Partial Liquid Ventilation Reduces Pulmonary Neutrophil Accumulation in an Experimental Model of...

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23/08/13 Ovid: Partial liquid ventilation reduces pulmonary neutrophil accumulation in an experimental model of systemic endotoxemia and acute lung injury.

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[Laboratory Investigations]

Critical Care Medicine

Issue: Volume 26(10), October 1998, pp 1707-1715

Copyright: Williams & Wilkins 1998. All Rights Reserved.

Publication Type: [Laboratory Investigations]

ISSN: 0090-3493

Accession: 00003246-199810000-00026

Partial liquid ventilation reduces pulmonary neutrophil accumulation in an experimental model of systemic

endotoxemia and acute lung injury

Rotta, Alexandre T. MD; Steinhorn, David M. MD

Author Information

From the Division of Pediatric Critical Care Medicine at The Children's Hospital of Buffalo and State University of New York at Buffalo, Buffalo, NY.

Supported, in part, by a grant from the Alliance Pharmaceutical Corporation and Hoechst Marion Roussel, and by The American Lung Association-NY Affiliate.

Presented, in part, at the 26th Educational and Scientific Symposium of the Society of Critical Care Medicine, San Diego, CA, February 1997.

Address requests for reprints to: Alexandre T. Rotta, MD, Division of Pediatric Critical Care Medicine, The Children's Hospital of Buffalo, 219 Bryant Street, Buffalo,

NY, 14222-2006.

Abstract

Objective: To determine whether pulmonary neutrophil sequestration and lung injury are affected by partial

liquid ventilation with perfluorocarbon in a model of acute lung injury (ALI).

Design: A prospective, controlled, in vivo animal laboratory study.

Setting: An animal research facility of a health sciences university.

Subjects: Forty-one New Zealand White rabbits.

Interventions: Mature New Zealand White rabbits were anesthetized and instrumented with a tracheostomy

and vascular catheters. Animals were assigned to receive partial liquid ventilation (PLV, n = 15) with perflubron (18

mL/kg via endotracheal tube), conventional mechanical ventilation (CMV, n = 15) or high-frequency oscillatory

ventilation (HFOV, n = 5). Animals were ventilated, using an FIO2of 1.0, and ventilatory settings were required to

achieve a normal PaCO2. Animals were then given 0.9 mg/kg of Escherichia coli endotoxin intravenously over 30

mins. Partial liquid ventilation, conventional mechanical ventilation, or h igh-frequency osc illatory ventilation was

continued for an additional 4 hrs before the animals were killed. A group of animals not challenged with

endotoxin underwent conventional ventilation for 4.5 hrs, serving as the control group (control, n = 6). Lungs

were removed and samples were frozen at -70[degree sign]C. Representative samples were stained for histology. A

visual count of neutrophils per high-power field (hpf) was performed in five randomly selected fields per sample in

a blinded fashion by light microscopy. Lung samples were homogenized in triplicate in phosphate buffer,

ultrasonified, freeze-thawed, and clarified by centrifugation. Supernatants were analyzed for myeloperoxidase

(MPO) activity by spectrophotometry with o-dianisidine dihydrochloride and hydrogen peroxide at 460 nm.

Measurements and Main Results: Histologic analysis of lung tissue obtained from control animals showed

normal lung architecture. Specimens from the PLV and HFOV groups showed a marked decrease in alveolar

proteinaceous fluid, pulmonary vascular congestion, edema, necrotic cell debris, and gross inflammatory

infiltration when compared with the CMV group. Light microscopy of lung samples of animals supported with PLV

and HFOV had significantly lower neutrophil counts when compared with CMV (PLV, 4 +/- 0.3 neutrophils/hpf;

HFOV, 4 +/- 0.5 neutrophils/hpf; CMV, 10 +/- 0.9 neutrophils/hpf; p < .01). In addition, MPO ac tivity from lung

extracts of PLV and HFOV animals was significantly lower than that o f CMV animals (PLV, 61 +/- 13.3 units of MPO

activity/lung/kg; HFOV, 43.3 +/- 6.8 units o f MPO activity/lung/kg; CMV, 140 +/- 28.5 units o f MPO activity/lung/kg;

p < .01). MPO activity from lungs o f uninjured con trol animals was significantly lower than that o f animals in the

PLV, HFOV, and CMV groups (control, 2.2 +/- 2 units of MPO activity/lung/kg; p < .001).

Conclusions: Partial liquid ventilation decreases pulmonary neutrophil accumulation, as shown by decreased

neutrophil counts and MPO activity, in an experimental animal model of ALI induced by systemic endotoxemia.

The attenuation in pulmonary leukostasis in animals treated with PLV is equivalent to that obtained by a

ventilation strategy that targets lung recruitment, such as HFOV. (Crit Care Med 1998; 26:1707-1715)

Key Words: perfluorocarbon; endotoxin; myeloperoxidase; liquid ventilation; acute respiratory distress

syndrome; respiratory failure; inflammation; neutrophil; pulmonary emergencies; critical illness

Acute respiratory distress syndrome (ARDS) is marked by profound impairment in pulmonary mechanics and

function. It is associated with a diffuse inflammatory reaction which may lead to secondary injury [1]. An early

event in the development of ARDS in experimental animal models [2,3]and humans [4,5]is the accumulation and

activation of neutrophils in the lung. Evidence of the neutrophil's role in the evolution of ARDS is provided by

reports that granulocyte depletion before an acute lung insult attenuates or prevents the development of

pulmonary dysfunction [6,7], although ARDS is also known to occur in the setting of severe neutropenia without

pulmonary neutrophil infiltration [8]. Ventilation strategies have been shown to play an important role in the

development and progression of ARDS [9,10]. Ventilation strategies that permit inhomogeneous lung inflation are

associated with progressive atelectasis, high inflation pressures with patchy overdistention of lung units, global
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decrease in lung compliance, and progressive structural injury [10,11]. Conversely, strategies that target early

establishment of a more homogeneous alveolar inflation, such as high-frequency oscillatory ventilation (HFOV), are

associated with better outcomes [10,12]. Sigiura et al. [13]demonstrated that HFOV minimizes neutrophil influx

and activation as well as attenuates lung injury in a surfactant deficient model when compared with conventional

mechanical ventilation.

Partial liquid ventilation with perfluorocarbons has been studied as a support modality in a variety of

experimental models of respiratory failure and acute lung injury (ALI). Gross inspection of lung specimens

supported with partial liquid ventilation in models of ALI has shown decreased atelectasis, hemorrhage, and

necrosis in comparison with similarly injured gas ventilated controls [14]. Under light microscopy, injured lungs

treated with partial liquid ventilation appear more homogeneously inflated with less evidence of inflammation and

tissue damage than spec imens from gas ventilated animals [14,15]. The precise mechanisms by which partial liquid

ventilation reduces the histologic evidence of lung injury are still unknown. However, we have previously shown

that partial liquid ventilation with perfluorocarbons decreases free radical release by alveolar macrophages [16]

and attenuates oxidative damage to lung tissue [17]. In view of neutrophil's important role in the evolution of

tissue damage following a pulmonary insult, we hypothesized that partial liquid ventilation might reduce neutrophil

accumulation in the lung during the early phase of ALI. To investigate this hypothesis, we undertook a controlled

laboratory investigation using a systemic, endotoxemia-induced model of acute alveolitis.

MATERIALS AND METHODS

Animals and Instrumentation. Forty-one New Zealand White rabbits, weighing 1.5 to 3.5 kg, were anesthetized

with ketamine (25 mg/kg im) and xylazine (4 mg/kg im). The animals were preoxygenated du ring spontaneous

breathing with 100% oxygen by nose cone. Muscle paralysis was induced by intravenous administration of

pancuronium bromide (0.2 mg/kg) and maintained with 0.1-mg/kg doses as needed to control movement.Anesthesia was maintained with a continuous intravenous infusion of ketamine (10 mg/kg/hr) and xylazine (4

mg/kg/hr).

The anterior neck was dissected carefully and a tracheostomy was performed. A cuffed endotracheal tube

(3.0 to 3.5 mm inner diameter) (Sheridan Catheter, Argyle, NY) was placed in the trachea and secured in position

with umbilical tape. A vascular cannula was inserted in the common carotid artery and a double-lumen catheter

was advanced into the superior vena cava through the jugular vein. Central venous and arterial blood pressures

were monitored by attaching the vascular c atheters to standard pressure transducers, connec ted to a monitor

(Horizon 2000, Mennen Medical, Clarence, NY). The temperature was monitored continuously, using an

esophageal probe, and normothermia was maintained with electric warming pads. Maintenance fluids were

provided by a continuous infusion of 0.9% saline solution containing 5% dextrose. The animals were assigned

sequentially in alternating fashion to receive conventional mechanical ventilation (CMV, n = 15), partial liquid

ventilation (PLV, n = 15), high-frequency oscillatory ventilation (HFOV, n = 5), or to a control group (control, n =

6). The animals in the CMV, PLV, and control groups were ventilated in the supine position with a ventilator (Servo

900C, Siemens-Elema, Solna, Sweden) in the volume control mode, using an effective tidal volume of 8 to 10 mL/kg,

FIO2of 1.0, positive end-expiratory pressure of 5 cm H2O, and a respiratory rate of 25 to 35 breaths/min, as

needed to maintain normocarbia (PaCO235 to 45 torr [4.7 to 6.0 kPa]).

After a stabilization per iod of 30 mins, the animals assigned to the PLV group had partial liquid ventilation

initiated by instilling perflubron (18 mL/kg, LiquiVent[registered sign], Alliance Pharmaceutical Corporation, San

Diego, CA) into the trachea over a 15-min period via a side port connector attached to the endotracheal tube.

Supplemental perflubron (2 to 4 mL/kg) was administered every hour in the same fashion to compensate for

evaporative losses, unless a liquid meniscus was visible in the endotracheal tube during a brief period of ventilator

disconnection. Animals assigned to the HFOV group were ventilated in the supine position with an oscillatory

ventilator (3100A, SensorMedics, Yorba Linda, CA) with an FIO 2of 1.0, mean airway pressure of 12 to 13.5 cm H2O,

frequency of 10 Hz, inspiratory time of 33%, and amplitude of 18 to 22 cm H2O to maintain normocarbia.

Animals were cared for in accordance with the guidelines published by the National Institutes of Health [18].

This study was approved by the Institutional Animal Care and Use Committee of the State University of New York

at Buffalo.

Induction of Lung Injury. Thirty minutes after initiating mechanical ventilation, i.e., conventional mechanical

ventilation, partial liquid ventilation, or h igh-frequenc y osc illatory ventilation, 0.9 mg/kg of Escherichia c oli

endotoxin (type F583, Sigma Chemical, St. Louis, MO) was administered over a 30-min period by intravenous

infusion through the central venous catheter. The animals in the control group did not receive intravenous E. coli

endotoxin but were otherwise treated identically to animals in the CMV group. Mean arterial blood pressure was

maintained at >65 mm Hg, as needed, by a continuous infusion of 10 to 20 [micro sign]g/kg/min of dopamine and

administration of 6% hetastarch in 0.9% sodium chloride (Hespan[registered sign], McGaw, Irvine, CA). Arterial

blood gas analysis was performed hourly, using an ABL-3 blood gas analyzer (Radiometer, Copenhagen, Denmark).

Conventional, partial liquid, or high-frequency oscillatory ventilation was continued for an additional 4 hrs beforethe animals were killed.

Tissue Extraction. The rabbits were killed with an intravenous dose of pentobarbital (100 mg/kg). The thorax

was opened carefully to observe for signs of a pneumothorax, to confirm proper catheter placement, and to

harvest tissue. The lungs were removed en bloc from the thoracic cavity, rinsed externally with sterile normal

saline, blotted dry, and weighed separately. A representative section of the left upper lobe was excised in full
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thickness (axial plane) and preserved in formalin for histologic examination. The right lung was frozen for

subsequent evaluation while the remaining left lung was divided into three portions and snap frozen at -70[degree

sign]C for batch analysis [19]. Samples from three different regions of the left lung were analyzed to minimize

sampling error related to inhomogeneous distribution of neutrophils throughout the injured lung. The lung

samples were homogenized in 0.5% hexadecyltrimethyl-amonium bromide (HTAB) (Sigma Chemical) in 50 mM of

phosphate buffer, with a pH of 6.0, in a ratio of 5 mL HTAB solution/g tissue, using a homogenizer (2000 Variable

Speed Tissue Homogenizer, Omni International, Waterbury, CT). The homogenates were sonicated in an ice bath

with an ultrasonic dismembrator (300, Dynatech Laboratories, Chantilly, VA) for 10 secs at 40% power. Specimens

were freeze-thawed three times (liquid nitrogen and 37[degree sign]C), after which sonication was repeated as

above. The suspensions were clarified by centrifugation at 20,000 rpm for 30 mins, and the supernatants were

reserved for analysis.

Myeloperoxidase (MPO) Assay. MPO activity was assayed spectrophotometrically, using the method of Bradley

et al [20]. In brief, 0.1 mL of the supernatant was mixed with 2.9 mL of 50-mM potassium phosphate buffer, pH of

6.0, containing 0.167 mg/mL of o-dianisidine dihydro chloride (Sigma Chemical) and 0.0005% hydrogen peroxide

(Sigma Chemical). The change in absorbance at 460 nm [18]was measured, using a spectrophotometer (U-2000,

Hitachi Instruments, Webster, NY). To minimize the effect of possible regional variations in neutrophil infiltration

throughout the injured lung, three separate regions were analyzed. MPO activity was then derived from the

observed change in absorbance per minute. MPO activity was expressed as total MPO activity/lung/kg body

weight and represents both lungs taken together. This measure was undertaken to avoid the weight artifact

produced by the presence of the heavy perflubron in the lungs of animals in the partial liquid ventilation group.

Histologic Analysis. Tissue samples preserved in formalin were fixed and embedded in paraffin before cutting

and staining with hematoxylin and eosin. Slides were then studied under light microscopy. To minimize possible

regional variations in neutrophil distribution which could lead to sampling bias, the visual count of neutrophils perhigh-power field (hpf) (500x) was performed in five randomly selected fields per sample in a blinded fashion by the

principal investigator (A.T.R.). A mean number of neutrophils/hpf for each sample was then obtained.

A lung injury score was used to quantify changes in lung architecture visible by light microscopy [21]. The

degree of microscopic injury was scored based on the following variables: alveolar and interstitial inflammation,

alveolar and interstitial hemorrhage, edema, atelectasis, and necrosis. The severity of injury was graded as follows

for each of the seven variables: no injury = 0; injury to 25% of the field = 1; injury to 50% of the field = 2; injury to

75% of the field = 3; and diffuse injury = 4. The highest possible score was 28 and the lowest was 0. In order to

minimize regional variations in lung histology, two different areas from each specimen were examined under light

microscopy.

Statistical Analysis. Results are expressed as mean +/- SEM, unless otherwise noted. Data were analyzed using

SigmaStat for Windows, Ve rsion 2.0 (1995, Jandel, Chicago, IL) on a personal computer. A Kruskal-Wallis one-wayanalysis of variance was used for comparison of multiple groups for each single variable. Post hoc analysis was

performed using the Dunn's method for all pairwise multiple comparison procedures. The strengths of the

relationships between neutrophil counts/hpf and M PO activity, and between M PO activity and lung injury sc ores

were estimated, using linear regression analysis based on data from all four experimental groups. Statistical

significance was observed at p < .05.

RESULTS

Four rabbits died before completion of the experimental protocol and were excluded from the final data

analysis. In the CMV group, one rabbit died with a tension pneumothorax and the other developed profound

hypotension and acidemia immediately after infusion of the E. coli endotoxin. In the PLV group, one animal

developed a fatal tachyarrhythmia shortly after instrumentation and the other animal had refractory hypotension

and acidemia early in the course of the experiment. Thirty-seven animals completed the experimental protocol,

leaving 13 in the CMV and PLV groups, 5 in the HFOV group, and 6 in the control group. The baseline

characteristics and values for the rabbits assigned to each group are shown in Table 1. As expected, the baseline

PaO2of animals in the liquid ventilation group was significantly lower than that of gas ventilated controls. This

finding is thought to be due to the obligatory oxygen gradient across the liquid-alveolar interface, as a

consequence of the relative rate limitation for the diffusion of oxygen through the thin liquid layer lining the

alveolus during inspiration, as oxygen is taken up by the capillary blood [22].
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Table 1. Baseline characteristics of rabbits assigned to control, partial liquid ventilation (PLV), conventional

mechanical ventilation (CMV), and high-frequency oscillatory ventilation (HFOV) groups (mean +/- SEM)

Gross visual inspection of the lungs of animals in the control group revealed normal anatomic features. Lungs

from animals in the CMV group had a congested appearance alternated with dark areas of patchy hemorrhage

throughout the external surface, with greater c oncentration over the dependent areas. The lungs supported

with partial liquid ventilation grossly exhibited a translucent pink appearance, with fewer hemorrhagic areas. The

lungs from animals in the HFOV group had few hemorrhagic areas, mostly over the dependent portions. In all the

experimental groups, the right and left lungs appeared similar by gross, visual examination. When representative

samples of lung tissue were analyzed under light microscopy, the control group exhibited normal histology (Figure

1), whereas the CMV group showed a markedly abnormal aeration pattern and evidence of intense inflammatory

response (Figure 2). There were extensive areas of atelectasis, as well as areas of severe injury, with alveoli filled

by proteinaceous material, necrotic debris, erythrocytes, and inflammatory cells. Thickened and deformed

alveolar walls also exhibited abnormal accumulation of erythrocytes and granulocytes. In contrast, lung tissue

from the PLV (Figure 3) and HFOV groups exhibited a more homogeneous expansion, with thin walled alveoli and

little evidence of lung injury. Congestion and inflammation were minimal, although a few areas had small amounts

of hyaline material within the alveoli. The mean number of neutrophils/hpf for each group is demonstrated in

Figure 4. Animals in the control group had fewer pulmonary neutrophils than did animals in the CMV, PLV, and

HFOV groups (p < .01). Animals in the PLV and HFOV groups had a significantly lower pulmonary neutrophil

count/hpf than animals in the CMV group (p < .01). The lung injury scores for each experimental group are shown

in Table 2. These data demonstrate a correspondingly lower injury score in those animals with fewer

neutrophils/hpf. The MPO activity for each experimental group is demonstrated in Figure 5. MPO activity was

significantly lower in lung samples from the control group when compared with lung samples from the CMV, PLV,

and HFOV groups (p < .01). Animals from the PLV and HFOV groups had intermediate MPO activity that was

significantly lower than that of animals in the CMV group (p = .01). The number of neutrophils/hpf was significantly

correlated with MPO activity (r2= .18, p = .01), and MPO activity was significantly correlated with lung injury

scores (r2= .46, p < .001) (Figure 6).

Figure 1. Photomicrographs of lung tissue obtained after 4.5 hrs of conventional mechanical ventilation (control

group) from rabbits not injured with an intravenous infusion of Escherichia coli endotoxin. Hematoxylin and eosin

stain, x100 (A) and x500 (B).
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Figure 3. Photomicrographs of lung tissue obtained after 4.5 hrs of partial liquid ventilation from rabbits injured

with an intravenous infusion of Escherichia coli endotoxin. Hematoxylin and eosin stain, x100 (A) and x500 (B).

Figure 4. Neutrophil counts per high-power field (hpf) in lung specimens of rabbits from the control, conventional

mechanical ventilation (CMV), partial liquid ventilation (PLV), and high-frequency oscillatory ventilation (HFOV)

groups. Mean +/- SEM values. *p < .01 vs. control; sup # p < .01 vs. CMV.

Table 2. Lung injury scores (mean +/- SD)
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Figure 5. Pulmonary myeloperoxidase activity of rabbits from the control (triangles), conventional mechanical

ventilation (CMV; squares), partial liquid ventilation (PLV; circles) and high-frequency oscillatory ventilation (HFOV;

diamonds) groups. Myeloperoxidase activity is expressed as activity/lung/kg body weight. Bars represent mean +/-

SEM. *p < .01 vs. contro l; sup # p < .01 vs. CMV.
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Figure 6. Scatter plots of correlations between myeloperoxidase (MPO) activity and lung injury scores (r 2= .46, p

< .001) (top) and neutrophil count per high-power field (hpf) and myeloperoxidase (MPO) activity (r 2= .18, p = .01)

(bottom). MPO activity is expressed as activity/lung/kg body weight. The regression lines (solid) and 95%

confidence intervals (dashed) are shown.

DISCUSSION

This study demonstrates that partial liquid ventilation significantly reduces neutrophil accumulation in the

lungs of animals exposed to a well-defined pulmonary insult. It represents the first published study of an objective

reduction in early pulmonary leukostasis following an acute injury treated with partial liquid ventilation.

The technique of perfluorocarbon-associated gas exchange, now commonly known as partial liquid

ventilation, was originally described by Fuhrman et al. [23]as a form of respiratory support in the normal piglet

model. Since then, partial liquid ventilation has been investigated as an adjunctive therapy in various experimental

models of acute lung injury, including oleic acid injury [24], gastric acid aspiration [14], meconium aspiration [25],

and neonatal respiratory distress syndrome [26]. In addition, limited c linical trials have demonstrated its safety and

efficacy in human disease [27,28]. A number of these studies [14,15,24]have hinted at a decrease in the degree of

injury observed during gross and microscopic examination of lung specimens from animals treated with either

partial [14,24]or total liquid ventilation [15]when compared with controls. The basis for this attenuation in lung

injury is not yet fully understood. Some investigators [15,29]have suggested that a "lavage" or dilutional effect

during liquid ventilation may remove inflammatory debris. Others [14]have proposed mechanisms involving the

mechanical stenting of the alveoli by the immiscible dense liquid perfluorocarbon in the alveolar spaces,

maintaining a more "open" lung for ventilation, as advocated by Amato and others [30]. The later conc ept of

reduced inflammation by maintaining a more "open" lung is further supported by the HFOV data, a modality

thought to maintain the lung in a more recruited state [13]. A further possible mechanism is that perflubron has

an anti-inflammatory effect. Virmani et al. [31]showed a decrease in superoxide release by circulating human

neutrophils exposed to a perfluorochemical emulsion. We [16]previously demonstrated a decrease in free radical

release by alveolar macrophages exposed in vitro to perfluorocarbons. We [17]have also shown that partial liquid

ventilation with perfluorocarbons reduces oxidative damage to lung tissue, as reflected by a decrease in tissue

content of thiobarbituric acid reactive substances (a measure of lipid oxidative damage) and carbonylated

proteins (a measure of protein oxidative damage).

Neutrophil accumulation within the pulmonary microvasculature has been implicated in the pathogenesis of

acute lung injury [2-5]. Sequestration of granulocytes in the lungs is thought to be an important early event in

ARDS as well as in the acute lung injury associated with sepsis and multiple organ system dysfunction. Human [4,5]

and animal models [2,3]have shown that the diffuse inflammatory picture seen in the lung tissue during ARDS is

generally preceded by accumulation and activation of neutrophils within that organ. During ARDS, pulmonary

neutrophils exhibit a state of functional activation as indicated by increased chemiluminescence activity [32],

increased superoxide generation [33], and altered chemotaxis [34]. The functional and metabolic activation of

neutrophils seen in patients with clinical ARDS is similar to that demonstrated in animal models of ARDS caused by

endotoxin infusion [33]. The importance of the neutrophil in the evolution of ARDS is further demonstrated by the

ability of granulocyte depletion to prevent the development of acute lung injury [6,7], although, as previously

noted, ARDS has also been well documented in patients with severe neutropenia [8], suggesting that neutrophil

sequestration is not the only factor implicated in this complex process. Based on these observations, the current

findings provide a unifying hypothesis which suggests that the reduced neutrophil sequestration in the lung and

attenuated activation of phagocytes may be contributing to the reduction in pulmonary tissue damage seen

during partial liquid ventilation.

The argument that the decrease in neutrophil count in histologic lung specimens following partial liquid

ventilation is solely due to a mechanical artifact must be carefully considered. One could postulate that the fluid-

filled lung might have a lower neutrophil count/hpf in comparison with a gas ventilated lung solely due to the fact

that the dense perfluorocarbon is capable of recruiting and maintaining patency of alveolar spaces that would
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otherwise have collapsed, thus decreasing the amount of actual tissue observed per field. This scenario does not

explain the attenuation in the overall inflammatory response (alveolar proteinaceous fluid, pulmonary vascular

congestion, and necrotic cell debris) of the lung tissue following partial liquid ventilation observed by us and

others [14,15,24]. Furthermore, the decrease in MPO activity in the lungs of animals supported with partial liquid

ventilation, compared with animals supported with conventional mechanical ventilation, provides objective

evidence that the reduction in pulmonary neutrophil infiltration is not merely a histologic artifact. MPO activity is

an accepted technique for measuring pulmonary leukostasis and has been shown to correlate linearly to the

absolute number of granulocytes found in a tissue sample [19,20]. Using a less common injury, cobra venom factor

challenge, to promote acute transient pulmonary sequestration of neutrophils, Bradley and colleagues [35]

presented preliminary data that showed a reduction in MPO activity in lungs rescued with partial liquid ventilation

in comparison with gas ventilated controls; these data thus corroborated our findings. The animals studied by

Bradley et al. [35]did not receive partial liquid ventilation until after being challenged with cobra venom factor,

suggesting that our findings are not solely dependent on the fact that the animals were pretreated before

endotoxin administration.

Comparing MPO activity per mass of lung tissue between gas ventilated and partial liquid ventilated groups

poses a significant problem, as an equal amount of lung tissue in the PLV group weighs more than that in the gas

ventilated group due to the presence of perfluorocarbon (density = 1.8 g/mL) in the air spaces. Therefore, simply

reporting MPO activity per mass of wet lung tissue would have underestimated the amount of MPO actually found

in that tissue in liquid ventilated lungs. Indexing MPO activity per mass of dry tissue or lung protein could

eliminate this problem; however, this procedure could also theoretically underestimate the MPO activity in

animals with significant capillary leak and third spacing of fluid in the pulmonary interstitium and alveolar spaces.

Therefore, we chose to express our results in each animal as units of MPO activity/lung/kg in an attempt to

estimate the total pulmonary MPO per animal. Although this method represents an extrapolation of MPO activity

in the whole lung, derived by the regional MPO activity in different areas of that organ, we believe it to be a

more reliable method for expressing these data in situations where variable capillary leak and edema are present,

when comparing gas and liquid ventilated lungs.

Sigiura et al. [13]demonstrated that the influx and activation of pulmonary neutrophils can be influenced by

different ventilator strategies. A possible implication of their study [13]is that the degree of neutrophil

infiltration, activation, and subsequent lung injury, could be attenuated by a ventilatory strategy that minimizes

cyclic alveolar distention and collapse in the injured or surfactant deficient lung. This scenario would be more

likely to occur during HFOV compared with conventional intermittent mechanical ventilation. Similarly, the

prevention of atelectasis seems to play an important role in this process. Thus, the proposition that mechanical

ventilation is not only a support modality, but also has the potential to influence inflammation, lung injury, and

the disease course follows logically from those data [13].

ARDS occ urs in a sequential fashion involving the complex interac tion of inflammatory mediators, inflammatory

cells, and injury to the target organ. While our model of endotoxin-induced lung injury produced a reliable andsignificant lesion in all rabbits, other investigators have proposed that a second stimulus is required to generate

neutrophil-mediated lung injury [3,36]. Henson et al. [3]reported that the neutrophil sequestration seen

following an endotoxin challenge did not cause lung injury or permeability changes, unless a second stimulus,

such as hypoxemia, was also present. Furthermore, hypoxemia is thought to induce pulmonary capillary

permeability changes, probably by local accumulation and activation neutrophils [3]. Prevention of atelectasis, as

suggested by Sigiura et al. [13], can alter neutrophil influx patterns. Partial liquid ventilation is thought to be a

ventilatory strategy that promotes the recruitment of alveolar units and the reduction of atelectasis [23]. Our

results suggest that the alteration in pulmonary leukostasis seen during liquid ventilation is comparable with that

of a ventilatory strategy that targets lung recruitment such as HFOV. The presence of oxygenated perflubron in

the airways may not only prevent the collapse of diseased alveoli but may also serve as a reservoir for oxygen

molecules to minimize local hypoxia assoc iated with atelec tasis. Thus, partial liquid ventilation may reduce

pulmonary neutrophil infiltration and subsequent injury by several mechanisms in concert.

The delivery of a fixed inspiratory tidal volume to lungs with significant atelectatic areas and heterogeneousdisease is capable of causing overdistention of the less involved regions, leading to the process of volutrauma

[30,37]. The high shear stresses within the alveoli may promote increased capillary permeability, protein leak, and

secondary surfactant deficiency. PLV has been shown to improve lung compliance in surfactant deficient models,

partially by its ability to recruit and maintain functional residual capacity [26]. This effect is probably achieved by

reducing surface tension in the alveolus and through the distending pressure exerted by the dense perflubron

itself. Partial liquid ventilation has also been shown to maintain surfactant syntheses [38]. The maintenance of

surfactant production by partial liquid ventilation in disease states associated with low compliance and

atelectatic lung segments could theoretically play a role in decreasing pulmonary neutrophil accumulation and

progression of lung injury by stabilizing the functional residual capacity.

This study provides new data demonstrating that partial liquid ventilation attenuates pulmonary neutrophil

influx during endotoxemia, a condition frequently leading to the development of ALI and ARDS in the clinical

setting. However, the current short-term experimental design does not allow for one to make extrapolations

attempting to correlate the observed attenuation in pulmonary leukostasis with clinical outcome. The attenuation

in pulmonary inflammatory response seen during partial liquid ventilation is likely to be multifactorial and appears

to be of similar magnitude to that observed with other ventilatory strategies that promote lung recruitment and

avoid patchy overdistention, e.g., HFOV. We speculate that partial liquid ventilation, instituted early in the course

of lung injury, could potentially blunt or delay the evolution of the pulmonary tissue injury that leads to ARDS.

This ventilatory strategy may not only support the patient and injured lungs but may also play a role in modifying

the disease process by maintaining the functional residual capacity, recruiting affected alveoli early on,

preventing surfactant inactivation, and suppressing neutrophil accumulation and activation.
http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


10/13



ACKNOWLEDGMENTS

The authors thank Mr. Paul Frisicaro, Mr . Mark Dowhy, and Mr. M ark Rath, RRT, for their expert tec hnical

assistance in carrying out the intact animal studies.

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35. Bradley JD, Spooner ML, Rusheen PD, et al: Intratracheal perflubron (PFB) liquid or vapor reduces lung

myeloperoxidase (MPO) levels following cobra venom factor (CVF) challenge in rats. FASEB J 1996; 626:A108

Bibliographic Links [Context Link]

36. Nahum A, Chamberlin AW, Sznajder JI: Differential activation o f mixed venous and arterial neutrophils in

patients with sepsis and acute lung injury. Am Rev Respir Dis 1991; 143:1083-1087 Bibliographic Links [Context

Link]

37. Tsuno K, Prato P, Kolobow T: Acute lung injury from mechanical ventilation at moderately high airway

pressures. J Appl Physiol 1990; 69:956-961 Bibliographic Links [Context Link]

38. Steinhorn DM, Leach CL, Fuhrman BP, et al: Partial liquid ventilation enhances surfactant phospholipid

production. Crit Care M ed 1996; 24:1252-1256 Ovid Full Text Bibliographic Links [Context Link]

IMAGE GALLERY

Table 1

Figure 1 Figure 2

Figure 3

Figure 4

Table 2
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