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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Because heliox has a lower density as compared with air, we postulated that heliox would improve gas exchange during high-frequency oscillatory ventilation (HFOV) in a model of acute lung injury. In a prospective, cross-over trial, we studied 11 piglets with acute lung injury created by saline lavage. With initial conditions of permissive hypercapnia (PaCO2 55-80 mm Hg), each piglet underwent HFOV with a fixed mean airway pressure, pressure oscillation, and ventilatory frequency. The following gas mixtures were used: oxygen-enriched air (60% O2/40% N2) and heliox (60% O2/ 40% He and 40% O2/60% He). Compared with oxygen-enriched air, the 40% and 60% helium gas mixtures reduced PaCO2 by an average of 10.5 and 20.3 mm Hg, respectively. A modest improvement in oxygenation was seen with the 40% helium mixture. We conclude that heliox significantly improves carbon dioxide elimination and modestly improves oxygenation during HFOV in a model of acute lung injury. On the basis of test lung data and plethysmography measurements, we also conclude that heliox improves carbon dioxide elimination primarily through increased tidal volume delivery. Although heliox improved gas exchange during HFOV in our model, increased tidal volume delivery may limit clinical applicability.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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 (FIO2) 1.0 and frequency 10 Hz. P and mean airway pressure
(
) were adjusted to obtain PaCO2 55-80 mm Hg and PaO2 > 100 mm Hg. After a period of stabilization, the FIO2 was weaned to 0.6.
Interventions and Measurements
Ten minutes after weaning the FIO2 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 PaCO2 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.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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, PaCO2 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 PaCO2 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 PaCO2
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 PaCO2 values obtained after 10 min of ventilation with each of the three gas mixtures. The mean PaCO2 values are summarized in Table 1. Compared with oxygen- enriched air, heliox40 reduced PaCO2 by 10.5 mm Hg, and heliox60 reduced PaCO2 by 20.3 mm Hg. The PaCO2 after ventilation with the second oxygen-enriched air mixture did not differ significantly from the trial baseline.
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Oxygenation
We examined PaO2/FIO2 in order to compare oxygenation with a varying FIO2. Gas composition had a significant effect on PaO2/FIO2 (p = 0.01) with heliox40 resulting in the best oxygenation. As summarized in Table 2, PaO2/FIO2 improved with heliox40 by 43 mm Hg when compared with oxygen-enriched air. PaO2/FIO2 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 PaO2/FIO2 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 PaCO2 by the alveolar gas equation.
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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).
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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).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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.
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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, PaCO2, 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 FIO2 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.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Ira M. Cheifetz, M.D., Division of Pediatric Critical Care Medicine, Duke University Medical Center; Box 3046, Durham, NC 27710. E-mail: Cheif002{at}mc.duke.edu
(Received in original form June 21, 2000 and in revised form March 27, 2001).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org
Acknowledgments:
The authors wish to thank Mr. Jerry Korten, Director of
Perinatal Product Development, Spacelabs Medical, Inc., for his technical assistance with the chest wall plethysmography measurements, as well as
for his thoughtful comments regarding many of the technical aspects of
this project.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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