Vol. 90, Issue 3, 839-849, March 2001
Effects of perfluorochemical distribution and elimination
dynamics on cardiopulmonary function
Thomas F.
Miller1,
Bart
Milestone2,
Robert
Stern1,2,3,
Thomas H.
Shaffer1,4, and
Marla R.
Wolfson1,4
Departments of 1 Physiology, 4 Pediatrics, and
2 Radiology, Temple University School of Medicine, Philadelphia,
Pennsylvania 19140; and 3 Veterans Administration
Hospital and University of Arizona, Tucson, Arizona 85721
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ABSTRACT |
Based on a physicochemical property
profile, we tested the hypothesis that different perfluorochemical
(PFC) liquids may have distinct effects on intrapulmonary PFC
distribution, lung function, and PFC elimination kinetics during
partial liquid ventilation (PLV). Young rabbits were studied in
five groups [healthy, PLV with perflubron (PFB) or with
perfluorodecalin (DEC); saline lavage injury and conventional
mechanical ventilation (CMV); saline lavage injury PLV with PFB or with
DEC]. Arterial blood chemistry, respiratory compliance (Cr),
quantitative computed tomography of PFC distribution, and PFC loss rate
were assessed for 4 h. Initial distribution of PFB was more
homogenous than that of DEC; over time, PFB redistributed to dependent
regions whereas DEC distribution was relatively constant. PFC loss rate
decreased over time in all groups, was higher with DEC than PFB, and
was lower with injury. In healthy animals, arterial PO2 (PaO2) and Cr decreased
with either PFC; the decrease was greater and sustained with DEC.
Lavaged animals treated with either PFC demonstrated increased
PaO2, which was sustained with PFB but deteriorated with DEC. Lavaged animals treated with PFB
demonstrated increased Cr, higher
PaO2, and lower arterial
PCO2 than with CMV or PLV with DEC. The results
indicate that 1) initial distribution and subsequent
intrapulmonary redistribution of PFC are related to PFC properties;
2) PFC distribution influences PFC elimination, gas
exchange, and Cr; and 3) PFC elimination, gas exchange, and Cr are influenced by PFC properties and lung condition.
perfluorocarbon; perflubron; perfluorodecalin; liquid ventilation; kinematic viscosity; vapor pressure; spreading coefficient
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INTRODUCTION |
EXTENSIVE INVESTIGATION
HAS demonstrated that liquid-assisted ventilation (LAV) utilizing
perfluorochemical (PFC) liquids can reduce surface forces, which allows
for effective ventilation at reduced alveolar pressures (7, 10,
12, 15, 16, 26, 29, 35, 39, 44). Other pulmonary applications of
PFC liquids, including drug delivery (40, 45) and imaging
(11, 32, 34, 43), have also shown great potential.
Although several types of PFC liquids have been explored for pulmonary
applications, a select few, based on the physicochemical profile, are
considered as viable breathable media (8). In general, PFC
liquids are characterized by high-respiratory gas solubility; are
nonreactive, nontransformable, and minimally absorbed; and have
no known deleterious histological, cellular, or biochemical effects on
the lung (3, 5, 20, 21). It is essential that certain
physical properties, such as respiratory gas solubility, vapor
pressure, density, viscosity, and tissue permeability, be within a
narrow, viable range for a PFC liquid to be considered as a possible
candidate for respiratory media (4, 8). Although studies
of LAV with various PFC liquids have been conducted over the past three
decades, none has focused on assessing the PFC physicochemical profile
relative to a specific therapeutic application.
For respiratory support and drug administration applications, it is
desirable to maintain homogenous distribution of the PFC liquid to
protect the lung from barotrauma and deliver agents throughout the
lung, respectively. To achieve this, it is important to have a means of
evaluating the intrapulmonary distribution and volume loss of PFC to
optimize the applications. Previous attempts at assessing these
parameters have been based on techniques such as plain film radiography
and qualitative visualization of a "meniscus" in an endotracheal
tube or "topping off" with additional PFC at a fixed rate,
independent of ventilation strategy (7, 24). Neither of
these techniques can adequately assess the volume or distribution
pattern of the instilled PFC liquid. We have recently described a
quantitative method of measuring PFC elimination from the respiratory
system utilizing a simple, on-line, dual-cell thermal detector
(27). In this technique, the expired gas is sampled and
the PFC saturation is measured. PFC loss rate, elimination, is then
calculated utilizing additional measurements of minute ventilation.
Using this approach, we have demonstrated in an in vitro model that the
PFC evaporation rate was modulated by differences in PFC vapor pressure
(27). In addition, in vivo studies have shown that PFC
elimination is influenced by repositioning, minute ventilation, dosing,
and PFC distribution (19, 27, 41).
In a previous study in healthy lungs, we showed that compliance
decreases over time during partial liquid ventilation (PLV) with
perflubron as the PFC is volatized from the lung in the expired gas
(19). In addition, our laboratory has shown that PLV with perfluorodecalin after saline lavage improved gas exchange but not
compliance (1). Furthermore, improvement in oxygenation with perfluorodecalin was much less dramatic than in previous studies
with PLV with perflubron (35). Reasons for the differences have not been evaluated. The objective of the present study was to
evaluate whether the intrapulmonary distribution, expired gas saturation, and elimination kinetics of PFC during PLV of the adolescent rabbit differed as a function of the type of PFC liquid (perflubron vs. perfluorodecalin) or lung condition (healthy vs. saline
lavage injury) and whether these differences affected pulmonary function and gas exchange. Imaging by computerized tomography was
performed in the healthy lung to determine the effects of the PFC
physicochemical properties on PFC distribution without the additional
potential influence of mechanical abnormalities of the lung.
Specifically, we hypothesized that, because physicochemical properties (i.e., kinematic viscosity, density, spreading coefficient, lipid solubility, and CO2 solubility) differ among PFC
liquids, PFC liquids may have differential effects on intrapulmonary
PFC distribution, pulmonary function, and subsequent PFC elimination from the respiratory system.
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MATERIALS AND METHODS |
Animal preparation.
The experimental protocol and procedures in this study were approved by
the Institutional Animal Care Committee at Temple University.
Twenty-nine adolescent New Zealand White rabbits (1.55 ± 0.05 kg)
were studied. After preanesthesia with an intramuscular injection of
ketamine (23 mg/kg), acepromazine (0.58 mg/kg), and xylazine (0.78 mg/kg), a pulse oximeter probe (Nellcor, N-100), electrocardiogram
leads, and rectal thermistor probe were applied. The skin and soft
tissues surrounding the trachea were then locally anesthetized
(subcutaneous injection: 4 mg/kg of 0.5% lidocaine HCl), catheters
(5-8 Fr) were placed in a jugular vein and carotid artery, and an
endotracheal tube (Hi-Lo Jet tube; Mallincrodkt, Glen Falls, NY) of
appropriate size (2.5 or 3.0 mm ID) was inserted into the trachea
through a tracheotomy with the tip proximal to the carina. Animals were
then connected to the ventilator circuit (Bear, BP-200) and paralyzed
(pancuronium bromide, 0.1 mg/kg). All animals received metabolic
substrate (5% glucose, 5 ml · kg
1 · h1),
supplemental paralytic (0.1 ml · kg1 · h1), and
anesthesia (pentobarbital sodium, 5 ml · kg1 · h1) during the protocol.
Pulmonary gas exchange was supported initially using conventional
mechanical gas ventilation (CMV) (inspired O2 fraction = 1). Baseline determinations of gas exchange from arterial blood samples (ABL 330 and OSM 3; Radiometer, Copenhagen, Denmark), pulmonary
mechanics by pneumotachography and airway manometry (PeDS-LAB, MAS,
Hatfield, PA), and functional residual capacity by a closed circuit
helium dilution technique (Panda, PeDS-LAB) were then performed. At
this point, the animals were randomized into the following groups:
healthy lungs, PLV with perflubron alone (n = 6);
healthy lungs, PLV with perfluorodecalin alone (n = 5);
saline injury and CMV (n = 6); saline injury and PLV with perflubron (n = 6); and saline injury and PLV with
perfluorodecalin (n = 6). Injury was created via serial
warm saline lavages (7-10 lavages; 10 ml · kg1 · lavage1). Injury
criteria included arterial PO2
(PaO2) <100 Torr and a 
50% decrease in dynamic
compliance from baseline for 1 h.
Animals treated with PFC liquid (perflubron, LiquiVent, Alliance
Pharmaceutical; perfluorodecalin, PP-5, F2 Chemicals)
received a volume of non-preoxygenated PFC equal to the measured
baseline gas functional residual capacity (16.8 ± 0.73 ml/kg).
The PFC liquid was instilled during inspiration over 5 min through the distal side port of the endotracheal tube, as the animal was
repositioned between the right and left lateral and supine positions.
Prone positioning was not used in order to simulate instillation
procedures in clinical trials (15). Pressure-volume loop
monitoring was performed to guide the rate of PFC infusion so as to
minimize opening pressure and prevent overdistension, as would be
reflected by reduction in respiratory compliance and tidal volume. The
PFC infusion rate was adjusted to prevent PFC reflux into the
ventilator lines or development of a visible fluid column in the
endotracheal tube. The animals were then ventilated for an additional
4 h. All animals were ventilated in the supine position at the
same frequency (30 beats/min), tidal volume [9.3 ± 0.3 (SE)
ml/kg], temperature (35°C), and inspiratory time (0.30 s) with no
additional postural rotation for the duration of the protocol to
eliminate variability due to ventilation strategy. Arterial blood
pressure, heart rate, and O2 saturation were monitored
continuously; pulmonary mechanics and arterial blood-gas chemistry were
assessed every 0.5 h.
Noninvasive perfluorocarbon elimination analysis was conducted hourly
utilizing a previously described thermal detector analyzer technique
(27). Mixed expiratory gas samples were obtained from a
collection reservoir that was attached to the proximal side port of the
endotracheal tube. Briefly, a deflated 200-ml anesthesia bag was
connected to the proximal side port of the endotracheal tube via a
two-way stopcock. Expiratory gas was allowed to passively fill the bag;
inspiratory gas was prevented from entering the bag by manual clamping.
Samples were collected over 15 breaths. After collection, the stopcock
was closed to the animal, and the volume within the sealed collection
reservoir was introduced to the thermal detector.
The thermal detector was calibrated to medical grade 21% and 100%
O2 and 0-100% PFC saturation to establish linearity.
Analyzer output was adjusted to account for humidification and
CO2 in expired gas (27).
Volume loss from the respiratory system was determined from the
following previously described relationship (27)
where 
E is minute ventilation and sat is
saturation. The PFC liquid-volume-per-gas-volume relationship is based
on the ratio of vapor pressure of PFC at a given temperature divided by
the barometric pressure and represents the volume of PFC vapor per
volume of carrier gas at 100% saturation at 25°C. This value is
multiplied by the measured gas saturation of PFC determined from the
analyzer. The neat PFC liquid/vapor relationship for PFC is a
calculated constant with temperature. This relationship is determined
from the specific gravity and the molecular weight of a PFC, the sample
temperature, and the volume per mole relationship for a gas.
Computed tomography (CT; 3.0-mm collimation, 10-cm field of view, 1-s
scan time, and 120 kVp/200 mA) was performed to determine distribution
of PFC 15 min immediately after instillation and every 30 min
thereafter for 4 h. Hounsfield unit analysis was conducted to
quantitate PFC distribution as a function of region and time. The field
of view accommodated the size of the lung, and scout images were
performed at each stage of the protocol to confirm fixed anatomic
orientation and slice selection. Hounsfield unit analysis (region of
interest density analysis expressed in Hounsfield units) was conducted
to quantitate PFC distribution as a function of region and time in
three lung slices around the fixed anatomic location in the caudal lung
defined by the airway branching point to the medial lobe of the right
lung. Each slice was measured along the ventral-dorsal axis and then
divided into three equal regions: nondependent (ventral most), middle
region, and dependent (dorsal). Densitometry analysis was repeated
three times for each slice and each outlined, entire individual region. Mean values representing <10% variance between repeated measurements from each region were used for subsequent statistical analysis. Imaging
by computerized tomography was performed in the healthy lung to
determine the effects of the PFC physicochemical properties on PFC
distribution without the additional potential influence of mechanical
abnormalities of the lung. Imaging was limited to the healthy animal,
as it was not possible to perform the injury and provide critical
respiratory support in the radiology suite at the time of this study.
At the end of the protocol, the animals were killed with an overdose of
pentobarbital sodium and KCl.
All values are reported as means ± SE. Data were analyzed using
two-way ANOVA with repeated measures for ventilation (before vs. after
PFC instillation) followed by Bonferroni Dunn's testing for between-
(untreated controls vs. PLV with perflubron vs. PLV with
perfluorodecalin) and within-group (before vs. after PFC instillation)
differences. Significance was set at P < 0.05.
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RESULTS |
Computerized tomography scans and Hounsfield unit analysis
depicting differences in intrapulmonary PFC distribution as a function of group and time are shown in Figs. 1
and 2. These images were obtained at 15 min and 4 h from the same rabbit treated with
perflubron and from another rabbit treated with perfluorodecalin. The
images demonstrated that the initial distribution of perflubron was
more homogeneous compared with that of perfluorodecalin. The
distribution of perflubron changed markedly over the 4-h study period
such that nondependent and middle regions of the lung demonstrated marked clearing, whereas dependent lung regions demonstrated little radiographic difference in the density of PFC liquid. This pattern is
demonstrated quantitatively by a significant (P < 0.01) decrease in Hounsfield units in the nondependent and middle
regions and little change in units in the dependent region. The
distribution of perfluorodecalin remained relatively constant during
the 4-h study period, with no significant differences in Hounsfield
units in the nondependent and dependent regions and a significant
(P < 0.05) decrease in Hounsfield units in the middle
region.
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Fig. 1.
Serial computerized tomography images of individual rabbits during
partial liquid ventilation with perflubron (left) or
perfluorodecalin (right) 15 min (top) and 4 h (bottom) after perfluorochemical (PFC) instillation.
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Fig. 2.
Hounsfield unit analysis of the nondependent, middle, and dependent
lung regions of serial computerized tomography images of rabbits during
gas ventilation before instillation of PFC [baseline (BL)] and during
partial liquid ventilation with perflubron (left) or
perfluorodecalin (right) 15 min and 4 h after PFC
instillation. Values are means ± SE.
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Results from the measured expired gas PFC saturation and calculated PFC
elimination profile are depicted in Figs.
3 and 4, respectively. Expired gas PFC saturation and rate of
elimination (PFC loss) decreased significantly (P < 0.01) with time, independent of the type of PFC or lung condition, and
were significantly greater (P < 0.05) in the healthy
compared with injured animals, independent of the PFC utilized for
treatment. In addition, the expired gas PFC saturation and loss over
time were significantly greater (P < 0.05) in all
animals treated with perfluorodecalin compared with perflubron-treated
lungs.
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Fig. 3.
Expired gas PFC saturation, expressed as a percentage, as a
function of time and lung condition during partial liquid ventilation
with perflubron (left) or perfluorodecalin
(right) in the healthy and saline-injured lung. Values are
means ± SE. Repeated-measures ANOVA indicated that the %PFC
saturation 1) decreased over time in all groups
(P < 0.05); 2) was greater for
perfluorodecalin than perflubron over time, independent of lung
condition (P < 0.05); and 3) decreased with
injury, independent of PFC (P < 0.05).
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Fig. 4.
PFC loss expressed as a rate
(ml · kg1 · h1) as a
function of time and lung condition during partial liquid ventilation
with perflubron (top) or perfluorodecalin
(bottom) in the healthy and saline-injured lung. Values are
means ± SE. Repeated-measures ANOVA indicated that the PFC
elimination 1) decreased over time in all groups
(P < 0.05); and 2) was greater for
perfluorodecalin than perflubron over time, independent of lung
condition (P < 0.05); and 3) decreased with
injury, independent of PFC (P < 0.05).
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The cardiopulmonary profiles of the healthy and saline-injured animals
are shown in Tables 1 and
2 and in Figs.
5 and 6, respectively. In healthy animals (Fig. 5), the overall ANOVA for PaO2 demonstrated significant
within-group (CMV vs. PLV) and between-group (perflubron vs.
perfluorodecalin) differences. Specifically, there was a significant
and sustained decrease in PaO2 (P < 0.05) after perfluorodecalin instillation. After perflubron, there was
biphasic PaO2 response, which initially decreased
significantly (P < 0.05), then returned toward CMV,
and then decreased to values comparable to perfluorodecalin. Over time,
PaO2 was significantly greater (P < 0.05) after perflubron (425 ± 49 Torr) than
perfluorodecalin (377 ± 19 Torr). Analysis of respiratory
compliance demonstrated significant within- (CMV vs. PLV) and
between-group (perflubron vs. perfluorodecalin) differences. In this
regard, respiratory compliance decreased significantly after perflubron
(P < 0.05) or perfluorodecalin (P < 0.001) instillation and was significantly (P < 0.001)
lower at all time points after perfluorodecalin compared with
perflubron instillation. Compared with the relatively small but
significant (P < 0.05) decrease in compliance during
the 4 h after perflubron instillation, the decrease in compliance
after perfluorodecalin (P < 0.05) was observed at the
first measurement and remained lower throughout the 4-h protocol. As
shown in Table 1, analysis of arterial PCO2
(PaCO2) demonstrated no significant differences
immediately after PFC instillation; however, PaCO2 after perflubron instillation was significantly (P < 0.001) lower than after perfluorodecalin instillation for up to 4 h. Mean arterial pressure and pH were not significantly different
during PLV with either PFC liquid compared with CMV (Table 1).
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Table 1.
Summarized ventilation, acid-base, and blood pressure data of healthy
animals during partial liquid ventilation with perfluorodecalin or
perflubron
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Table 2.
Summarized ventilation, acid-base, and blood pressure data of
saline-injured animals during conventional ventilation (control) or
partial liquid ventilation with perfluorodecalin or perflubron
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Fig. 5.
Arterial oxygen tension (PaO2;
top) and respiratory compliance (bottom) in
healthy animals during conventional mechanical ventilation at BL and
during 4 h of PLV with perflubron or perfluorodecalin. Values
are means ± SE. ANOVA indicated 1) a significant and
sustained decrease in PaO2 (P < 0.05)
after perfluorodecalin instillation; 2) a biphasic
PaO2 response after perflubron, initially decreasing
significantly (P < 0.05), then returning toward
conventional mechanical ventilation, and then decreasing to values
comparable to perfluorodecalin; and 3) that
PaO2 was significantly greater
(P < 0.05) after perflubron (425 ± 49 Torr) than
after perfluorodecalin (377 ± 19 Torr). ANOVA indicated that
respiratory compliance 1) decreased significantly after
perflubron (P < 0.05) or perfluorodecalin
(P < 0.001) instillation; 2) was
significantly (P < 0.001) lower at all time points
after perfluorodecalin compared with perflubron instillation; and
3) decreased significantly (P < 0.05) over
time after perflubron instillation, whereas the significantly
(P < 0.05) greater decrease in perfluorodecalin was
sustained throughout the 4-h protocol.
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Fig. 6.
PaO2 (top) and respiratory
compliance (bottom) in saline lavage-injured rabbits during
conventional mechanical ventilation at BL, after injury (INJ), and
during 4 h of conventional mechanical ventilation (control) or
partial liquid ventilation with perflubron or perfluorodecalin. Values
are means ± SE. ANOVA indicated 1) a significant
increase in PaO2 (P < 0.05) from
injury values in animals treated with either PFC; 2)
significantly greater increase (P < 0.001) in
PaO2 with perflubron than perfluorodecalin, which was
sustained with perflubron compared with perfluorodecalin for which
PaO2 decreased to injury values by 4 h; and
3) a significant initial increase (P < 0.001) in respiratory compliance from injury values after perflubron,
whereas compliance was not significantly different from injury values
after perfluorodecalin. Insert: time-dependent change in
compliance during partial liquid ventilation. Over time, ANOVA
indicated that compliance 1) decreased significantly
(P < 0.05) during partial liquid ventilation with
either fluid; and 2) remained significantly greater
(P < 0.05) in perflubron-treated animals than in
nontreated control and perfluorodecalin-treated animals throughout the
protocol, whereas that for perfluorodecalin-treated animals was not
significantly different from nontreated controls by 4 h.
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After saline injury (Fig. 6), analysis demonstrated significant within-
and between-group differences for PaO2 and respiratory compliance. Animals treated with either liquid demonstrated a significant increase in PaO2 (P < 0.05) from injury values. The increase in PaO2 was
significantly greater (P < 0.001) with perflubron than
perfluorodecalin and was sustained with perflubron compared with
perfluorodecalin for which PaO2 decreased to injury
values by 4 h. Respiratory compliance initially increased
significantly from injury values (P < 0.001) after
perflubron but was not significantly different from injury values after
perfluorodecalin. Over time, compliance decreased significantly
(P < 0.05) during PLV with either fluid. Compliance
in perflubron-treated animals remained significantly greater
(P < 0.05) than in nontreated control and perfluorodecalin-treated animals throughout the protocol, whereas compliance in perfluorodecalin-treated animals was not significantly different than in nontreated controls by 4 h. Animals treated with
perflubron also demonstrated significantly (P < 0.05)
lower PaCO2 and higher pH than did nontreated control
animals and those treated with perfluorodecalin (Table 2). There were
no significant differences in mean arterial pressure between or within
the injury groups over the 4 h (Table 2).
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DISCUSSION |
Various preclinical and clinical investigations of LAV have
demonstrated the ability to successfully provide ventilatory support to
surfactant-deficient preterm animals (16, 26, 29, 30, 39, 42,
44), animals of various gestational ages with induced lung
injury (6, 12, 23, 31, 35), and critically ill human
neonates (10, 15). However, conclusions regarding
guidelines for optimal management with PFC have not been reached.
Whereas investigators have addressed the effect of the initial PFC dose on oxygenation and reduction in ventilatory pressure (36,
42), none has focused on defining indexes to guide the
maintenance of therapeutic PFC lung volume and homogenous distribution
in an effort to maximize the protective benefit of PFC to the lung. The
purpose of this study was to evaluate two PFC liquids under consideration as alternative respiratory media with respect to intrapulmonary distribution, elimination profile, and pulmonary function profile with time.
Intrapulmonary distribution of PFC.
The results of this study demonstrate dramatic differences in both
initial and time-dependent intrapulmonary distribution patterns of
perflubron compared with perfluorodecalin PFC liquid. Whereas the
initial distribution pattern was more homogenous with perflubron
compared with perfluorodecalin, the distribution of perflubron changed
markedly during the 4 h of study, with a marked heterogeneous
elimination pattern. In contrast, the distribution of perfluorodecalin
remained relatively constant with fewer differences in regional
clearing patterns throughout the protocol. There may be several
physicochemical factors that influence the differences between the
distribution patterns of the PFC liquids studied. The effect of gravity
associated with PFC density is likely to contribute to PFC
redistribution over time. Although the densities of
perfluorodecalin and perflubron are orders of magnitude greater than gas and almost twice as great as water, they are relatively similar to each other. Because of this property, coupled with the fact
that there was a small, vertical height differential between the
perfluorodecalin- and perflubron-filled rabbit lungs (Fig. 1),
there may have been an attenuation of the redistribution of
perfluorodecalin compared with perflubron. However, whereas the
nondependent regions of the perfluorodecalin lungs appear somewhat less
dense at 4 h, perfluorodecalin remains clearly present, in
contrast to the absence of perflubron in similar areas at 4 h.
Therefore, it is likely that physicochemical properties other than
density have an interactive role with gravity to produce the observed
differences in PFC distribution patterns. Fluids of higher spreading
coefficients (a parameter related to the surface tension of the liquid,
gas-liquid, or liquid-liquid interfacial surface tension and lipid
solubility of the lung media) may be distributed more readily in the
lung than fluids of lower spreading coefficients. Although surface
tension is similar between these fluids (perflubron = 18.1 dyn/cm;
perfluorodecalin = 19.3 dyn/cm), the spreading coefficient (2.7 dyn/cm) and lipid solubility (1.7 µg PFC · mg
lipid1 · mmHg1) of perflubron are
greater than those of perfluorodecalin (spreading coefficient:
1.5 dyn/cm; lipid solubility: 0.96 µg PFC · mg
lipid1 · mmHg1) (13, 25,
38). On this basis, the relatively more homogenous initial
distribution of perflubron compared with perfluorodecalin immediately
after instillation may be associated with differences in the spreading
coefficient and lipid solubility. Over time, the same properties may
promote redistribution resulting in the greater stratification of
perflubron relative to perfluorodecalin observed at the 4-h time point.
Alternatively, the pattern of apparent redistribution may be due to
"clearing" of perflubron from the nondependent regions, possibly
associated with selective evaporation if these areas received a greater
proportion of the minute ventilation.
On the basis that the viscosity of a liquid can be defined as the
internal friction of fluid, which produces resistance to change in form
(37), fluids of higher viscosity or kinematic viscosity
(e.g., viscosity/density) may resist distribution in the lung. Whereas
there is little difference in the density of perflubron (1.89 g/ml) and
perfluorodecalin (1.93 g/ml) (8), kinematic viscosity of
perfluorodecalin (2.61 cS) is ~2.5 times greater than that of
perflubron (1 cS) (8). As such, differences between the
distribution patterns with perfluorodecalin and perflubron may also be
related to the kinematic viscosity. Within this context, the higher
kinematic viscosity of perfluorodecalin could impede both initial
distribution and redistribution over time, compared with the relatively
more homogenous initial distribution and subsequent clearing of
perflubron from the nondependent regions.
It is also possible that differences in respiratory gas solubility
between the PFC liquids may have influenced the distribution pattern.
Early studies of volume-controlled saline lavage demonstrated that lung
priming by instilling saline at a rate equal to the measured
O2 consumption facilitated effective volume distribution (14). This concept of coupling fluid instillation rate to
metabolic gas exchange has since been extended to liquid ventilation
studies in large and small animals to foster lung priming with PFC, a fluid of greater O2 solubility than saline, and prevent gas
pocket accumulation (28, 39, 44). This concept can be
further extended to the effect of CO2 solubility on priming
rates. In this regard, if the CO2 solubility and rate of
CO2 absorption by the liquid exceeds metabolic
CO2 production, then the reduced gas pressure within the
alveolus will foster "wicking" or distal displacement of fluid to
the source of CO2. Within this context, the more homogenous initial distribution and subsequent greater stratification pattern of
perflubron compared with perfluorodecalin may be associated with the
relatively greater CO2 solubility of perflubron (210 ml/dl)
than perfluorodecalin (140 ml/dl). Collectively, differences in
spreading coefficient, kinematic viscosity, and CO2
solubility foster more homogenous initial distribution of perflubron
compared with perfluorodecalin. However, these same properties may
contribute to subsequent redistribution of perflubron (stratification
to the dependent regions) and maintenance of the initial distribution pattern of perfluorodecalin. Ideally, the physicochemical properties of
a breathable PFC liquid should promote homogenous and sustained intrapulmonary distribution of PFC to maximize lung protection from barotrauma.
PFC elimination.
During PLV, PFC liquid is eliminated from the lung by volatilization
into the expired gas. The rate at which the PFC is eliminated is
influenced by a number of previously described factors, including the
driving force created by the PFC vapor pressure and the gas flow (i.e.,
minute ventilation) (27). In order for the PFC to be
expired, there must also be contact between the inspired gas and PFC
liquid. In this study, the PFC elimination profile demonstrated a
time-dependent decrease in expired gas saturation and rate of elimination in all animals, independent of the type of PFC or lung
condition. Additionally, expired gas saturation and rate of elimination
with PFC were significantly greater in the perfluorodecalin-treated compared with perflubron-treated lungs, independent of lung condition. It is unlikely that differences in this profile were solely due to
differences in driving force because minute ventilation was constant
throughout the protocol in all animals and there is very little
difference in the vapor pressure between the two fluids (at 37°C,
perflubron = 10.4 mmHg and perfluorodecalin = 13.6 mmHg). The
differences in expired gas PFC saturation and elimination profile are
more likely associated with the unique distribution patterns conferred
by the physicochemical properties of the respective PFC fluids. In this
regard, we speculate that the initial distribution of perfluorodecalin
was maintained because of the higher kinematic viscosity, lower
spreading coefficient, and, possibly, the lower CO2
solubility relative to perflubron. The sustained distribution pattern
of perfluorodecalin provided greater gas-PFC liquid contact, thus
favoring greater elimination over the duration of the protocol relative
to the pattern seen with perflubron. With perflubron, redistribution
and/or selective evaporation from the nondependent regions would
decrease the relative overall contact of gas to perflubron, thus
contributing to the relatively lower rate of perflubron loss compared
with perfluorodecalin.
Lung condition also influenced PFC elimination: PFC expired gas
saturation, as well as elimination profile, was significantly greater
in the healthy groups compared with injury groups, independent of PFC
utilized for treatment. This finding may be explained by the relatively
greater distribution of ventilation and thus gas-PFC liquid contact in
the healthy compared with injured lungs. It is also possible that PFC
liquid may have migrated to noncommunicating air spaces in the injured
lungs, thus preventing volatilization.
Integrative effects of PFC liquid dynamics on cardiopulmonary
function.
With respect to cardiopulmonary stability, differences were observed as
a function of the type of PFC liquid utilized and lung condition. In
healthy animals, there was less effect on gas exchange and compliance
after perflubron instillation compared with animals receiving
perfluorodecalin, in which there was a significant and sustained
decrease in both PaO2 and compliance. As has been
shown previously (6, 12, 16, 23, 26, 29-31, 35, 39, 42,
44), in the injured animals, both PFC liquids increased
PaO2 compared with conventional ventilation alone.
However, it is noteworthy that perfluorodecalin did not increase
compliance, whereas treatment with perflubron resulted in an increase
in dynamic respiratory compliance, as well as a greater improvement in
pH and gas exchange compared with the perfluorodecalin rescue group. The different effects of the PFC liquids on compliance and gas exchange
may have occurred because of the following mechanisms.
In the healthy lung, interfacial tension between PFC liquids and lung
surface is greater than the normal air-lung interfacial tension
(2). On this basis, we expected that both perflubron and
perfluorodecalin would have reduced compliance. However, we found that,
after perflubron instillation, compliance was initially maintained and
then gradually decreased over time. As shown by the CT images, it
appears that the initial dose of perflubron effectively maintained
overall lung volume, which would foster homogenous recruitment and thus
compliance. Over time, clearance and/or redistribution of perflubron
would lead to regional differences in interfacial tension,
nonhomogenous expansion, and thus decreased compliance. In contrast,
after perfluorodecalin instillation, we found a greater and sustained
decrease in compliance, significantly greater than that after
perflubron. Our findings may be related to the differences in the
kinematic viscosity and spreading coefficients of these fluids. In this
regard, PFC liquids with elevated kinematic viscosity (i.e.,
perfluorodecalin) offer resistance to change of form and thus may
require more driving pressure to move the fluid through the airways and
into air spaces compared with PFC liquids of lower kinematic viscosity
(i.e., perflubron). These properties may be associated with the
observed decrease in volume excursion of the inspired gas (i.e.,
decreased compliance). In addition, the lower spreading coefficient of
perfluorodecalin compared with perflubron may limit alveolar
distribution of the liquid. Therefore, the same properties that impair
intrapulmonary distribution of perfluorodecalin, as evidenced by CT
images, may have also impaired lung distensibility in the normal lung.
Thus, despite a higher rate of elimination of perfluorodecalin compared with perflubron over the 4-h protocol, the relatively less homogenous distribution of perfluorodecalin would cause nonhomogenous distribution of inspired gas volumes and lung overdistension and thus a sustained decrease in compliance compared with that of perflubron.
In the injured lung, PFC liquid recruits lung volume and reduces
collapsing forces by replacing the air-lung interface with a
liquid-liquid interface, and the interfacial tension between the
surfactant-deficient lung and PFC liquid is lower than the surface
tension of the surfactant-deficient lung (33). Compared with no liquid or perfluorodecalin, perflubron effectively increased compliance of the saline-injured lung. The decrease in compliance over
time with perflubron may be related to the evaporative loss leading to
derecruitment. In addition, clearing and/or redistribution of
perflubron from the nondependent to the dependent region would allow
reintroduction of gas-liquid interface in the nondependent regions of
the lung, thus contributing to the decrease in compliance. In contrast,
the lack of improvement in compliance with perfluorodecalin may have
been related to the effects of high-kinematic viscosity and
low-spreading coefficients to limit initial homogenous distribution and
lung volume recruitment. In addition, these properties would serve to
maintain the perfluorodecalin distribution pattern. Thus, despite the
higher elimination rate compared with perflubron in the injured lung,
over time perfluorodecalin would present a relatively greater
interfacial tension across more of the lung surface and thus lower
compliance compared with perflubron.
Differences in gas exchange in the healthy and injured animals treated
with perflubron compared with perfluorodecalin may be attributed to the
PFC distribution patterns and physicochemical properties of the
liquids. In this regard, whereas the diffusion coefficients of
O2 and CO2 are not available for the PFC
liquids studied, it is known that gases diffuse more slowly in liquid compared with gas volumes. As such, PFC liquids may impose diffusional limitations on gas exchange. Diffusional limitations may explain, in
part, the initial decrease in PaO2 in healthy animals
for both liquids at the 1-h time point. Over time, as perflubron was
cleared and/or redistributed, PaO2 decreased during
the final 2 h, reflecting ventilation-to-perfusion mismatch.
Compared with perflubron, there was a sustained decrease in
PaO2 after perfluorodecalin instillation. Because
equal volumes of perflubron and perfluorodecalin were used across
groups and elimination rates of perfluorodecalin over the 4-h protocol
were generally greater than those of perflubron, differences in
oxygenation may also be related to the differences in kinematic
viscosity and spreading coefficients between the two fluids. Based on
CT images, it appears that the lower kinematic viscosity of perflubron
supported more homogenous distribution of liquid, which would, in turn,
support more homogenous distribution of ventilation and improved gas
exchange compared with that of perfluorodecalin. In addition, the
higher spreading coefficient and homogenous distribution of an equal
volume of perflubron would favor a thinner PFC liquid diffusional
barrier at the alveolar-capillary membrane compared with those of
perfluorodecalin. Regional and sustained differences in
perfluorodecalin distribution and relatively thicker PFC diffusional
barriers associated with perfluorodecalin, particularly in the
dependent lung, would contribute to a sustained reduction in
PaO2. This explanation is consistent with the
previously demonstrated dose-dependent ventilation-perfusion
heterogeneity and diffusional limitations during PLV in healthy piglets
(17, 18). Because gas diffusion in the gas-filled region
of the healthy lung can offset the diffusional barriers of the
perfluorodecalin-filled regions, the reduction in PaO2
does not represent a substantial clinical compromise in healthy animals.
However, because of the previously discussed properties that impede
perfluorodecalin distribution, recruitment of the injured lung by
perfluorodecalin may be less effective than that by perflubron with
respect to gas exchange. Although we were unable to obtain CT images in
the injured animals while providing critical care support, it is
reasonable to speculate that, after saline lavage injury, in contrast
to the healthy gas-filled lung, the lung is relatively atelectatic.
Atelectatic areas not recruited by the liquid would substantially
attenuate an overall improvement in PaO2 supported by
the liquid-filled regions. Within this context, the relatively less
robust initial increase in PaO2 and subsequent deterioration in PaO2 over time after perfluorodecalin
compared with perflubron may reflect the nonhomogenous distribution
of the liquid limiting recruitment, the diffusional barrier in the dependent regions limiting gas exchange, and the higher elimination rates, which would contribute to derecruitment. Summarily, PFC maldistribution and ventilation heterogeneity coupled with increased diffusional barriers associated with the sustained pattern of perfluorodecalin distribution could explain the relatively lower oxygenation and higher CO2 tensions in the injured animals
treated with perfluorodecalin compared with perflubron. On this basis, it may be suggested that a PFC with an intermediate viscosity between
perflubron and perfluorodecalin, surface tension and vapor pressure
comparable to these two fluids, and high-respiratory gas solubility
similar to perflubron may optimize distribution and pulmonary mechanics
while supporting pulmonary gas exchange.
In summary, there are several physicochemical factors that one must
consider when choosing a PFC liquid as a potential alternative breathable medium. Our findings indicate that the rate of PFC elimination from the respiratory system is not constant, despite a
constant ventilation strategy. The results indicate that PFC elimination appears to be influenced by the type of PFC utilized, gas-PFC communication, and lung condition. Differences between PFC liquids appear to influence intrapulmonary distribution and elimination patterns, which subsequently influence lung function. Within this context, this study indicates that the physicochemical profile is an important criterion when a PFC liquid is selected for a
particular clinical application. For example, a fluid of higher
kinematic viscosity and lower spreading coefficient may be appropriate
if the goal is to deliver PFC liquids to selective regions for the
purposes of lung growth of the hypoplastic lung (22) or
recruitment and prevention of atelectasis/fluid flux during lung rest,
in which gas exchange is supported by extracorporeal membrane
oxygenation (9). However, if the goal is to support pulmonary gas exchange and achieve homogeneous distribution for global
lung protection, drug/vector delivery, or imaging, then a fluid of
lower kinematic viscosity and higher spreading coefficient may be more
appropriate. Further study is required to identify the functional role
of each of the physicochemical properties to match existing PFC liquids
with, or synthesize the most appropriate PFC liquid for, a specific
pulmonary application for the purposes of respiratory (i.e., partial
and tidal liquid ventilation) as well as nonrespiratory support (i.e.,
lavage, drug delivery, imaging).
| |
ACKNOWLEDGEMENTS |
We gratefully acknowledge the assistance of Cynthia Cox, Robert F. Roache, Dr. Raymond Foust III, and Joyce Forge in the completion of
this work.
| |
FOOTNOTES |
This work was performed at Temple University School of Medicine and was
supported in part by Alliance Pharmaceutical, San Diego, CA.
Address for reprint requests and other correspondence: M. R. Wolfson, Dept. of Physiology, Temple Univ. School of Medicine, 3420 North Broad St., Philadelphia, PA 19140 (E-mail:
marlar{at}astro.ocis.temple.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 1 August 2000; accepted in final form 15 September 2000.
| |
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TOP
ABSTRACT
INTRODUCTION
![PFC liquid loss<IT>=</IT>[(<IT><A><AC>V</AC><AC>˙</AC></A></IT><SC>e</SC><IT>×%</IT>PFC sat)<IT>×</IT>(ml PFC fluid/ml vapor)<IT>×</IT>time]](/content/vol90/issue3/fulltext/839/img001.gif)
