Ann Thorac Surg 1999;67:332-339
© 1999 The Society of Thoracic Surgeons
Original Articles
Partial liquid ventilation for acute allograft dysfunction after canine lung transplantation
Hideki Itano, MDa,
Motoi Aoe, MDa,
Shingo Ichiba, MDa,
Motohiro Yamashita, MDa,
Hiroshi Date, MDa,
Akio Andou, MDa,
Nobuyoshi Shimizu, MDa
a Department of Surgery II, Okayama University Medical School, Okayama, Japan
Accepted for publication June 30, 1998.
Address reprint requests to Dr Shimizu, Department of Surgery II, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama City, Okayama, 700-8558 Japan
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Abstract
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Background. This study was designed to investigate the efficacy of partial liquid ventilation (PLV) on acute allograft dysfunction after lung transplantation.
Methods. The canine left lung allotransplantation model was used, with the graft preserved in 4°C low-potassium dextran glucose solution for 18 hours. The control group (n = 6) had conventional mechanical ventilation, and the PLV group (n = 6) had perfluorooctylbromide instilled into the airway 30 minutes after reperfusion. For 360 minutes, allograft function and hemodynamics were evaluated. After the evaluation, myeloperoxidase activity of the graft tissue was assayed.
Results. All dogs survived for 360 minutes. In the PLV group, PaO2, shunt fraction, and alveolar to arterial gradient for O2 were significantly better than those in the control group after 120, 180, and 120 minutes, respectively (p < 0.05). After 240 minutes, peak airway pressure became significantly lower than that in the control group (p < 0.05). The PaO2 at 360 minutes was 102 ± 55 mm Hg in the control group and 420 ± 78 mm Hg in the PLV group (p < 0.0001), and the peak airway pressure was 21.4 ± 4.1 mm Hg in the control group and 14.7 ± 5.0 mm Hg in the PLV group (p < 0.05). Myeloperoxidase activity in the PLV group was lower than that in the control group.
Conclusions. The study shows that PLV alleviated acute allograft dysfunction after lung transplantation.
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Introduction
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Lung transplantation has become an established therapeutic procedure for terminal respiratory failure. Since the early successful results of clinical lung transplantation in the first half of the 1980s [1], more than 6,000 cases have been registered so far. In the last 2 years, more than 1,000 operations per year were performed [2, 3]. Acute graft dysfunction (ischemia–reperfusion injury) after lung transplantation continues to present a potentially life-threatening problem for many recipients and remains one of the most significant problems in lung transplantation. Despite many improved strategies, as many as 20% of transplanted pulmonary allografts might experience severe graft dysfunction immediately after implantation. Consequently postoperative morbidity within 30 days after operation because of early allograft dysfunction is seen in 25.9% of all cases.
Numerous respiratory support techniques have been introduced and clinically investigated with the goal of arriving at the optimal ventilation therapy to improve lung function and avoid high airway pressure in respiratory insufficiency. As a new way of recruiting dependent regions and keeping small airways open, partial liquid ventilation (PLV) has been shown to result in improved lung mechanics and oxygenation in a variety of animal models of lung injury since it was first reported by Fuhrman and colleagues in 1991 [4]. It is characterized by filling and maintaining the lung with a functional residual capacity (FRC) of perfluorochemical liquid while conventional gas ventilation is performed.
Perfluorooctylbromide (PFOB, C8F17Br, Green Cross Co., Osaka, Japan) is a liquid ventilation agent that consists of an eight-carbon perfluorochemical liquid, in which nearly all carbon-bound hydrogen atoms have been replaced by fluorine atoms. For prevention of both accumulation in the lung for longer duration and wasteful frequent supplementation during PLV, it has a more appropriate vapor pressure (37°C, 14 mm Hg) than other perfluorocarbons, evaporating much faster than water at body temperature. It is chemically very stable, nonbiotransformable, and virtually nontoxic, and has one-quarter the surface tension, 16 times the oxygen solubility, and three times the carbon dioxide solubility of water. It is hydrophobic and lipophobic, and does not wash out surfactants. Because of these features, PFOB has been used as one of the most suitable perfluorocarbons for PLV. Recent clinical experiences in adults, children, and neonates have established a role of PLV with PFOB to support gas exchange [5].
To our knowledge, no published reports have examined the role of PLV in lung or heart-lung transplantation. In view of the positive experience with PLV therapy in the adult respiratory distress syndrome, the role of this treatment modality in lung transplantation should be investigated. Therefore, the present study was designed to investigate the effects of PLV on allograft function.
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Material and methods
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Twelve weight-matched pairs (8.8 to 16.3 kg) of adult mongrel dogs were used for this study.
Donor procedure
Donor animals were premedicated with intramuscular ketamine hydrochloride (8 mg/kg) and atropine sulfate (0.03 mg/kg) injection, and anesthetized with thiopental sodium (10 mg/kg) and pancuronium bromide (0.2 mg/kg) intravenously, followed by intubation with an endotracheal tube. The lungs were ventilated (Harvard pump respirator, model 613, Harvard Apparatus, Inc., South Natick, MA) with 100% oxygen, at a tidal volume of 20 mL/kg, a rate of 20 breaths per minute, and 5 cm H2O of positive end-expiratory pressure (PEEP). After a median sternotomy, the superior and inferior venae cavae, the ascending aorta, the trunk of the pulmonary artery (PA), and the trachea were isolated. Animals were heparinized (500 U/kg) and cannulated with a curved, metal-tipped cannula through a pursestring suture into the main PA just distal to the pulmonary valve. Cardiac inflow was occluded by ligation of the superior and inferior venae cavae after the cannulation, followed by cutting the proximal inferior vena cava and amputating the left atrial appendage for decompression of the left atrium.
The lungs were perfused immediately, at a pressure of 50 cm H2O, with 50 mL/kg of cooled (4°C) low-potassium dextran glucose solution. During the flush, the lungs were cooled topically by flooding the thoracic cavity with cold (1°C) saline solution. When the flushing was completed, the trachea was clamped at end inspiration (tidal volume, 35 mL/kg; PEEP, 0 cm H2O), and the heart-lung block was excised. The harvest organs were stored in low-potassium dextran glucose solution (4°C) for 18 hours before implantation. In this model, 18 hours’ storage produces a uniformly reliable ischemic injury in control allografts.
Recipient procedure
Adult mongrel dogs weight-matched to donors were used as recipients. Left single lung allotransplantation was performed as previously described [6]. Recipient animals were anesthetized in the same manner as the donor animals and ventilated with a Harvard pump respirator with 100% oxygen at a tidal volume of 20 mL/kg, a rate of 20 breaths per minute, and 5 cm H2O of PEEP. Anesthesia was maintained with a 50:50 mixture of nitrous oxide and oxygen and 0.5% to 1.0% halothane. A femoral artery line and Swan-Ganz catheter (Comocardio TD Catheter 5F Terumo Co, Tokyo, Japan), introduced through the femoral vein, were placed, and pressures were continuously monitored and intermittently recorded (polygraph 363, NEC Sanei, Tokyo, Japan). After left pneumonectomy, the contralateral main PA and the upper and intermediate bronchi were mobilized and encircled separately. A left atrial line was placed through a pursestring suture in the left atrial appendage. The donor left lung was separated from the heart-lung block, and left single lung allotransplantation was performed using standard techniques.
The allograft was topically cooled with ice slush during implantation. The left atrial anastomosis was performed first, using a continuous everting over-and-over suture. The PA and the bronchus were also anastomosed by a continuous over-and-over suture. Fifteen minutes after reperfusion of the allograft, the contralateral main PA and bronchus were ligated and the left single lung allograft was ventilated with 100% oxygen, at a tidal volume of 10 mL/kg, a rate of 20 breaths per minute, and 5 cm H2O of PEEP. During the next 30 minutes after reperfusion, the chest was closed in layers and animals were turned to the supine position with a chest tube inserted. Allograft function and hemodynamics were assessed for 360 minutes.
Study groups
Recipient animals were allocated randomly to two groups, ie, the control group (n = 6), with conventional mechanical ventilation, and the PLV group (n = 6). In the PLV group, just after chest closure and turning to the supine position, animals had a dose of 15 mL/kg body weight of PFOB, which is equivalent to FRC of the left single lung, administered into the airway through the endotracheal tube in approximately 5 minutes; PFOB was subsequently supplemented at a rate of 1 mL/kg hourly.
Measurement
Recipients were placed in the supine position for the 360-minute assessment period. During the assessment interval, pancuronium bromide was infused at a rate of 2 mg/h. Aortic, PA, central venous, and left atrial pressures were continuously monitored and intermittently recorded throughout the assessment period. Cardiac output and arterial and mixed venous blood gases were determined hourly. After the final measurement, recipients were sacrificed, and samples from the posterior aspect of the lower lobe of the allografts were submitted for histologic study and tissue myeloperoxidase (MPO) activity assay.
Histopathologic study
All lungs were inflated to 5 cm H2O constant pressure, and the endotracheal tubes were clamped. Approximately 5-g samples from the posterior aspect of the lower lobe were ligated with 2-0 sutures in situ, excised, and placed in formalin. Routine histologic preparation of the specimens with hematoxylin and eosin staining and light microscopic analysis was performed.
Myeloperoxidase assay
Lung samples from the posterior aspect of the lower lobe were frozen immediately by immersion in liquid nitrogen and stored at -40°C until assay. Quantitative MPO activity was determined as previously described [7]. Frozen lung tissue (100 mg) was homogenized in 1 mL of 0.5% hexadecyltrimethyl-ammonium bromide, 5 mmol/L EDTA (ethylene diamine-tetraacetic acid), and 50 mmol/L potassium phosphate buffer (pH 6.2) with a Broeck tissue grinder. Hexadecyltrimethyl-ammonium bromide is a detergent that releases MPO from the primary granule of the neutrophil. The homogenate was centrifuged at 10,000 g for 15 minutes at 4°C. The supernatant was subsequently assayed for total soluble protein by the method of Smith and coworkers [8] and for MPO activity. Myeloperoxidase activity was measured spectrophotometrically: a pair of 10 µL of tenfold diluted supernatant from each specimen was respectively combined with 0.6 mL Hank’s bovine serum albumin (0.25% bovine serum albumin added to Hank’s solution), 0.5 mL of 100 mmol/L potassium phosphate buffer (pH 6.2), 0.1 mL 0.05% H2O2, and 0.1 mL of 1.25 mg/mL o-dianisidine. Color development was stopped by addition of 0.1 mL of 1% NaN3 to one sample after 5 minutes and to the other after 20 minutes at room temperature. The optical density was measured at 460 nm with a spectrophotometer (Model 2550 EIA Reader, Japan Bio-Rad Laboratories, Tokyo, Japan). After confirming that the color development from 5 to 20 minutes was linear, enzyme activity was defined as the amount of MPO that produced an absorbance change of 1.0 optical density units per minute per milligram of tissue protein at room temperature.
Statistical analysis
All data are presented as the mean ± standard deviation. All physiologic data throughout this study were evaluated by analysis of variance with repeated measures within each group over time after 15 minutes, and unpaired Student’s t test between groups at each data point (significance at p < 0.05). These analyses were performed with the use of Stat View J-4.5 (Abacus Concepts Inc., Berkeley, CA).
Animal care
All animals have 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 85-23, revised 1985).
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Results
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No differences existed between the two groups with respect to donor weight, recipient weight, warm ischemic time, and total ischemic time (Table 1).
Survival
All recipient animals in the two groups survived for the 360-minute observation period.
Gas exchange
Changes in arterial oxygen tension (PaO2) and carbon dioxide tension (PaCO2) are shown in Fig 1. The PaO2 in the PLV group was significantly higher than that in the control group after 120 minutes (p < 0.05 versus control) and after 180 minutes (p < 0.01 versus control). The two groups showed no significant difference in PaCO2 level after 15 minutes.
The alveolar to arterial gradient for O2 and shunt fraction are shown in Fig 2. The alveolar to arterial gradient for O2 in the PLV group was significantly lower than that in the control group after 120 minutes (p < 0.05 versus control) and after 240 minutes (p < 0.001 versus control). The shunt fraction in the PLV group was also significantly lower than that in the control group after 180 minutes (p < 0.05 versus control) and after 240 minutes (p < 0.001 versus control).
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Fig 2. Alveolar to arterial gradient for O2 (A-aDO2) and shunt fraction (Qs/Qt) in the two groups: the control group (•) and the PLV group ( ); n = 6 dogs in each group. Data are shown as the mean ± standard deviation. The A-aDO2 in the PLV group was significantly lower than that in the control group after the 120 minutes (* p < 0.05 versus control; § p < 0.001 versus control). The Qs/Qt in the PLV group was significantly lower than that in the control group after 180 minutes (* p < 0.05 versus control; § p < 0.001 versus control).
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Lung mechanics
Changes in the difference of peak airway pressure are shown in Fig 3. Peak airway pressure in the PLV group was significantly lower than that in the control group after 240 minutes (p < 0.05 versus control).
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Fig 3. Peak airway pressure (peak AwP) in the two groups: the control group (•), and the PLV group (); n = 6 dogs in each group. Data are shown as the mean ± standard deviation. After 180 minutes, peak AwP in the PLV group was significantly lower than that in the control group (* p < 0.05 versus control).
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Hemodynamics
Mean PA pressure and pulmonary vascular resistance (PVR) are shown in Fig 4. After analysis of variance with repeated measures, we observed no significant difference between the two groups after 15 minutes.
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Fig 4. Mean pulmonary artery pressure (mean PAP) and pulmonary vascular resistance (PVR) in the two groups: the control group (•), and the PLV group (); n = 6 dogs in each group. Data are shown as the mean ± standard deviation. After approximately 180 minutes, both mean PAP and PVR in the PLV group were lower than those in the control group, but differences were not significant.
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Cardiac output and mean aortic pressure are shown in Fig 5. After analysis of variance with repeated measures, we observed no significant difference between the two groups after 15 minutes.
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Fig 5. Cardiac output (CO) and mean aortic pressure (mAoP) in the two groups: the control group (•) and the PLV group (); n = 6 dogs in each group. Data are shown as the mean ± standard deviation. After 15 minutes, there was no significant difference between the two groups with respect to these parameters.
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Myeloperoxyidase assay
Allograft MPO activity in the two groups is shown in Fig 6. In the PLV group, MPO activity tended to be lower compared with that in the control group, although the difference was not significant.
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Fig 6. Myeloperoxidase (MPO) activity in the two groups: n = 6 dogs in each group. Data are shown as the mean ± standard deviation. There was a tendency for lower MPO activity in the PLV group compared with that in the control group.
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Histopathologic study
Reductions in pulmonary vascular congestion, alveolar hemorrhage, alveolar proteinaceous fluid accumulation, and inflammatory infiltration were noted in the specimens from the PLV group compared with those from the control group. Thus, the lung architecture is well preserved and the alveoli were dilated in the PLV group (Fig 7).
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Fig 7. Specimens from the posterior aspect of the lower lobe of an allograft after the completion of assessment, which represent both groups. Views of the control group, x40 magnification (A) and x100 (B), as well as the PLV group, x40 (C) and x100 (D) (hematoxylin and eosin stain). Reductions in pulmonary vascular congestion, alveolar hemorrhage, alveolar proteinaceous fluid accumulation, and inflammatory infiltration are noted, and consequently lung architecture is well preserved in the PLV group.
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Comment
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The lung dysfunction associated with adult respiratory distress syndrome has many clinical and pathologic features in common with that associated with lung reperfusion injury after transplantation [9]. These lungs have a strikingly gravity-dependent distribution of abnormalities found to be most severe in the posterior dependent region. Repeated opening and closing of alveoli in this region during mechanical ventilation has been suggested as an important contributor to maintaining and aggravating the lung injury in adult respiratory distress syndrome [10, 11]. Current ventilation practices therefore aim at minimizing barotrauma or volume trauma by limiting peak airway pressures, using PEEP to maintain an open lung, and limiting tidal volumes [12]. However, application of various types of PEEP ventilation large enough to overcome the collapse in the dependent area will tend to overinflate more compliant, nondependent, and relatively normal lung areas without improvement of the lung mechanics of the dependent lung. Generally, recruitment of the atelectatic dependent zone is obviously important in the evolution and outcome of acute lung injury, and PLV affords the gravity-dependent distribution of PFOB liquid to the most severely diseased dependent lung. Many PLV studies have revealed that immediately after its instillation, PFOB, which is radiopaque because of a single terminal bromide atom, symmetrically opacifies the lung in a gravity-dependent distribution in both normal lungs and injured lungs such as with adult respiratory distress syndrome [13]. The alveolar pressure in the dependent lung depends on both the airway pressure and PFOB’s hydrostatic pressure [14]. The high density (1.9 g/mL) and low surface tension of PFOB enhance alveolar volume and thus facilitate recruitment of the atelectatic lung. Furthermore, the redistribution of pulmonary blood flow from the dependent region to the nondependent region might correct the total lung ventilation-perfusion mismatch. Consequently, oxygenation is improved [15, 16].
In our control group, PVR increased as the experiment proceeded. In ischemia–reperfusion lung injury, the primary site of injury is the pulmonary capillary endothelium, which normally modulates the tone of the pulmonary vascular bed through the release of endothelium-derived relaxation factor. Impaired endothelial function causes high PVR, and a loss of endothelial integrity might further cause fluid extravasation after transplantation, with the subsequent development of pulmonary edema and hypoxic vasoconstriction [17]. On the other hand, Lowe and Shaffer [15] demonstrated that PVR was increased and cardiac output was decreased with filling of the lungs with perfluorocarbon during total volume liquid ventilation in the excised lungs of normal cats. They suggested that this increment of PVR may be caused by increased transmural pressure, which leads to compression of the pulmonary capillary bed. They also demonstrated, using radioactive carbon microspheres, that redistribution of pulmonary blood flow occurred in the fluorocarbon-filled lung, that is, the blood flow to the dependent region was decreased, and conversely, the less-dependent regions of the lungs received a relatively greater percentage of blood flow. Furthermore, Gauger and colleagues [16] demonstrated the same redistribution of pulmonary blood flow during PLV (with 30 mL/kg PFOB) using positron emission tomography, which was attributed to increased regional PVR in the dependent region. They proposed that the factor contributing control of regional PVR might be not only the hydrostatic transmural pressure but also improved regional hypoxia, with resultant reduction in vasoconstriction, by improving regional inflation in the dependent lung. Parent and associates [18] demonstrated progressive increase in PVR index during increasing doses of PFOB using a lamb lung-injured model and found that increasing in PFOB dose beyond the estimated FRC appeared to result in a further decrease in cardiac index without the enhancement of arterial oxygenation. They suggested that the apparently optimal PFOB dose appeared to be at or near the normal FRC. From such a viewpoint, in the PLV settings, the higher the dose of PFOB beyond FRC instilled into the airways, the greater might be the regional transmural vascular compression and PVR. Thus, using a PFOB dose equivalent to FRC, the reduction in PVR by improving regional or the whole lung oxygenation might be much greater than the PVR increment caused by hydrostatic pressure of PFOB. This may be the reason why our results showed a tendency for PVR to be lower in the PLV group compared with that in the control group, because we used a dose of 15 mL/kg, which is equivalent to canine single lung FRC.
Lungs that have sustained severe ischemia–reperfusion injury have a highly damaged surfactant system. Alveoli in such lungs have a high interfacial surface tension and a greater tendency to collapse during expiration [13]. It has been reported that serum protein moving into the alveolar spaces causes this condition [14]. Immediately after lung transplantation in animals, the composition and biophysical function of pulmonary surfactant is affected, that is, there is a compositional change of surfactant and deficiency of surfactant-associated protein [19]. Immediately after being administered at volumes equal to FRC, PFOB homogeneously spreads over the surface of peripheral alveoli because of its high spreading coefficients and low surface tension, and a thin film of PFOB liquid replaces the high surface tension at the air–liquid interface with the low surface tension at the liquid–liquid interface, acting as if it were a surfactant substitute [14]. Therefore, PFOB easily opens atelectatic alveoli and prevents intermittent alveolar collapse in a surfactant-depleted lung, so that lung inflation with the same volume occurs at lower airway pressure.
Myeloperoxidase activity has been widely accepted as an enzyme marker to measure and quantify neutrophil accumulation in organs. We observed lower levels of MPO activity in the PLV group, showing an insignificant difference compared with that in the control group. Although some in vitro studies have demonstrated PFOB’s direct suppressive effect on both macrophages [20] and neutrophils [21] with regard to oxygen free radical production or chemotaxis, our results could not elucidate this. At the very least, PFOB functions as a direct mechanical barrier that interferes with inflammatory cells, such as neutrophils, interacting with the alveolar epithelium [22]. Instillation of PFOB into the airway displaces the proteinaceous exudate, associated inflammatory mediators, and cellular components in the alveoli of the edematous injured lung, expands these alveoli, and probably facilitates surfactant function by diluting or removing the exudate in these alveoli. This exudate is displaced to float on PFOB and be washed out into the central, larger airways where it can be aspirated and removed. Furthermore, PFOB might even reduce intraalveolar protein flux by its tamponade effect, or to some extent, prevent inflammatory cells from migrating from pulmonary capillaries into the alveoli [23].
It is said that the ischemia–reperfusion injury is biphasic in nature, with an early component developing within the first 30 minutes of reperfusion and a delayed phase developing during at least the next several hours [24]. The early phase is known to be independent of neutrophils and the late phase is neutrophil-dependent. In our experimental protocol, PFOB was instilled into the airway approximately 30 minutes after reperfusion and periodically supplemented after that. Therefore, this study chiefly examined PFOB efficacy on the later-phase injury. Further studies are required to clarify how instillation of PFOB before reperfusion improves lung function. Such a study would examine PFOB efficacy on the first component of injury. Furthermore, the study of PFOB instillation before harvesting or during graft preservation, with the alveoli containing PFOB, might also elucidate its efficacy on cold-preservation lung injury.
Our results regarding PaCO2 showed no significant difference between the two groups. Mates and coworkers [25] have shown that CO2 tends to be retained during PLV in both healthy and lung-injured piglets. Partial liquid ventilation lungs with PFOB distributed heterogeneously have a wide distribution of time constants (asynchronous emptying of lung regions), creating uneven PACO2. The more slowly emptying compartments, which are those with large PFOB volumes, would have an increased alveolar to arterial gradient for CO2 and lower PACO2 secondary to diffusion resistance. On exhalation, areas with less liquid, shorter time constants, and higher PACO2 (little or no alveolar to arterial gradient for CO2) empty first, followed by regions containing more PFOB and thus a lower PACO2, producing a negative phase III slope of exhaled CO2. In healthy homogeneous lung, without ventilation heterogeneity, PaCO2 equals PACO2 and an alveolar to arterial gradient for CO2 does not exist, and the lung shows a plateau or upward phase III slope for exhaled CO2. Usually in injured lungs, the causes of alveolar to arterial gradient for CO2 seem to be shunt, diffusion limitation, and ventilation-perfusion mismatch, and the high PaCO2 in our control group is caused by inhomogeneous lung injury, the cause of which may be different from that in the PLV group. To what degree PaCO2 is influenced by lung injury and PLV respectively is unclear and will require future investigation.
An important limitation of this work is its short-term nature. Understanding the full consequences of PLV on lung ischemia–reperfusion injury after transplantation would require observation for several days.
We conclude that PLV alleviated short-term allograft dysfunction, especially with regard to oxygenation and lung mechanics. It had no significant effect on PaCO2, and tended to lower PVR and MPO activity.
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Abstract
Introduction
p < 0.01 versus control). The PaCO2 showed no significant difference after 15 minutes. INT = the point of intubation.