PEDIATRICS Vol. 100 No. 5 November 1997,
p. e5
Copyright © by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
Pulmonary Administration of Gentamicin During Liquid Ventilation
in a Newborn Lamb Lung Injury Model
William W. Fox*,
Carla M. Weis*,
Cynthia Cox
,
Clotilde Farina§,
Henry Drott
,
Marla R. Wolfson¶, and
Thomas H. Shaffer¶
From * Children's Hospital of Philadelphia, Neonatology
Division, Philadelphia, Pennsylvania;
John S. Sharpe Research
Foundation of the Bryn Mawr Hospital, Bryn Mawr, Pennsylvania;
§ University of Milan, Milan, Italy;
Children's Hospital of
Philadelphia, Clinical Laboratories, Philadelphia, Pennsylvania; and
¶ Temple University School of Medicine, Department of Physiology,
Philadelphia, Pennsylvania.
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGMENTS
ABBREVIATIONS
REFERENCES
ABSTRACT
Objectives. Newborns with pulmonary
infection frequently present with acute lung injury leading to
ventilation/perfusion abnormalities in which intravenous delivery of
antibiotics to the lung can be suboptimal. Tidal liquid ventilation
(TLV) has been shown to be an effective means for delivering drugs
directly to the pulmonary system. The objective of this study was to
compare, with lung injury, antibiotic delivery achieved by conventional
techniques (gas ventilation and intravenous gentamicin) with that using
pulmonary administration of drug (PAD) during TLV.
Methods. Twelve newborn lambs with an acid lung injury
were randomized to receive gentamicin either intravenously during gas ventilation or via PAD during TLV using LiquiVent (Alliance
Pharmaceutical Corporation, San Diego, CA, and Hoechst-Marion Roussel,
Bridgewater, NJ) perfluorochemical. Gentamicin (5 mg/kg) was
administered over 1 minute, and serum levels were obtained at 15-minute
intervals. Arterial blood gases and pulmonary mechanics were measured.
Ventilation efficiency index and arterial/alveolar oxygen ratio were
calculated. Lung-tissue gentamicin levels were measured 4 hours after
administration and corrected to dry weight.
Results. Serum gentamicin levels were similar in both
groups. Lung gentamicin levels (µg/g) were significantly higher for TLV. Also, TLV resulted in significantly more of the total delivered dose in the lung after 4 hours. Ventilation efficiency index and arterial/alveolar oxygen ratios were significantly higher for TLV.
Conclusions. In this lung injury model, both methods
achieved equivalent serum gentamicin levels with higher lung levels
using PAD during TLV. This study suggests that TLV may provide an
effective vehicle for gentamicin delivery in infants with severe
pulmonary infection and ventilation/perfusion abnormalities.
Key words:
perfluorochemical,
liquid ventilation,
gentamicin,
newborn,
lung injury,
pulmonary administration of drug,
antibiotic,
intratracheal.
INTRODUCTION
Newborn infants with pulmonary infection frequently present
with an acute lung injury leading to ventilation and perfusion abnormalities. In the presence of irregular pulmonary perfusion, intravenous (IV) delivery of antibiotics to the lung can be less than
optimal. However, the circulation is currently the only viable route by
which to attack pulmonary infections.
Direct delivery to the pulmonary system can be effective for several
types of drugs by utilizing aerosolization or direct endotracheal tube
delivery. For example, bronchodilators1,2 and many
resuscitation drugs3 are effectively delivered in this way.
More recently it has been proposed that nebulization may be a
preferable route of delivery for corticosteroids4 and
diuretic5,6 therapy in the neonate. However, the need for
higher drug doses, problems related to particle size, and distribution
of drug to the lung periphery can hinder the effectiveness and/or
usefulness of this type of drug delivery.7
Liquid ventilation (LV), while providing a revolutionary mode for
respiratory support, has also been shown experimentally to be an
effective alternative means for drug administration.11 For example, priscoline and gentamicin have been delivered to the
uninjured lung of full-term animals and preterm animals with respiratory distress syndrome more effectively in this way as compared
with IV administration.11,13 Some of the same physical properties that enable perfluorochemical (PFC) liquids to behave as a
medium for total respiratory support make them advantageous for
pulmonary administration of drugs (PAD). Biochemical inertness precludes any interaction with the drug, low surface tension enhances distribution of the drug, and high respiratory gas solubility supports
gas exchange during delivery of the drug. Also, with the ability of PFC
LV to improve ventilation-perfusion matching,14 drug
exposure to the circulation is optimized and therapeutic serum drug
levels can be achieved.
Pulmonary infection is a common malady seen in the intensive care
nursery. It can be seen in premature infants with immature defense
mechanisms, infants requiring ventilatory support, and infants who have
prolonged hospitalization. These infants may benefit not only from LV,
but also from direct PADs, particularly antibiotics.
In this study we evaluated and compared serum uptake and lung uptake
and distribution of gentamicin using PFC as a vehicle for pulmonary
drug delivery during tidal liquid ventilation (TLV) as compared with
that of conventional IV administration during gas ventilation (GV) in
the lung-injured newborn lamb. We hypothesized that an equal dose of
gentamicin delivered to the injured newborn lung via PAD during TLV
would result in similar serum levels and higher lung tissue levels
compared with IV administration during GV.
METHODS
Animal Preparation
Twelve full-term newborn lambs (mean weight, 4.8 ± 0.35 kg; <1 week of age) were studied and managed according to the
National Institutes of Health Regulations and the Guiding Principles in the Care and Use of Animals of the American Physiological Society. The
study was performed with the approval of the institutional animal care
committee. Animals were anesthetized with sodium pentobarbital (20 to
30 mg/kg). Arterial and venous catheters were placed in the carotid
artery and jugular vein. The trachea was cannulated with a 5.0 Hi-Lo
Jet (Mallinckrodt Medical, St Louis, MO) endotracheal tube. This tube
has a side-port catheter at midlength that was used to administer the
drug during TLV. This port was also used for airway pressure
measurement during LV. Lambs were paralyzed with pancuronium bromide,
0.1 mg/kg/h, and ventilation was supported using a Harvard Small Animal
Ventilator (Harvard Apparatus, Inc, South Natick, MA). Anesthesia was
maintained using sodium pentobarbital (10 mg/kg/h).
Experimental Procedures and Protocol
Lung Injury
A lung injury model was created in newborn lambs to cause
pathophysiological perturbations experienced by infants including: 1)
pulmonary hypoperfusion secondary to hypoxia and pulmonary hypertension, and 2) maldistribution of ventilation attributable to
consolidation and pulmonary edema. This injury was intended to produce
a situation of severe ventilation-perfusion mismatch simulating the
lung condition of the newborn with pneumonia, adult respiratory
distress syndrome, or neonatal respiratory distress syndrome
complicated by pneumonia. Saline was acidified using hydrochloric acid
to achieve a pH in the range of 1.6 to 1.8. This solution was warmed to
37°C and used to lavage the lung. The fluid was instilled by gravity
using approximately 20 cm H2O pressure to fill the
lung, and immediately after instillation, gravity was used to empty the
lung. Serial lavages (10 mL/kg/lavage) were performed to establish an
injury defined as a 50% decrease from baseline of both the
PaO2 and the dynamic lung compliance (CL). Ten to 20 minutes were allowed between every two
lavages to assess injury. All animals were gas-ventilated during the
lung injury process. Lambs were then assigned to different ventilation groups.
TLV (n = 6)
A functional residual capacity volume (30 mL/kg) of warm
(37°C), oxygenated (FIO2 = 1.0)
LiquiVent PFC was delivered to the lungs by gravity followed by TLV
using time-cycled, pressure-limited TLV as previously
described.15 Animals were ventilated with a breathing
frequency of 5, tidal volumes of 25 to 30 mL/kg, inspiratory to
expiratory ratio of 1:3, and FIO2 = 1.0.
GV (n = 6)
GV was achieved using a volume-limited gas ventilator at a
breathing frequency of 50 to 60 breaths/minute and pressures of
40/8
cm H2O and FIO2 = 1.0.
In both groups, ventilation strategy was adjusted as dictated by
arterial blood gas data obtained to achieve the best possible gas
exchange. Infusion of sodium bicarbonate or THAM (trometh-amine, Abbott Laboratories, Chicago, IL) was used to correct metabolic acidosis. Dopamine and dobutamine (
20 µg/kg/min) were used if necessary to maintain mean arterial blood pressure (MAP) values >50 mm
Hg.
Drug Delivery
Gentamicin sulfate (5 mg/kg) was diluted with normal
saline to a total volume of 5 mL. During GV, this dose was administered via continuous IV injection for 1 minute. During TLV, this dose was
administered intratracheally via the midlength catheter port of the
endotracheal tube in five 1-mL bolus aliquots during each inspiration,
directly into the PFC liquid stream, throughout five consecutive tidal
breaths. This multiple bolus technique was used in an attempt to
enhance mixing of the drug with the inspiratory PFC liquid stream while
duplicating the delivery time of the IV administration. Lambs were
studied for 4 hours postgentamicin administration.
Measurements
Arterial pressure was measured (Statham P23Db transducer
and Hewlett Packard (Andover, MA) cardiorespiratory monitor-Model 78910A) and arterial blood gases (Radiometer [Copenhagen, Denmark] ABL 330) were obtained throughout the study. Dynamic lung compliance measurements (PEDS Lab, Medical Associated Services, Hatfield, PA) were
performed during GV. Ventilation efficiency index (VEI) and
arterial-alveolar (a/A) ratios were calculated to normalize for
variations in different ventilation strategies and relate ventilatory
support to alveolar ventilation, and to assess oxygenation requirements, respectively.
VEI was determined as previously described:19
|
(1)
|
where
P = Pinsp
Pexp, f = ventilator rate and
A =
CO2/PaCO2/760 mm
Hg.
Assuming
CO2 (CO2
production) as 5 mL/kg/min, then
A = 3800/PaCO2. Therefore,
|
(2)
|
Note that normal VEI = 0.3 mL/mm Hg/kg.
a/A ratio was determined as:
|
(3)
|
where
|
(4)
|
FIO2 is inspired oxygen
concentration, Patm is atmospheric pressure (760 mm Hg),
PH2O is water vapor pressure (47 mm
Hg), R is respiratory exchange ratio, and PaCO2
is the partial pressure of carbon dioxide in the alveolus, which is
assumed to be equal to the partial pressure of carbon dioxide in the
blood.
For FIO2 equal to 1.0, Equation 4 reduces to
the following:
|
(5)
|
Note: Water vapor pressure is not considered during TLV because
water and water vapor are not miscible with PFC.
Gentamicin Assays
Blood samples for gentamicin assay were obtained before
administration of gentamicin and at 15-minute intervals after the administration of gentamicin throughout the study. The blood was collected in glass tubes without anticoagulant and allowed to clot. The
tubes were centrifuged and the serum removed for assay.
At the end of each experiment, heart and lungs were block-dissected.
Using the main pulmonary artery, the pulmonary vasculature was perfused
with 200 mL of normal saline to remove residual intravascular blood.
Individual lobe weights were obtained. Representative sections of each
lobe of the lung were dissected (five to eight sections/lobe using a
predetermined lung matrix), weighed, and homogenized in 15 mL of a
buffered phosphate solution (pH 7.4). The homogenate was centrifuged
and the supernatant assayed for gentamicin.
Assay of gentamicin levels in both serum and tissue was performed
using a fluorescent polarization method.20 Tissue
levels were normalized to dry lung weight. Large airways were not
included in lung samples. The absolute gentamicin concentration for
each lobe was then used to calculate a percentage representing the fraction of the total gentamicin dose that was delivered to each lobe.
Data Analysis
Results are presented as mean ± SE. Values for
CL and PaO2 before and after
injury were compared using one-way analysis of variance. Gentamicin
blood and tissue levels and blood gas data were analyzed using two-way
analysis of variance to evaluate differences as a function of time and
method of administration. Statistical differences were analyzed further
using a Bonferroni post hoc. A P value
.05 indicated
statistical significance.
RESULTS
Lung Injury
Figures 1A and B show preinjury
and postinjury CL and
PaO2 measurements. Preinjury values for
CL and PaO2 were not significantly different between groups. A total of two to seven lavages were required
to cause a 50% decrease in CL and at least a 50% decrease in PaO2 with this injury. Approximately 75% of
the lavage fluid was recovered. Similar decreases in both
CL and PaO2 were attained for both
groups of animals. One animal in the GV group died 3 hours after
gentamicin was given.
Fig. 1.
A, Comparison of injury-induced compliance changes in study groups
before randomization. Injury resulted in a significant (P < .001) decrease in dynamic lung compliance
independent of subsequent randomization. Asterisks indicate that
preinjury versus postinjury compliance is significantly greater
independent of ventilation. B, Comparison of injury-induced
PaO2 changes in study groups before
randomization. Injury resulted in a significant (P < .001) decrease in
PaO2 independent of subsequent randomization. Asterisks indicate that preinjury versus postinjury
PaO2 is significantly greater independent of
ventilation.
[View Larger Version of this Image (43K GIF file)]
Gas Exchange and Blood Pressure
Mean values (±SE) for VEI and a/A ratio throughout the time
for both groups are presented in Table 1
and Table 2. Postinjury values for VEI
(GV, 0.078 ± 0.017; TLV, 0.072 ± 0.017) and a/A ratio (GV,
0.13 ± 0.034; TLV, 0.22 ± 0.063) were not significantly different between groups. Animals supported with TLV after injury had
significantly higher a/A ratios (P < .001) and
VEI values (P < .001) as compared with those
supported with GV. There was no significant difference in either a/A
ratios or VEI values as a function of time for either group.
|
Table 1.
Ventilation Efficiency Index Values (mL/mm Hg/kg)*
[View Table]
|
After the injury, vasopressors and/or volume boluses were necessary in
most animals to maintain MAP values greater than 50 mm Hg. The mean MAP
values during the time after injury for each group were: GV = 57.3 ± 2.44 mm Hg; TLV = 56.5 ± 3.46 mm Hg. There was
no significant difference between MAP for the two groups throughout this time. In addition, there was no difference in the amount of
vascular support between groups.
Gentamicin Serum Levels
Figure 2 shows the serum gentamicin
levels obtained as a function of time. Serum levels were highest at 15 minutes after gentamicin administration and were not significantly
different between delivery modes. There was a progressive, significant,
and comparable decline in mean serum drug level throughout time in both
groups. The mean serum value at 15 minutes after administration for all
animals was 10.1 ± 1.44 µg/mL and after 4 hours was 3.0 ± 0.197 µg/mL. In the GV group, 15 minutes after IV administration,
mean serum level was 12.2 ± 1.45 µg/mL, and after 4 hours was
2.7 ± 0.22 µg/mL. In the TLV group, mean serum level was
8.0 ± 2.31 µg/mL after 15 minutes and 3.3 ± 0.287 µg/mL
after 4 hours.
Fig. 2.
Comparison of gentamicin serum levels. There was no difference in
gentamicin serum levels throughout time when comparing intravenous administration with pulmonary administration.
[View Larger Version of this Image (17K GIF file)]
Gentamicin Lung Tissue Levels
Table 3 summarizes intralobar and
whole lung tissue gentamicin levels 4 hours after drug administration
for each group of animals. During TLV, administering gentamicin via
PAD resulted in sig-nificantly higher (P < .01) mean lung tissue concentrations for the entire lung as compared
with IV administration with GV.
Figure 3 depicts the distribution of
lung tissue gentamicin levels expressed as a percentage of the total
gentamicin dose delivered. Compared with IV during GV, PAD delivery of
gentamicin during TLV resulted in a significantly higher
(P < .01) percentage of total delivered drug in
the lung 4 hours after administration. Gentamicin concentrations seem
to be relatively higher in the right lung compared with the left lung
when using PAD during TLV. However, this difference did not reach
statistical significance.
Fig. 3.
Comparison of gentamicin lung tissue levels expressed as a percentage
of the total dose given. Pulmonary administration resulted in a
significantly greater (P < .005) percentage of
the total delivered drug dose in the lung 4 hours after administration. CA indicates cranial apical lobe; RUL, right upper lobe; RML, right
middle lobe; RLL, right lower lobe; LUL, left upper lobe; and LLL, left
lower lobe.
[View Larger Version of this Image (25K GIF file)]
DISCUSSION
The results of this study demonstrate that pulmonary
administration of an equal dose of gentamicin during TLV is an
effective means to achieve higher (approximately 2 times) lung tissue
gentamicin levels in the injured newborn lung 4 hours after dosing
compared with conventional IV administration during GV, while achieving comparable and therapeutic serum levels. A significantly greater percentage (approximately 5 times) of total drug administered after PAD
was found in the lung after 4 hours compared with that achieved with IV
administration. Concomitantly, PAD with TLV resulted in lung tissue
levels 10 times that of serum levels 4 hours after dosing. Furthermore,
TLV demonstrated more effective respiratory support for this injury
model compared with conventional GV.
Improved delivery of an antibiotic to the injured or infected lung
using pulmonary delivery is of great clinical importance. In the
intensive care nursery setting, the concern for and presence of
pulmonary infection is ubiquitous. It can be seen in infants requiring
ventilatory support, premature infants with immature defense
mechanisms, and infants who have prolonged hospitalization. These
infants may benefit not only from LV, but also from PFC facilitated
delivery of drugs, particularly antibiotics.
Selection of an antibiotic depends on the sensitivity of the
microorganism. Those infections caused by Gram-negative bacilli often
require use of an aminoglycoside. Gentamicin is a widely used
aminoglycoside in the newborn intensive care setting as the clinician
is often interested in treating or covering for infections produced by
Escherichia coli, Klebsiella pneumoniae, Pseudomonas sp, or
Serratia sp. Also, gentamicin may be used to act
synergistically with ampicillin against certain Gram-positive
infections.
Previous work has demonstrated that gentamicin can be more effectively
delivered to the uninjured lung in the full-term lamb and to the lung
of an immature lamb with respiratory distress during TLV using PAD when
compared with IV administration.13 That is, lung tissue
gentamicin levels were significantly higher after PAD. Also, pulmonary
distribution of drug was similar with both modes of administration.
Given the ventilation/perfusion (V/Q) disturbances that exist with
pulmonary infections in the newborn as well as in those neonatal
conditions predisposing to pulmonary infection, the effectiveness of
this mode of therapy compared with conventional therapy needed to be
evaluated in an injured newborn lung model. This is the first study to
look at pulmonary administration of an antibiotic during LV using an
injured lung model.
For the neonate with respiratory tract infection, successful treatment
depends not only on immune defenses both systemically and locally, but
also on the ability of therapeutic intervention to optimize the
delivery of an appropriate antimicrobial agent to the site of infection
in concentrations that exceed those needed to inhibit bacterial growth.
For intraparenchymal lung infections, monitoring of serum antibiotic
levels can closely approximate antibiotic concentrations in alveolar
and interstitial fluids.21 However, these measurements may
not imply adequate therapy for pneumonia. Many pneumonias represent a
mixture of purulent tracheobronchitis plus parenchymal infection. The
intubated patient in particular can have large areas of infected
respiratory tissues in the airways, far from alveolar and interstitial
fluids. Consequently, serum antibiotic levels may be misleading in
assessment of the adequacy of antibiotic delivery.
The concept of a blood-bronchus barrier has been used to describe the
problems of antibiotic delivery into the respiratory tract.21 Parenteral antibiotics are often associated with
low antimicrobial activity in bronchial secretions.22
Pennington21 studied gentamicin in bronchial secretions and
found that 1 hour after IV infusion, bronchial levels were
approximately 45% of serum levels and that these levels may not reach
the minimum inhibitory concentration required by the pathogen involved.
In addition, an antibiotic that reaches bronchial secretions can be
inhibited by local conditions of inflammation.23 These
circumstances can demand high serum levels that carry associated renal
toxicity and ototoxicity. The fact that it is difficult to permeate the respiratory system with IV gentamicin is of particular concern in the
presence of consolidated pulmonary infection with associated V/Q
abnormalities and decreased pulmonary perfusion to affected parenchyma.
Concern escalates for the neonate in this situation who is further
compromised by an immature immune response. It is intriguing to
consider direct pulmonary delivery.
For many types of drugs, direct endotracheal tube administration is an
approved delivery mode, especially for naloxone, atropine, diazepam,
epinephrine, and lidocaine.3 Endotracheal tube
administration often requires the use of higher drug doses (compared
with IV),8 which can create airway irritation and interfere
with gas exchange.
Aerosolization, compared with endotracheal delivery, may allow the use
of less drug and may yield more uniform distribution, but efficacy
still depends on peripheral delivery.10,26 Bronchodilators are routinely nebulized to the pulmonary system, however, antibiotic solutions are more viscous than water or saline and thus more difficult
to nebulize.9 Experimental and clinical data support the
delivery of antibiotics to the respiratory tract.25,27 In addition, there is evidence that direct pulmonary exposure to
aminoglycosides protects lung epithelial cells against oxidant injury.31 Aerolized aminoglycosides have yielded
inconsistent yet encouraging results for patients with cystic
fibrosis.29 Ramsey et al.30 have shown safety
and efficacy with short-term administration of aerosolized tobramycin
in stable cystic fibrosis patients using 1800 mg/day, which can be up
to 5 to 10 times the IV dose. A prevailing problem when evaluating the
usefulness of aerosol therapy is the estimation of the dose of
medication actually delivered to the patient's lungs, which depends on
many variables including nebulizer type and output, particle size, and
patient breathing pattern.10,32,33 In addition, the
presence of uneven distribution of ventilation attributable to severe
airway obstruction or mucus hypersecretion can further limit the
usefulness of aerosols and prevent them from reaching the appropriate
receptor sites in the lung.9 Poor peripheral lung delivery
with aerosolization is reflected in very low serum aminoglycoside
levels.34
Using TLV to deliver gentamicin to a newborn lung with profound V/Q
abnormalities, we have shown significantly higher lung tissue
concentrations as well as therapeutic serum levels comparable to those
obtained with the same dose administered intravenously. The
distribution of drug across lung lobes seems relatively uniform for IV
delivery and seems relatively higher in the right lung for PAD during
TLV. Although not reaching statistical significance, this trend may be
the result of subtle differences in animal position during delivery or
perhaps attributable to subtle differences in the flow mechanics during
delivery given that an aqueous drug solution is not dissolved in the
PFC liquid during delivery. Future development of a suitable
emulsion/suspension of drug in PFC may improve the distribution pattern
of pulmonary drug delivery during TLV.
With regard to the total delivered dose of gentamicin, the data (Fig 3)
reveal that by 4 hours the majority of drug delivered by either
technique has ultimately been delivered to the systemic circulation. As
the antibiotic is continually cleared from the circulation, the
antibiotic concentration within the lung after PAD should likewise be
continually declining as the antibiotic follows the concentration
gradient from the lung into the circulation. Because equal doses were
given and yielded comparable serum levels throughout time with
significantly different lung levels, we speculate that drug exposure to
tissues other than the lung may be less after PAD. Further studies
would need to define the pharmacokinetics involved with this type of
drug delivery, particularly with regard to lung levels throughout time.
PAD delivery of an antibiotic for pulmonary infection may allow
decreased dose and/or increased dosing interval, which in turn may
decrease systemic exposure and the risk of associated toxicities.
Although all newborns with pulmonary infections will not require
mechanical ventilation, those who do may sometimes be served by TLV,
and in those cases, PAD delivery of antibiotics seems to offer the
advantage of higher lung tissue levels than those of IV. Whether the
higher lung tissue levels of gentamicin that we have demonstrated can
affect on the morbidity and mortality of these infants beyond that of
TLV remains to be seen.
We believe that in the injured lung with ventilation and perfusion
abnormalities, TLV can provide improved distribution of ventilation and
improved pulmonary blood flow providing not only superior ventilatory
support, but also a mode for improved antibiotic delivery, resulting in
higher drug levels in the injured lung. Newborns with severe
ventilation and perfusion abnormalities may not only benefit from TLV,
but in the presence of pulmonary infection, may benefit from this
unique method for pulmonary administration of antibiotic.
FOOTNOTES
Received for publication Mar 12, 1997; accepted Jun 5, 1997.
Reprint requests to (T.H.S.) Temple University School of
Medicine, Department of Physiology, 215 Medical Research Building, 3420 North Broad Street, Philadelphia, PA 19140.
ACKNOWLEDGMENTS
This work was conducted at Temple University School of Medicine,
Department of Physiology, and was supported in part by Alliance Pharmaceutical Corporation and the Sharpe Research Foundation. Thomas
H. Shaffer, PhD, and Marla R. Wolfson, PhD, have served as consultants
to Alliance Pharmaceutical Corporation, which manufactures the PFC used
in this project. Two investigators (T.H.S. and M.R.W.) are coinventors
of university-filed patents licensed to Alliance Pharmaceutical
Corporation and related to the use of PFCs for biomedical applications.
We thank Robert Roache of the pulmonary physiology laboratory at Temple
University and to the medical laboratory technicians of the clinical
chemistry laboratory at the Children's Hospital of Philadelphia. They
provided the technical support that made this study possible.
ABBREVIATIONS
IV, intravenous.
LV, liquid ventilation.
PFC, perfluorochemical.
PAD, pulmonary administration of drug.
TLV, tidal
liquid ventilation.
GV, gas ventilation.
PaO2, arterial partial pressure of oxygen.
CL, dynamic lung compliance.
FIO2, fraction of inspired oxygen.
MAP, mean arterial (blood) pressure.
VEI, ventilation efficiency index.
a/A, arterial/alveolar (oxygen ratio).
PaCO2, partial pressure of carbon dioxide.
PO2, partial pressure of oxygen.
V/Q, ventilation/perfusion.
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