Negative-Pressure Ventilation
Better Oxygenation and Less Lung Injury
Francesco Grasso1–4, Doreen Engelberts1, Emma Helm5,6, Helena Frndova1,2, Steven Jarvis2, Omid Talakoub7,
Colin McKerlie1,8, Paul Babyn5,6, Martin Post1,8,9, and Brian P. Kavanagh1–4,9,10
1
Physiology and Experimental Medicine, and Departments of 2Critical Care Medicine and 3Anesthesia, Hospital for Sick Children, Toronto,
Ontario, Canada; 4Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada; 5Department of Radiology, Hospital for Sick
Children, Toronto, Ontario, Canada; 6Department of Radiology, University of Toronto, Toronto, Ontario, Canada; 7Department of Electrical
Engineering, Ryerson University, Toronto, Ontario, Canada; and Departments of 8Laboratory Medicine and Pathobiology, 9Physiology, and
10
Medicine, and the Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada
Rationale: Conventional positive-pressure ventilation delivers pressure to the airways; in contrast, negative pressure is delivered globally to the chest and abdomen.
Objectives: To test the hypothesis that ventilation with negative
pressure results in better oxygenation and less injury than with positive pressure.
Methods: Anesthetized, surfactant-depleted rabbits were ventilated for 2.5 hours in pairs (positive or negative). Tidal volume was
12 ml kg21, normocapnia was maintained by adjusting respiratory
rate, and FIO2 was 1.0.
Measurements and Main Results: Lung injury was assessed with histologic scoring, perfusion using thermodilution (global perfusion),
and injected intravascular microspheres (regional perfusion); and
dynamic computed tomography was used to determine inflation
patterns. Negative pressure was associated with a higher PaO2,
a lower Pa–PETCO2 gradient (despite identical minute ventilation),
and less lung injury. Lung perfusion (global and regional) was similar
with positive and negative pressure. Positive end-expiratory pressure applied to the airway was more efficiently transmitted to the
pleural space than comparable levels of negative end-expiratory
pressure applied to the chest wall; however, the oxygenation associated with any level of end-expiratory lung volume was greater
when achieved by negative versus positive pressure. Dynamic computed tomography suggested that lung distension achieved with
negative pressure is characterized by greater proportions of normally aerated lung (with less atelectasis) during inspiration and at
end-expiration.
Conclusions: Negative-pressure ventilation results in superior oxygenation that is unrelated to lung perfusion and may be explained by
more effective inflation of lung volume during both inspiration and
expiration.
Keywords: lung injury; mechanical ventilation; oxygenation
Inflation of the lung occurs when the difference between pressure inside versus outside the lung overcomes tissue and airway
factors that impede distension. Such transpulmonary pressure
represents the difference between the pressure in the alveolus
(Received in original form July 9, 2007; accepted in final form November 16, 2007)
Supported by the Canadian Institutes of Health Research (CIHR). B.P.K. is the
recipient of a New Investigator Award (CIHR), and a Premier’s Research
Excellence (PREA) award (Ontario Ministry of Science and Technology). M.P. is
the holder of a Canadian Research Chair in Fetal, Neonatal, and Maternal Health.
Correspondence and requests for reprints should be addressed to Dr. Brian P.
Kavanagh, M.B., Department of Critical Care Medicine, Hospital for Sick
Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8. E-mail:
brian.kavanagh@sickkids.ca
This article has an online supplement, which is accessible from this issue’s table of
contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 177. pp 412–418, 2008
Originally Published in Press as DOI: 10.1164/rccm.200707-1004OC on December 13, 2007
Internet address: www.atsjournals.org
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Trials of ventilation have focused on limitation of tidal
volume and setting levels of positive end-expiratory pressure; no further approaches using conventional ventilation
have altered outcome.
What This Study Adds to the Field
Negative-pressure ventilation is fundamentally different
from positive pressure ventilation, and results in better
oxygenation and less lung injury.
(i.e., inside the lung) versus that in the pleural cavity (i.e.,
outside the lung). With positive-pressure ventilation (PPV), the
transpulmonary pressure is increased by making the alveolar
pressure more positive; in contrast, with negative-pressure ventilation (NPV), the transpulmonary pressure is increased by
making the pleural pressure more negative.
In the simplest possible scenario, the lung may be considered
as a uniform, homogeneous, distensible sphere; in such a situation, a given increase in the distending transpulmonary pressure
would result in exactly the same degree of lung distension
whether caused by the alveolar pressure being made more
positive or by the pleural pressure being made equally—but
inversely—more negative. Although the distribution of inflation
may be similar with positive versus negative pressure in normal
lungs, the distribution may be more complex in injured lungs
(1–4).
In the context of acute lung injury, the distribution of open—
or atelectatic—lung units is far from homogeneous (5, 6), as is
the distribution of pleural pressure (7). Such heterogeneity in
regional ventilation has long been recognized, and has been the
rationale for many imaginative therapies, including prone positioning (8), external chest wall compression, perfluorocarbon
administration, and abdominally directed ventilator assist (9).
Although PPV delivering high tidal volumes is known to
cause ventilator-associated lung injury, the effects of comparable tidal volumes generated with negative pressure are unknown.
It is possible that negative pressure, because it is distributed
across a broad surface of the chest wall and abdomen, may
result in more homogeneous distension, which would improve
oxygenation and be less injurious.
We hypothesized that NPV would result in better oxygenation and less lung injury in the surfactant-depleted rabbit; we
found this hypothesis to be true. Compared with PPV, negative
pressure resulted in greater FRC where transpulmonary pressure was similar, and resulted in greater oxygenation where
Grasso, Engelberts, Helm, et al.: Negative-Pressure Ventilation and Lung Injury
FRC was similar. NPV may distend lungs in a fundamentally
different manner to positive pressure, resulting in more homogeneous ventilation, less injury, and superior oxygenation.
METHODS
After institutional ethics approval (conforming to the guidelines of the
Canadian Committee for Animal Care), female New Zealand white
rabbits (2.5–3.5 kg) were used in all experiments. Anesthesia was
induced, and the model of surfactant depletion using saline lavage was
used as previously reported (10). Stable physiologic conditions were
obtained before group allocation, and animals excluded where baseline
inclusion (i.e., hemoglobin, acid-base status, oxygenation, compliance,
hemodynamic status) criteria were not met (10). Five experimental
series were performed.
Series 1: Lung Injury and Oxygenation
During baseline conditions, a Harvard ventilator (Harvard Apparatus,
South Natick, MA) was used. When baseline criteria were satisfied, the
animals were allocated, in pairs, to either a positive- or a negativeventilation strategy (Figure E1 of the online supplement). The ‘‘positive’’
ventilation strategy consisted of the following: VT of 12 ml kg21, FIO2
of 1.0, positive end-expiratory pressure (PEEP) titrated to keep PaO2
between 65 and 130 mm Hg, and respiratory rate titrated to keep PaCO2
between 35 and 45 mm Hg; a pressure-controlled mode was used
(Newport E100i; Newport Medical Instruments Inc., Newport Beach,
CA). The negative-ventilation animal in that pair was ventilated as
follows: VT of 12 ml kg21 and FIO2 of 1.0, and negative end-expiratory
pressure was adjusted to match exactly the PEEP in the corresponding
‘‘positive’’ animal; the respiratory rate was titrated to keep PaCO2
between 35 and 45 mmHg, and the ventilation was performed using
a commercially available device (Hayek 1000; Breasy Medical Equipment Ltd., London, UK) in a custom-made whole-body chamber where
the head and neck protruded through an airtight neck seal. Tidal
volume was measured in all cases using continuous spirometry (Cosmo
8100; Nova Metrix Medical Systems Inc., Wallingford, CT). After
ventilation for 2.5 hours, the animals were exsanguinated under
anesthesia, the lung–heart block removed via sternotomy, and the left
lung inflation fixed (10% neutral buffered formalin) for histologic
scoring, as previously described (11), by a pathologist blinded to group
allocation.
Series 2: Global Pulmonary Perfusion
Eight additional animals were anesthetized and had a pulmonary artery
catheter inserted via the femoral vein. The heart–lung block was exposed by thoracotomy, and the pericardium opened without disturbing
the pleura or diaphragmatic ligaments. The catheter was then advanced
until the tip was in the pulmonary artery, and the chest closed. At the
413
end of the experiment, we visually confirmed the catheter location.
After allocation to either positive or negative -pressure ventilation
(settings as described above) and stabilization, the right ventricular
cardiac output was measured by a 4 Fr thermodilution catheter (Arrow;
7 cm; Reading PA), as previously described (12). Each rabbit was ventilated with positive and negative ventilation. As an additional control,
four animals were ventilated with the above negative-pressure device
that was directed to the chest only.
Series 3: Regional Pulmonary Perfusion
The animal preparation and ventilation were performed as in series 1.
Colored microspheres (NuFlow microspheres; Interactive Medical
Technologies, Irvine, CA) were suspended in a saline/Tween 80 solution (0.05%) by sonication in an ultrasonic bath and were injected via
the external jugular vein. Three different colored microspheres were
injected, one color each at 30, 60, and 90 minutes after the start of
experimental ventilation. Five minutes after the last injection of microspheres, the chest was opened, the inferior vena cava transected, the
pulmonary artery gently flushed with saline, and the heart–lung block
removed. Lung tissue samples collected from the dependent and the
nondependent lung regions were homogenized and the number of
spheres of each color per gram of tissue calculated (13).
Series 4: Transpulmonary Pressures, Lung Volumes,
and Oxygenation
Esophageal pressure, a surrogate for pleural pressure, was measured
using a water-filled conventional feeding tube (8.0 Fr) connected to
a pressure transducer, placed in the lower one-third of the esophagus,
and calibrated as previously described (14). The end-expiratory lung
volume (EELV), a surrogate for functional residual capacity was
measured by occluding the endotracheal tube at end-expiration,
discontinuing ventilation, releasing the occlusion, and measuring the
volume of exhaled gas with a spirometer (Bear Neonatal Volume
Monitor NVM1; Bear Medical Systems, Riverside, CA) until flow
ceased. End-expiratory pressures of 4, 6, 8, and 10 cm H2O were
established for both positive pressure and negative pressure, and the
resulting values for transpulmonary pressure, PaO2, and EELV
recorded. Eight additional measurements were made of end-expiratory
pressure (outside the above range) to capture a broader range of
transpulmonary pressure and EELV.
Series 5: Computed Tomography Scanning
After surfactant depletion, each rabbit was ventilated using both PPV
and NPV alternately (half the group commenced with PPV and half
with NPV). When the ventilation strategy was changed, the lungs were
recruited to clear the lung history. The rabbit was ventilated with
a targeted transpulmonary pressure of 5 cm H2O at end-expiration and
25 cm H2O at peak inspiration. Arterial blood gas was taken and
ventilation was maintained for 15 minutes before scanning to ensure
Figure 1. PaO2 was similar in both groups at baseline, and
during the surfactant-depletion process. After group allocation, the PaO2 was significantly greater in negativeversus positive-pressure ventilation throughout the remainder
of the experiment. *P , 0.05.
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stable conditions. When the animal was stable, the respiratory rate
was changed (TI 5 1.5 s, TE 5 6 s; for positive and negative) to allow
comparisons of the two forms of ventilation at end-expiration.
Dynamic computed tomography (CT) was performed on an eightdetector multislice CT scanner (GE Lightspeed; GE Medical Systems,
Milwaukee, WI). Imaging consisted of simultaneous acquisition of
four slices (one volume) every 0.2 seconds. A radiopaque marker was
inserted at peak inspiration, to mark the start of an entire respiratory
cycle.
An automated software program was developed that allowed
segmentation of the lungs from the soft tissues of the thorax using
a wavelet-based algorithm for edge detection, and aeration versus
atelectasis was defined as follows: aerated lung (2900 to 2500 Hounsfield units [HU]) and atelectatic lung (2300 to 1200 HU) (15).
Data Acquisition and Statistical Analysis
Data were acquired and processed using the computerized software
ANADAT/LABDAT (version 4, McGill University, Montreal, PQ,
Canada), and are presented as mean 6 SD or proportions. Groups
were compared using unpaired t tests or analysis of variance, and
statistical significance was inferred where P , 0.05.
RESULTS
Series 1: Gas Exchange and Lung Injury
Oxygenation was similar in both groups (n 5 9, each group)
during baseline ventilation (Figure 1), but was significantly
greater with NPV versus PPV throughout the experimental period. Respiratory rate and PaCO2 were similar in both groups,
and did not significantly change in either group over the course
of the experiment (Table 1); however, the differences between
the arterial and end-tidal PCO2 were similar at baseline, and
were greater in the positive-pressure group throughout the experimental period (Figure 2).
The composite histologic lung injury score was significantly
lower in NPV versus PPV (Figure 3). The details of the individual elements of the histologic injury—alveolar versus airway—
are provided in Table 2.
The wet-to-dry lung weight ratios (positive vs. negative:
10.3 6 1.6 vs. 9.7 6 0.7), as well as the protein concentration
in the bronchoalveolar lavage fluid (positive vs. negative: 5.8 6
2.1 vs. 4.2 6 1.8), were similar in both groups, consistent with
protective effects of positive airway pressure against alveolar
edema (16).
Series 2: Global Pulmonary Perfusion
Figure 2. The gradients between PaCO2 and PETCO2 were similar in both
groups at baseline, and the minute ventilation was identical in both
groups throughout. After group allocation, the gradients were significantly less in negative- versus positive-pressure ventilation throughout the remainder of the experiment, reflecting less physiologic dead
space with negative-pressure ventilation. *P , 0.05.
lung perfusion was significantly greater than with the PPV
(Figure 4).
Series 3: Regional Pulmonary Perfusion
Two groups (n 5 3 in each) of animals were studied to examine
the regional distribution of perfusion in negative versus positive
pressure, by examining the distribution of injected microspheres,
where perfusion is proportional to the number of spheres per
gram of sampled lung tissue (13). The relative (i.e., ratio of)
perfusion between the upper (nondependent) and lower (dependent) lung regions was similar in the positive- versus negativepressure groups (Figure 5).
Series 4: Transpulmonary Pressures, Lung Volumes,
and Oxygenation
PPV (n 5 6) or NPV (n 5 5) was used to determine the relationship among applied expiratory pressure, transpulmonary
pressure, FRC, and oxygenation over a range of applied positive
and negative end-expiratory pressures. At each of these levels,
Eight animals were ventilated sequentially with PPV and NPV
using a whole-body device. Global lung perfusion was not different between PPV versus NPV (Figure 4). Because a wholebody device was used, the lung perfusion was measured in an
additional group (n 5 4) in which negative pressure was applied
using a device applied only to the chest (Curiass; Breasy Medical
Equipment, Ltd., London, U.K.) and positive pressure applied in
the usual way; with the negative-pressure chest device, the global
TABLE 1. RESPIRATORY RATE AND PaCO2 VALUES
0 min
Respiratory rate,
Positive
Negative
PaCO2, mm Hg
Positive
Negative
30 min 60 min 90 min 120 min 150 min
min21
25 6 4 22 6 3 20 6 7 20 6 8
23 6 1 23 6 2 21 6 3 18 6 4
21 6 5
19 6 4
20 6 6
17 6 5
39 6 8 37 6 8 37 6 4 40 6 2
40 6 6 36 6 5 36 6 4 34 6 5
42 6 5
37 6 3
39 6 4
37 6 3
There were no between-group differences in respiratory rate or PaCO2 at any
time.
Figure 3. Lung injury histology score was calculated in both groups,
and was significantly less after negative-pressure ventilation (*P ,
0.05). For comparison, normal lungs would have histology scores in
the range of 0–2.
Grasso, Engelberts, Helm, et al.: Negative-Pressure Ventilation and Lung Injury
415
TABLE 2. HISTOLOGIC FINDINGS
Airspaces
PPV
NPV
Airways
Inflammatory
Cells (Septal)
Inflammatory
Cells (Alveolar)
Alveolar
Edema
Hyaline
Membranes
Epithelial
Changes*
Inflammatory
Cells
Interstitial
Edema
4.5 6 0.5†
3.8 6 0.04
4.3 6 0.7†
3.3 6 0.7
2.8 6 0.4
2.2 6 0.9
4.1 6 0.7†
3.3 6 0.8
4.1 6 0.9†
3.0 6 0.6
2.5 6 0.3
1.8 6 1.0
2.3 6 0.5
1.2 6 1.0
Definition of abbreviations: NPV 5 negative-pressure ventilation; PPV 5 positive-pressure ventilation.
* Abnormalities include flattening, hyperplasia, or sloughing of the epithelium.
†
P , 0.05, versus NPV.
conditions were stabilized for 30 minutes, and the corresponding transpulmonary pressures and PaO2 measured, followed by
measurement of the EELV. The transpulmonary pressure generated by negative end-expiratory pressure was consistently less
than that generated for a comparable level of PEEP (Figure
6A). For given levels of transpulmonary pressure, the overall
EELV achieved was consistently greater when distension was
with negative versus positive pressure (Figure 6B). Finally, for
a given level of EELV, the resultant PaO2 (FIO2 5 1.0 in all
cases) was greater where the EELV was achieved by NPV
compared with PPV (Figure 6C).
Series 5: CT Scanning
Six animals were assigned sequentially to both positive and
negative ventilation and studied in the CT scanner to illustrate
the distribution of lung volume during ventilation. Compared
with positive pressure, the end-expiratory lung volume during
NPV was associated with a smaller proportion of atelectatic
lung (Figure 7A). Dynamic CT of the six animals indicated that,
at all times during inspiration, the percentage of normally
aerated lung was greater with negative pressure (Figure 7B).
A specimen video recording illustrates the differences in inflation patterns between PPV and NPV (Video E2).
DISCUSSION
The current study demonstrates that a given level of EELV
attained with negative pressure is more effective (i.e., associated with better oxygenation) than a comparable lung volume
achieved with positive pressure. This effect appears to be due to
the differential distribution of lung volume in which negative
pressure is associated with greater volumes of normally aerated
Figure 4. Global pulmonary perfusion was similar with positive- versus
negative-pressure ventilation in which negative pressure was applied
using a whole-body device (P 5 not significant [NS]); however, when
negative pressure was applied using a chest device only, the pulmonary
perfusion was significantly greater than with positive-pressure ventilation (*P , 0.05).
lung. These effects were not restricted to end-expiration, because dynamic CT indicated that a similar pattern develops
during inspiration with negative pressure. The superior gas exchange was unrelated to global or regional pulmonary perfusion
(at least in terms of dependent vs. nondependent perfusion),
and the lesser gradient between arterial versus end-tidal PCO2
suggested that the recruitment involved optimally ‘‘perfused’’
lung tissue rather than overdistended pulmonary dead space. In
addition, NPV may be associated with less ventilator-induced
lung injury. These observations could have important implications for how ventilation is delivered, and suggest that assessment of lung recruitment might ideally include a measure of
pulmonary dead space.
Applied Pressure and End-Expiratory Volume
The characteristics of the EELV were fundamentally different
in PPV compared with NPV. This is not readily explained on
the basis of a unitary ‘‘transpulmonary pressure,’’ because such
a measurement (in our case, esophageal pressure) is not a weighted
average of all the regional transpulmonary pressures throughout
the lungs. Indeed, regional differences may be on the basis of liquid airway plugs that have previously been postulated to cause regional atelectasis (17).
Nonetheless, using the esophageal pressure to calculate the
transpulmonary pressure (18), we report that the transpulmonary pressure was greater with a given level of positive pressure
(i.e., applied to the airways, internal), compared with application of the same magnitude of negative pressure (i.e., applied to
the chest wall, external). This is readily understood, as has been
previously demonstrated (19), because the negative pressure
must take effect through the chest wall before impacting on
Figure 5. Regional lung perfusion, measured using injected colored
microspheres, was expressed as the ratio of blood flow in the dependent versus nondependent lung tissue. There was no significant difference in the regional flow ratio between positive- and negative-pressure
ventilation. NS 5 not significant.
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b
Figure 6. The relationships among applied end-expiratory pressure,
transpulmonary pressure, and end-expiratory lung volume (n 5 6,
positive; n 5 5, negative). (A) The transpulmonary pressures corresponding to end-expiratory pressure (EEP) applied as either positive (via
airway) or negative (via chest and abdominal wall) end-expiratory pressure, are shown. Overall, for given levels of EEP, the transpulmonary
pressure was less when applied with negative- compared with positivepressure ventilation (*P , 0.05, ANOVA), reflecting the elastance of the
chest wall that must be overcome by the negative pressure. The
number of the observations represented in (A) is 42 (4 observations
reported per animal, 11 animals and 2 missing values). (B) The endexpiratory lung volume (EELV) resulting from the corresponding transpulmonary pressures is shown, and demonstrates that, for a given level
of transpulmonary pressure, the overall EELV was greater when derived
from negative versus positive pressure (*P , 0.05, ANOVA). The total
number of observations represented in (B) is 49 (7 additional observations in the 11 animals). (C) The PaO2 levels associated with each level
of EELV are shown. The overall PaCO2 values associated with given levels
of EELV were greater where the EELV was achieved with negativeversus positive-pressure ventilation (*P , 0.05, ANOVA), suggesting
that, with negative-pressure ventilation, EELV—or FRC—more effectively oxygenates the perfusing blood. The total number of observations represented in (C) is 50 (8 additional observations in the 11
animals).
One of two conditions is necessary to demonstrate that this is
the case: either ventilation can be applied through different
routes (i.e., regionally, or positive vs. negative as in the current
study) or pleural pressure can be measured on a regional basis
and not assumed from a measurement at a single site.
In summary, although this is complex and its basis uncertain,
we offer the following explanation. The different effects of positive pressure versus negative pressure on lung distension might
result from a more even distribution of aeration associated with
negative pressure. A comparable pressure gradient between the
trachea and the outside of the chest wall would result in greater
recruitment if the distribution of aeration has made the lung
more compliant; in this context, the transpulmonary pressure
would be lower and the transthoracic pressure higher, and the
sum of both would remain constant.
Distribution of Tidal Volume and End-Expiratory Volume
the pleural space, and the greater the chest wall elastance, the
greater the gradient between the external (applied) pressure and
the intrapleural (effective) pressure.
However, the relationship between the effective pressure
(measured at the midesophagus) and the resultant lung volume
was more complex. When the levels of transpulmonary pressure
were ranked in intervals, it was apparent that, for any given
level of transpulmonary pressure, the developed EELV was
less for positive pressure than it was for negative pressure. Of
course, it is not possible that negative pressure confers a greater
compliance than positive pressure in any given regional unit,
but, over a whole lung and chest wall, there are significant
regional differences (20). Comparison of negative pressure, because it applies pressure to the overall lung surface, with positive pressure supports previous reports that a singular measurement of pleural pressure (i.e., esophageal manometry) does not
represent all of the regional pleural pressure gradients (21).
The distribution of lung volumes was also considered during
respiration, using dynamic CT. The spatial differences were
striking, with dependent atelectasis persisting over most of the
respiratory cycle in PPV. Such patterns have previously been
reported in patients undergoing PPV in the setting of acute lung
injury (6). In contrast, with NPV, we observed a different topographic distribution, in which normally aerated lung volumes
were greater and atelectasis was reduced. The findings in the
current study are similar to the altered distribution of lung volume as has been demonstrated for ventilation in the prone
versus supine position (22, 23).
Pulmonary Perfusion
Two important issues concerning pulmonary perfusion are reported. First, there were no differences in pulmonary perfusion,
either on a global or a regional basis, between PPV and NPV;
global or regional perfusion does not therefore explain the
oxygenation differences, suggesting that such differences must
be explained by differences in lung aeration.
NPV can have very different hemodynamic effects compared
with positive pressure. In general, positive pressure decreases
ventricular afterload and preload. Negative pressure applied
only to the chest (19), in contrast to that applied to the whole
body (4), could conceivably augment right ventricular preload
Grasso, Engelberts, Helm, et al.: Negative-Pressure Ventilation and Lung Injury
417
Figure 7. Standardized lung sections were partitioned into atelectatic (A) and aerated (B) lung, based on the Hounsfield unit density (see text). With
negative-pressure ventilation, the percentage of atelectatic lung was significantly less during expiration (A: *P , 0.05, ANOVA), and the percent of
aerated lung was significantly greater during inspiration (B: *P , 0.05, ANOVA).
and thereby increase lung perfusion and improve oxygenation;
this could be particularly important where the circulation is
critically dependent on right ventricular filling (e.g., hypovolemia or restrictive physiology). This phenomenon was confirmed
in the current study by demonstrating no change in cardiac
output when negative pressure was applied using the wholebody device, but there was a significant increase when negative
pressure was applied to the chest only.
The second issue concerns ventilation of perfused lung versus
dead space. The gradient between arterial and end-tidal CO2
reflects alveolar dead space, in which reduced dead space is
characterized by a lower arterial to end-tidal PCO2 gradient, provided that the minute ventilation is unchanged (24). In the current
study, this gradient was increased with positive pressure, without
any differences in minute ventilation; this suggests that the recruited
lung consisted of ‘‘perfused’’ rather than ‘‘dead space’’ lung (25).
not resolve the local pressure differences between the two types
of ventilation.
The current study provides indirect evidence for the recruitment of better-perfused airspace with NPV compared with
_ ratios were not measured
_ A/Q
PPV. However, the regional V
and the evidence, although suggestive (i.e., CO2 clearance), is
indirect. Finally, it is possible that the high FIO2 used exacerbated local injury in ventilated, overdistended regions, and
further altered the distribution of injury. Indeed, we cannot
be certain whether there is an important interaction between
high FIO2 and high tidal volume, whereby high FIO2 caused
a greater exacerbation of focal stretch-induced injury in regions
that were overdistended and less synergistic injury in physically
less stressed regions; the current design cannot exclude this
possibility.
Impact on Pulmonary Edema
The clinical implications of any approach that improves oxygenation or diminishes lung injury are potentially very great.
Extrapolation of the current experimental model to the clinical
context is difficult because the chest wall compliance is far
greater in a rabbit than an adult human (although the difference
is less for neonates). Others have reported, however, that where
the chest wall is less deformable (e.g., dogs [27] and humans
[19]), the chest wall may be less compliant with negative pressure, and for a given distending pressure may therefore cause
greater diaphragmatic displacement and more even aeration
and better lung compliance.
An important practical point is whether simply increasing
PEEP in positive pressure would result in the same net effect as
NPV; however, this issue cannot be resolved with the current
experimental design.
Finally, despite a large clinical experience with the technique, practical difficulties, especially where the respiratory system compliance is low, have to date precluded widespread use.
Positive airway pressure is believed to attenuate the development of alveolar edema (26). The exact mechanism is unclear,
but among other possibilities, the increased pressure on the
alveolar side of the gas–blood barrier may attenuate the tendency for net fluid flux into the alveolus; indeed, others have
shown that negative pressure can worsen established permeability edema (16). In the current study, negative pressure reduced the severity of lung injury, but did not alter the amount of
lung water in terms of wet-to-dry lung weight ratio or histologic
quantification of alveolar edema. It is possible that the injuryassociated edema in the positive-pressure animals was offset by
the reduced tendency for edema with positive pressure; if this
were true, then the combination of simultaneous PPV and NPV
could together lessen overall lung injury and attenuate the
formation of alveolar edema.
Limitations of Study
An important limitation of this study is the use of a conventional
measure of pleural pressure—that is, esophageal pressure. Although
assessed using the best possible technique, this singular measure
cannot take account of the regional differences in local pleural
(and therefore transpulmonary) pressures, and can therefore
Clinical Implications
Conclusions
The current study provides compelling evidence that, in certain
circumstances, ventilation with negative pressure may fundamentally differ to that achieved with positive pressure in terms of
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 177
transmission of applied pressure, development of transpulmonary distending pressure, volumes of recruited lung, and
distribution of lung aeration during inspiration and expiration.
The observations suggest that clinical reliance on a single
transpulmonary pressure measurement (e.g., esophageal manometry) may be inadequate to describe the overall forces acting
on the lung, and that use—or incorporation—of NPV should be
reinvestigated in the clinical context in which oxygenation is
problematic or lung injury is likely.
12.
13.
14.
Conflict of Interest Statement: None of the authors has a financial relationship
with a commercial entity that has an interest in the subject of this manuscript.
15.
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