our objective in this study was to identify the approach to ventilation in association with PLV that resulted in the best gas exchange, hemodynamics and lung mechanics, not to compare PLV with gas ventilation.

In conclusion, during low PEEP gas exchange deteriorated during VCV with long inspiratory time and in PCV. With PEEP set at the LIP, adequate gas exchange with better lung mechanics could be obtained in all modes assessed.