INTRODUCTION

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Recent efforts to minimize the potential risk of ventilator associated lung injury have resulted in ventilatory strategies that limit tidal volume (VT) and airway pressure and allow permissive hypercapnia (1). However, permissive hypercapnia is not without risk. Acute acidosis may extend cardiovascular instability (5), increase intracranial pressure (6) and in general is contraindicated in the presence of severe metabolic acidosis (7). Tracheal gas insufflation (TGI) has been proposed as an adjunct to mechanical ventilation in the presence of permissive hypercapnia (8). TGI flushes the anatomic dead space, improving CO₂ removal (11, 12). Systems designed to administer TGI can provide TGI flow continuously (C-TGI, during both inspiration and exhalation) (8, 13) or insufflation only during exhalation (Ex-TGI) (12, 14, 15). With either approach the efficiency of CO₂ removal appears to be primarily dependent upon the volume of TGI flow (12) and the size of the anatomic dead space (11, 12). However, the effect of inspiratory/ expiratory (I:E) ratio on TGI efficiency has not been completely addressed (12).

C-TGI with volume-controlled ventilation (VCV) results in increased VT, peak airway pressure, and positive end-expiratory pressure (PEEP) (16), because the TGI flow is added to the delivered VT, unless ventilator-delivered VT is decreased by the amount of TGI volume added during inspiration (volume-adjusted TGI) (10, 12, 13). Combining C-TGI with pressure control ventilation (PCV) corrects some of these problems (11, 17, 18) but is limited by the function of the ventilator's exhalation valve (16). Exhalation valves in most ventilators are active only during the expiratory phase. Thus, system pressure and VT increase during C-TGI with PCV once flow delivered by the ventilator decreases to zero. At this time the C-TGI flow adds additional volume increasing airway pressure. Most of the problems associated with C-TGI can be resolved by the use of Ex-TGI (14, 17) because Ex-TGI has little effect on the inspiratory phase. In healthy dogs Ex-TGI with VCV has been shown to be as effective in removing CO₂ (22% reduction) as C-TGI with VCV (36% reduction) and Ex-TGI results in minimal changes in airway pressures and VT (14). To date no controlled trial has evaluated the effect of Ex-TGI with PCV in acute lung injury.

TGI flow can be directed toward the carina (direct flow) or directed toward the mouth (reverse flow) (19). The first evaluation of reverse flow TGI was in healthy dogs using C-TGI and VCV (20). In this study direct flow TGI was more effective in reducing Pa_CO2 than reverse flow TGI (20). However, more recently Ravenscraft and coworkers have shown that CO₂ elimination is primarily based on TGI flush volume not on TGI flow direction (12). It has also been demonstrated in dogs (20) and in a lung model (19) that reverse flow Ex-TGI results in less change in PEEP than does direct flow TGI (19). Currently there are no controlled evaluations of the effects of reverse flow TGI in acute lung injury or with Ex-TGI and PCV.

In this study we evaluated the effects of Ex-TGI with PCV on gas exchange, system pressure and volume, as well as hemodynamics in a sheep lung lavage, acute lung injury model during permissive hypercapnia, and compared the effects of direct and reverse flow Ex-TGI with normal and inverse I:E ratios.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Lung Injury Model

This study was approved by the Subcommittee on Research and Animal Care of the Massachusetts General Hospital. A total of nine Hampshire sheep (27 to 30 kg body weight) were anesthetized with halothane and endotracheally intubated, after which pulmonary (7.5 Fr; Baxter Healthcare Corp., Irvine, CA) and femoral artery catheters were inserted, tracheostomy performed, and an esophageal balloon (14 Fr; Mallinckrodt Laboratories Ltd., Athlone, Ireland) placed. Sheep were maintained anesthetized and paralyzed throughout the study with continuous intravenous administration of butorphanol (2 mg/h), diazepam (10 mg/h), and pancuronium bromide (2 mg/h) (21).

Lung injury was produced by bilateral lung lavage with 1 L instillation of isotonic saline warmed to 39° C (21, 22). With the saline in the lung, the animals' position was rotated among supine, right, and left lateral positions. The lavage was repeated until the Pa_O2 decreased to approximately 70 mm Hg at a fraction of inspired oxygen (FI_O2) of 0.5 and PEEP of 10 cm H₂O (21). After lung lavage, the sheep were allowed to stabilize for a period of at least 60 min with VCV, FI_O2 0.5, ventilator rate 15 breaths/min, VT 250 ml, inspiratory flow 24 L/min, and PEEP 10 cm H₂O. Lactated Ringer's solution was administered intravenously at a rate sufficient to maintain cardiac output at baseline (5 ~ 10 ml/kg/h). Core temperature was maintained at 39° C by an electric heater and blankets. Before and after the lavage, a static pressure-volume curve was established with a 500-ml calibration syringe (23). After establishing a volume history (VCV, VT 400 ml, inspiratory flow 24 L/min, end-inspiratory pause 0.7 s, PEEP 10 cm H₂O, FI_O2 0.5, rate 15 breaths/min), the lungs were inflated stepwise in 50-ml increments to 500 ml with a 3-s pause at each step. The procedure was repeated three times. From each curve the lower inflection point was determined and the results averaged. At the end of the experiment, the lower inflection point was again determined in a similar manner.

TGI System

Following establishment of lung injury, the tracheostomy tube was replaced with a prototype double-lumen endotracheal tube (Sherwood, St. Louis, MO) with its tip positioned 2.5 cm above the carina. This tube (Figure 1) has a 7.8-mm internal diameter (i.d.) main lumen and a 3.5-mm i.d. second lumen that directs a secondary flow toward the mouth (reverse flow TGI) (19). An 8-Fr catheter (30800; Healthcare Group Inc., Cumberland, RI) was passed alongside the tube and advanced to the bifurcation of the carina with fiberoptic bronchoscopic guidance to measure carinal pressure.

View larger version (27K): [in this window] [in a new window]   Figure 1.   (Top panel ) Illustration of the double-lumen endotracheal tube used to provide reverse flow expiratory phase TGI. The main lumen of this tube has an internal diameter (i.d.) of 7.8 mm while the TGI channel has an i.d. of 3.5 mm. Note the TGI channel is directed upward into the main lumen. (Bottom panel ) With direct flow TGI a 16-gauge catheter was inserted into the main lumen of the double-lumen endotracheal tube and positioned 0.5 cm beyond the tip of the endotracheal tube.

Two different flow directions of Ex-TGI were applied: direct flow and reverse flow. In direct flow, a TGI flow of 10 L/min directed toward the carina was provided by a 16-gauge catheter (Intracath; Desert Medical Inc., Sandy, UT) inserted into the main lumen of the endotracheal tube (16). The catheter tip was positioned 0.5 cm beyond the tip of the prototype endotracheal tube (i.e., 2 cm above the bifurcation of the carina). In reverse flow, a TGI flow of 10 L/min was provided via the second lumen of the endotracheal tube and was directed toward the mouth by a nozzle at the tip of the reverse flow tube (19) (Figure 1). Ex-TGI was established with an external three-way solenoid valve (model A3314-S8; Precision Dynamics Inc., New Britain, CT) that was electrically connected to the exhalation valve solenoid of a 7200ae ventilator (Nellcor Puritan Bennett, Carlton, CA) as we reported previously (17, 24). Oxygen concentration of the TGI flow was set identical to the gas delivered by the ventilator using an oxygen blender (Bird/3M, Palm Springs, CA).

Experimental Protocol

After the stabilization period, the ventilator setting was changed to PCV with permissive hypercapnia. PEEP was set 1 cm H₂O above the inflection point noted on the static pressure-volume curve (23). Respiratory rate was 15 breaths/min with FI_O2 0.5 and inspiratory time (TI) 1.32 s or 2.66 s. Each inspiratory time provided an I:E ratio of 1:2 or 2:1. The PCV level was selected to ensure a Pa_CO2 near 80 mm Hg without TGI. Then total PEEP was measured using the auto-PEEP function incorporated into the 7200ae ventilator. Total PEEP was maintained identical throughout the complete study of each animal. Sodium bicarbonate solution (1 mEq/ml) was administered to maintain arterial pH over 7.2 when hypercapnia was induced.

After the initial control period, two directions of TGI flow (direct and reverse) were randomly evaluated at TI of 1.32 s and 2.66 s. When Ex-TGI was applied to PCV with direct flow, the development of auto-PEEP increased total PEEP, decreased the driving pressure and, as a result, decreased VT delivered from the ventilator (17). Therefore, the PEEP setting on the ventilator was decreased to maintain total PEEP identical to the baseline value. In addition, PCV level was increased to maintain peak airway opening pressure and VT identical. During reverse flow TGI PEEP changed less than 1 cm H₂O during both I:E ratios; as a result, total PEEP was not corrected. During the total PEEP measurement (on the 7200 ventilator), the solenoid valve of the TGI system eliminated the TGI flow at end-expiration. Total PEEP was measured by the auto-PEEP function of the 7200 ventilator, by the establishment of an end-expiratory hold. However, because of the high resistance of the direct flow TGI catheter (16-gauge), additional volume (~ 25 ml compressed volume) was delivered into the lungs during the total PEEP measurement. Using total patient/ventilator system compliance, we calculated the pressure generated by the compressed volume added during total PEEP measurement with direct flow TGI and subtracted this pressure from the total PEEP measured. With the reverse flow TGI tube, additional volume was small (< 2 ml) because of the low resistance of the tube and was not compensated. These adjustments ensured that both peak inspiratory pressure and total PEEP remained constant regardless of TGI flow direction or inspiratory time. To confirm a constant level of lung injury throughout the experiment, baseline data were collected before and after each trial, resulting in six baseline measurements. Each experimental setting and baseline period was maintained for at least 25 min with blood gases analyzed every 5 min until the Pa_CO2 stabilized.

Measurements

Measurements of hemodynamics, gas exchange, and pulmonary mechanics were obtained before lavage, at the end of each baseline period, and following each of the four TGI trials.

Hemodynamics. Mean arterial and pulmonary artery pressures were monitored (pressure transducers 049924-507A, Argon; Maxxim Medical, Athens, TX) and amplified (8805B; Hewlett-Packard, Waltham, MA) with the zero reference level at midthorax in the supine position. Pressures were displayed on screen and recorded (WINDAQ; Dataq Instruments, Inc., Akron, OH) at 100 Hz/channel. Pulmonary capillary wedge pressure (PCWP) and central venous pressure (CVP) were measured at end-expiration. Cardiac output was measured by thermodilution (9520A; American Edwards Laboratories, Irvine, CA) as the average of three sequential measurements obtained by injecting 5 ml of 0° C lactated Ringer's solution.

Gas exchange. Arterial blood gases were analyzed for pH, Pa_CO2, and Pa_O2. Expired gas was gathered into a large collection bag (Vacu-Med 25 L balloon; Vacumetrics Inc., Ventura, CA) and mean expired CO₂ concentration was measured with an infrared capnometer (Model 2200; Traverse Medical Monitors, Saline, MI). The capnometer was calibrated with 5% CO₂ in N₂ (BOC Gases, Murray Hill, NJ).

Airway pressure and volume. Airway opening pressure, carinal pressure, and esophageal pressure were measured with differential pressure transducers (45-32-871, ± 100 cm H₂O; Validyne, Northridge, CA) and amplified (8805C; Hewlett-Packard). The transducers were calibrated simultaneously at 20 cm H₂O using a water manometer. The proper position of the esophageal balloon in the midesophagus was confirmed by cardiac oscillations observed on the esophageal pressure trace (25). The esophageal balloon was filled with 1 ml air. These data provided peak, mean, and end-expiratory pressures at the airway opening and at the carina and the change in esophageal pressure. Pneumotachometers (3700A; Hans-Rudolph Inc., Kansas City, MO) were placed at both the inspiratory and expiratory limbs of the ventilator as close to the Y-piece as possible. The pressure differential across the pneumotachometers was measured (45-142-871, ± 2 cm H₂O; Validyne), digitized, and converted to flow (WINDAQ). Pneumotachographs were calibrated in series with a 0.5 L/s flow delivered by precision flow meter (Brooks Instruments, Hatfield, PA). Tidal volume was integrated from flow and confirmed with a 500-ml syringe. Inspired tidal volume was corrected for the compressible volume of the expiratory circuit (compliance 1.3 ml/cm H₂O) (11, 20). Expired gas included the volume delivered by the TGI system during expiration and compressible volume of the whole ventilator circuit (compliance 2.7 ml/cm H₂O).

where PIP is peak airway opening pressure and TE is expiratory time. All measurements were made during the last 5 min of each trial. All signals were digitized at 100 Hz, recorded, and analyzed using WINDAQ.

Statistical Analysis

Three breaths were analyzed for each experimental setting after stabilization. All values were expressed as mean ± standard deviation (SD). The data obtained from the six baselines were first compared to detect any variation over time. Because there was no such effect, the six controls were averaged and analyzed as a group. Statistical analysis was performed by analysis of variance (ANOVA) with repeated measurements. Post hoc analysis was done with the Scheffe test (SPSS, Chicago, IL). Significance was set at p < 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

After lung lavage, an inflection point was observed in all sheep, ranging from 17 to 21 cm H₂O (19.0 ± 1.2 cm H₂O). The lung lavage decreased compliance from 30.7 ± 5.0 ml/cm H₂O to 17.0 ± 2.3 ml/cm H₂O (p < 0.01). At the end of the experiment, compliance was the same as postlavage (18.6 ± 2.8 ml/cm H₂O). Lung lavage decreased the Pa_O2 (71 ± 15 mm Hg, FI_O2 0.5, PEEP 10 cm H₂O) from prelavage values (245 ± 155 mm Hg, FI_O2 0.5, PEEP 10 cm H₂O) and increased the dead space to tidal volume ratio to 0.61 ± 0.06 from prelavage values (0.51 ± 0.07).

Gas Exchange

Table 1 and Figure 2 present the blood gas, dead space to tidal volume ratio (VD/VT), and VT data for all trials. Tidal volume was constant during all trials averaging about 180 ml at 1:2 I:E ratios and about 190 ml at 2:1 I:E ratios. Pa_CO2 significantly decreased with both TGI directions and both I:E ratios (p < 0.05). With an I:E ratio of 1:2, Pa_CO2 decreased from 78 ± 4 mm Hg to 60 ± 7 mm Hg (23.5 ± 8.9%, range 14 to 43%) with direct flow and to 64 ± 5 mm Hg (18.5 ± 5.5%, range 9 to 26%) with reverse flow. During extended inspiratory time (2:1 I:E ratio), Pa_CO2 decreased from 80 ± 6 mm Hg to 69 ± 8 mm Hg (13.7 ± 9.2%, range 0.4 to 28%) with direct flow and to 66 ± 4 mm Hg (17.2 ± 4.4%, range 11 to 25%) with reverse flow. There were no significant differences in Pa_CO2 change observed between direct and reverse flow TGI. The reverse flow showed a similar decrease in Pa_CO2 regardless of inspiratory time, while the direct flow showed a larger decrease in Pa_CO2 with normal inspiratory time than with extended inspiratory time (23.5 ± 8.9% versus 13.7 ± 9.2%, p < 0.05). Similar changes were observed for PE_CO2 and VD/VT (Table 1). No significant change was observed in the Pa_O2; however, in both 1:2 and 2:1 I:E ratios the Pa_O2 tended to increase with the reverse flow TGI.

View larger version (22K): [in this window] [in a new window]   Figure 2.   PaCO2 changes in each animal studied with both direct flow (Direct) and reverse flow (Reverse) expiratory phase TGI. (Top panel ) Normal (1:2) I:E ratio. (Bottom panel ) Inverse (2:1) I:E ratio. *p < 0.05 versus baseline.

System Pressures

Table 2 lists airway pressures at baseline and during all trials. Peak airway pressure and total PEEP remained constant throughout all trials. However, the amount of PEEP as a result of the TGI flow varied based on direction of flow. With the direct flow, 2.8 ± 1.2 cm H₂O PEEP was established with the 1:2 I:E ratio and 4.0 ± 1.4 cm H₂O with the 2:1 I:E ratio. This differed significantly (p < 0.05) from the PEEP established during reverse flow (0.9 cm H₂O I:E 1:2; 0.4 cm H₂O I:E 2:1). Measurement of PEEP at the carina tended to be higher than at the airway opening with the direct flow. No differences in mean airway opening or carinal pressure were observed regardless of trial except with direct flow and a 1:2 I:E ratio. Here the carinal pressure tended to be greater than airway opening pressure. No differences in esophageal pressure change were observed regardless of TGI direction or I:E ratio.

Hemodynamics

Table 3 lists hemodynamic measurements at baseline and during all trials. No differences from baseline were observed regardless of TGI direction or I:E ratios.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The most important findings of this study are: (1) The efficiency of direct flow Ex-TGI decreased at short expiratory time. (2) The efficiency of reverse flow Ex-TGI was not affected by alterations in expiratory time. (3) Direct flow TGI increased total PEEP, which was underestimated by carinal pressure monitoring, whereas with reverse flow TGI only minor changes in total PEEP were observed. (4) The combination of Ex-TGI and PCV minimized changes in PIP and VT regardless of I:E or direction of insufflated flow.

Pa_CO2, I:E, and TGI Direction

Regardless of TGI direction or I:E ratio, the Pa_CO2 decrease was similar. However, direct flow TGI demonstrated a trend toward more effective CO₂ elimination with short inspiratory time, whereas reverse flow TGI demonstrated identical CO₂ elimination with both normal and long inspiratory times. In fact, there was a difference in the efficacy of CO₂ elimination between I:E ratios with direct flow TGI. Our data differ from that reported by Nahum and coworkers (20) in hypoventilated healthy dogs. They reported better CO₂ removal with a direct flow catheter (Pa_CO2 changes from 56.0 to 39.5 mm Hg, 29.5% decrease) than with a reverse flow catheter (Pa_CO2 decrease from 56.0 to 44.1 mm Hg, 21.3% decrease) at 10 L/min Ex-TGI flow. Their protocol differed from ours on a number of points. They studied healthy dogs, using VCV with short inspiratory times and adjusted their VT and end-expiratory lung volume by respiratory inductive plethysmography. As a result airway pressure may have varied between methods because of the difference in PEEP established by TGI approach. Our data are somewhat in agreement with that of Ravenscraft and coworkers (12) who showed in healthy dogs that CO₂ elimination was dependent on TGI flush volume not on TGI direction. Ravenscraft and coworkers (12) used VCV and Ex-TGI and also noted no difference in the efficacy of CO₂ removed as inspiratory time was adjusted when flush volume was constant. With both direct and reverse flow TGI flush volume was cut in half (447 ml versus 223 ml/breath) as expiratory time decreased. However, the efficiency of CO₂ removal was affected to a greater extent with direct than with reverse flow TGI. It can be speculated that the impaired exhalation during direct TGI, as reflected by an increased auto-PEEP, may explain this observed difference in efficacy. Because the auto-PEEP measurement by an end-expiratory hold only reflects a static-average value, the regional distribution of PEEP may have been very different between TGI approaches. This may have resulted in greater differences in / with direct versus reverse TGI. This is illustrated by the fact that VD/VT increased to a greater extent with direct TGI (0.35 to 0.48, p < 0.05) than reverse TGI (0.41 to 0.46, p = NS), andalthough not significantthe Pa_O2 tended to improve during reverse flow TGI. However, this would also mean that these results are very dependent on the inhomogeneity of the lung (e.g., different lung models) and the distribution of alveolar time constants within the lung. In addition, as shown by Takahashi and coworkers (26) with reverse TGI, the jet drag effect establishes a negative pressure at the carina, which may have enhanced molecular activity increasing TGI efficiency.

Development of PEEP

The most important difference between the effects of TGI direction is the development of PEEP. With direct flow TGI at 10 L/min in our model 2.8 to 3.8 cm H₂O PEEP was established by the TGI flow, whereas with reverse flow TGI PEEP was decreased by 0.4 to 0.9 cm H₂O. These observations agree with our previous lung model data (16, 19, 24) and data in healthy dogs (12, 20). Direct flow TGI establishes an end-expiratory threshold increasing PEEP and lung volume, whereas reverse flow TGI, as a result of the jet drag effect, decreases PEEP and lung volume. The small effect of reverse flow TGI on PEEP observed in our study may be a direct result of TGI catheter design. The reverse flow catheter we used had a 3.5-mm i.d. with a 2.6-mm injection orifice, while the direct flow catheter had an internal lumen of 0.9 mm the total length of the catheter (16-gauge). As a result of the differences in flow resistance between systems the gas velocity from the reverse flow catheter may have been too low to establish a large jet drag effect, thus minimal change in PEEP. Alternate design catheters may cause a greater decrease in PEEP during reverse flow TGI.

Hemodynamic Effects

No differences in hemodynamic parameters were observed across baseline and TGI method regardless of I:E ratio. The consistency of hemodynamic data is a result of maintaining inspiratory time, total PEEP, VT, and mean carinal pressure essentially unchanged during all trials at each I:E ratio.

Limitations. This study was performed in a sheep lung lavage model of adult respiratory distress syndrome (ARDS), which may not reflect the same pathophysiology observed in human ARDS or in other ARDS models (oleic acid, sepsis, etc.) and as a result should only cautiously be applied to these settings without further study. In addition, because our Ex-TGI system was designed in our laboratory, its functional characteristics may differ from those of other groups (12, 15) and the eventual systems developed by industry.

Expiratory resistance between the two TGI approaches was different (reverse 3.92 cm H₂O/L/s; direct 4.98 cm H₂O/L/s at 0.5 L/s expiratory flow without TGI flow and 3.83 cm H₂O/ L/s [reverse] and 11.42 cm H₂O/L/s [direct] at 0.5 L/s expiratory flow during 10 L/min TGI flow). With the reverse flow design a prototype double-lumen endotracheal tube was used. The internal diameter of the main lumen was unaltered during reverse flow TGI. Direct flow TGI was established by inserting a 16-gauge catheter into the main lumen of the reverse flow TGI tube; as a result expiratory resistance was higher, potentially affecting CO₂ washout. The tip of the reverse flow tube and the direct flow tube were different distances from the carina (2.5 versus 2.0 cm, respectively) and the velocity of gas flow was much greater with the direct flow method than the reverse flow method. These two differences may have enhanced CO₂ removed with the direct flow method.

In conclusion, the use of Ex-TGI with PCV is an efficient method of enhancing CO₂ elimination in a sheep lung lavage model of ARDS. Neither the direction of TGI flow nor the I:E ratio markedly affects CO₂ elimination. Direct flow TGI causes an increase in total PEEP whereas reverse flow TGI decreases total PEEP.