INTRODUCTION

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Despite advances in the design and therapeutic use of conventional mechanical ventilation in acute pediatric respiratory failure, ventilator-induced lung injury remains a major concern. This is especially pertinent in patients who require "high" airway pressures for adequate oxygenation. In such individuals, high-frequency oscillatory ventilation (HFOV) offers an attractive strategy of maintaining a higher mean airway pressure with less cyclic volume and pressure loading of lung units. In fact, in pediatric patients with respiratory failure, Arnold and coworkers (1) demonstrated that HFOV was associated with improved oxygenation acutely and with a reduced supplemental oxygen requirement at 30 d. HFOV has been used in a variety of clinical situations, including neonatal respiratory distress syndrome, congenital diaphragmatic hernia, acute respiratory distress syndrome (ARDS), and persistent air leak syndrome (2).

Although beneficial from the standpoint of oxygenation and reduced cyclic stress on the lungs, the decreased tidal volume during HFOV may result in inadequate ventilation. To improve carbon dioxide elimination, the clinician may increase the forcing amplitude (P) or change the ventilatory frequency in an attempt to increase tidal volume and thereby improve ventilation. Additionally, a strategy of permissive hypercapnia may be employed (5), as long as acidosis does not become "severe." Despite these measures, hypercapnia may be refractory because of limitations in the volume output of currently available oscillators and, thus, require a change to conventional mechanical ventilation. This is especially problematic in "larger" patients.

Heliox has a reduced density (and hence lower resistance in turbulent flow and more favorable diffusion characteristics) when compared with oxygen-enriched air. Thus, we postulated that heliox would improve gas exchange during HFOV. Because heliox is known to decrease resistance to flow in narrow airways (6), it has been used in nonintubated pediatric populations for postextubation stridor (7, 8) and croup (9). Additionally, heliox has been studied and shown to have beneficial effects in children with bronchiolitis (10). The use of heliox in children with asthma has been investigated as well, although two published trials reached conflicting conclusions regarding benefit (11, 12). In a small study of conventionally ventilated adults with status asthmaticus, heliox reduced airway pressure and carbon dioxide retention (13).

In a recent case series of five pediatric patients, Winters and coworkers (14) reported a marked improvement in ventilation with the use of heliox during HFOV. However, to our knowledge, the effect of heliox on gas exchange during HFOV in animals or humans with acute lung injury has not been studied prospectively. The goal of our study was to examine the effects of heliox on gas exchange and hemodynamics in an animal model of acute lung injury during high-frequency oscillatory ventilation. We hypothesized that when compared with oxygen-enriched air, heliox would improve both carbon dioxide elimination and arterial oxygenation.

	METHODS

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Animal Preparation

Eleven swine (4.5-7.0 kg) were anesthetized and instrumented in a manner previously described by Cheifetz and coworkers (15). After induction of anesthesia, the animals were orotracheally intubated and conventionally ventilated. A median sternotomy was performed. Hemodynamic and blood gas monitoring was facilitated by placement of femoral artery and internal jugular vein catheters. An ultrasonic flow probe was placed around the pulmonary artery. Acute lung injury (A-a gradient > 400 mm Hg; decrease in dynamic compliance of > 50%) was created by repeated saline lavage (16, 17). After creation of lung injury, the chest was closed. Then, the animal was transitioned to a Sensormedics 3100B high-frequency oscillator with fraction of inspired oxygen (FI_O2) 1.0 and frequency 10 Hz. P and mean airway pressure () were adjusted to obtain Pa_CO2 55-80 mm Hg and Pa_O2 > 100 mm Hg. After a period of stabilization, the FI_O2 was weaned to 0.6.

Interventions and Measurements

Ten minutes after weaning the FI_O2 to 0.6 (the remaining 40% nitrogen), an arterial blood gas (ABG) was obtained and hemodynamic data were recorded. The animal was then switched to 60% oxygen/ 40% helium (heliox40) and allowed 10 min to stabilize before obtaining data. Subsequently, the animal was changed to 40% oxygen/60% helium (heliox60) and allowed 10 min to stabilize before data collection. , P, and frequency were held constant as the gas mixture was changed. After data collection with heliox60, the animal was returned to 60% oxygen/40% nitrogen and data were collected. The second data set with oxygen-enriched air served to ensure that the Pa_CO2 returned to baseline after the removal of heliox. The cycle of changing gas mixture from oxygen-enriched air to heliox40 to heliox60 and back to oxygen-enriched air was performed two to four times per animal.

Bench Tests

To elucidate the physical effects of reducing gas density during HFOV, we performed two bench tests utilizing an Ingmar PMG 3000 test lung. In our animal study, when carrier gas was changed from nitrogen to helium and the power setting held constant, P dropped by 2-3 cm H₂O. To maintain P, power was increased. We postulated that the decrease in P occurred secondary to decreased resistive forces in the airways. To test this hypothesis, we connected the oscillator to the test lung, held the power constant, varied the test lung resistance settings, and recorded the corresponding P measured by the ventilator.

To investigate whether heliox increases tidal volume delivery, we placed a CO₂SMO Plus pneumotachometer between the oscillator circuit and the test lung. The CO₂SMO Plus contains built-in calibration for both oxygen-enriched air and heliox. was held constant. For three values of P at 8 Hz and 10 Hz, we measured tidal volume per oscillation with oxygen-enriched air and heliox60. For each parameter set, 580 tidal volume measurements were made with each gas mixture.

Data Analysis

Animal data were analyzed using ANOVA with repeated measures (18) and Student's t test with Bonferroni correction for multiple comparisons (19). The CO₂SMO Plus tidal volumes were compared by the unpaired Student's t test.

	RESULTS

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Eleven animals with a weight range of 4.5-7.0 kg were studied. Data from 32 trials were collected from the 11 animals (2.9 trials per animal). In four of these trials, Pa_CO2 did not return to baseline at the end of the trial, and thus, the data sets from those trials were discarded. In these discarded cases, sodium bicarbonate was administered just prior to the start of the trial, and Pa_CO2 was significantly higher at the start than at the end of the trial. Data from the remaining 28 trials were analyzed, each with equal weight. Although all animals did not yield an equal number of data sets, every animal demonstrated improved ventilation with heliox. The average was 14.5 ± 0.3 cm H₂O (range 13-20 cm H₂O), and average P was 30.8 ± 1.3 cm H₂O (range 20-45 cm H₂O). Ten hertz was the frequency used for every trial except two, which required a frequency of 8 Hz in order to obtain a baseline Pa_CO2 of less than or equal to 80 mm Hg. In three animals, we performed a sustained inflation maneuver to improve oxygenation during the stabilization period.

Carbon Dioxide Elimination

We compared the Pa_CO2 values obtained after 10 min of ventilation with each of the three gas mixtures. The mean Pa_CO2 values are summarized in Table 1. Compared with oxygen- enriched air, heliox40 reduced Pa_CO2 by 10.5 mm Hg, and heliox60 reduced Pa_CO2 by 20.3 mm Hg. The Pa_CO2 after ventilation with the second oxygen-enriched air mixture did not differ significantly from the trial baseline.

Oxygenation

We examined Pa_O2/FI_O2 in order to compare oxygenation with a varying FI_O2. Gas composition had a significant effect on Pa_O2/FI_O2 (p = 0.01) with heliox40 resulting in the best oxygenation. As summarized in Table 2, Pa_O2/FI_O2 improved with heliox40 by 43 mm Hg when compared with oxygen-enriched air. Pa_O2/FI_O2 with heliox60 was greater than oxygen-enriched air by 27 mm Hg, although this difference was not significant. Oxygenation tended to improve over the duration of each trial (by a mean of 24 mm Hg), though this difference was not significant. The trend of improving oxygenation with time within each animal reached significance when we compared Pa_O2/FI_O2 across trials (p = 0.0001). ANOVA revealed that the oxygenation improvement for heliox40 within each trial remained significant when the factor of time was excluded. The improvement in oxygenation was greater than that expected to occur secondary to a decrease in Pa_CO2 by the alveolar gas equation.

Hemodynamics

Each animal experienced a minimal but progressive decline in cardiac output and blood pressure over time. Compromised hemodynamics are not surprising given the repeated episodes of hypoxia inherent in saline lavages, the relatively high mean airway pressures associated with high-frequency oscillatory ventilation, and the respiratory acidosis of permissive hypercapnia present in our study design. With respect to the effect of gas mixture, no significant difference in cardiac output (p = 0.13), heart rate (p = 0.72), or systolic blood pressure (p = 0.18) was found. However, there was a trend toward modestly decreased cardiac output and systolic blood pressure with heliox60 compared with oxygen-enriched air. This effect was significant in a post hoc analysis of trials with a central venous pressure (CVP)  3 mm Hg (see Table 3).

Bench Tests

Investigating the effect of airway resistance on P as measured by the oscillator for a fixed power setting, we found that as resistance on the Ingmar test lung was decreased, measured P decreased (see Table 4). Tidal volume delivery as measured by the CO₂SMO pneumotachometer increased significantly with heliox60 compared with oxygen-enriched air (see Table 5).

	DISCUSSION

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Heliox has been examined previously in healthy animals using high-frequency ventilation and shown to improve carbon dioxide elimination minimally (20, 21). However, these studies differ from ours in two important ways. First, they were done in normocapnic animals with noninjured lungs. Second, these studies held tidal volume fixed, whereas our study holds pressure oscillation (P) (as well as mean airway pressure and frequency) fixed. Our investigation of the use of heliox during HFOV in a piglet model of acute lung injury revealed significant reductions in arterial carbon dioxide tensions with 40% and 60% helium concentrations, and a modest improvement in oxygenation with 40% helium. A post hoc analysis found modest negative hemodynamic effects associated with 60% helium when CVP was  3 mm Hg. As outlined below, we believe that the principal mechanism responsible for improved gas exchange with heliox is increased tidal volume delivery per pressure oscillation presented at the endotracheal tube. Further, we hypothesize that the increased tidal volume is a consequence of decreased resistive forces.

Bench Tests/Tidal Volume Delivery

In our bench experiment, we found that decreasing resistance in the test lung resulted in a decrease in P as measured by the oscillator. By analogy, if the properties of the airway are held constant, but the gas density is lowered to result in decreased resistive forces (as with changing carrier gas from nitrogen to helium), a similar effect would be expected. Indeed, this was seen in our animal experiments. With a reduction in resistive forces, more energy is transmitted distally to lung segments. Hence, a given amount of oscillatory energy (power setting on the oscillator) is distributed more evenly over a larger volume of gas and proximal pressure oscillation falls (by Boyle's law). The power setting must be increased in order to hold proximal P constant. A similar phenomenon is seen clinically when endotracheal tube size is increased. As airway resistance falls with a larger diameter tube, power must be increased to maintain the same proximal P. The decrease in P that is seen both when test lung resistance is decreased and when the gas mixture is changed to heliox provides supporting evidence that resistive forces are reduced with heliox during HFOV.

If proximal P is held constant, as was done in our animal protocol, reducing resistance by decreasing gas density should result in a larger tidal volume delivery per oscillation. This theory is supported by the tidal volume measurements made by the CO₂SMO Plus pneumotachometer. As gas density was lowered, there was a marked increase in tidal volume delivery. The two bench test observations can be related by considering the fact that power is the time derivative of work, which equals P V, where P is pressure and V is volume. Lowering gas density results in larger tidal volume delivery; thus, for a given pressure oscillation, P V becomes larger. Hence, the power requirement is increased.

To further explain the relative tidal volume delivery with heliox verses oxygen-enriched air, we measured the frequency response of chest wall excursion in a modification of a method described by Smith and Lin (22). After injury in two animals, an impedance band (Respibands; Ambulatory Monitoring, Inc., Ardsley, NY) was placed around the chest, and P were held constant, and oscillation frequency was varied with each of the three source gas mixtures. The impedance band output, which has a flat frequency response below 25 Hz, was recorded with a sampling frequency of 500 Hz. The amplitude of the impedance band output oscillation, which is linearly proportional to oscillation of the chest cross-sectional area (23), was recorded as a function of frequency for the three different gas mixtures.

Figure 1 depicts the frequency response of chest wall excursion for the three gas mixtures in one animal. Similar results were obtained for the second animal. A resonance peak is found near 7.0 to 7.5 Hz. Across the frequency range of 5 to 12 Hz, heliox40 produced an increase in oscillation amplitude of 15-30%, whereas heliox60 resulted in an increase of 35-60% when compared with oxygen-enriched air. It was not possible to convert the chest wall oscillation to a corresponding tidal volume. As an increase in diaphragmatic movement also likely occurs with heliox, the percentage increase in oscillation of chest cross-sectional area is a conservative estimate for the increase in delivered tidal volume.

View larger version (63K): [in this window] [in a new window]   Figure 1.   Relative oscillation amplitude of cross-sectional area of chest. Note marked increase in chest oscillation with increasing concentration of helium. Paw, 16 cm H2O; P, 38 cm H2O; resonance frequency near 7.0-7.5 Hz.

Note that the resonance frequency did not change significantly with changing gas density, indicating that the inertance of the gas within the airways is negligible when compared with the inertance of the lungs and chest wall. Thus, changing the density of the gas mixture (and its contribution to the total inertance of the system) is unlikely to change the delivered tidal volume through a mass effect. Instead, tidal volume increases with heliox because resistive forces (rather than inertial forces) are reduced as a consequence of the lighter density.

Gas Exchange with Heliox in HFOV

Heliox may alter gas exchange during HFOV by a number of mechanisms. Because helium is less dense than nitrogen, the frictional forces in turbulent flows are reduced with heliox as compared with oxygen-enriched air (6). Additionally, with heliox, the calculated Reynolds number is lower for any given velocity, which may change regions of turbulent flow to laminar flow, reducing resistance and energy dissipation. As resistive forces and energy dissipation are decreased, the tidal volume per oscillation at constant input P increases. Several investigators have shown that carbon dioxide elimination increases with both increasing tidal volume and increasing frequency (assuming tidal volume is constant as frequency is increased). In fact, the effect of increasing tidal volume seems to be dominant (24).

The precise mechanisms of gas exchange during HFOV are complex and incompletely understood (24, 25). In theory, because of its lower density, heliox may favorably alter gas exchange via pendulluft effect, inhalation/exhalation flow asymmetry, Taylor dispersion, and molecular diffusion. However, our investigation did not examine how these mechanisms are altered with heliox.

Clinical Implications

Theoretical considerations predict that the use of heliox during HFOV will result in increased tidal volume delivery per unit pressure oscillation presented at the endotracheal tube. The increased carbon dioxide clearance seen in our animals as well as the tidal volume measurements made by pneumotachography and plethysmography are consistent with this prediction. Although improved carbon dioxide clearance may be desirable in some clinical scenarios, such as extreme hypercapnic acidosis, larger delivered tidal volumes mean greater lung tissue deformations (i.e., larger strain amplitudes and strain rates) and could increase the risk of ventilator-induced lung injury. Additionally, hypercapnic acidosis may be protective against lung injury (26), and, thus, improved carbon dioxide clearance may be harmful in some circumstances. However, heliox may prove to be a useful therapy during HFOV in patients who cannot be adequately ventilated despite maximal P. The use of heliox in such a setting would serve as a surrogate for increasing P when such an increase is not technically possible.

Rather than being used to improve carbon dioxide removal as was done in this study, the clinician may inquire if heliox could be used to reduce the P required for a given rate of carbon dioxide clearance. Although this is likely, P as measured at the proximal end of the endotracheal tube is a meaningless indicator of the risk for barotrauma when comparing ventilation with gas mixtures of different densities (or, by analogy, ventilation through different size endotracheal tubes). With regard to lung injury what matters is intrapulmonary strain. For equivalent tidal volumes, intrapulmonary strain would be on average equal whether using heliox at a lower P or oxygen-enriched air at a higher P. However, it is theoretically possible that heliox may alter regional ventilation in such a manner that with a reduced P, some lung units, specifically those located relatively proximal on the tracheobronchial tree, may experience lower local tidal volume oscillations when compared with ventilation with oxygen-enriched air. We stress that we did not measure the effect of gas mixture on regional ventilation, and any proposal that a reduction in proximal P may be beneficial in terms of reducing stress in proximal lung units is entirely speculative. On the contrary, it is possible that regional stresses in some areas would be increased, rather than decreased, with heliox.

Study Limitations

A limitation of our study is that the lung injury imposed on the animals may not have been severe enough to model clinical ARDS. However, given the need to wean the animals to 60% and then 40% oxygen, a more severe lung injury model was not possible. Also, as time increased, oxygenation improved and hemodynamics deteriorated. The hemodynamic deterioration was unavoidable, and the improvement in oxygenation was merely a product of lung recruitment by HFOV. However, our statistical analysis allowed for conclusions to be drawn regarding oxygenation and hemodynamics despite the slowly changing baseline with respect to these variables. Our primary variable of interest, Pa_CO2, was stable as a function of time, and changed only with gas mixture.

With regard to our tidal volume measurements using the CO₂SMO Plus pneumotachometer, it is emphasized that the pneumotachometer is not designed for use during high-frequency ventilation. The frequency response of the device has not been measured by our laboratory, nor is it known whether the frequency response with oxygen-enriched air is the same as with heliox. Consequently, the accuracy of the tidal volume measurements must be viewed with caution. However, although the frequency response of the device with oxygen- enriched air as compared with heliox is unknown, the results of our tidal volume measurements with the CO₂SMO Plus that tidal volume increases with helioxare consistent with our plethysmography data.

Future Investigations

Based upon this investigation, we believe that the mechanism by which heliox improves ventilation is through increased tidal volume delivery. To confirm this hypothesis, a future study will hold tidal volume fixed (as measured by plethysmography) and evaluate gas exchange comparing oxygen- enriched air and heliox. If improved ventilation is seen with heliox when tidal volume is held constant, mechanisms other than improved tidal volume delivery may be involved, and potential clinical applicability may be broadened.

Conclusions

In a piglet model of an acute lung injury with permissive hypercapnia during high-frequency oscillatory ventilation, heliox improved carbon dioxide elimination significantly with only 40% helium, and markedly with 60% helium. Additionally, for gas mixtures with an FI_O2 of 60%, heliox improved oxygenation. The principal mechanism of action responsible for improved gas exchange is concluded to be increased tidal volume delivery with heliox as a result of reduced resistive forces. Given the increased tidal volume delivery, clinical applicability may be limited.