INTRODUCTION

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Tracheal gas insufflation (TGI) decreases dead space (VD) during mechanical ventilation (MV) and allows reduction in tidal volume (VT) or in Pa_CO2 (1). In spontaneously breathing patients with chronic respiratory failure, TGI results in decreases in minute volume (VE), Pa_CO2 (2, 3), and oxygen cost of breathing (4).

TGI may also benefit spontaneously breathing patients with acute lung injury (ALI), characterized by low lung compliance and high airway resistances (5), by lowering VT and VE to significantly reduce inspiratory work of breathing. Hence, TGI might permit earlier resumption of spontaneous breathing during or after ALI (6) and might be combined with continuous positive airway pressure (CPAP).

As observed by Hoyt and colleagues (7), TGI combined with CPAP may increase work of breathing imposed by the apparatus depending on ventilatory drive, TGI flow, and the type of circuit and valves used. When CPAP is delivered through a balloon system, work of breathing caused by the circuit is lower than with a mechanical ventilator (7). A balloon circuit is hence a better choice than a mechanical ventilator to reduce work of breathing when TGI is combined with CPAP.

TGI has reportedly led to pulmonary hyperinflation when delivered through a straight flow catheter (SFC) (8, 9). We developed a reverse thrust catheter (RTC) that delivers gas in a mouthward direction. This avoids hyperinflation by creating a venturi and decreasing airway pressure at the carina (10). In addition, the RTC can increase mucus clearance through the endotracheal tube (ETT) and avoid accumulation of secretions within its lumen (11). We reasoned that the RTC could be safely used to deliver TGI during CPAP.

Nahum and colleagues (9) showed that a reverse flow catheter of their own design had a lower efficiency for CO₂ washout than did a SFC in healthy (8) and in OA-injured (12) dogs, and that the decrease in VD is near optimal at a TGI flow of 10 L/min. We do not know the gas flow required to optimize CO₂ removal with the RTC and its efficacy compared with a SFC.

It was the aim of this study to investigate the effects of TGI combined with CPAP (CPAP-TGI) on gas exchange, ventilation, and effort of breathing in sheep with OA-induced lung injury. We delivered CPAP through a balloon system. In addition, we compared the performance of the RTC and the SFC at an identical TGI flow (10 L/min), as well as the efficacy of two different insufflation flows (10 and 15 L/min) delivered through the RTC.

	METHODS

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Animal Preparation, Instrumentation, and Measurements

The protocol was approved by the Animal Care and Use Committee of the National Heart, Lung, and Blood Institute of the National Institutes of Health (Bethesda, MD). We studied 11 young female sheep (mean weight, 28.4 ± 4.9 kg). The animals were anesthetized with a loading dose of 7 mg/kg ketamine. The sheep were orotracheally intubated with a standard 8-mm ETT, and were connected to a mechanical ventilator (Servo 900C; Siemens Elema, Solna, Sweden) in the pressure support (PS) mode with a PS level of 5 cm H₂O, PEEP of 5 cm H₂O, and FI_O2 of 1.0. Anesthesia was maintained by continuous infusion of ketamine (21.4 to 35.7 mg/kg/hr), adjusted to obtain cessation of spontaneous movements after painful stimulation. The sheep were tracheotomized, and a 9-mm Jet Ventilation ETT (Mallinckrodt, Glenn Falls, NY) was positioned under bronchoscopic guidance with its tip 2 cm proximal to the carina. The ETT was connected to the ventilator circuit through a swivel connector. The femoral artery was percutaneously cannulated for systemic arterial pressure (Pa) monitoring and collection of blood samples, analyzed on an Anova Statplus 9 blood gas analyzer (Nova Biomedical, Waltham, MA). Through the right external jugular vein, we introduced a 7-Fr, 4-lumen pulmonary artery catheter (Abbott Critical Care Systems, Chicago, IL) to measure pulmonary artery pressure (Ppa), central venous pressure (CVP), pulmonary artery wedge pressure (Ppaw), core blood temperature, and cardiac output () by thermodilution (9520A Cardiac Output Computer; American Edwards Laboratories, Irvine, CA). The core temperature was kept constant at 38° C with a heating pad. Through the left external jugular vein, we inserted a modified 7-Fr pulmonary artery catheter (Abbott Critical Care Systems), with its tip in the right atrium. The distal 80 cm of the catheter had been previously cut off, exposing the two larger lumens of equal size, through which we injected OA and saline (see below).

We made a 2-cm incision into the left pleural cavity through the ninth intercostal space to insert a Smartcath esophageal balloon catheter (Bicore Monitoring Systems, Irvine, CA). Any resulting pneumothorax was evacuated through an 8-Fr pneumothorax evacuation catheter (Cook Critical Care, Bloomington, IN), inserted through the same incision. After carefully sealing the incision, pleural suction was maintained until no more air could be aspirated, after which the catheter was clamped off. The complete evacuation of any pneumothorax, the proper positioning of the ETT, and of the pleural, pulmonary artery, and atrial catheters were confirmed by chest radiographs.

The pleural balloon catheter and a Varflex flow transducer (Bicore), placed between the Y-piece of the ventilator (or CPAP) circuit and the swivel connector, were part of a Bicore CP100 pulmonary monitoring system (Bicore). A second Varflex flow transducer was connected to the exhaust of the CPAP circuit to obtain the exhaust flow (EX). The digital output of the monitor was connected to a personal computer for storage and subsequent analysis of airway opening, gas flow, and pleural pressure signals, sampled at 100 Hz. A pressure transducer (Statham P23D; Gould Inc., Cleveland, OH) was connected to the distal line of the Mallinckrodt Jet Ventilation ETT to measure carinal pressures. This transducer was connected to an analog amplifier and recording system (3800 Signal Conditioner; Gould Inc.). The signal was analogically averaged to obtain the mean carinal pressure (). All exhaust gas exiting from the CPAP circuit was collected in a 40-L mixing bag, from which gas was sampled and analyzed with an infrared CO₂ analyzer (LB2; Beckman Instruments, Fullerton, CA) to obtain the mean CO₂ concentration (FEX_CO2).

CPAP Circuit

We used a custom-designed circuit to provide CPAP (Figure 1). A 7-L balloon was connected to the inspiratory line of the circuit, consisting of flexible tubing with an ID of 22 mm, a Conchatherm III temperature-controlled humidifier (Hudson, Temecula, CA), and a Y-piece. A Siemens Elema adjustable PEEP valve was inserted at the exhaust end of the expiratory line. The balloon was positioned in a wedge holder kept at an angle of 20 to 30 degrees to maintain the balloon volume at its point of maximum compliance, reducing airway pressure swings (13), and, hence, decreasing imposed work of breathing. The angle of the wedge was regulated by adjusting the pressure in a low resistance piston that was connected to an external source of compressed air, connected through a pressure regulator to a reservoir tank. The bias flow in the CPAP circuit was set at 20 L/min and was monitored on a rotameter. The FI_O2 was adjusted through a Model 960 Siemens Elema O₂/air mixer.

View larger version (12K): [in this window] [in a new window]   Figure 1.   Balloon CPAP circuit used throughout the study. (1) 7-L balloon, (2) wedge holder, (3) piston, (4) rotameter, (5) humidifier, (6) Y-piece, (7) swivel connector, (8) PEEP valve, (9) source of compressed air.

TGI System

TGI was delivered through a RTC or a SFC. Both 7-fr catheters (Cook) were made of nylon. The RTC had a closed tip, distal side holes, and a 1.5-cm-long cap mounted on its tip to allow gas to exit in a reverse direction through a narrow annular space (10). The SFC had an open end but no side holes. The RTC or the SFC were inserted into the ETT through a swivel connector. The tip of the RTC was advanced to 1 cm within the tip of the ETT, at the site of carinal pressure measurement. Hence, all gas emerged from the RTC about 1.5 cm proximally to this point. The end of the SFC was placed approximately at the same distance from the tip of the ETT as the opening of the RTC. The insufflation gas, obtained from the same Siemens O₂/air mixer used for the CPAP circuit, passed through a rotameter, through a Conchatherm III temperature controlled humidifier, and through a 120-cm-long insulated PVC tubing connected to the RTC or the SFC. The humidifier was a reinforced, low volume prototype canister (Hudson), designed to withstand pressures as great as 4 ATM. The temperature in the canister was maintained at 39° C.

Protocol

After surgery, sheep were positioned prone and administered PS ventilation for 30 min, after which we took arterial blood samples and hemodynamic measurements. We then performed three end-inspiratory and three end-expiratory occlusions with the hold buttons of the ventilator while we stored airway pressure, pleural pressure, and flow tracings in the computer.

One line of the cut pulmonary artery catheter was connected to a 100-ml glass syringe filled with saline, and the other line was connected to a 3-ml syringe filled with OA (Fischer Chemical Co., Fair Lawn, NJ). Every 10 min we infused 0.2 ml of OA at an infusion rate of 3 ml/min while we simultaneously infused saline at a rate of 135 ml/ min, using two separate Harvard Apparatus infusion pumps. We infused a total of 0.06 ml/kg of OA. With this technique, OA is dispersed by the rapid flow of saline during the injection and forms droplets 125 ± 25 µm in diameter, as determined by bench tests. During infusion of OA over an approximately 1-h period, Ppaw was maintained at 10 mm Hg through the infusion of 500 ml of hetastarch, followed by 0.9% sodium chloride, to enhance the formation of pulmonary edema. After the last injection, we observed the animals closely for 2 h and infused 0.9% sodium chloride as needed to maintain Ppaw above 5 mm Hg. A complete set of measurements and recordings was repeated as above.

Sheep were then connected to the CPAP circuit and were randomized to two groups. Group A (n = 7; weight, 27.4 ± 4.2 kg) was placed on CPAP and on CPAP-TGI through the RTC at flows of 10 and 15 L/min. Group B (n = 4; weight, 30.0 ± 6.2 kg) was placed on CPAP and on CPAP-TGI through the RTC and the SFC at a constant gas flow of 10 L/min. During CPAP alone, no insufflation catheter was inserted into the ETT. During CPAP and CPAP-TGI, the PEEP valve was adjusted to maintain Pcar at 5 cm H₂O, and the FI_O2 was set at 0.6. We applied each step in random order for 30 min; we then obtained arterial blood samples, hemodynamic measurements, and FEX_CO2, and stored outputs from the pulmonary monitor in files 120 s long. At the end of the experiment, sheep were killed with an intravenous injection of KCl. The lungs were excised and inspected.

Data Analysis

All flow, airway pressure, and esophageal pressure signals were analyzed using a data analysis software (Computo; Elekton, Agliano Te., Italy). Volume tracings were obtained by integration of the flow signal. We inspected the recordings obtained during airway occlusions on PS ventilation from which we obtained: (1) the end-inspiratory plateau pressure of the airways (Paw,i) and of the pleura (Ppl,i), (2) the end-expiratory plateau pressure of the airways (Paw,e) and of the pleura (Ppl,e), and (3) the inspiratory VT. We judged the adequacy of the plateaus indicating relaxation by visual inspection. Any plateau that was shorter than 0.25 s was discarded (14). We then computed the static compliance of the respiratory system (CRS) as VT/(Paw,i  Paw,e), of the chest wall (CCW) as VT/(Ppl,i  Ppl,e), and of the lung (CL) as 1/(1/CRS  1/CCW).

We then analyzed the files recorded during CPAP and CPAP-TGI (Figure 2). During CPAP-TGI, the continuous flow of gas from the catheter led to a constant offset in the flow signal recorded at the proximal opening of the ETT. This resulted in an error from a drift in the volume tracing. The flow offset was obtained as the slope of the volume drift over 120 s and was subtracted from the flow signal. We then obtained flow and volume tracings that were corrected for the effect of insufflated gas.

View larger version (11K): [in this window] [in a new window]   Figure 2.   Representative recordings of airway opening pressure (Pao), flow (), and pleural pressure (Ppl) during CPAP alone and during CPAP-TGI at 10 L/min of insufflation flow through the RTC. The flow of gas from the RTC results in a negative offset in the flow signal at the airway opening. A higher Pao was set during insufflation through the RTC, compared with CPAP alone, but the end-expiratory Ppl was the same.

We examined seven nonconsecutive breaths in each file. For each breath, we measured VT, the duration of inspiration (TI), calculated from the corrected flow tracing, the duration of respiratory cycle (Ttot), and the mean airway opening pressure (Pao), defined as the average airway pressure value during Ttot. We computed respiratory rate (RR) as 60/Ttot and VE as RR · VT. For each analyzed breath, we identified the inspiratory deflection on the pleural pressure tracing, indicating the end of expiration and the beginning of the inspiratory effort, and we measured the end-expiratory pleural pressure (Ppl,ee). We then obtained the pressure time product of the respiratory system (PTP) using a method modified after Sassoon and colleagues (15). Starting from Ppl,ee, we integrated the area subtended by the pleural pressure signal versus time up to the end of TI to obtain the pressure time product of the lung (PTPL). We estimated the change in elastic recoil pressure of the chest wall (Pel,CW) as CCW/VT, and obtained the pressure time product of the chest wall (PTPCW) as Pel,CW · TI/2. We added PTPCW to PTPL and we finally multiplied this sum by RR, obtaining PTP. We obtained the inspiratory work of breathing (WOB) of the respiratory system according to Agostoni and colleagues (16): starting from Ppl,ee, we integrated the area subtended by the pleural pressure signal versus volume and by the static curve of the chest wall. Work of breathing was obtained per single breath (WOB/b), per minute (WOB/min) as WOB/b · RR, and per liter (WOB/L) as WOB/min/VE. We computed the mean of seven breaths for PTP, WOB/b, WOB/min, WOB/L, VT, VE, and RR.

EX was averaged over 20 s, we then calculated the CO₂ production (CO₂) as FEX_CO2 · EX, and the estimated expired CO₂ fraction (FE_CO2) as _CO2/VE. We calculated the total physiologic dead space fraction (VD/VT) from Enghoff's modification of Bohr's equation, and VD as the product of VD/VT and VT.

Statistical Analysis

All data are expressed as mean ± standard deviation. Data obtained before and after OA infusion were compared using paired t test analysis. For each of the two groups, data obtained during CPAP were compared with data obtained during CPAP-TGI using two way analysis of variance. When a statistically significant difference was detected, the between-treatments variance was partitioned into two orthogonal contrasts (17). In Group A, we studied separately the effect of insufflation (10 and 15 L/min versus CPAP alone) and the effect of the two different levels of flow (10 L/min versus 15 L/min). In Group B, we studied separately the effect of insufflation (RTC and SFC versus CPAP alone) and the effect of catheter design (RTC versus SFC) at the same flow rate. A p value < 0.05 was considered significant.

	RESULTS

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Lung Injury

Data obtained before (Pre-OA) and after (Post-OA) OA infusion for all animals are shown in Table 1. OA infusion led to a fall in Pa_O2 (p < 0.01), an increase in Pa_CO2 (p < 0.01), and a decrease in pH (p < 0.01). After OA infusion, VT decreased (p < 0.01), whereas RR increased (p < 0.01). We observed no changes in VE. After OA infusion, Crs and CL decreased significantly by 63% (p < 0.01) and by 76% (p < 0.01) of Pre-OA values, respectively, whereas CCW was not significantly affected (0.062 ± 0.024 L/cm H₂O Pre-OA, 0.072 ± 0.044 L/cm H₂O Post-OA). After OA-induced lung injury, we observed no changes in CVP, Ppaw, and (Pre-OA values were 3.6 ± 2.1 mm Hg, 7.2 ± 2.8 mm Hg, and 3.0 ± 0.8 L/min, respectively), whereas there was a significant increase in Ppa from 14.4 ± 2.7 to 19.3 ± 3.6 mm Hg (p < 0.01) and a decrease in Pa from 112.2 ± 10.6 to 85.9 ± 22.7 mm Hg (p < 0.01). At autopsy, the lungs appeared edematous and all pulmonary lobes appeared involved by the injury process with less than 5% of the external lung surface spared. The airways were filled with foamy and bloody secretions.

Effect of Insufflation

When compared with CPAP alone, during CPAP-TGI we found significantly lower VD/VT (p < 0.01) and VD (p < 0.01) in Groups A (Table 2) and B (Table 3). In both groups, CPAP-TGI resulted in significant (p < 0.01) decreases in VE, VT, and RR, compared with CPAP.

During CPAP-TGI, we observed significant decreases in PTP (p < 0.01), in WOB/b (p < 0.01), and in WOB/min (p < 0.01) when compared with CPAP alone in Groups A and B (Table 4). Statistically significant decreases were observed also in WOB/L in Group A (p < 0.01) and in Group B (p < 0.05) (Table 4).

In both groups, CPAP-TGI resulted in a statistically significant decrease in Pa_CO2 (p < 0.05) and in an increase in pH (p < 0.01) when compared with CPAP, with no statistically significant difference in Pa_O2. After insufflation, there was no statistically significant difference in hemodynamic variables (Tables 2 and 3). We found no significant differences in Pcar and in Ppl,ee between CPAP and CPAP-TGI through the RTC and through the SFC (Tables 2 and 3).

Effect of Insufflation Flow and of Catheter Design

In Group A, we detected no statistically significant differences in gas exchange or in ventilatory and hemodynamic variables between gas flows of 15 and 10 L/min (Table 2), using the RTC. We found no significant differences in WOB and in PTP between the two flows (Table 4). In Group B, VD/VT, VD, and VE (Table 3), together with WOB/b, WOB/min, and PTP (Table 4), tended to be lower with the SFC than with the RTC, but the differences did not reach the statistical significance. No significant difference between the two catheters in gas exchange or in hemodynamic variables was observed (Table 3). In Group A, at constant Pcar and Ppl,ee, Pao was higher during CPAP-TGI than during CPAP (p < 0.01). There was a significant increase in Pao when insufflation flow was increased from 10 to 15 L/min (p < 0.01). In Group B, at constant Pcar and Ppl,ee, Pao was the highest with the RTC, followed by CPAP alone and CPAP-TGI with the SFC (p < 0.01).

	DISCUSSION

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We have shown that, compared with CPAP, CPAP-TGI decreased VD, VE, WOB, and PTP in sheep with OA-induced lung injury. During CPAP-TGI, Pa_CO2 decreased with no change in Pa_O2. In this animal model, we found no additional benefits from raising insufflation flow from 10 to 15 L/min during CPAP-TGI with the RTC.

Lung Injury

We increased Ppaw to enhance the formation of pulmonary edema. This method has been shown to result in stable gas exchange and lung mechanics 90 min after the OA infusion (18). Our method of OA infusion resulted in a significant decrease in Pa_O2 and CL at a relatively low dose of OA (0.06 ml/kg), with a homogeneous appearing lung injury at autopsy. The pulmonary lesions from OA-induced lung injury are often patchy (19) from uneven distribution of OA (20). Our method disperses OA into small droplets, likely resulting in a more homogeneous distribution in the lungs.

The breathing pattern during PS ventilation was significantly altered after lung injury. There was a substantial increase in RR and a decrease in VT, likely because of decreased CL and CRS.

Effect of Catheter Design and Insufflation Flow on VD

Enhanced removal of CO₂ during TGI is commonly ascribed to washout of proximal VD, but turbulent gas mixing distal to the tip of the catheter has also been suggested (6). This mechanism can account for the lower VD/VT found in healthy animals by Nahum and colleagues (8) using a SFC, compared with an inverted flow catheter. The distal effect of TGI through a SFC has been observed by the same investigators also in animals with OA-induced lung injury (12). In our study, the VD volume with the SFC was only slightly smaller than the RTC and the difference was not statistically significant. However, the observed trend to lower RR, VE, WOB, and PTP with the SFC suggests a slightly higher efficacy of this catheter. It is possible that a larger sample size in Group B would have allowed us to detect significant differences.

We found no additional decrease in VD from increased insufflation flow through the RTC. This finding is in agreement with the results of Nahum and colleagues (8), who observed no additional decrease in VD when increasing gas flow from 10 to 15 L/min with both their SFC and their inverted catheter.

Effect of TGI on Ventilation and Effort of Breathing

TGI resulted in a decrease in VE with decreases in both VT and RR, as also found by Long and colleagues (21) in anesthetized dogs. In patients with COPD, TGI leads to a decrease in VT, but no change in RR (2, 3). The effect of TGI on VE can be ascribed to a response to the decrease in VD (22) and to a reduced respiratory drive from lower Pa_CO2.

In OA-induced lung injury, the efficacy of TGI on CO₂ removal is attenuated because of increased alveolar VD (18). We observed a significant reduction in VE with TGI, which compared well with the decreases in VE found by Long and colleagues (21) in healthy dogs with ventilatory failure induced by muscle relaxants. Three factors may account for the relatively high efficiency of TGI in our study. First, the proximal VD was probably high because we used adult size ETTs as sheep have large tracheas. Second, the effect of the washout of proximal anatomic VD on CO₂ removal was probably enhanced because our sheep breathed at low VTs, with a relatively high VD/VT (23). Third, our sheep developed hypercapnia after lung injury, which might have magnified the effect of TGI on VE. In animals with OA-induced lung injury, TGI is more effective during hypercapnia than during normocapnia (24).

The effect of TGI on effort of breathing is a balance between decreased VE requirement and increased breathing work load imposed by the apparatus. In our study, the decrease in VE with TGI corresponded to significant decreases in both PTP and WOB. This can be partly ascribed to the balloon CPAP system we adopted, which had no valves and was designed to minimize the breathing work load imposed by the circuit (13). The effects of TGI on PTP and WOB could have been different if we had delivered CPAP using a mechanical ventilator. Under these conditions, additional inspiratory effort is required to overcome the insufflation flow and trigger the ventilator valves (7).

The use of a catheter positioned in the airways increases the resistive work load and reduces the effectiveness of TGI in lowering WOB. Nevertheless, TGI effectively reduced PTP and WOB, even though the catheter was inserted in the ETT only during CPAP-TGI and not during CPAP alone.

PTP and WOB measurements can be affected by the presence of expiratory muscle contraction, which cannot be detected by pleural pressure measurement alone. Gastric pressure recording can unmask expiratory activity (25) and can allow the estimation of diaphragmatic WOB and PTP. We did not measure gastric pressure. However, the absence of end-expiratory flow (Figure 2) suggests that the presence of active expiratory effort at end expiration was unlikely.

Effect on Pa_O2

TGI through SFCs is known to result in a flow-dependent increase in lung volume from a buildup of back pressure by the insufflation gas (8, 9). Unless lung volume is kept constant by reducing applied external PEEP, Pa_O2 can rise (18). In contrast, the RTC was designed to avoid back pressure from TGI. A venturi mounted on its tip provides a flow-dependent decrease of pressure near the carina (10). External PEEP must be increased to prevent decreases in lung volume. During CPAP and CPAP-TGI, we adjusted PEEP to maintain Pcar constant at 5 cm H₂O. Although we did not measure lung volumes directly, Ppl,ee was not significantly different between CPAP and CPAP-TGI at different flows and with the two catheters. This finding suggests that major changes in end- expiratory lung volumes were probably avoided in this protocol. The lack of statistically significant differences in oxygenation between CPAP-TGI and CPAP in both groups may be related to the stability of lung volumes during CPAP-TGI.

Limitations and Clinical Implications

PTP and WOB are commonly used indexes of inspiratory effort (15, 16). The decrease in PTP and WOB during CPAP-TGI suggests that TGI can increase tolerance to unassisted spontaneous breathing in ALI. Sheep with barotrauma-induced severe lung injury treated with CPAP-TGI were successfully weaned to room air at normocapnia, whereas a group treated with CPAP alone developed lethal hypercapnia (26). Early resumption of spontaneous unassisted breathing may limit diaphragm weakness related to mechanical ventilation (27) and lead to improved outcome.

We believe that the RTC can be beneficial during CPAP-TGI because it prevents hyperinflation at all gas flows. Importantly, the RTC effectively removes secretions from the ETT, as seen in mechanically ventilated sheep (11), and reduces/ eliminates the need for tracheal suctioning. We believe these advantages could offset a lower efficacy of the RTC on dead space and ventilatory needs compared with the SFC, but further research is required to confirm this hypothesis.

Our findings cannot be extrapolated to adult humans. The large VD/VT and the relatively high anatomic dead space of this model may have magnified the results of this study. Further studies are needed to explore the effectiveness of CPAP-TGI in spontaneously breathing patients with ALI.

Our results suggest that TGI can be combined with CPAP in ALI to reduce ventilation and decrease effort of breathing.