Ann Thorac Surg 2006;82:124-130
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Total Liquid Ventilation Reduces Lung Injury in Piglets After Cardiopulmonary Bypass
Lijun Jiang, MD
*
,
Qiang Wang, MD
*
,
*
,
Yinglong Liu, MD,
Ming Du, MD,
Xiangdong Shen, MD,
Xiaogang Guo, MD,
Song Wu, MD
Department of Surgery and the Research Center of Congenital Heart Disease, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Accepted for publication February 4, 2006.
* Address correspondence to Dr Wang, Department of Surgery, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China (Email: qiang.wan{at}163.com).
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Abstract
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BACKGROUND: Cardiopulmonary bypass may cause lung injury that does not respond to traditional therapies. Total liquid ventilation has been developed as an alternative ventilatory strategy for severe lung injury. The aim of this study is to investigate the effect of total liquid ventilation on lung injury in piglets after cardiopulmonary bypass.
METHODS: After exposure to 60 minutes of cardiac arrest and weaning from cardiopulmonary bypass, 12 piglets (4.2 ± 0.3 kg) were randomly treated with conventional gas ventilation (control group) or total liquid ventilation (study group) for 240 minutes. Samples for blood gas analysis were collected before, and at 30-minute intervals after, cardiopulmonary bypass. The degree of lung injury was quantified by histologic examination. The inflammatory cells and the levels of interleukin-6, interleukin-8, and myeloperoxidase in bronchoalveolar lavage were analyzed.
RESULTS: Neutrophil and macrophage count in bronchoalveolar lavage were significantly decreased in the study group (52.4 ± 6.82 vs 0.46 ± 0.11 104/mL; 58.33 ± 0.88 vs 4.37 ± 0.90 105/mL; p < 0.001, respectively). The inflammation score and the total lung injury score were also reduced in the study group (4.39 ± 1.14 vs 2.61 ± 1.09; 11.06 ± 1.66 vs 6.94 ± 1.43; p < 0.05, respectively). The concentrations of interleukin-6 and myeloperoxidase in bronchoalveolar lavage were significantly reduced in the study group (81.32 ± 15.23 vs 53.55 ± 15.48 pg/mL, 75.00 ± 9.19 vs 50.00 ± 7.37 u/mL; p < 0.05, respectively), whereas the interleukin-8 levels were similar between both groups (551.63 ± 119.34 vs 563.68 ± 137.14 pg/mL, p > 0.05).
CONCLUSIONS: Total liquid ventilation with FC-77 (3M, St. Paul, MN) reduces biochemical and histologic lung injury in piglets after cardiopulmonary bypass.
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Introduction
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Cardiopulmonary bypass (CPB) causes acute lung dysfunction, which remains a significant clinical problem resulting in increased morbidity, prolonged ventilation support, and intensive care unit stay. The clinical severity of lung injury after CPB varies from subclinical changes in most patients to acute respiratory distress syndrome in less than 2% of cases [1]. Conventional gas ventilation, assisted by protective ventilatory strategies such as low tidal volume, positive end-expiratory pressure, and inhalation of pulmonary vasodilators, is the commonly accepted supportive care for CPB-related lung dysfunction and has shown satisfactory results in most patients [2–4]. However, there remain a small number of patients who suffer from severe lung injury after CPB and in whom pulmonary gas exchange cannot be improved by the abovementioned methods. Furthermore, conventional gas ventilation may exacerbate the CPB-induced lung injury in these patients, resulting in progressive structural damage and release of inflammatory mediators within the lung [5, 6]. Consequently, mortality and morbidity remain extremely high in this patient population. New strategies to support pulmonary gas exchange while reducing lung injury after CPB are still required.
Liquid ventilation with perfluorocarbons, which sustains gas exchange with tracheal instillation of perfluorocarbons to replace nitrogen as the carrier for oxygen and carbon dioxide, has been investigated as a novel treatment approach for severe lung injury. Liquid ventilation is usually performed by two methods. One is partial liquid ventilation that has been applied for CPB-related lung injury, resulting in improved cardiopulmonary function and reduced intrapulmonary neutrophil sequestration [7–9]. Unfortunately, the randomized clinical trials reached a disappointing conclusion that partial liquid ventilation does not improve the outcome in adult and pediatric acute respiratory distress syndrome compared with conventional gas ventilation, suggesting partial liquid ventilation might not contribute much to the treatment of severe lung injury [10, 11]. The other is total liquid ventilation (TLV) that has been shown to enhance pulmonary function and reduce histologic lung damage as suggested by several studies [12–16]. When compared with partial liquid ventilation, TLV avoids overdistention of the nondependent regions of the lung, minimizes alveolar surface tension with the complete elimination of air-fluid interface, recruits maximal collapsed lung regions, and removes the inflammatory exudates by effective alveolar lavage. Therefore, total liquid ventilation was considered an alternative ventilatory strategy for severe lung injury [17]. However, to date there are scarce published data regarding the effect of TLV on lung injury after cardiopulmonary bypass. Thus, the present study was conducted to test the hypothesis that total liquid ventilation would attenuate lung injury in piglets after cardiopulmonary bypass.
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Material and Methods
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Animal Preparation
All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 83-23, revised 1985).
Twelve 26 to 28 day old Chinese experimental minipigs, weighing 4.2 ± 0.3 kg, were premedicated with intramuscular ketamine (35 mg/kg) and diazepam (1.5 mg/kg). A cuffed endotracheal tube, 4.5 mm in diameter, was placed through a tracheotomy and was connected to a SV900 ventilator (Siemens-Elema; Solno, Sweden) in the volume control mode. Initial ventilatory settings included inspired oxygen fraction, 1.0; respiratory rate, 30 per minute; delivered tidal volume, 10 mL/kg; positive end-expiratory pressure, 4 cm H2O; and inspiratory time, 0.65 seconds. Anesthesia and paralysis were maintained by intermittent boluses of fentanyl (0.5 mg/kg), diazepam (0.5 mg/kg), and pipecuronium bromide (0.1 mg/kg). A catheter was inserted by cutdown into the femoral artery to obtain blood samples.
Induction of Lung Injury: Cardiopulmonary Bypass
After median sternotomy and heparinization (400 IU/kg), the pericardium was incised and suspended. Conventional, nonpulsatile CPB was established by cannulation of an 8F infant arterial cannula in the ascending aorta and a single 20F venous cannula in the right atrium. The CPB circuit was composed of roller pumps (Sarns Inc, Ann Arbor, MI), membrane oxygenator (Capiox, Terumo, Tokyo, Japan), and standard arterial filter (Xijing Co, Xian, China). The pump priming solution consisted of lactated Ringer's solution (150 mL), whole blood (400 mL), heparin (400 U/kg), and 5% sodium bicarbonate solution (25 mL).
Each animal was cooled over 10 minutes to the nasopharyngeal temperature of 26°C. Left atrial drainage was established. The ascending aorta was clamped and cold cardioplegia was perfused to arrest the heart through a cannula inserted in the root of the ascending aorta in the volume of 20 mL/kg at first and 10 mL/kg 30 minutes later. The pump flow was adjusted to 80 mL/kg per minute. The ventilator was standby during the period of cardiac arrest. After 60 minutes of cardiac arrest, the aorta cross-clamp was removed with a dopamine infusion of 5 µg/kg per minute. After 20 to 30 minutes of rewarming, the animals were removed from CPB and were ventilated at the same settings as those before CPB. All blood within the oxygenator was recycled into a bottle. The recycled blood and an additional 200 mL whole blood were slowly instilled into each animal during the whole observation period. No other fluid was instilled into the animal.
Within 30 minutes after weaning from CPB, which was arranged as a stabilization period, all animals received the following treatments: (1) heparin was reversed by protamine (1.3 mg/100 U heparin); (2) the sternum was closed; (3) metabolic acidosis and blood electrolytes were corrected to their normal ranges. After the stabilization period, 12 piglets were randomly assigned to the control and study group.
Study Protocol
Control group
Six animals were randomized to the control group and received conventional gas ventilation without further intervention for 240 minutes. The ventilation settings such as tidal volume were the same as those described in the initial procedures.
Study group
Six animals were randomized to the study group and received total liquid ventilation for 240 minutes. Total liquid ventilation was performed with respiratory rate (5 breaths/minute), inspiratory time (4 seconds), expiratory time (8 seconds), and tidal volume (24 ± 2.13 mL/kg). Total liquid ventilation was started by a modified method based on the literature described by Matsuda and colleagues [18]. Briefly, the lungs were first filled with warmed (37°), oxygenated (FIO
2, 1.0) perfluorocarbon (FC-77; 3M) (20 mL/kg) within 30 minutes and were debubbled by light compression of the chest with the animals in the supine position. This time-cycled, gravity-dependent liquid ventilator functioned in the following manner. At the beginning of the inspiratory phase, an electromagnetic pinch valve on the inspiratory limb of the circuit opened at the same time that the other electromagnetic pinch valve occluded the expiratory limb. The FC-77 was infused into the lung by gravity from the upper reservoir of 2,000 mL volume placed 25 cm high above the animal. At the end of the inspiratory phase, the pinch valve on the expiratory limb was opened as the pinch valve on the inspiratory limb was occluded. The FC-77 was then drained by siphon pressure from the lung into the lower reservoir of 2,000 mL volume that was placed at a height of about 30 cm below the animal. A timer that allowed adjustment of inspiration-expiration time controlled both electromagnetic pinch valves. A roller pump (Sarns, Ann Arbor, MI) drew the FC-77 in the lower reservoir to a blood membrane oxygenator (Capiox, Terumo, Tokyo, Japan). The FC-77 was warmed by a heater-cooler (Sarns) and exposed to 9 L /minute of countercurrent O2 flow, which oxygenated the FC-77 and stripped it of CO2. The oxygenated and warmed perfluorocarbon was then recycled into the upper chamber. Tidal volume was monitored by the change in body weight of the animals during the respiratory cycles.
Measurements
Analysis of lung bronchoalveolar lavage and blood sample
Arterial blood gases were measured before CPB and every 30 minutes after weaning from CPB during the observation period. A 3 mL blood sample was collected at the end of the observation period and was centrifuged at 1,000 G for 10 minutes. The supernatant was frozen at –80°C and stored for subsequent chemical analysis.
When the animals were killed, the expiratory limb of total liquid ventilation was kept open to retrieve the FC-77 from the lung as much as possible. Subsequently, tracheal suction with an 8F suction catheter was performed to remove the residual FC-77 in the lung. At necropsy, the heart and lungs were excised en bloc. The right lower lobe was subsequently excised with the connection to the trachea maintained. Saline (50 mL at 4°C) was slowly injected into the right lower lobe as 2 aliquots of 25 mL each and then withdrawn gently to obtain an optimal bronchoalveolar lavage (BAL) specimen. The combined aliquots of BAL fluid were strained through surgical cotton gauze to remove mucus and centrifuged at 1,000 G for 10 minutes to remove cells. The supernatant was frozen at –80°C for subsequent chemical analysis. The pellet was resuspended in 15 mL phosphate-buffered saline solution and total cell count was achieved using the hemocytometer method. A slide smear was stained with Wright-Giemsa for cell differentiation. Cells were counted under a microscope at 100x magnification.
The concentrations of interleukin-6 (IL-6) and interleukin-8 (IL-8) in plasma and bronchoalveolar lavage were measured by porcine-specific enzyme-linked immunosorbent assays (R&D, Minneapolis, MN), which were performed according to the supplier‘s instructions. The minimum detection levels of porcine IL-6 and IL-8 were 10 pg/mL and 4.6 pg/mL, respectively. Myeloperoxidase (MPO) activity in the plasma and BAL was determined kinetically. Briefly, 150 µL of plasma was incubated with 3 mL of assay reagent containing o-dianisidine dihydrochloride (0.167g/L), hydrogen peroxide (0.0005%), and potassium phosphate buffer (50 mmol/L) (pH 6.0). Product formation was linear for 2.5 minutes and measured spectrophotometrically at 460 nm. Myeloperoxidase activity was expressed as absorbance change per liter. Plasma concentrations of the measured inflammatory factors were corrected for hemodilution according to the following formula: corrected concentration = measured concentration x pre-CPB hematocrit/measured hematocrit.
Lung Histology
Immediately after the piglets were killed, the left lower lobe was fixed in 10% neutral buffered formalin for 24 hours at a constant pressure of 20 cm H2O through the airway. The specimens were stained with hematoxylin and eosin for histologic assessment. Two pathologists who were blinded to this study evaluated the pathologic changes. A four-point, semiquantitative, scoring system described by Merz and colleagues [19] was adopted. The pathologic findings were graded as negative = 0, slight = 1, moderate = 2, and severe = 3. We chose four main characteristics based on 12 characteristics: (1) atelectasis; (2) edema (based on septal edema, interstitial edema, lymphangiectasis, intraalveolar exudate); (3) inflammation (based on alveolar leukocyte infiltration, interstitial neutrophil infiltration, interstitial monocyte infiltration, granulocyte sticking); and (4) various (based on alveolar hemorrhage, hyaline membrane formation, congestive hyperemia). The results of each variable obtained from all animals in each investigated group were summarized. The sum of all 12 variables then was divided by the number of animals in each group, resulting in the total lung injury score. The sum of four variables belonging to inflammation was divided by the number of animals in each group, resulting in the inflammation score.
Data Analysis and Statistics
The data were expressed as mean ± standard deviation. The inflammation score, the total lung injury score, and the percentage of inflammatory cells in BAL were compared between groups by the Wilcoxon rank sum test. Data for nonrepetitive measurements were analyzed by one-way analysis of variance (ANOVA) for between-group comparisons. Data at different time points were analyzed by variance analysis of repeated measures. All analyses were performed using SPSS software for windows (SPSS Inc, Chicago, IL) and differences were considered statistically significant at a probability level of less than 0.05.
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Results
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Gas Exchange
At baseline (pre-CPB), the data of gas exchange were similar between both groups. Repeated measures ANOVA indicated there was an effect of time on partial pressure of arterial oxygen (PaO
2) as a function of pre-CPB and post-CPB times (p < 0.001) and no significant effect of study group on PaO
2 (0.166). There was no significant effect of time (p = 0.529) and study group (p = 0.484) on arterial carbon dioxide (PaCO
2) (Table 1).
Analysis of BAL Fluid and Blood Sample
There was no significant difference in the percentage of recovered BAL fluid between both groups (64% vs 62%, p > 0.05). The total cell count and neutrophil count in BAL were significantly lower in the study group. Although the percentage of macrophages in BAL was increased in the study group, the macrophage count in BAL was decreased significantly (Table 2). Total liquid ventilation attenuated the increase of IL-6 and MPO levels in BAL at the end of the observation period while the BAL concentrations of IL-8 were similar in both groups (Fig 1), whereas there was no statistically significant difference in both groups in terms of plasma concentrations of IL-6, IL-8, and MPO (Fig 2).
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Fig 1. BAL concentrations of interleukin-6 (pg/mL), interleukin-8 (pg/mL) and myeloperoxidase (MPO) (u/L) at the end of the observation period. Results are presented as mean and SD. There was a significant difference in the interleukin-6 and MPO levels between groups. (*p< 0.05;  p< 0.001 by one way analysis of variance; black bar = control; grey bar = total liquid ventilation.)
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Fig 2. Plasma concentrations of interleukin-6 (pg/mL), interleukin-8 (pg/mL), and myeloperoxidase (MPO) (u/L) at the end of the observation period. Results are presented as mean and SD. There was no significant difference in the interleukin-6, interleukin-8, and MPO levels between groups. (Black bar = control; grey bar = total liquid ventilation.)
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Histologic Examination
The best histopathologic finding was observed in the normal animals without lung injury (Fig 3). Light microscopic findings in the control group demonstrated extensive morphologic lung damage including alveolar edema, nonhomogeneous lung expansion, hemorrhage, intraalveolar and interstitial infiltration of neutrophil and monocyte, congested alveolar capillaries, and local proteinaceous exudate (Fig 4), which was more severe than that in the study group (Fig 5). The inflammation score and the total lung injury score were reduced significantly in the study group (Fig 6).
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Fig 3. Representative lung section indicates an unimpaired lung tissue from a normal animal that did not receive cardiopulmonary bypass (hematoxylin and eosin, x200).
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Fig 4. Representative lung section from an animal treated with conventional gas ventilation after cardiopulmonary bypass indicates significant lung injury (hematoxylin and eosin, x200).
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Fig 5. Representative lung section from an animal treated with total liquid ventilation after cardiopulmonary bypass indicates significantly reduced lung injury (hematoxylin and eosin, x200).
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Fig 6. Inflammation score and total lung injury score. Results are presented as mean and SD. There was a significant difference in the inflammation score and total lung injury score between groups. (*p < 0.05; black bar = control; grey bar = total liquid ventilation.)
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Comment
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In this study we evaluated the treatment effect of total liquid ventilation on lung injury after cardiopulmonary bypass. The results of this study demonstrated the following: (1) total liquid ventilation resulted in a marked reduction of neutrophil and macrophage infiltration in bronchoalveolar lavage and lung interstitium; (2) TLV reduced the pulmonary inflammatory response after CPB with a significant decrease of BAL IL-6 and MPO levels; and (4) our data demonstrated that the suppression of pulmonary neutrophil sequestration by TLV with FC-77 was independent of IL-8 expression.
The lung injury after CPB is characterized by an intensified pulmonary inflammatory response. Intrapulmonary sequestration of neutrophils with release of inflammatory products plays a key role in the development of lung injury after cardiopulmonary bypass [20–22]. The present study first demonstrated that TLV reduced neutrophil sequestration in BAL and in lung interstitium with a lower MPO activity (a marker of neutrophil infiltration) in piglets after CPB, which was consistent with previous studies in other lung injury models [16, 23, 24]. Although the precise mechanism was not elucidated, several explanations were discussed. First, the homogeneous distribution of FC-77 in the lungs with elimination of the gas-liquid interface tension could protect all the alveoli from the malignant stimuli of high pressure and overdistension caused by conventional gas ventilation that would ultimately aggravate the underlying pulmonary inflammatory response [6]. Second, the lower BAL neutrophil count in the study group suggested that the tidal movement of perfluorocarbon in the lungs could effectively wash out intraalveolar inflammatory cells. Third, FC-77 may also reduce pulmonary neutrophil infiltration by inhibiting the production of intercellular adhesion proteins, which was supported by the recent study [25] indicating that the pulmonary messenger ribonucleic acid expression of intercellular adhesion proteins was reduced by aerosol treatment with FC-77. Fourth and final, the inhibition of monocyte migration into the lungs during TLV may also contribute to reducing lung injury. After the onset of pulmonary inflammatory response, it was speculated that circulatory monocytes migrated earlier into the lungs than neutrophils and that these migrated monocytes were then activated and secreted chemoattractants to recruit more neutrophils, which consequently amplified pulmonary inflammatory reaction[1, 26]. Therefore, it would be expected that FC-77 might block the pulmonary inflammatory cascade by restraining monocyte migration.
Serum and BAL IL-6 levels are sensitive indicators of the severity of lung injury and correlate with postoperative morbidity of children undergoing CPB [27, 28]. In the present study, TLV demonstrated a significantly lower BAL IL-6 expression, suggesting a milder pulmonary inflammatory reaction in the study group. This finding supported the in vitro observation in which FC-77 inhibited IL-6 production in lipopolysaccharide-stimulated macrophages [29]. Interleukin-8 is a potent chemokine and its level has been correlated with the degree of neutrophil recruitment in the lung [30]. The lack of significant difference of the BAL IL-8 level between the control and study groups confirmed the concept that the inhibition effect of perfluorocarbons on neutrophil recruitment may be independent of IL-8 expression [31]. However, even if BAL IL-8 levels were similar in both groups, the inert liquid FC-77 might prevent neutrophils from contacting with IL-8 in the alveoli and thus reduced the response intensity of neutrophils to IL-8. In addition, the different change pattern of BAL IL-6 and IL-8 concentrations in this study suggested the inhibitive effect on the production of cytokines rather than the continuous lung lavage could be the primary mechanism for the impact of TLV with FC-77 on the BAL cytokines levels.
A recent study demonstrated that the protective ventilatory strategies could reduce both systemic and BAL levels of IL-6 and IL-8 in patients who have undergone CPB surgery when compared with conventional gas ventilation [2]. However, the plasma concentrations of IL-6 and IL-8 were not significantly different in both groups of this study. One reason for this phenomenon is that circulating cytokine levels after CPB were influenced by many factors other than different ventilation modes. For example, considerable amounts of IL-6 and IL-8 could be released from various organs, such as the heart and muscles, other than the lungs during CPB [32, 33]. Additionally, proinflammatory cytokines in the recycled blood from the oxygenator were transfused into each animal in this study. All these factors would result in the substantial increase of the circulating levels of IL-6 and IL-8 in piglets after CPB. Therefore, the impact of the different ventilation modes on the circulating levels of IL-6 and IL-8 could have been overshadowed by these miscellaneous factors in this study.
The study has some limitations. First, the exact mechanisms of the reduction of lung injury by TLV cannot be elucidated so far by our experimental approach. Second, the potential complications such as fluorothorax and cardiac tamponade by incompressible perfluorocarbons during TLV were not fully assessed in this study. Total liquid ventilation is still far from clinical application. Finally, since TLV is an alternative treatment approach for acute respiratory distress syndrome or ventilator-related lung injury after CPB, it will be more persuasive to investigate the effect of TLV in the animal models with acute respiratory distress syndrome caused by CPB.
In conclusion, this study suggests that total liquid ventilation with FC-77 reduces biochemical and histologic lung injury in piglets after cardiopulmonary bypass.
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Acknowledgments
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This study was supported by National Natural Science Foundation of China (Grant 30471721).
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Footnotes
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* These authors contributed equally to this work. 
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Abstract
Introduction
