Ann Thorac Surg 2004;77:918-924
© 2004 The Society of Thoracic Surgeons
Original article: cardiovascular
Lung perfusion with protective solution relieves lung injury in corrections of Tetralogy of Fallot
Bo Wei, MD*a,
Yinglong Liu, MDa,
Qiang Wang, MDa,
Cuntao Yu, MDa,
Cun Long, MDa,
Yongnan Chang, MDa,
Yingmao Ruan, MDa
a Department of Surgery, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Accepted for publication September 10, 2003.
* Address reprint requests to Dr Wei, Department of Surgery, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
e-mail: wei1bo1208{at}hotmail.com
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Abstract
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BACKGROUND: The aim of this study was to evaluate the protective effect of pulmonary perfusion with hypothermic protective solution on lung function after cardiopulmonary bypass in corrections of Tetralogy of Fallot.
METHODS: Sixty-four consecutive children with Tetralogy of Fallot were randomly divided into a control group (n = 30) and a protective group (n = 34). Hypothermic protective solution was infused to the main pulmonary artery in the protective group. Hemodynamics and lung functions were monitored. Concentrations of malondialdehyde, tumor necrosis factor-alpha, von Willebrand factor, and endothelin in plasma were measured. The interleukin-6 and interleukin-8 levels in bronchoalveolar lavage fluid were also determined. Lung biopsy specimens were obtained after weaning from cardiopulmonary bypass.
RESULTS: Oxygenation values (oxygen index and alveolar-arterial O2 gradient) were better preserved in the protective group than in the control group. The time of mechanical ventilation and length of intensive care unit stay were shorter in the protective group compared with the control group. The tumor necrosis factor-alpha and malondialdehyde levels in plasma increased in both groups after operations, and the rising extents were lower in the protective group than in the control group. The von Willebrand factor and endothelin levels in plasma increased more significantly in the control group than in the protective group. The concentrations of interleukin-6 and interleukin-8 in bronchoalveolar lavage fluid were lower in the protective group than in the control group. The examination of histopathology demonstrated capillary hyperemia and hemorrhage, intra-alveolar edema, leukocytes accumulation, mitochondria swelling and vacuolation, and gas-blood barrier broadening in the control group, whereas there were no significant changes in the protective group. The intercellular adhesion molecule-1 expression on lung vascular endothelial cells was stronger in the control group.
CONCLUSIONS: Lung perfusion with hypothermic protective solution during cardiopulmonary bypass relieved lung injury in corrections of Tetralogy of Fallot. The inhibition of lung vascular endothelial cell injury may be the major mechanism of relieving cardiopulmonary bypass-induced lung injury.
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Introduction
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Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease. In recent years, the mortality and morbidity of corrections of TOF have apparently decreased. However, cardiopulmonary bypass (CPB)-induced lung injury is the most important complication in corrective operations of TOF. An Infant's immature lung is more vulnerable to cardiopulmonary bypass. A higher rate of pulmonary complications has been reported in those infants than in the adult population. The signs of lung injury after CPB are evidenced by significantly increased pulmonary vascular resistance, increased alveolar-arterial O2 gradients, and decreased pulmonary compliance. They result in prolonged hospitalization and increased hospital cost. Prophylaxis and treatment of lung injury are very important to corrections of TOF. On the basis of animal studies [1], the purpose of the present pilot study was to evaluate the protective effect of pulmonary perfusion with hypothermic protective solution on lung function after CPB in corrections of TOF.
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Patients and methods
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Patients
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Between May 2000 and May 2001, a total of 64 children with TOF participated in this prospective study after having been allocated to the control group (n = 30) and the protective group (n = 34) randomly. There were 26 females and 38 males, ranging in age from 5 months to 6 years (mean, 2.3 years) and a weight of 6.0 kg to 22.1 kg (mean, 11.3 kg). The basic variables (age, weight, cardiothoracic ratio, and oxygen saturate) were similar between the control group and the protective group (21.6 ± 17.2 months, 10.8 ± 3.6 kg, and 0.57 ± 0.05, and 80% ± 8% vs 24.4 ± 19.5 months, 13.4 ± 3.4 kg, 0.58 ± 0.06, and 83% ± 6%, respectively). Preoperative diagnosis depended on the clinical situation, electrocardiogram, chest roentgenogram, ultrasound-Doppler examination, or angiography. The study was approved by the ethics committee of our institution. The institutional review board approved this study protocol. Parents of the patients were informed about potential risks of the perfusion as well as the lung biopsy. Only those patients whose parents had given adequate, informed consent were eligible for this study.
Clinical management
After pre-medication with diazepam (0.1 mg/kg), morphine (0.1 mg/kg), and scopolamine (0.01 mg/kg), all patients underwent general anesthesia with fentanyl (10 ug/kg) and vecuronium (0.2 mg/kg) for induction, and fentanyl (10 ug/kg/h), vecuronium (0.2 mg/kg/h), and enflurane (0.5 to 2%) for maintenance. Cardiopulmonary bypass with colloid priming and antegrade hypothermic crystalloid cardioplegia was used. The establishment of CPB and the procedure of correcting cardiac malformations were similar between the groups. Patients in the control group had routine approaches of corrections of TOF performed, whereas patients in the protective group had lung perfusions with 4°C protective solution during initiation of bypass.
The solution was infused through a cannula inserted into the main pulmonary artery after the ascending aorta was clamped. The perfusion (20 mL/kg) flow ranged from 70 to 80 mL per minute. The solution entered the bypass circuit through a drain from the left atrium. The perfusion was repeated if cross-clamp time was more than 70 minutes. The urosemide and ultrafiltration were routinely used shortly after bypass.
The solution contained anisodamine (1 mg/kg) (Minsheng Pharmaceutical Corp, Hangzhou, China), L-arginine (0.2 g/kg) (Changjiang Pharmaceutical Corp, Shanghai, China), aprotinin (50,000 KIU/kg) (Trasylol Bayer, Leverkusen, Germany), 5% sodium hydrogen carbonate (1 mL/kg) (Minsheng Pharmaceutical Corp), and methylprednisolone (30 mg/kg) (Pharmacia MC China, Shanghai, China). The amount of all additives was 20 to 30 mL. The basic solution was dextran 40 (7 to 8 mL/kg) (Huajun Pharmaceutical Corp, Tianjin, China). Oxygenated blood (10 mL/kg) was added to the solution. The proportion of oxygenated blood to the solution was 1 to 1. The total amount of protective solution was 20 mL/kg body weight. The protective solution was stored at 4°C.
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Measurements
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Lung function measures
A series of arterial blood samples were analyzed with a blood gas analyzer (Mallinckrodt Sensor Systems Inc, Ann Arbor, MI) at five different time points: 0 hours, 6 hours, 12 hours, 24 hours, and 48 hours in the intensive care unit (ICU). Pulmonary function indexes were calculated by the following formulas:
- Airway peak pressure = measured airway peak pressure-positive end-expiratory pressure
- Oxygen index = PaO2/FiO2
- Alveolar-arterial O2 gradient = (Patm-47 mm Hg) x FiO2-PaCO2-PaO2
in which FiO2 is the concentration of inspired oxygen, PaCO2 is the partial pressure of carbon dioxide in arterial blood, PaO2 is the partial pressure of oxygen in arterial blood, and Patm is the pressure of atmosphere.
Blood samples collection
Blood samples were collected for measuring concentrations of malondialdehyde and tumor necrosis factor-
at six different time points: preoperation, 0 hours, 6 hours, 12 hours, 24 hours, and 48 hours in the ICU. The tumor necrosis factor- levels in plasma were measured in duplicate by using a commercial radioimmunoassay kit (Radio-immunity institution of People Liberation Army General Hospital, Bingjing, China). The malondialdehyde levels in plasma were measured by a thiobarbituric acid-reactive assay. Blood samples were collected for measuring concentrations of von Willebrand factor and endothelin at four different time points: preoperation, 0 hours, 12 hours, and 24 hours in the ICU. The endothelin levels in the plasma were measured in duplicate by using a commercial radioimmunoassay kit (Radio-immunity Institution of People Liberation Army General Hospital, Bingjing, China). The von Willebrand factor levels in plasma were determined by double antibody sandwich enzyme-linked immunoadsorbent assay. Commercial available tests (Sun Medical Biotechnology Institution, Shanghai, China) were used.
Small-volume lavage procedure
For small-volume lavage, an open-ended suctioning catheter was inserted blindly through the endotracheal tube and wedged in a distal airway at 6 hours in the ICU. Then 0.9% saline solution was instilled at an amount of 0.5 mL/kg body weight and withdrawn by gentle suctioning. After filtration through gauze and centrifugation at 200 g for 10 minutes to remove the cells and debris, the cell-free supernatants obtained were stored at -70°C.
The interleukin-6 and interleukin-8 levels in the bronchoalveolar lavage fluid were measured in duplicate by using a commercial radioimmunoassay kit (Radio-immunity Institution of People Liberation Army General Hospital).
Histologic assessment
Lung biopsies obtained after weaning from CPB were approved by parents of the patients and the Ethics Committee of our Institution. Some pieces of the tissue were fixed in 10% buffered formalin for light microscopy, which were examined with hematoxylin and eosin, elastic, and Masson's trichrome stains. Some pieces of the tissue were immersed in universal fixative (1% glutaryl-aldehyde pH 7.4) immediately after biopsy, postfixed in 2% osmium tetroxide, dehydrated in graded acetones, and embedded in an Epon-Araldite mixture for electron microscopy. Selected blocks were thin-sectioned, mounted on copper grids, and contrasted with uranyl acetate and lead citrate. The grids were examined in a Philips 201 electron microscope (NV Philips, Gloeilampenfarbrieken, Eindhoven, The Netherlands). The others were snapfrozen in liquid nitrogen for intercellular adhesion molecule-1 (ICAM-1) expression detection using immunohistochemical analysis.
Immunohistochemical analysis was performed on 4-um frozen sections of lung tissue. Endogenetic peroxidase activity of the sections was blocked by incubation for 5 minutes in 3% hydrogen peroxide. The sections were preincubated for 30 minutes with 10% normal goat serum to avoid nonspecific immunoreactivity. After decanting the preincubation fluid, the primary antibody 1:50 diluted rabbit anti-ICAM-1 was incubated overnight at 4°C. Horseradish peroxidase-labeled goat antirabbit immunoglobulin antiserum was used as a second-step reagent. The horseradish peroxidase label was detected with diaminobenzidine. The sections were counterstained with hematoxylin, and then distribution and expression of ICAM-1 on pulmonary endothelial cells were observed under microscope. Lung vascular endothelium was counted by four grades of 0, 1, 2, and 3 depending on the degree of ICAM-1 expression by a blinded pulmonary pathologist. The grade of 0 indicated staining negative, the grade of 1 indicated staining weak positive, the grade of 2 indicated staining positive, and the grade of 3 indicated staining strong positive. We randomly observed six blood vessels in one section. The results were expressed by an average value.
Statistical analysis
All values were expressed as mean ± standard error. Differences between groups were tested for significance by the Student's t test for unpaired samples or repeated measures of analysis of variance. All analyses were performed using SPSS 10.0 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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Comparison of clinical measurements
There was no mortality in this study. Aortic cross-clamp time had no statistical difference between the protective group and the control group (63 ± 13 minutes vs 62 ± 15 minutes; p > 0.05). The diameter ratio of aorta artery to pulmonary artery was similar in the two groups (protective group, 2.0 ± 0.7; control group, 1.8 ± 0.5; p > 0.05). The rates of transannular patch in the protective group and the control group were 64% and 60%, respectively. The time of mechanical ventilation and the length of ICU stay were shorter in the protective group compared with the control group (16.8 ± 10.4 hours and 3.1 ± 1.5 days vs 30.5 ± 26.5 hours and 4.1 ± 2.3 days; p < 0.05 and p < 0.01, respectively).
Assessment of lung function
Oxygen indexes were higher in the protective group than in the control group and the differences were significant at 6 hours, 12 hours, and 24 hours in the ICU (p < 0.05; p < 0.01; and p < 0.01, respectively) (Fig 1). Alveolar-arterial O2 gradients in the protective group were lower compared with the control group at 6 hours, 12 hours, and 24 hours in the ICU (p < 0.05; p < 0.01; and p < 0.01, respectively) (Fig 2). Airway peak pressures were not significantly different between two groups (protective group: 14.9 ± 2.7, 14.2 ± 2.7, 13.8 ± 3.5, 15.2 ± 3.6, and 16.1 ± 1.4 cmH2O; control group: 14.9 ± 2.4, 15.2 ± 1.9, 15.1 ± 1.9, 16.3 ± 2.7, and 17.2 ± 2.2 cmH2O; p > 0.05).
Analysis of blood and bronchoalveolar lavage fluid samples
The tumor necrosis factor- levels increased in both groups after operations. The rising extent of tumor necrosis factor- levels were lower in the protective group and were significantly different at 0, 6, and 24 hours in the ICU (p < 0.01; p < 0.01; and p < 0.05, respectively) (Fig 3).
The malondialdehyde levels increased in both groups after operations. The rising extents of malondialdehyde levels were lower in the protective group than in the control group at 0 and 6 hours in ICU, respectively (p < 0.01 and p < 0.05, respectively) (Fig 4).
The von Willebrand factor levels increased more significantly in the control group than in the protective group at 0 hours in the ICU (p < 0.05) and the restored preoperative level at 24 hours in the ICU (55.24 ± 7.81, 114.88 ± 10.87, 99.42 ± 6.89, and 70.62% ± 6.38% vs 57.61 ± 9.33, 80.43 ± 8.15, 91.09 ± 11.12, and 60.29% ± 10.38%, respectively).
The endothelin levels increased more significantly in the control group than in the protective group at 0 hours in the ICU (p < 0.05) and the restored preoperative level at 24 hours in the ICU (3.8 ± 1.1, 10.2 ± 1.3, 8.4 ± 2.5, and 5.6 ± 1.1 µg/mL vs 3.4 ± 0.4, 7.2 ± 1.7, 7.0 ± 1.4, and 5.7 ± 0.9 µg/mL, respectively).
There were less interleukin-6 and interleukin-8 in the bronchoalveolar lavage fluid in the protective group compared with the control group (6.46 ± 1.84 µg/L and 89.03 ± 15.11 µg/L vs 8.91 ± 2.34 µg/L, and 130.40 ± 43.60 µg/L; p < 0.05 and p < 0.01, respectively).
Analysis of tissue
Pathologic studies with a light microscope disclosed capillary hyperemia and hemorrhage and leukocytes accumulation. Electron microscopic studies revealed intra-alveolar edema, gas-blood barrier broadening, and vascular endothelial cell mitochondria swelling and vacuolation in the control group, whereas there were no significant changes in the protective group (Fig 5–8).
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Fig 5. Histologic appearance of the control group showing (A) capillary hyperemia and hemorrhage (B) leukocytes accumulated. (Hematoxylin and eosin; x200.)
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Fig 6. Histologic appearance of the protective group showing normal lung parenchyma (Hematoxylin and eosin; x200.)
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Fig 7. Histologic appearance showing (A) broadened gas-blood barrier in the control group (arrow) and (B) normal gas-blood barrier in the protective group (arrow). (Electron microscope; x8,000.)
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Fig 8. Histologic appearance showing (A) vascular endothelial cell mitochondria swelling and vacuolation in the control group (arrow) and (B) normal vascular endothelial cell construction in the protective group (arrow). (Electron microscope; x8000.)
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The ICAM-1 expression on lung vascular endothelial cells was stronger in the control group than in the protective group (2.22 ± 0.60 vs 1.36 ± 0.43; p < 0.05) (Fig 9).
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Fig 9. The expression of intercellular adhesion molecule-1 on lung endothelial cells in the control group was stronger than in the protective group using immunohistochemical analysis (A) in the control group and (B) in the protective group (hematoxylin & eosin: x200).
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Comment
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Accumulating evidence indicates that a combination of whole body inflammatory response and ischemia-reperfusion injury led to CPB-induced lung injury. The whole body inflammatory response is most likely caused by contact between blood and artificial surfaces of the perfusion circuit. Plasma levels of inflammatory mediators such as complement, interleukin, and tumor necrosis factor- are increased. Lungs are hurt by large amounts of toxic oxygen metabolites, and proteases are released by activated polymorphonuclear leukocytes [2–4]. On the other hand, CPB delivery of oxygenated blood to the pulmonary parenchyma is completely maintained by the bronchial arteries. As a result, the lung may experience some degree of ischemia during CPB. A further ischemia-reperfusion injury from oxygen free radicals, calcium paradox, and abnormal energy metabolism may occur when normal antegrade flow is reestablished through pulmonary artery after CPB [5–7].
Although many techniques such as heparin-coated CPB circuits, membrane oxygenator or ultrafiltration have been tried to ameliorate CPB-induced injury, there was no effective method to coping with lung injury directly. As enlightened by cardioplegia and storing the lung in vitro, we designed the method of lung perfusion with hypothermic protective solution to relieve lung injury during CPB in the early 1990s [1]. The method could decrease pulmonary temperature, improve pulmonary ischemia, and avoid reperfusion injury. Lung protective solution contained anisodamine, aprotinin, L-arginine, and methylprednisolone. Anisodamine appears effective in inhibiting granulocyte and platelet aggregation [8]. Aprotinin, a nonspecific serine protease inhibitor, reduces inflammatory reaction [9–10]. L-arginine is an amino acid precursor of nitric oxide. As an endothelial-derived relaxing, nitric oxide dilates microvasculature and reduces neutrophil interaction with the endothelium. It has been proven that L-arginine could preserve endothelial function and promote metabolic recovery in the ischemic myocardium by increasing coronary blood flow [11]. Methylprednisolone significantly inhibits the formation of the inflammatory mediators and restores hemodynamic stability [12]. Moreover, oxygenated blood could increase osmotic pressure of protective solution and provide energy sources.
Cardiopulmonary bypass-induced whole body inflammatory reaction leads to lung injury. Tumor necrosis factor-, interleukin-6, and interleukin-8 are important inflammatory mediators. In the present study, concentrations of tumor necrosis factor- in plasma were lower in the protective group. As the levels of tumor necrosis factor- were influenced by many factors, levels of inflammatory proteins in the bronchoalveolar lavage fluid may be more sensitive than those in the plasma in evaluating the severity of lung inflammation. Other inflammatory proteins in the bronchoalveolar lavage fluid were also examined in this study. The levels of interleukin-6 and interleukin-8 in the bronchoalveolar lavage were lower in the protective group. The conclusion was given that pulmonary inflammation reaction in the protective group was significantly milder compared with the control group. Release of oxygen free radicals may cause tissue injury by peroxidation of lipids and nucleic acids. One product of lipid peroxidation was plasma malondialdehyde. The lower concentrations of malondialdehyde in the protective group indicated that ischemia-reperfusion injury caused by oxygen-free radicals was gentler. Importantly, lung biopsies were evaluated by both light microscopy and electron microscopy and demonstrated much healthier tissue and cells in the protective group. In a word, lung perfusion with hypothermic protective solution relieved lung injury and improved lung function after CPB.
Pulmonary vascular endothelial dysfunction plays an important role in CPB-induced lung injury. The acute response of endothelial cells to CPB results in systemic inflammation, coagulation abnormalities, and vasomotor changes that may all be critically important to perioperative outcome [13–14]. Neutrophil and endothelial cell adhesion promoted by systemic inflammatory response is the premise of neutrophil-mediated tissue injury [15–18]. The expression of ICAM-1 on pulmonary vascular endothelial cells is very important to the adhesion of neutrophils in lung tissue. The expression of ICAM-1 on pulmonary vascular endothelial cells is increased rapidly and dramatically on exposure to chemotactic stimuli such as complement C5a and interleukin-8 [19–20]. The ischemia-reperfusion injury produced oxygen-free radicals. Release of oxygen free radicals may cause endothelial damage by peroxidation of lipids and nucleic acids [21]. The von Willebrand factor is the largest plasma protein that mediates platelet activation in the subendothelium of damaged blood vessels [22–23]. The endothelin (a strong vasoconstriction factor in plasma) causes sequential trapping of platelets and neutrophils in pulmonary microcirculation [24–25]; they are synthesized and stored in endothelial cells and after stimulation or cell damage are secreted into the blood. It is suggested that their measurement may be diagnostic markers of endothelial cell injury. In this study, concentrations of von Willebrand factor and endothelin in plasma were lower in the protective group than in the control group. The expression of ICAM-1 on lung vascular endothelial cells was stronger in the control group compared with the protective group. Electron microscopic studies showed the same conclusion by revealing the edema of lung vascular endothelial cells and the damage of mitochondria in the control group. These results revealed that lung perfusion with hypothermic protective solution during CPB inhibited the injury of the lung vascular endothelial cells, and this may be the major mechanism of relieving lung injury during CPB.
In conclusion, lung perfusion with hypothermic protective solution during CPB relieved lung injury in corrections of TOF. The inhibition of lung vascular endothelial cell injury may be the major mechanism of relieving CPB-induced lung injury. However, the mechanisms of lung perfusion are obscure. Studies need to be performed to further confirm these protective effects and elucidate mechanisms.
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Acknowledgments
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This project was supported by National Natural Science Foundation of China. Dr Liu is in charge of this project.
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Abstract
Introduction
= protective group; 
= control group. *p less than 0.05; **p less than 0.01; protective group versus control group.
