(Chest. 1999;116:1032-1038.)
© 1999
American College of Chest Physicians
The Effect of Varying Inspiratory to Expiratory Ratio on Gas Exchange in Partial Liquid Ventilation*
Chae-Man Lim, MD;
Younsuck Koh, MD;
Tae S. Shim, MD;
Sang D. Lee, MD;
Woo S. Kim, MD;
Dong S. Kim, MD and
Won D. Kim, MD, FCCP
*
From the Division of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Correspondence to: Chae-Man Lim, MD, Division of Pulmonary and Critical Care Medicine, Asan Medical Center, Songpa PO Box 145, Seoul, Korea, 138–600
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Abstract
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Background: In partial liquid ventilation (PLV), the
nondependent lung was observed to be inflated first and the dependent
lung later. The inflational time difference between the lung regions
can lead to maldistribution of tidal gas and inefficient gas bubbling
in the slow-inflating region during PLV. In this situation, increasing
the inspiratory to expiratory (I:E) ratio of the mechanical ventilator
would lessen the heterogeneity of regional ventilation and improve gas
exchange possibly to a greater degree than in gas ventilation
(GV).
Design and setting: Animal study at the
Asan Institute for Life Sciences, Seoul, Korea
Subjects: Eighteen rabbits (2.6 ± 0.5 kg) with acute
lung injury by saline solution lavage.
Interventions:
Three I:E ratios were tried in GV and then in PLV. I:E ratios were
changed by adjusting pause (1:2, 1:1, and 2:1; group 1) or by adjusting
inspiratory flow rate (1:3, 1:1, and 2:1; group 2).
Measurements and results: With increasing I:E ratio in all
animals, PaO2/FIO2
increased (80 ± 24, 143 ± 74, and 147 ± 88 mm Hg;
p = 0.001), and PaCO2 decreased (74 ± 15,
66 ± 16, and 66 ± 15 mm Hg; p = 0.006). The increases of
PaO2/FIO2 from 1:2/1:3
to 1:1 (p = 0.006) and from 1:1 to 2:1 (p = 0.036) were both
greater in group 1 than in group 2. PaCO2
decreased with increasing I:E ratio in group 1, but not in group 2. The
change of PaO2/FIO2 by
varying the I:E ratio was 49 ± 65% in PLV and 14 ± 14% in GV
(p = 0.003).
Conclusions: Extending the I:E ratio,
especially by adding pause, improved gas exchange in PLV. Oxygenation
in PLV was affected by the I:E ratio to a greater degree than in
GV.
Key Words: gas exchange • inspiratory flow rate • inspiratory pause • inspiratory to expiratory ratio • partial liquid ventilation
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Introduction
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Partial
liquid ventilation (PLV) is one of the innovative methods of
respiratory support for severe respiratory failure.1
PLV
has been tested in patients with ARDS or in experimental
respiratory failure, and it showed better oxygenation2
3
4
5
and less histologic injury2
6
7
when compared to gas
ventilation (GV). In contrast to total liquid ventilation, in which gas
exchange is done extracorporeally,8
9
gas exchange using
PLV is accomplished in situ within the lung . For the
in situ gas exchange to occur, gas bubbling into and out of
the perfluorocarbon (PFC) liquid by the mechanical ventilator is
necessary to replenish O2 and remove
CO2.1
6
Despite this essential role
in PLV, little is established yet about how to set the variables of the
mechanical ventilator, including the inspiratory to expiratory (I:E)
ratio.
In the first observation of PLV performed in sheep, the nondependent
lung was observed to be inflated first and the dependent lung
later.1
This visible difference of inflation between the
superior and inferior parts of the lung, or "sequential lung
inflation," was also described later by Wolfson et al.6
As PFC is twice as dense as water and distributes preferentially to the
dependent lung,5
10
11
regional inertia caused by PFC is
thought to differ along the vertical axis of the lung. Gas coming from
the ventilator will face less inertia in the nondependent lung but
greater inertia in the dependent lung. Two consequences are possible in
this situation: (1) more tidal gas would distribute to the
fast-inflating region11
; and (2) gas bubbling of PFC would
terminate prematurely in the slow-inflating region. Considering that
the dependent lung is in the greatest need of recruitment in acute lung
injury (ALI),12
these consequences of sequential inflation
in PLV may be disadvantageous for gas exchange.
The I:E ratio in conventional GV is an important variable, either as
independent or as dependent, for the ventilatory support of the lung
with hypoxia. A high I:E ratio, ie, a long inspiratory time
(TI) of a given respiratory cycle, increases mean
airway pressure (Pmean), generates auto-positive end-expiratory
pressure (PEEP), and improves gas mixing between lung units with
heterogeneous time constants.13
14
15
All of these effects
of a high I:E ratio during GV serve to improve oxygenation in the lung
with ARDS. In the context that lung inflation is regionally
heterogeneous during PLV,1
6
16
the I:E ratio also can
play a role in determining gas exchange in PLV. We postulated that a
high I:E ratio will provide the dependent (slow-inflating) region with
extended time to catch up with inflation. The longer that the dependent
region is allowed to be inflated, the less the difference of regional
ventilation would be. Therefore, an extended I:E ratio in PLV could
favorably influence gas exchange, possibly to a greater degree when
compared to GV. We also wanted to compare the efficacy of the two
methods of increasing the I:E ratio on gas exchange in PLV: adding
inspiratory pause (in which the inspiratory flow rate is unchanged
until the pause) vs lowering the inspiratory flow rate.
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Materials and Methods
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Animal Preparation and Instrumentation
Eighteen New Zealand White rabbits (2.6 ± 0.5 kg) were
used for this study. In group 1 (n = 9), the I:E ratio was changed by
adjusting the inspiratory pause at a fixed inspiratory flow rate. In
group 2 (n = 9), the I:E ratio was changed by adjusting the
inspiratory flow rate. The experimental protocol was approved by the
Animal Care Committee of our institute, and the rabbits were cared for
and handled according to the guidelines of the National Health
Institute. The rabbits were placed supine under a radiant warmer to
keep rectal temperature between 38° and 39°C. After administering
ketamine, 25 mg/kg, intramuscularly on the thigh, a marginal ear vein
was cannulated with a 24-gauge angiocath that was later used for the
route of IV anesthesia. Under additional local anesthesia at the
neck with 2% lidocaine, the rabbits were tracheostomized. After
tracheostomy, a 3.5-mm cuffless endotracheal tube was inserted 3 to 4
cm deep into the trachea and firmly tied to prevent leaks of gas or
liquid. The carotid artery was cannulated with an 22-gauge angiocath
and connected to a pressure monitor (Escort II; Medical Data
Electronics; Arleta, CA) to record pulse rate and arterial pressure
referenced to the midthoracic level. Arterial blood was obtained via
the carotid artery, and blood gases were analyzed within 5 min of
sampling using standard blood-gas electrodes (Blood Gas System 288;
Ciba-Corning; Medfield, MA). Expired gas from the rabbit was collected
in a 1.0-L mixing chamber positioned distally to the expiratory valve
of the ventilator, and mixed expired CO2 was
measured using a side-stream infrared capnograph (Normocap; Datex;
Helsinki, Finland). Anesthesia was induced with IV thiopental sodium,
20 mg/kg, given in two divided doses and maintained at 3 mg/kg/h with
intermittent muscle paralysis using IV vecuronium, 0.1 mg/kg, every 30
min. The rabbits were given a solution of half saline, 5% dextrose and
water IV by an infusion pump at 7.5 mL/kg/h. A mechanical
ventilator (Servo 900C; Siemens-Elema; Solna, Sweden) was initially set
with tidal volume (VT) of 18 mL/kg and frequency of 24
breaths/min; FIO2 of 1.0; PEEP of 2
cm H2O; and an I:E ratio of 1:1 (TI,
33% and pause 20% in group 1; TI, 50% without pause in
group 2).
ALI
ALI was induced by a warmed saline solution (38°C)
lavage, one lavage amount being 20 mL/kg. The saline solution was
allowed to remain in the lung of the rabbit while mechanical
ventilation continued for 1 min or until severe bradycardia (< 40
beats/min) ensued. Throughout the lavage period, peak airway
pressure (Ppeak) was kept < 40 cm H2O by
temporarily, if necessary, lowering the VT. The saline
solution was removed from the lung by gravity using a siphon that was
1 m long. Lavage was repeated two to three times at 10-min
intervals; after the last lavage, 60 min was allowed for the rabbit to
be stabilized in BP and PaO2.
ALI was determined if the
PaO2/FIO2
ratio was < 100 mm Hg at the end of the stabilization period
(38 ± 8 mm Hg).
Trial of Different I:E Ratios in GV and PLV
From the baseline ratio of 1:1 in GV, the I:E ratio was then
randomly changed to 1:2 or 2:1 (in group 1) or to 1:3 or 2:1 (in group
2) by flipping of a coin. After the completion of GV, PLV was started
at a ratio of 1:1, which was altered likewise in GV. PLV was done using
perfluorodecalin (perfluor-decahydronapthalin,
C10F18; Fluka Chemie AG; Buchs, Switzerland), 9
mL/kg. This somewhat lower dose of PFC was deliberately chosen
to amplify the unequal distribution of liquid between the nondependent
and dependent lung regions. The PFC liquid was prewarmed to 38°C in
an incubator before instillation. Each dose of perfluorodecalin was
instilled into the lung over 20 to 30 s via a swivel connector
positioned between the endotracheal tube and the Y connector of the
ventilator circuit. The dose of PFC was halved, and each half was given
with the rabbit in the left or right lateral decubitus position,
respectively. The evaporative loss of perfluorodecalin was not replaced
because the total PLV time was < 1 h and the application of different
I:E ratios was randomized.
In group 1, the I:E ratio was varied by adding inspiratory pause at the
same inspiratory flow rate (TI fixed at 33%; pause time
varying 0%, 20% and 30%, resulting in I:E ratios of approximately
1:2, 1:1 and 2:1, respectively). In group 2, the I:E ratio was varied
by adjusting inspiratory flow rate (TI varying 25%, 50%
and 67%, resulting in I:E ratios of 1:3, 1:1 and 2:1, respectively).
Physiologic Measurements
Hemodynamic data (mean arterial pressure and pulse rate) and
respiratory data (Ppeak, inspiratory pause pressure [Ppause], Pmean,
total PEEP [PEEPt], and blood gases) were determined at the
establishment of ALI, and at 15 min of each I:E trial in GV and PLV.
Ppause was measured by an inspiratory hold of 5 s. PEEPt was
measured by an end-expiratory hold of 5 s. Physiologic dead space
ventilation (VD/VT) was calculated according to
the Enghoff's modification of the Bohr's
equation.17
Statistics
All data are expressed as mean (± SD), unless otherwise
stated. Friedman's nonparametric analysis of variance was performed
for the two groups in PLV, with a Wilcoxon signed rank sum test for the
comparison among the different I:E ratios. An unpaired t
test was used for the overall change of variables between GV and PLV. A
p value < 0.05 was considered significant.
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Results
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With increasing I:E ratio in all animals,
PaO2/FIO2
increased (80 ± 24 mm Hg at 1:2/1:3; 143 ± 74 mm Hg at 1:1; and
147 ± 88 mm Hg at 2:1; p = 0.001) and
PaCO2 decreased (74 ± 15 mm Hg,
66 ± 16 mm Hg, and 66 ± 15 mm Hg, respectively; p = 0.006).
With an increasing I:E ratio in group 1,
PaO2/FIO2
increased (p = 0.001) and PaCO2 and
VD/VT decreased (both p < 0.05; Table 1
). In group 2, on the other hand,
PaO2/FIO2
at 2:1 was lower than at 1:1 (p < 0.05), and
PaCO2 and
VD/VT did not change (Table 2
). Increases of
PaO2/FIO2
from 1:2/1:3 to 1:1 (p = 0.006) and from 1:1 to 2:1 (p = 0.036)
were both greater in group 1 than in group 2 (Fig 1
).
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Table 1. Effects of Varying the I:E Ratio by Adding Pause Time
on Gas Exchange and Respiratory Mechanics in PLV vs GV for Rabbit ALI
Model*
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Table 2. Effects of Varying the I:E Ratio by Adjusting the
Inspiratory Flow Rate on Gas Exchange and Respiratory Mechanics in PLV
vs GV for Rabbit ALI Model*
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Figure 1. A comparison of the change in
PaO2/FIO2 with a
varying I:E ratio from 1:2/1:3 to 1:1 (p = 0.006;
left, a) and from 1:1 to 2:1
(p = 0.036; right, b) between group 1
and group 2 in PLV.
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In all animals, the amount of change in
PaO2/FIO2
by varying I:E ratios was 49 ± 65% in PLV and 14 ± 14% in GV
(p = 0.003). Changes of
PaO2/FIO2
from 1:2/1:3 to 1:1 (p = 0.023) or from 1:1 and 2:1 (p = 0.038)
were both greater in PLV than in GV (Fig 2
). The change of PaCO2 in all animals
was 11 ± 7% in PLV and 11 ± 9% in GV (p = 0.912). Changes of
PaCO2 from 1:2/1:3 to 1:1
(11 ± 6% vs 12 ± 10%; p = 0.668) or from 1:2 to 2:1
(11 ± 8% vs 9 ± 9%; p = 0.543) were not different between PLV
and GV.
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Figure 2. A comparison of the amount of change in
PaO2/FIO2 (mean ± SE)
with a varying I:E ratio from 1:2/1:3 to 1:1 (p = 0.003;
left, a) and from 1:1 to 2:1
(p = 0.023; right, b) between PLV and
GV.
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Discussion
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In at least two animal studies, the superior lung and the inferior
lung were observed to be inflated in sequence during
PLV.1
6
The current study was intended to evaluate the
effect of an increased I:E ratio on gas exchange in this situation of
sequential lung inflation. In our results, extending the I:E ratio in
PLV increased oxygenation and decreased
PaCO2 of acutely injured rabbit lung.
In the application of a high I:E ratio in PLV, adding inspiratory pause
was superior to lowering inspiratory flow for both oxygenation and
CO2 elimination. The impact of a changing I:E
ratio on oxygenation was greater in PLV compared to GV.
Although the conventional mechanical ventilator is an integral
part of PLV, little is established about a ventilating strategy,
including the I:E ratio, for improving the efficiency of gas exchange
mediated by PFC. In the first experiment of PLV by Fuhrman et
al,1
an I:E ratio of 1:3 was used. The I:E ratio in
succeeding studies of PLV ranged from 1:3 to 1:118
19
20
21
22
23
or
was varied as a dependent variable.4
To our knowledge, no
systematic study has yet been reported concerning the role of the I:E
ratio on gas exchange during PLV. Our results showed that oxygenation
of acutely injured lung in PLV improved as the I:E ratio was increased,
which was more pronounced when compared to GV. The superiority of 1:1
over 1:3 or 1:2 agrees to the finding of Hernan et al23
that an I:E of 1:1 was better than their previous ratio (1:3) for
oxygenation (although data was not presented). Interestingly, auto-PEEP
did not develop in our rabbits in PLV despite an increasing I:E ratio
up to 2:1. Conceivably, the column of incompressible PFC (liquid
auto-PEEP) not only stabilizes alveoli, but also prevents
noncartilaginous small airways from tidal collapse during the
expiratory phase. Therefore, expiratory flow limitation as might occur
in GV can be circumvented, and the shortened expiratory time would not
be translated into the elevation of end-expiratory alveolar pressure.
Lack of auto-PEEP development in our rabbits suggests that the
mechanism of improved oxygenation at high I:E ratio in PLV differs from
that in GV. It seems to rest with the inspiratory phase rather than
with the curtailed expiratory time. It is likely that longer I:E ratios
(1:1 and 2:1) have provided the slow region (the dependent lung) with
longer TI, which could have lessened the heterogeneity of
ventilation between the nondependent and dependent regions.
Increases of
PaO2/FIO2
with a change of the I:E ratio from 1:2/1:3 to 1:1, and from 1:1 to 2:1
were both greater by adding pause (group 1, unchanging inspiratory flow
rate) than by lowering the flow rate (group 2; Fig 1
). Especially, the
mean change of
PaO2/FIO2
from 1:1 to 2:1 in group 2 was negative. As the changes in Pmean and
PEEPt from 1:1 to 2:1 were not different between the two groups, the
different response of oxygenation to inverse ratio (2:1) may be
attributable to different inspiratory flow rates. In view of the need
of gas bubbling by the mechanical ventilator in PLV,1
extending inspiratory phase from 1:1 to 2:1 at the expense of the
inspiratory flow rate could have deteriorated the efficiency of
oxygenation of PFC itself. Regarding the efficiency of
CO2 elimination,
PaCO2 decreased stepwise with adding
inspiratory pause, while it did not change with lowering the
inspiratory flow rate. Because other factors governing
PaCO2 (minute ventilation and the
metabolic rate of the rabbit) were controlled in both groups,
inspiratory phase characteristics might have been also responsible for
the difference in the level of PaCO2.
From the comparisons of gas exchange between the two methods of I:E
change, maintaining an adequate flow rate along with an extended
TI was thought to be more desirable in PLV than merely
having a long TI at a compromised flow rate.
Compared to GV, oxygenation in PLV was affected by the I:E ratio
to a greater degree. This can be anticipated, considering the
exaggerated inflational time difference between lung regions during
PLV. PaCO2 was affected to a similar
degree between PLV and GV. Although the influence of varying the I:E
ratio on PaCO2 and
VD/VT were not different, the values of
PaCO2 and
VD/VT were significantly lower in PLV than in
GV at all of the tested I:E ratios. Elimination of
CO2 from the alveoli may be different in PLV than
in GV. In GV, after CO2 is released into
the alveoli from pulmonary capillaries, it undergoes convective
dilution along the conducting airways. In PLV, on the other hand,
CO2 readily dissolves in PFC (140 to 210 mL/100
mL), which is found from the alveoli to the conducting airways, and the
phenomenon of convective dilution can be theoretically reduced.
This was supported by the capnogram taken during PLV, in which the
midindentation of CO2 rise seen during GV
disappeared (Fig 3
).
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Figure 3. A capnogram of one of the rabbits during GV
(upper panel) and during PLV (lower
panel). Note the indentation of the expired CO2
curve at midexpiration in GV (arrow) and its disappearance in
PLV.
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In testing our hypothesis, we confined our study to the
volume-controlled mode. Although extended TI can be
achieved in the pressure-controlled mode as well, an alteration in
inspired VT will confound the oxygenation response in
PLV.23
VD/VT as determined by the
Bohr's equation turned out to be very high in our study. We used an
adult ventilatory circuit, the bore of which was obviously too large
for the rabbit. Considering that the VT of the rabbit was
around 50 mL, the compression volume of the ventilator circuit
could have diluted expired CO2 in the mixing
chamber, causing VD/VT values to be calculated
high. In comparing the two methods of varying I:E ratio in PLV, the
shortest I:E ratios were not identical between group 1 (1:2) and group
2 (1:3). This was inevitable with the volume-controlled mode on the
Servo 900C. This limitation, however, does not seem to
invalidate our results, because the overall change in
PaO2/FIO2
and PaCO2 showed the same trend when
the two groups were analyzed separately. Also in comparing the two
groups, the more favorable results of gas exchange were obtained in
group 1, in which the change of the I:E ratio was relatively smaller
than in group 2. Although 5 s of expiratory pause hold was long
enough for the animal we used, the pause method adopted from GV may not
hold true in a lung filled with a variable amount of liquid. The
concept and/or measurement of auto-PEEP may need to be redefined in
liquid ventilation. In interpreting gas exchange with a varying I:E
ratio, the change in the distribution of pulmonary blood flow should be
taken into consideration. Pulmonary blood flow during PLV is known to
favor the nondependent lung regions in a vertical
plane24
25
and the apical regions on a transverse plane in
the normal lung.25
It is not yet
known how pulmonary blood flow is altered in diseased lung during PLV.
Our results, therefore, are currently not amenable to interpretation in
terms of pulmonary blood flow change accompanying sequential inflation
or a varying I:E ratio. The latter issue, however, needs to be
investigated in view of the increasing interest about the different
dosing of PFC6
16
and about the combination of PFC with
PEEP.21
In conclusion, extending the I:E ratio in PLV improved gas exchange of
acutely injured rabbit lung. In increasing the I:E ratio, the method of
adding inspiratory pause was superior to the method of lowering the
inspiratory flow rate for both oxygenation and
CO2 elimination. The impact of a changing I:E
ratio on oxygenation was greater in PLV compared to GV. These findings
suggest that an appropriate adjustment of the variables on the
mechanical ventilator (synchronization of the inflation between the
dependent and nondependent lungs, and providing an adequate inspiratory
flow rate) are necessary for optimal gas exchange in PLV.
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Footnotes
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Abbreviations: ALI = acute
lung injury; FIO2 = fractional concentration
of inspired oxygen; GV = gas ventilation; I:E ratio = inspiratory
to expiratory ratio; PEEP = positive end-expiratory pressure;
PEPPt = total PEEP; PFC = perfluorocarbon; PLV = partial liquid
ventilation; Pmean = mean airway pressure; Ppause = inspiratory
pause pressure; Ppeak = peak airway pressure;
TI = inspiratory time;
VD/VT = physiologic dead space
ventilation; VT = tidal volume
This study was supported in part by the Asan Institute for Life
Sciences, Seoul, Korea.
Received for publication December 8, 1998.
Accepted for publication May 7, 1999.
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Abstract
Introduction
