| HOME | HELP | CONTACT US | SUBSCRIPTIONS | CME | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
||||||||
|
||||||||||
(Pediatrics in Review. 1999;20:e134-e142.)
© 1999 American Academy of Pediatrics
Associate Professor of Physiology and
Pediatrics, Temple University School of
Medicine, Philadelphia, PA.
OBJECTIVES
After reading this article, the reader should be able to:
Introduction
With the advent of modern technology and the evolution of intensive care units, the ability to treat respiratory problems has improved remarkably. This accomplishment is particularly remarkable with respect to the 40,000 preterm infants born each year of whom thousands have severe respiratory problems. Fortunately, the number of smaller and more immature infants who are treated, survive respiratory distress, and recover uneventfully is increasing. However, the overall success of treating neonatal respiratory distress remains limited by the inherent problems of surfactant deficiency and structural immaturity of the lung. Consequently, infants delivered preterm who have respiratory insufficiency experience diminished lung distensibility that results in progressive atelectasis and respiratory failure requiring mechanical ventilation. Currently, many of these infants improve over time when their ventilation is supported mechanically and surfactant is introduced into their lungs. However, as many as 37% of these severely impaired infants are left with bronchopulmonary dysplasia related to damage of pulmonary tissues and structures from conventional mechanical ventilation (CMV).
Of equal importance, acute respiratory distress syndrome (ARDS) due to trauma, aspiration, or infection strikes more than 100,000 adults in the United States annually. Despite aggressive therapeutic procedures, 60% to 70% of these patients die, and as in infants, many suffer complications associated with CMV.
Although structural damage in adults or immaturity in infants cannot be altered acutely, current advances, such as exogenous surfactant replacement therapy to reduce alveolar interfacial surface tension and subsequent inflation pressures, have allowed clinical improvement in gas exchange and decreases in ventilatory requirements, barotrauma, and mortality. Therefore, it appears that the complications associated with respiratory distress can be lessened in proportion to the therapeutic reduction of interfacial surface tension and ventilatory requirements. The concept of maximally reducing surface tension has been explored through liquid ventilation (LV) techniques with perfluorochemical (PFC) liquids.
In addition to respiratory support, other possible medical applications for liquid-assisted ventilation (LAV) are being investigated. Liquid in the lung can remove debris caused by cystic fibrosis, alveolar proteinosis, or aspiration syndromes. In addition, with the aid of liquid in the lungs, pharmacologic agents can be administered with greater effectiveness in lung diseases involving infection and cancer. For example, therapeutic treatment of lung cancer with drugs can have devastating effects on other tissues in the body. By using LV as a carrier for the drug, adverse side effects can be minimized because the agent is administered directly to the surface of the lung. Furthermore, recent studies have shown that it is possible to enhance high-resolution computed tomography (HRCT) images of the respiratory system by administering PFC to the lungs. Finally, as depicted in the underwater science-fiction novel and film, The Abyss, liquid breathing has the potential to allow humans to survive in unusual environments such as in great deeps, in space, and under great acceleration.
The biomedical application of LAV has been explored in animal models for more than 3 decades. More recently, clinical investigational trials have shown that it is possible to maintain gas exchange in critically ill neonates, children, and adults using LV. This review discusses the physiology and methodology of LAV techniques, the rationale and current status of animal and human experiences, and the broad-based potential applications.
Respiratory Liquids
PFC liquids are fluorinated
hydrocarbons in which the hydrogen
atoms have been replaced by fluorine atoms; for perflubron a bromine
atom is added as well (Fig. 1
).
These fluids are stable chemicals
that are clear, colorless, odorless,
and insoluble in water. The
dielectric strength and heat capacity of the
PFC fluids are high; they are denser
than both water and soft tissue, and
surface tension and viscosity are
generally low. Certain PFC liquids
have higher vapor pressure than
water and will evaporate much
faster than water at body
temperature. Of particular importance is the
fact that these liquids have an
exceptionally high gas solubility and
can dissolve as much as 20 times
the amount of oxygen and more
than three times as much carbon
dioxide as water. Oxygen solubility
is two to three times that of whole
blood. In general, PFC fluids are
nontoxic and biochemically inert. In
addition, they are radiopaque. More
than 100 different PFC liquids exist,
although only a few commercially
available liquids meet both the
physicochemical property requirements
and purity specifications for
respiratory applications.
PFC liquids diffuse from the lung into the circulation and are distributed with blood flow to body tissues. Because PFC liquid is nearly insoluble in water, essentially all of the PFC in the blood and tissues is dissolved in lipid. Extensive studies in animals and adult humans have examined the physiology, toxicity, and biodistribution of PFC when used intravascularly as a blood substitute. The concentrations of PFC in the blood after intravascular administration were several orders of magnitude greater than any blood or tissue level reported following LV. All studies reporting uptake as a result of LV have shown very low levels of PFC in the blood and tissues. The most current studies report PFC levels of less than 5.8 mcg/mL of blood. Tissue levels were both PFC- and organ-dependent, with the lowest levels in the liver and the highest levels in the lung, followed by fat tissue. Excluding lung and fat, tissue levels were less than 250 mg/g of tissue after 24 hours of LV. PFC is not metabolized and is eliminated intact by evaporation during exhalation or transpiration through the skin.
|
Respiratory Support Methods
TOTAL LIQUID VENTILATION (TLV)
Several techniques have been
investigated for using PFC liquids as a
respiratory support medium. Early
work with PFC breathing in animals
employed total immersion of several
small animal species. In these
experiments, animals survived for hours if
the liquid was oxygenated
continually, but the increased work of
breathing led to fatigue. Another
early technique used gravity-assisted
ventilation with oxygenated PFC
draining from a reservoir into the
lungs of intubated animals. Neither
of these early methods proved
adequate for prolonged ventilation. In
an attempt to improve on these
techniques, the concept of
demand-regulated LV was demonstrated by
Shaffer and Moskowitz. This
technique allowed experimental animals
to control the cycling of the
respirator that circulates oxygenated liquid
to and from the lungs. This method
established tidal volume and
breathing frequency requirements and
reduced breathing effort by
providing mechanical assistance. The early
experiments with this type of
ventilation reported effective oxygenation
and better removal of carbon
dioxide. This particular device was cited
explicitly in the novelization of The
Abyss and formed the conceptual
basis for the deep diving device
depicted in the movie.
Experiments with this type of
ventilation established the necessary
system components as well as tidal
volume and breathing frequency
requirements for mechanical
ventilation with liquids. A system for
time-cycled, pressure-limited TLV was
developed, and animals of various
gestational ages and lung
abnormalities were maintained with adequate
gas exchange for extended periods
of time. This LV strategy allows for
fine control of tidal volume, airway
and alveolar pressure, and functional
residual capacity (FRC).
Functionally, the system resembles an
extracorporeal membrane oxygenation
(ECMO) circuit in that it has a
pump to regulate flow, an
oxygenator (for oxygenation of the expired
fluid), a heater, and a condensing
system to recapture PFC (Fig. 2
).
Because PFC liquids have a high
heat capacity, the patient’s body
temperature can be regulated easily
and closely by the liquid
temperature during ventilation.
|
Over the years, the liquid ventilator has been refined sufficiently to allow computer operation using the same control modes as gas ventilators; that is, it is time-cycled and can be pressure- or volume-limited, have the inspiratory-to-expiratory time (I:E) ratio be changed, and have the waveform altered. Many of the same general principles used for gas ventilation are applied during LV. The ventilatory rate generally remains constant at 5 breaths/min during TLV (due to longer diffusion times of gases through liquids), and the tidal volume is used to regulate minute ventilation and, therefore, Paco2. With a time-cycled system, tidal volume is regulated by changing flow rates or pressure limits. Unlike gas ventilation (GV), TLV allows unique control and measurement of FRC by monitoring the change in weight as liquid is exchanged between the subject and the LV system. FRC and inspired oxygen concentration can be adjusted to optimize oxygenation. All manipulations can be made within the boundaries of set pressure, volume, and flow limits.
PARTIAL LIQUID VENTILATION (PLV)
Because initial TLV studies
demonstrated residual improvements in
respiratory function after a return to
GV, it was suggested that the
administration of PFC liquid to the
lungs may function similarly to an
artificial surfactant for respiratory
distress syndrome (RDS) or a lavage
medium for certain other types of
pulmonary dysfunction. More
recently, several investigators have
explored tracheal instillation of PFC
liquids in combination with GV in a
variety of neonatal, juvenile, and
adult animals as well as in preterm
human infants and adults who have
respiratory failure. Currently, this
combined ventilation scheme with
PFC liquids and GV is known as
PLV and is characterized by filling
and sustaining the lung with a
volume of PFC liquid less than or
equal to the FRC while conventional
GV is maintained (Fig. 3
).
It has
been proposed that residual PFC is
oxygenated and carbon dioxide is
exchanged in the lung by means of
the tidal gas movement provided by
GV. During PLV, the air-liquid
interface in the lungs is not
eliminated completely, so some of the
major mechanical advantages of a
liquid-liquid interface may not be
appreciated. However, this technique
offers specific advantages over GV
for many pulmonary disorders,
particularly where surfactant therapy is
not an option.
|
A number of techniques have been explored for LAV. Thus far, investigators have considered continuous TLV, brief periods (3 to 5 min) of TLV, rapid instillation of a bolus (30 mL/kg) of oxygenated PFC, and a slow infusion of unoxygenated PFC in doses up to 30 mL/kg over 15 minutes. The optimum PFC filling strategy and the effect of any subsequent GV scheme, including high-frequency, assist-controlled, synchronized, and spontaneous breathing strategies, are still under extensive investigation.
It has been reported that the addition of small amounts of PFC liquid (3 mL/kg) to high-frequency oscillatory ventilation (HFOV) resulted in a more rapid improvement in oxygenation for lung-injured piglets compared with HFOV alone (piston-driven). Although oxygenation improved over time in both groups with HFOV, increasing doses of PFC did not result in any significant differences in oxygenation compared with HFOV alone. Neither values for Pco2 and pH nor cardiovascular stability differed between groups. The combination of HFOV and small-dose PFC liquid may permit more effective oxygenation at lower mean airway pressures by facilitating alveolar expansion and decreasing intrapulmonary shunt.
Respiratory Support Applications Using LAV
RESPIRATORY DISTRESS SYNDROME (RDS)
Preterm infants characteristically
have homogeneous surfactant
deficiency and immature parenchyma
and initially present with a purely
restrictive lung disease that leads
quickly to atelectasis. The use of
surfactant replacement therapy and
prenatal steroids has substantially
improved the clinical course of these
infants, but they seem to have the
most to gain from LAV, particularly
when applied early. Surface tension
forces are reduced or eliminated,
atelectasis is prevented or remedied,
and the liquid environment of the
developing fetal lung can be
reproduced. The need for excessive
ventilator pressures and inspired oxygen
concentrations is diminished.
Multiple animal studies over the years
have demonstrated significant
improvements in pulmonary
mechanics, gas exchange, and
histology in models of premature lung
disease (Fig. 4
).
|
CONGENITAL DIAPHRAGMATIC HERNIA (CDH)
The newborn who has CDH faces
the dilemma of pulmonary
hypoplasia potentially complicated by
surfactant deficiency. PFC liquids have
the potential to maximize
recruitment of the hypoplastic lung while
minimizing the surface tension
forces related to surfactant
deficiency, thus allowing more efficient
ventilation and minimization of
barotrauma. Investigation of a lamb
preparation of CDH supported with
PLV, either prophylactically at birth
or rescued after a period of GV,
showed improved gas exchange and
compliance compared with
conventional GV. The group
prophylactically treated with PFC liquid at
delivery demonstrated improved
function compared with rescue
treatment.
ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)
Term infants, pediatric patients, and
adults all can present with ARDS.
Whether they are receiving or are
candidates for ECMO, they often
have consolidated, collapsed lungs
with an aggressive inflammatory
process and extremely poor
compliance. Therefore, they potentially can
be helped by lung recruitment and
improved compliance. Multiple
laboratory studies have shown the ability
of LAV to improve gas exchange,
mechanics, and cardiopulmonary
stability in both large animal models
and neonatal animal models of
ARDS.
ASPIRATION SYNDROMES
Patients who have aspiration
syndromes can benefit from the ability
of PFC liquids to support pulmonary
mechanics and
gas exchange
while lavaging
the lung. PFC
liquid has been
used to ventilate
lambs that have
meconium
aspiration. In these
lambs, poor gas
exchange,
acidosis, and low
pulmonary
compliance were
present during
GV; during
subsequent TLV,
meconium was
observed in the
expired liquid.
Improvements
were noted
during TLV and
PLV in Pao2,
alveolar-arterial
(A-a) oxygen
gradient, and
pulmonary
compliance, and
pulmonary blood
flow was more
uniform. Based
on these findings, it was concluded
that TLV improved pulmonary
perfusion and ventilation-perfusion
matching.
Nonrespiratory Applications
DRUG DELIVERY
Delivering drugs through the
endotracheal tube is not a new concept
for intensive care clinicians;
management of pulmonary dysfunction
often includes delivery of
biologically active agents to the lung. The
physiologic properties of the lung as
an exchanger for biologic agents
include its large surface area, thin
walls, and accessibility to the entire
cardiac output. Theoretically,
insufflation of an agent directly to the
lung presents advantages for
distribution and uptake. Over the years,
this concept has led not only to
direct endotracheal drug delivery,
but to various methods for
aerosolization of drugs during ventilation.
In the diseased lung supported with
liquid, pulmonary blood flow is
distributed more homogeneously and
ventilation/perfusion is matched
more evenly. Gas exchange can be
supported during pulmonary drug
delivery in the liquid-filled lung, and
the nonbiotransformable liquid
precludes any interaction between the
agent being delivered and the
vehicle by which it is delivered.
Several studies using LAV in
preterm lambs that had RDS,
healthy and lung-injured term lambs,
and healthy rabbits have
demonstrated the feasibility of using LV
techniques to deliver aqueous and
lipid-soluble pharmacologic agents
to the lung, including vasoactive
agents, antibiotics, anesthetics, and
vectors for gene transfer. Because
aqueous solutions are not readily
soluble in PFC liquids, the success
of this approach for homogenous
distribution and physiologic impact
has relied primarily on bulk flow
and turbulent mixing during TLV.
A newly developed nanocrystal
technology affords the opportunity
to increase the relative solubility of
agents by suspension in a PFC
liquid (Fig. 5
).
This approach has been
shown to yield therapeutic serum
levels and higher and more
homogenous pulmonary concentrations of
gentamicin in healthy and
lung-injured neonatal animals than
intravenous delivery when delivered
either within the initial dose of PFC
or sometime during PLV. In
addition to the previously mentioned
biologic agents, halothane has been
delivered in PFC liquid and was
found to induce anesthesia
effectively in experimental animals while
supporting cardiopulmonary
function.
|
Inspired gases also lend themselves well to this type of drug administration. Recent studies have demonstrated physiologic responses to inspired nitric oxide (NO) during PLV. The ability to deliver NO during PLV probably is related to recruitment of lung volume, distribution of NO in the gas-ventilated regions of the lung, and the solubility and diffusion of this gas in the PFC.
Results of these studies suggest that PFC-assisted ventilation may be a useful adjunct in delivering other therapeutic agents, such as bronchodilators, exogenous surfactant, antibiotics, steroids, chemotherapeutics, mucolytics, antioxidants, and gene therapy products, directly to the lung while protecting nontargeted organs from iatrogenic pharmacologic effects. This approach appears to have vast potential for a therapeutic role in the management of a variety of respiratory problems, including surfactant deficiency, consolidation, exudative processes, malignancy, persistent or acquired pulmonary hypertension, pneumonia, and airway reactivity.
RADIOGRAPHIC IMAGING
PFC liquids are useful contrast
media. Because they are inert,
nonbiotransformable, and of varying
radiopacity; support gas exchange;
and can be vaporized from the lung,
they provide a useful diagnostic
imaging adjunct to evaluate
pulmonary structure and function without
intrinsic problems related to existing
contrast agents. The presence of
bromine atoms in PFCs, as in
perflubron (LiquiVentTM), can confer
relatively greater radiopacity
(Fig. 6
).
In the PFC-filled lung,
conventional radiography and HRCT can
be used not only to illustrate lung
structures, but also to evaluate PFC
lung distribution and sequential
elimination qualitatively and
quantitatively. Anteroposterior radiographs
with cross-table lateral views are
required to evaluate the distribution
pattern of the PFC during PLV
qualitatively. Whereas plain films
indicate a predominate central clearance
pattern, sequential HRCT images
identify both central and peripheral
clearance, with a calculated 45%
decrease in overall density related to
PFC clearance by 30 minutes.
Radiographic studies of the
perflubron-filled lungs of animals
and humans who had CDH have
proven informative to delineate
qualitatively the degree of
pulmonary hypoplasia and distribution and
elimination patterns of the PFC
liquid.
|
Virtual bronchoscopy is a
relatively new technique that adds
postprocessing software to the
three-dimensional presentations of helical
computed tomography and can allow
four-dimensional imaging of the
inside of hollow viscera (Fig. 7
).
Evaluating small airway pathology
of the tracheobronchial tree has been
limited by poor resolution of the
bronchioles at the secondary lobule
level. Use of the PFC liquid
perflubron as a bronchographic contrast
agent has enhanced markedly the
navigation of substantially more
distal airways as small as 0.8 mm.
|
PFC liquids can be used for nuclear magnetic resonance (NMR) imaging because hydrogen atoms are absent and the NMR spectra of the 19F natural fluorine atom can be measured. Because PFCs are devoid of hydrogen atoms, no magnetic resonance imaging signal is produced, and PFC-filled body cavities appear dark. In addition, because oxygen dissolved in PFCs affects T1 in the NMR signal, regional differences in oxygen tension can be mapped by assessing calibrated spin-lattice relaxation times. NMR imaging of the PFC-filled lung may be clinically useful in monitoring regional gas exchange, organ function, biochemical mechanisms, and therapeutic measures. Finally, because fluorine corresponds to a proton image, the PFC liquid may provide a way of assessing ventilation-perfusion functions in relationship to anatomic structure.
LUNG EXPANSION AND GROWTH OF THE HYPOPLASTIC LUNG
Recent studies by several
laboratories have demonstrated the potential
of LAV to support gas exchange
and lung mechanics in the presence
of pulmonary hypoplasia. The basis
of this application is related to low
pressure alveolar recruitment and
respiratory support that facilitates
improved ventilation-to-perfusion
matching. PLV studies of CDH in a
lamb preparation supported either
from birth or rescued after a period
of GV showed improved gas
exchange and compliance compared
with animals supported with
conventional GV. Lung histology in
animals that had CDH and were
rescued with PLV was not improved
relative to animals treated with
CMV, although the CDH lamb
preparation prophylactically treated with
PFC at delivery demonstrated
improved function and histology
compared with rescue treatment.
These data suggest that early
intervention and reduction of ventilatory
pressures may reduce barotrauma of
the hypoplastic lung.
Exciting evidence is accumulating that suggests that lung growth may be accelerated postnatally by continuous PFC-based intrapulmonary distension. Neonatal lambs were studied for 21 days following isolation and PFC distension of the right upper lobe to maintain up to 10 mm Hg intrabronchial pressure. The results demonstrated accelerated lung growth based on increased right upper lobe volume-to-body weight ratio, total alveolar number, total alveolar surface area, normal histologic appearance, normal airspace fraction, and normal alveolar numerical density compared with controls. Because clinical investigational trials have been limited to a 7-day exposure, the lung growth study was repeated in lambs with intrapulmonary PFC distension for 7 days after which the airway catheter was removed and the animals were recovered to spontaneous breathing until 3 to 6 months of age. Although 7 days of PFC distension was insufficient to promote lung growth, the gas exchange, ventilation/perfusion scans, airway epithelium, and alveoli of all experimental animals were normal despite variable amounts of intrapleural and interstitial PFC. These studies suggest a strong potential for the use of PFC liquid as a mechanical stimulus for lung growth without pathophysiologic consequences.
CELLULAR EFFECTS
Growing evidence from several
laboratories suggests that intratracheal
administration of PFC liquids may
reduce pulmonary inflammation and
injury. The mechanism of action has
been speculated as a direct
modification of cell function and
chemotaxis. In one study, pulmonary
neutrophil infiltration, as assessed from
myeloperoxidase levels in adult
injured and immature lungs, was
reduced during PLV compared with
conventional GV support. This
response was observed with PFC
doses as low as PFC-saturated
inspired gas and as early as 30
minutes posttreatment. In other studies,
alveolar or circulating macrophages
obtained from different species,
including humans, and exposed in
vitro to perflubron demonstrated
decreased responsiveness to potent
stimuli. Recent in vitro studies of
Escherichia coli lipopolysaccharide
(LPS)-stimulated macrophages in the
presence of perflubron showed that
perflubron decreased NO production
by approximately 50%, as assessed
indirectly from combined
nitrite/nitrate levels in the cell media.
Pretreatment with perflubron, however,
did not alter the LPS-stimulated
macrophages to elevate NO end
products, which indicates that the
PFC had to be present during
stimulation for the response to be blunted.
This same PFC liquid, perflubron, has been shown to decrease cytokine production (tumor necrosis factor [TNF] alpha, interleukin [IL] 1, IL 6, IL 8) and chemotaxis of activated human alveolar or circulating macrophages. One study of human circulating macrophages indicated that perflubron had little or no effect on leukotriene, chemotaxis, or superoxide anion release following activation by LPS, TNF-alpha, and -formyl-Met Leu-Phe stimulation. In addition, basal concentrations of TNA-alpha, IL 1, and IL 6 from unstimulated alveolar macrophages were not altered by perflubron.
Data from humans treated with intratracheal PFC is emerging from ongoing adult clinical trials with PLV. The oxidant-generating capacity of neutrophils obtained from bronchoalveolar lavage of PFC-treated humans who had ARDS was similar to that of peripheral blood neutrophils. In another study of adult humans who had ARDS and were treated with either CMV or PLV, the white blood cell count, neutrophils, protein, IL 1, and IL 6 in the bronchoalveolar lavage were higher with CMV than PLV; IL 8 concentrations did not differ between CMV and PLV, and IL 10 levels were lower with PLV.
PFC liquids also appear to affect neutrophil-epithelial cell interactions. When neutrophils and epithelial cells were exposed simultaneously to PFC, adhesion and target cell injury following stimulation were reduced. Prior exposure to PFC with subsequent washing and stimulation did not alter neutrophil release of proinflammatory stimuli or adhesion to epithelial cells. More importantly, because the presence of perflubron does not cause direct suppression of the neutrophil response system, it would be expected that perflubron would not impede the ability of neutrophils to respond to an inflammatory challenge during acute lung injury.
In summary, it appears that the presence of PFC may provide a mechanical barrier or direct cytoprotective effect to reduce lung injury by attenuating leukocyte infiltration and the effects of local or circulating proinflammatory mediators on lung structures.
TEMPERATURE CONTROL
PFC liquids have very high heat
capacity relative to respiratory gases.
The pulmonary vasculature
vasoconstricts less in response to
hypothermia than does the skin vasculature.
In addition, because the lung surface
area is large (35 times that of the
body surface area), the entire cardiac
output essentially comes in contact
with the pulmonary surface, and
because the epithelial barrier is thin,
the lung is an excellent heat
exchanger. As a result of these
anatomic and physiologic factors, much
more effective warming/cooling can
occur via the pulmonary
administration of heat/cold (especially through
breathing a heated/cooled liquid)
than by warming/cooling the skin.
Hence, there is a potential benefit to
using LV techniques to provide
hyper- and hypothermia. These heat
exchange principles employing LV
techniques have been demonstrated
experimentally in both newborn and
adult animals. Temperatures of
inspired liquid must be controlled
carefully in the normothermic
patient. It is noteworthy that the
adjunctive support of this media
may help to maintain temperature
control in the thermally unstable
neonate.
Clinical Studies
NEONATAL
The first human trials of PFC liquid
breathing were conducted in
Philadelphia, Pennsylvania in 1989 and
were initiated in near-death infants
who had severe respiratory failure.
TLV was administered in two 3- to
5-minute cycles separated by
15 minutes of GV. A
gravity-assisted approach was used, and
tidal volumes of liquid were given
to a liquid-filled lung for two
sequential 5-minute cycles. The
infants tolerated the procedure and
showed improvement in several
physiologic parameters, including
lung compliance and gas exchange.
Improvement was sustained after LV
was discontinuated, but the infants
eventually deteriorated. Hence,
although the protocol used a form of
TLV, the benefit of GV was
sustained after administration of PFC
liquid to the immature injured lung.
All of the infants in these studies
ultimately died from their
underlying respiratory disease, but TLV was
shown to support gas exchange and
allow residual improvement in
pulmonary function following return to
GV. Further clinical trials were
limited by the need for a medically
approved liquid ventilator and
medical-grade breathing fluid.
Subsequent human protocols have used
a PLV approach to LV.
Over the past 6 years, several PLV studies using sterile perflubron (LiquiVentTM) have been completed or are ongoing in humans. Leach and collaborators reported on 13 preterm infants who had severe RDS in whom conventional treatment had failed. The infants were treated with PLV for up to 96 hours by protocol (maximal time on PLV for any infant was 76 h). Their lungs were filled with LiquiVentTM to approximately 20 mL/kg, and supplemental doses generally were administered hourly. The study was not randomized or blinded. The arterial oxygen tension increased by 138%, the dynamic compliance increased by 61%, and the oxygenation index was reduced from a mean of 49 to 17 within 1 hour of initiation of PLV. It was concluded that clinical improvement and survival occurred in some infants who were not predicted to survive.
Pranikoff and associates reported results for four patients who had CDH and were being managed for up to 5 days on extracorporeal life support (ECLS). PLV was performed in a phase I/II trial for up to 6 days with daily dosing. This technique appeared to be safe and possibly was associated with improvement in gas exchange and pulmonary compliance. In a similar study, Greenspan and coworkers treated six term infants who had respiratory failure and were failing to improve while receiving ECLS. They administered PLV with hourly dosing of LiquiVentTM for up to 96 hours. They concluded that the technique appeared to be safe, improved lung function, and recruited lung volume in these infants.
These initial studies of PLV in neonates are encouraging and suggest the feasibility of this technique in the neonate who has severe RDS and ARDS. The response of the sick term infant to PLV frequently is more gradual than typically is observed in the preterm infant who has RDS. The preterm infant often experiences improvement in lung compliance and gas exchange within hours of PLV initiation, most likely due to reductions in surface tension and volume recruitment. Improving lung function in the term infant often requires debris removal, which occurs gradually over several days.
PEDIATRIC
Three studies have evaluated PLV in
children, and none has used a
control group. Gauger et al reported on
six pediatrics patients who had
ARDS requiring ECLS. Children
were treated with daily dosing of
LiquiVentTM PLV for 3 to 7 days.
Some improvement in gas exchange
and pulmonary compliance occurred
over time, and all patients survived.
Similarly, Hirschl and coworkers
treated seven pediatric patients who
had ARDS requiring ECLS. They
found an improvement in gas
exchange and pulmonary compliance
without adverse events related to the
drug or technique when
administering PLV for 1 to 7 days. Finally,
Toro-Figueroa et al treated 10
children up to 17 years of age who had
ARDS with PLV for up to 96 hours.
Nine of the patients who tolerated
initial dosing experiencing
improvement in gas exchange. However,
lung function did not improve.
Results of these studies suggest that
PLV may be safe and efficacious in
the treatment of pediatric ARDS.
ADULT
To date, there have been two phase
I/II PLV studies with LiquiVentTM
reported in adults. Hirschl and
colleagues treated 10 adults who had
ARDS and were receiving ECLS
with daily dosing of PLV for up to
7 days. The authors reported a
decrease in the physiologic shunt
and an increase in pulmonary
compliance; 50% of the patients
survived. Based on their clinical
experiences, they concluded that PLV
appeared safe in this patient
population and may be associated with
observed improvements in gas
exchange and pulmonary
compliance. In another study, Bartlett and
others presented a phase II
randomized, controlled trial of PLV in
65 adult patients who had acute
hypoxemic respiratory failure. Forty
patients received LiquiVentTM for
5 days, and 25 patients served as
controls. Ventilator-free days and
mortality did not differ between the
groups, but there was a statistically
significant improvement in
ventilator-free days in subjects
treated with PLV who were younger
than 55 years of age. The authors
concluded that PLV can be
accomplished with safety in this
population and suggested that larger trials
be initiated with special
consideration to age stratification.
As of this writing, a 480-patient, phase III, PLV adult trial with LiquiVentTM is ongoing in North America and Europe. It is designed to distinguish the effectiveness of PLV over CMV in a clearly defined ARDS population. Although the use of other PFCs for clinical trials is emerging, it is noteworthy that PLV studies with LiquiVentTM in the neonatal and pediatric population are currently on hold awaiting the results of this pivotal adult trial. Results of initial phase I/II trials have demonstrated the potential safety and efficacy of this therapy, particularly in younger populations of sick patients, but a full understanding of the utility of PLV awaits the results of ongoing studies.
Conclusion
The use of PFC liquids as an alternative respiratory medium originally was based on mechanical and biophysical mechanisms to support pulmonary gas exchange and function. Over the years, the pulmonary application of PFC liquids has evolved to include their use as a vehicle to deliver agents directly to the lung, as a substance to facilitate lung growth, as a bronchopulmonary contrast agent, and as a potential cytoprotective medium to attenuate inflammatory processes. However, the primary application of LV techniques remains the potential to treat lung disease with less risk of barotrauma and to provide a means for complementing existing forms of respiratory management such as surfactant therapy, ECMO, HFOV, and inhaled NO. To date, nearly 500 patients in hospitals across North America and Europe have been enrolled in various clinical trials of PLV, and preliminary results are encouraging.
The future availability of additional biomedical-grade PFC liquids with varying physicochemical characteristics will enable further tailoring of LAV techniques for individual applications. With continued efforts toward establishing the efficacy and safety of the biologic interaction of PFC fluids, LAV undoubtedly will assume an integral role in clinical medicine. Continued laboratory and clinical research should define further the applications and limitations of this alternative therapeutic approach to respiratory management.
Suggested Reading
Bartlett R, Croce M, Hirschl RB, et al. A phase II randomized, controlled trial of partial liquid ventilation (PLV) in adult patients with acute hypoxemic respiratory failure (AHRF). Crit Care Med. 1997;25:A135
Cox C, Wolfson MR, Shaffer TH. Liquid ventilation: a comprehensive overview. Neonatal Network. 1996;15:31-43
Day SE, Gedeit RG. Liquid ventilation. Clin Perinatol. 1998;25:711-732
Gauger PG, Pranikoff T, Schreiner RJ, Moler FW, Hirschl RB. Initial experience with partial liquid ventilation in pediatric patients with acute respiratory distress syndrome. Crit Care Med. 1996;24:16-22
Greenspan JS, Cleary GM, Wolfson MR. Is liquid ventilation a reasonable alternative? Clin Perinatol. 1998;25:137-152
Greenspan JS, Fox WW, Rubenstein SD, Wolfson MR, Spinner SS, Shaffer TH. Partial liquid ventilation in critically ill infants receiving extracorporeal life support. Pediatrics. 1997;99:E2
Hirschl RB. Liquid ventilation in the setting of respiratory failure. ASAIO Journal. 1998;44:231-233
Hirschl RB, Pranikoff T, Wise C, et al. Initial experience with partial liquid ventilation in adult patients with acute respiratory distress syndrome. JAMA. 1996;275:383-389
Jacobs HC, Mercurio MR. Perfluorocarbons in the treatment of respiratory distress syndrome. Semin Perinatol. 1993;17:295-302
Kylstra JA. Liquid breathing. Undersea Biomed Res. 1974;1:259-269
Leach CL, Greenspan JS, Rubenstein SD, et al. Partial liquid ventilation with perflubron in premature infants with severe respiratory distess syndrome. N Engl J Med. 1996;335:761-767
Leonard RC. Liquid ventilation. Anaesth Intensive Care. 1998;26:11-21
Pranikoff T, Gauger PG, Hirschl RB. Partial liquid ventilation in newborn infants with congenital diaphragmatic hernia. J Pediatr Surg. 1996;31:613-618
Shaffer TH. A brief review: liquid ventilation. Undersea Biomed Res. 1987;14:169-178
Shaffer TH, Greenspan JS, Wolfson MR. Liquid ventilation. In: Boyton B, Carlo W, Jobe A, eds. New Therapies for Neonatal Respiratory Failure: A Physiologic Approach 1994 Cambridge University Press New York, NY
Shaffer TH, Moskowitz GD. Demand-controlled liquid ventilation of the lungs. J Appl Physiol. 1974;36:208-213
Shaffer TH, Wolfson MR. Liquid ventilation. In: Polin R, Fox WW, eds. Fetal and Neonatal Physiology, ed 2. 1997 WB Saunders Philadelphia, Penn
Shaffer TH, Wolfson MR. Liquid ventilation: an alternative ventilation strategy for management of neonatal respiratory distress. Eur J Pediatr. 1996;155((suppl 2)):530-534
Shaffer TH, Wolfson MR. Principles and applications of liquid breathing: water babies revisited. 1992 Yearbook of Neonatal and Perinatal Medicine. 1992 Mosby-Year Book, Inc St. Louis, Mo
Shaffer TH, Wolfson MR, Clark LC. State of art review: liquid ventilation. Pediatr Pulmonol. 1992;14:102-109
Toro-Figueroa LO, Meliones JN, Curtis SE, et al. Perflubron partial liquid ventilation (PLV) in children with ARDS: a safety and efficacy pilot study. Crit Care Med. 1996;24:A150-
Weis CM, Wolfson MR, Shaffer TH. Liquid-assisted ventilation: physiology and clinical application. Ann Med. 1997;29:509-517
Wolfson MR, Greenspan JS, Shaffer TH. Liquid assisted ventilation: an alternative respiratory modality. State-of-Art Review Pediatric Pulmonol. 1998;26:42-63
Wolfson MR, Shaffer TH. Liquid assisted ventilation: an update. Eur J Pediatr. In press.
Wolfson MR, Shaffer TH. Liquid assisted ventilation: from concept to clinical application. Semin Neonatol. 1997;2:115-127
Wolfson MR, Shaffer TH. Liquid ventilation during early development: theory, physiologic processes, and application. J Develop Physiol. 1990;13:1-12
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | CONTACT US | SUBSCRIPTIONS | CME | ARCHIVE | SEARCH | TABLE OF CONTENTS |
 |
|
 |
