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Anesth Analg 2005;100:964-971 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000146438.87584.A9
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Abstract |
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We conducted the current study to compare the efficacy of partial liquid ventilation (PLV), pulmonary surfactant (PSF), and their combination in ameliorating the acidified infant-formula-induced acute lung injury (ALI). In the Part I study, 42 rabbits receiving volume-controlled ventilation with positive end-expiratory pressure 10 cm H2O were randomly divided into 6 groups (groups noninjuryi, gas ventilation [GVi], PLVi, PSFi, PLVi
PSFi, and PSFiPLVi). ALI was induced by intratracheal acidified infant formula (2 mL/kg, pH 1.8). Group GVi received neither PLV nor PSF therapy. Groups PLV and PSF received intratracheal fluorocarbon 15 mL/kg or surfactant 100 mg/kg, respectively, 30 min after acidified infant formula. Groups PLViPSFi and PSFiPLVi received both treatments at 30-min intervals. In Part II, 42 rabbits (in 6 groups) undergoing pressure-controlled ventilation received the same drug therapies as in Part I. The lungs were excised to assess biochemical and histological damage 150 min after induction of ALI. In Parts I and II, PSF, fluorocarbon, and their combination attenuated lung leukosequestration and edema and superoxide production of neutrophils, consequently improving oxygenation, lung mechanics, and pathological changes. Independent of ventilation mode, PSF followed by fluorocarbon provided the most beneficial effects and fluorocarbon followed by PSF produced the least efficacy. |
Introduction |
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Acidified milk products cause acute lung injury (ALI), characteristics of which resemble pulmonary pathophysiological alterations of acute respiratory distress syndrome (ARDS) observed in the pediatric population (1,2). We previously reported that exogenous administration of pulmonary surfactant (PSF) improves oxygenation, lung compliance, and histopathological changes in this experimental ALI model (2). Furthermore, we have recently demonstrated successful use of partial liquid ventilation (PLV) with fluorocarbon for the same purpose (3). The expense of PSF may preclude clinical application of the therapeutic strategy using PSF replacement. Additional treatment with fluorocarbon to PSF therapy may reduce the dose of PSF required to improve ALI, allowing cost reduction for treatment of ALI. Thus, the aim of the current study was to determine whether a sequential combination of PLV and PSF can be a therapeutic approach superior to single-agent treatment for acidified milk products-induced ALI. To make this assessment, we gave fluorocarbon and PSF in both sequential orders (fluorocarbon after PSF and PSF after fluorocarbon) because pulmonary responses to the combination therapy in ALI by repeated saline lavage depend on the treatment order of fluorocarbon and PSF (4). Volume-controlled ventilation (VCV) provides better improvement in neonatal piglets with ALI induced by saline lung lavage than pressure-controlled ventilation (PCV) (5). VCV may also optimize the beneficial effect of the combined therapy on milk products-induced ALI. Thus, we first assessed the efficacy of combination treatment in volume-controlled mode in the current study (Part I study). Because infants and children often receive PCV in clinical respiratory management, we next determined the effectiveness in this ventilation mode (Part II study). The current study was the first to assess the effectiveness of combination therapy in an ALI model induced by acidified milk products. Furthermore, data from the current study would be a basis for future clinical trials to elucidate whether the combination remedy could be a promising therapeutic approach in pediatric patients with ARDS induced by aspiration of acidified milk products.
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Methods |
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After institutional approval, we used 84 male Japanese White rabbits (2.0–2.4 kg) anesthetized with IM ketamine (60 mg/kg) and intubated with an endotracheal tube through a tracheotomy. A catheter was inserted into an ear vein for infusion of lactated Ringer's solution (8 mL · kg–1 · h–1). Anesthesia was maintained with IV infusion of ketamine (30 mg · kg–1 · h–1) and xylazine (8 mg · kg–1 · h–1). An arterial catheter was placed in the right femoral artery to monitor arterial blood pressure and take blood samples. The lungs were initially ventilated with 100% oxygen using volume-controlled (R60; Aika, Tokyo, Japan) and pressure-controlled (IV100B; Sechrist, Anaheim, CA) ventilators in Parts I and II, respectively. The initial tidal volume was set to 10 mL/kg in VCV and peak inspiratory pressure was set at 20 cm H2O in PCV. Chin et al. (6) reported that positive end-expiratory pressure application before and after PSF administration failed to improve gas exchange and pathological deterioration. Thus, positive end-expiratory pressure 1 cm H2O was only initially added to both modes. Respiratory rate was initially adjusted to produce normocapnia (Paco2 = 31–38 mm Hg). Inspiratory to expiratory (I:E) ratios were 1:1 and 1:2 in Parts I and II, respectively. Central venous pressure was also monitored via a catheter inserted through the femoral vein. Body temperature was kept at 38.1°C–40.2°C at the esophagus.
In Part I study, 42 animals receiving VCV were randomly divided into 6 groups (n = 7 each group): groups noninjuryi, gas ventilation (GVi), PLVi, PSFi, PLViPSFi, and PSFiPLVi. ALI was induced by intratracheal acidified infant formula (2 mL/kg, pH 1.8; Sukoyaka; Yukijirushi, Sapporo, Japan) in all groups except group noninjuryi. Each study solution was titrated to a pH level of 1.8 by the addition of 6 N hydrochloric acid. The pH level was determined using a pH meter (F-8L; Horiba, Kyoto, Japan). Group noninjuryi received intratracheal normal saline instead of the acidified milk product. Group GVi did not receive any pharmacological therapy. Thirty min after the infant formula, groups PLVi and PSFi received intratracheal preoxygenated fluorocarbon (FC-84; Sumitomo-3M, Tokyo, Japan) 15 mL/kg alone and PSF (Surfacten®, Mitsubishi Pharma, Osaka, Japan) 100 mg/kg, respectively. Group PLViPSFi received fluorocarbon 15 mL/kg followed by PSF 100 mg/kg. Group PSFiPLVi received PSF 100 mg/kg followed by fluorocarbon 15 mL/kg. The 2 medications were administered 30 min apart. Each animal was rotated and the head was elevated and lowered throughout instillation of fluorocarbon and PSF. In all groups, positive end-expiratory pressure was increased to 10 cm H2O because high positive end-expiratory pressure is required to optimize the efficacy of PLV or PSF in several ALI models (7–10). In part I, the respiratory rate was increased after ALI induction to maintain a level between normocapnia and mild hypercapnia (33–48 mm Hg). In Part II, 42 rabbits undergoing PCV received the same drug treatment as in the Part I study (groups noninjuryii, GVii, PLVii, PSFii, PLViiPSFii, and PSFiiPLVii). The respiratory rate was increased to ensure mild or moderate hypercapnia (45–63 mm Hg) in the ALI groups.
Surfacten used in the current study is a freeze-dried modified natural PSF isolated from bovine lungs. It consists of approximately 85% phospholipids and 1% hydrophobic PSF-associated proteins, the remainder being other lipids (glyceride and free fatty acids). These components of Surfacten are basically the same as Survanta (Abbott, North Chicago, IL), which is commercially available in the United States. Surfacten was suspended in saline at a concentration of 50 mg dry weight/mL for use. In previous studies, Surfacten 100 mg/kg has proven to improve gas exchange, lung mechanics, and histological changes in ALI induced by acidified milk products (2,6).
Hemodynamics, lung compliance, and resistance were recorded at specified points. Arterial blood samples for gas analysis and peripheral leukocyte counts were obtained during the study. Arterial blood gases (Pao2, Paco2, and pH) were analyzed with a blood gas analyzer (ABL2; Radiometer, Copenhagen, Denmark), and the number of leukocytes was measured with an automated blood cell counter (Sysmex K-1000; Sysmex, Kobe, Japan). The alveolar to arterial oxygen tension difference (A-aDO2) was calculated as A-aDO2 = Fio2 [PB-PH2O] – [Paco2/RQ] – Pao2 = 713 – Paco2/0.8 – Pao2.
Lung mechanics were measured by the passive expiratory flow-volume technique (2) using a Fleish 00 pneumotachograph, a differential pressure transducer (model MP045; Validyne Engineering, Northbridge, CA), and a computer interface (PC9801; NEC, Tokyo, Japan).
The thorax was opened and blood (15 mL) was drawn from the pulmonary artery for chemiluminescence assay 150 min after induction of ALI (intratracheal instillation of acidified infant formula). Immediately after the blood sampling from the pulmonary artery, the animals were killed by overdose of thiamylal to excise the lungs for assessment of the degree of lung damage.
The left upper lobe of each lung was weighed within 2 min after excision of the lung, and then dried to constant weight at 60°C for 24 h in an oven. The ratio of wet weight to dry weight (W/D) was calculated to assess tissue edema.
Within 5 min after death, the left lower lobe of the lung was fixed by instillation of 10% formaldehyde solution at 20 cm H2O. The specimens were embedded in paraffin wax, stained with hematoxylin and eosin, and examined under a light microscope. The ALI was scored by a blinded observer according to four items (alveolar congestion, hemorrhage, infiltration or aggregation of neutrophils in air space or vessel wall, and thickness of alveolar wall/hyaline membrane formation). Severity for each item was rated on a scale graded from 0 (minimal) to 4 (maximal). Maximum and minimum possible scores are 16 and 0, respectively. Seven microscopic images were obtained from each tissue sample using ACT-1 (Nikon, Tokyo, Japan) and the area of alveolar space was morphologically determined with an image analysis software (WinRoof; Mitani, Tokyo, Japan). Alveolar size was expressed as a ratio of the alveolar/parenchymal area.
Within 10 min after death, 30 mL saline with EDTA-2Na at 4°C was slowly infused into the right lung and withdrawn to obtain bronchoalveolar lavage fluid (BALF). This procedure was repeated three times. Indomethacin was added to the BALF to inhibit the further metabolism of arachidonic acid to prostaglandins during analysis. The BALF was analyzed for cell count and cell differentiation. A cytocentrifuged preparation (Cytospin 2; Shandon Southern Products, Pittsburgh, PA) of the BALF was stained with Diff-Quick (Harleco, Gibbstown, NJ) for cell differentiation. The cells present in BALF were counted by the Brker-Trk method. The fluid was centrifuged at 250g at 4°C for 10 min to remove the cells. The cell-free supernatant was divided into several aliquots and stored at –70°C until assay. The following substances and mediators in the BALF were measured: albumin concentrations were determined by nephelometry with immunoglobulin G fraction of goat anti-rabbit albumin (Cappel, Durham, NC), leukotriene B4 (LTB4) was measured by enzyme immunoassay (Amersham-Pharmacia, Buckinghamshire, UK), thromboxane A2 was quantified by radioimmunoassay kit (NEN, Boston, MA and Amersham) as 11-dehydro-thromboxane B2 (11-DTxB2), and the stable metabolite; and nitrite plus nitrate (NOx) was measured using NOX 1000m (Tokyo Kasei, Tokyo, Japan).
Chemiluminescence of neutrophils was assessed according to methods described previously (2). Briefly, neutrophils were isolated from the pulmonary artery using Histopaque (Sigma, St. Louis, MO) density gradient. Neutrophils were washed in Hank's balanced salt solution (HBSS; Sigma). The cell analysis showed that more than 97% of the cells were neutrophils, and the trypan blue dye exclusion test confirmed that more than 95% of the cells were viable. Neutrophils (2 x 105 cells/mL) and HBSS were preincubated for 3 min and the reaction was initiated by the simultaneous addition of 1 µM N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; Sigma) and 40 µM Cypridina luciferin analog, (CLA; Sigma). CLA-dependent chemiluminescence, which represents superoxide (O2–) production, was monitored with a luminescence reader (Lumicounter-1000; Nichion, Chiba, Japan). Ketamine and xylazine have no effect on O2– production by neutrophils at doses used in the current study (11,12).
The ALI score was given as median (range), whereas the other data were expressed as mean ± sd. Repeated measures data (i.e., oxygenation, lung mechanics, peripheral leukocytes, and hemodynamics) were statistically analyzed using repeated-measures analysis of variance. The data of BALF, W/D weight ratio, and alveolar size were analyzed by one-way analysis of variance followed by the Tukey-Kramer post hoc test. The ALI score was analyzed using Kruskal-Wallis rank test followed by Dunnett test. P < 0.05 was deemed statistically significant.
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Results |
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Hemodynamics and Peripheral Leukocytes
Part I.
There were no significant differences in arterial blood pressure, heart rate, or central venous pressure among the groups at any point (data not shown). Acidified infant formula gradually decreased peripheral circulating leukocyte counts (data not shown). The number of blood leukocytes was significantly greater in rabbits receiving PSF alone, fluorocarbon alone, or PSF followed by fluorocarbon than in those receiving GV alone (data not shown).
Part II.
Hemodynamics were similar among the 6 groups during the study (data not shown). The peripheral leukopenia was less severe in groups PSFii and PSFiiPLVii compared with GVii (P < 0.05) (data not shown).
Gas Exchange and Lung Mechanics
Part I.
Intratracheal acidified infant formula dramatically impaired A-aDO2, compliance, and resistance (Fig. 1). Fluorocarbon or PSF improved deterioration of the variables during VCV. Fluorocarbon after PSF and PSF after fluorocarbon produced the most and the least satisfactory improvement, respectively. There was no statistically significant difference in Paco2 between the ALI groups.
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P < 0.05 versus Group PSFi or PSFii, #P < 0.05 versus Group PLVi or PLVii.
Part II.
In PCV, treatment with PSF or fluorocarbon improved the impairment of A-aDO2, compliance, and resistance by acidified infant formula (Fig. 1). PSF followed by fluorocarbon was the most effective therapy, whereas fluorocarbon followed by PSF provided a minimal improvement. Paco2 did not significantly differ between the ALI groups.
Lung Edema and BALF Analysis
Part I.
Acidified infant formula increased lung W/D weight ratio (Table 1). Recovery percentages of BALF were similar in all 6 groups (71%–79%). The milk product increased albumin levels, leukocyte counts, and %neutrophils (neutrophils-to-total leukocytes ratio) in BALF. PSF or fluorocarbon attenuated the increase. Fluorocarbon after PSF appeared to provide the most favorable effect. Fluorocarbon or PSF did not significantly change BALF NOx levels (Table 1). PSF followed by fluorocarbon attenuated the increase in BALF eicosanoids concentrations, although the other three pharmacological interventions failed to do so (Table 1).
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Part II.
There was no significant difference in recovery ratio of BALF among the 6 groups (73%–80%). PSF alone or PSF followed by fluorocarbon during PCV attenuated the increase in W/D weight ratio, BALF leukocytes number, %neutrophils, and albumin although fluorocarbon alone and PSF after fluorocarbon failed to do so (Table 2). The BALF NOx concentrations were comparable among the 6 groups. PSF followed by fluorocarbon attenuated the increase of the eicosanoids in BALF although not significantly (Table 1).
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Histopathology
Part I.
Acidified infant formula morphologically caused edema, hemorrhage, ruptured and thickened alveolar walls, infiltration of inflammatory cells in alveolar spaces and walls, and diffuse proteinaceous exudate. The damage was improved in the rabbits receiving PSF or fluorocarbon (Fig. 2). Fluorocarbon after PSF produced the least severe morphological damage. The four therapeutic strategies improved the ALI score in the following decreasing order of efficacy: PSFiPLVi > PSFi > PLVi > PLViPSFi (Table 1). Aerated alveolar area was larger in groups PSFiPLVi and PSFi than in group GVi (Table 1).
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Part II.
Fluorocarbon after PSF most effectively improved lung damage (Figs. 2). Improvement of ALI with fluorocarbon followed by PSF was the least (Fig. 2). The aerated alveolar area was larger in the rabbits receiving PSF alone or PSF followed by fluorocarbon than in those not receiving therapy (Table 2).
Chemiluminescence
Part I.
Acidified infant formula increased FMLP-stimulated, CLA-dependent chemiluminescence (O2–) by neutrophils (Table 1). The O2– production was significantly blunted by PSF alone and PSF followed by fluorocarbon (Table 1).
Part II.
In PCV, the increase in O2– production was attenuated by fluorocarbon alone, PSF alone, and fluorocarbon after PSF and not by PSF after fluorocarbon (Table 2).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the current study, we have shown that fluorocarbon or PSF improved physiological, biochemical, and pathological lung damage induced by acidified infant formula compared with GV. In VCV and PCV, the efficacy was in the following order: PSF
PLV > PSF > PLV > PLVPSF. These data suggest that PSF replacement is a primary mechanism for improvement of ALI with the combination therapy. The important role in PSF replacement is also evidenced by our recent study (13), in which recombinant human PSF protein-C (rSP-C) has been demonstrated to improve physiological and morphological ALI changes induced by acidified milk products. The degree and time course for the beneficial effects of rSP-C seemed to be similar to Surfacten used in the current study. The inhibitory action of rSP-C on inflammatory mediators correlated well with Surfacten. Thus, rSP-C ought to be an alternative to Surfacten in combination therapy for the ALI model. The major mechanism for PSF-induced improvement of physiological and histological changes reduces surface tension at the air-water interface in the terminal airways by the formation of a surface-active film, thereby preventing alveolar collapse leading to amelioration of lung mechanics and oxygenation. The initial direct damage of acidified milk product-induced ALI develops immediately after instillation of acidified infant formula, and impairment of gas exchange and the increase in permeability reach a peak at 1 hour with pathological alterations consisting of alveolar/capillary destruction, alveolar hemorrhage, and influx of protein-rich edema fluid (14). The intraalveolar blood components and plasma exudates easily lead to atelectasis and a mismatch of the ventilation-perfusion ratio by inhibiting PSF function (15). Furthermore, the acidified infant formula can damage type II pneumocytes, which produce PSF directly. Thus, PSF replacement may be a more important and indispensable treatment in acidified milk product-induced ALI than in endotoxin-induced ALI in which alveolar hemorrhage and pulmonary edema are probably less severe. Although PSF replacement therapy is ineffective for alveolar areas with histologically complete destruction, the remedy would be able to restore aeration in atelectatic alveoli (without morphological disruption) induced by PSF inhibitors. PSF also plays a regulatory role in fluid balance in interstitial and alveolar spaces (16). Attenuation of lung edema formation with exogenous PSF appears to be caused by this mechanism.
The second phase of ALI occurs 2–3 hours after aspiration of acidified milk and is consistent with an acute inflammatory response mediated mainly by neutrophils. Activated neutrophils are capable of damaging alveolar architecture and impairing PSF function by releasing O2– (17). PSF per se has anti-neutrophil activities. Prevention of alveolar collapse by PSF treatment probably reduces shear stress-induced production of inflammatory mediators. Chemiluminescence and BALF data in the current study suggest that PSF also provided beneficial effects on ALI through these mechanisms. Fluorocarbon has antiinflammatory actions. In the current study, fluorocarbon enhanced the inhibitory effect of PSF on alveolar collapse and production of O2–, TxB2, and LTB4. The additive effects of fluorocarbon on PSF-induced improvement of physiological and morphological changes may be attributable not only to recruitment and maintenance of lung volume but also to suppression of cellular and humoral inflammatory mediators.
There are several contradictory studies that compared the efficacy of PLV alone and PSF alone in animal experimental ALI. Exogenous treatment with PSF attenuates protein leak into BALF, reduces conversion of active to nonactive endogenous PSF components, and ameliorates pathological lung injury in rats receiving repeated lung lavage, although exogenous fluorocarbon fails to do so (18). Leach et al. (19), however, have demonstrated that fluorocarbon alone is more effective in improving gas exchange and lung mechanics in premature lambs with respiratory distress syndrome than Exosurf alone. However, Exosurf seems to be less effective than Survanta (the same as Surfacten) because the drug does not contain PSF protein (19). In newborn piglets with repeated saline lavage-induced ALI, fluorocarbon therapy is also superior for improvement of oxygenation, compliance, and pathological changes to PSF therapy (4). These conflicting results may be explained by different experimental protocols: differences in animal models, observation period, ventilatory strategy including positive end-expiratory pressure levels, and types of PSF.
The combination of PLV and PSF fails to provide additive beneficial effects on oxygenation and lung mechanics compared with PLV therapy alone in premature lambs with respiratory distress syndrome (19). Merz et al. (20) have also shown that the combination of PSF and FC-77 conversely impairs gas exchange and fails to protect the animal from a lung injury model of PSF deficiency using newborn piglets. The combined therapeutic strategy produces more beneficial effects on physiological and pathological changes than each therapy alone (4,21). An experiment using excised preterm lamb lungs has indicated that exogenous PSF before PLV further reduces surface tension as compared with PSF alone and PLV alone, producing greater improvement of lung compliance (22). PLV enhances PSF phospholipid production and secretion in an experiment using BALF of mature rabbits (23). This may partly explain the mechanism through which the combined therapeutic approach is more satisfactory than each therapy alone.
Administration order in PSF and fluorocarbon therapy seems to influence the efficacy of the combined therapy (4). Fluorocarbon after PSF produces better oxygenation, compliance, and pathological pulmonary injury scores than does the pharmacological intervention in the reverse order (4). Fluorocarbon treatment after PSF may deliver both of the drugs more effectively into gas exchange areas. Acidified infant formula produces hemorrhage, debris, edema, exudates, and desquamation of bronchiolar epithelium, all of which obstruct the airway or fill alveolar spaces, consequently leading to atelectasis. Fluorocarbon with its high density facilitates removal of these obstacles from distal to proximal airways. This physicochemical characteristic of fluorocarbon may be conversely disadvantageous for combination therapy using PSF. Fluorocarbon in the airway may hamper PSF distribution to peripheral gas-exchange regions (alveoli) because PSF with low density is liable to float on fluorocarbon. This would be why PSF after fluorocarbon provided the least efficacy in the current study although the precise mechanism remains unclear. Furthermore, PSF suspended in saline may disturb oxygen diffusion into fluorocarbon probably because PSF in saline makes a layer on the top of fluorocarbon. Mrozek et al. (24) also found that priming the lung with fluorocarbon neither improved the physiological effects of exogenous PSF nor improved lung pathology in newborn piglets with ALI induced by saline washout.
Although hyperproduction of nitric oxide (NO) is responsible for inflammatory lung damage (25), NOx changes in BALF were minimal in the ALI groups of the current study despite a significant increase in O2– production. Although the precise mechanism for dissociation of the two inflammatory mediators remains to be elucidated, the following may explain our observation. O2– is produced dominantly from neutrophils (rather than macrophages), whereas NO is released mainly from macrophages rather than neutrophils. In our ALI model, most inflammatory cells infiltrating the alveolar septa and spaces were neutrophils and alveolar macrophages infiltration was less prominent.
The current study has several limitations. The longevity of morphological and physiological improvements attained with PSF and fluorocarbon, as well as the need for additional doses of these drugs, remains unclear because the ALI model was followed for only 2.5 hours. Second, since the current study was devoid of dose-response relationships for PSF and fluorocarbon, the response needs additional examination and characterization. Third, it is unclear whether the improvements in oxygenation and lung mechanics will indeed translate into an improvement in clinical outcomes and a decrease in mortality. Finally, the aim of the current study was to assess the efficacy of PSF, fluorocarbon, and their combination in both of the ventilatory modes and was not to determine which mode is better. Thus, we are unable to draw a conclusion concerning the optimal ventilation mode from our findings.
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Footnotes |
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Accepted for publication September 14, 2004.
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References |
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