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From the Cardiovascular Research Unit, Center for Experimental Surgery Anaesthesiology (C.E.H.A.), K.U. Leuven, Leuven, Belgium.
Address correspondence to: Prof. Dr. Paul Herijgers, C.E.H.A., K.U. Leuven, Provisorium 1, Minderbroedersstraat 17, B-3000, Leuven, Belgium. Phone: +32-16-337298; Fax: +32-16-337855; E-mail: paul.herijgers{at}med.kuleuven.ac.be
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Abstract |
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Methods: Nine sheep (Group-RPC) underwent RPC by three episodes of five-minute occlusion and five-minute reperfusion of the iliac artery. Five sheep (Group-C) were time-matched controls. Afterwards, ten-minute occlusion and reperfusion of the left anterior descending, the first diagonal and the left circumflex coronary arteries were performed consecutively. Hemodynamic and respiratory parameters and arterial blood gases were measured until 120 min after the final coronary reperfusion. Anesthesia was maintained with halothane in oxygen and nitrous oxide. Animals were ventilated with a tidal volume of 15–20 mL•kg-1 in a non-rebreathing system, and a respiratory rate 14–16 min, with 5-cm H2O positive end expiratory pressure after thoracotomy.
Results: Repeated coronary occlusion and reperfusion was associated in this experimental model with an increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) and a decrease in PaO2 and PaO2/FIO2 in Group-C. After 120 min reperfusion, PaO2 and PaO2/FIO2 in Group-RPC were higher (192 ± 69 mmHg and 241 ± 78 vs 115 ± 54 mmHg and 129 ± 64, P < 0.05), while PVR and PAP were lower than in Group-C. At 120 min of reperfusion, PaO2 and PaO2/FIO2 were inversely correlated with PVR (P < 0.01).
Conclusions: RPC by transient occlusion of the iliac artery improves lung gas exchange after repeated coronary artery occlusion and reperfusion mimicking OPCAB surgery, and preserves low PVR in sheep.
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Introduction |
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It has been reported that brief ischemia of remote organs (remote preconditioning, RPC), such as mesentery8 or gastrocnemius muscle,9 can reduce myocardial infarct size following prolonged ischemia and improve myocardial function. This RPC is much more attractive than the classical cardiac ischemic preconditioning since it avoids aortic cross clamping with its inherent risk of cerebral emboli. Moreover, in the case of beating heart OPCAB surgery, aortic cross clamping is, of course, impossible. It was shown recently that cardiac ischemic preconditioning protects pulmonary function in heart valve surgery.10 The effect of RPC on pulmonary function has not yet been fully explored. We postulated that RPC could improve lung gas exchange following myocardial ischemia/reperfusion. We tested this hypothesis using a clinically relevant animal model of OPCAB surgery in which RPC was achieved by three episodes of brief iliac artery occlusion and reperfusion, and myocardial ischemia and reperfusion was achieved by consecutive occlusion/reperfusion of three main coronary arteries.
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Methods |
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Anesthesia and surgical procedure
The sheep were given im ketamine 15–20 mg•kg-1. Anesthesia was induced with halothane (1–4 vol%) in oxygen and maintained after endotracheal intubation with halothane (1.5–2.0 vol%) in a mixture of oxygen and nitrous oxide. The animals were ventilated mechanically (Engström model 200, Engström, Sweden) at a respiratory rate of 14–16•min-1, an in-to expiratory cycle ratio of 1:2, and the tidal volume (15–20 mL•kg-1) was individually adjusted to maintain arterial carbon dioxide tension (PaCO2) between 35 to 45 mmHg. The tidal volume and respiratory rate for individual animals was not further adjusted during the experiment after baseline normal PaCO2 was achieved. Sigh breaths were given to treat increasing airway pressures. Angiocatheters (18 G and 20 G) were inserted respectively into a peripheral vein and a left ear artery for iv infusion and for arterial blood pressure monitoring and arterial blood sampling. A catheter was introduced into the right atrium through the jugular vein for continuous monitoring of central venous pressure. The electrocardiogram was monitored continuously. Fentanyl (0.1 mg, Janssen, Beerse, Belgium) was given before surgery and was further administered in boluses during thoracotomy. Physiological saline was given intravenously at a constant rate of 6 mL•kg-1•min-1 throughout the procedure. Heparin (400 IU•kg-1 iv) was administered before any vascular occlusion.
After a left thoracotomy was performed in the third intercostal space and the fourth rib was removed, a positive end-expiratory pressure of 5 cm H2O was established. A 20-mm ultrasonic flow probe connected to a flow meter (Transonic System, Ithaca, NY, USA) was placed around the pulmonary artery for cardiac output (CO) measurement. Three fluid-filled pressure catheters were placed to measure left atrial, pulmonary artery, and aortic pressures. Suture snares were put respectively around the left anterior descending coronary artery distal to the first diagonal branch, the first diagonal branch itself and the left circumflex coronary artery. The left external iliac artery was exposed for RPC. All the hemodynamic variables were continuously recorded on a heat-writing recorder (Nihon-Kohden, Tokyo, Japan) after signal conditioning with a carrier-amplifier (Triton Technology, San Diego, CA, USA). All signals were digitized on-line at 200 Hz with an analogue to digital converter equipped in the Conduct-PC hardware (CardioDynamics, Leiden, the Netherlands) and recorded on a computer. Blood gas variables were obtained from an automated blood gas analyzer (ABL3, Radiometer, Copenhagen, Denmark). The pulmonary vascular resistance (PVR) was calculated as: PVR = 80*(PAP-LAP)/CO from PAP, left atrial pressure (LAP) and CO.
Experimental protocol
Fourteen sheep were randomly assigned by using sealed envelopes to a control group (Group-C, n = 5) and a RPC group (Group-RPC, n = 9). Blood gases, respiratory and basic hemodynamic variables were recorded after induction of anesthesia. During instrumentation, basic hemodynamic variables did not change, and baseline data were recorded ten minutes after completion of the surgical instrumentation. RPC was subsequently achieved by three episodes of five-minute occlusion followed by five-minute reperfusion of the iliac artery, and data after preconditioning were recorded ten minutes after the final reperfusion of the iliac artery, or time-matched in Group-C which did not undergo iliac artery occlusion and reperfusion.
Subsequently, animals in both groups were subjected to repeated coronary occlusion and reperfusion. Firstly, the left anterior descending coronary artery was occluded for ten minutes. Ten minutes after left anterior descending coronary reperfusion, the first diagonal branch was occluded for ten minutes followed by reperfusion, ten minutes afterwards, the circumflex was occluded for ten minutes and then reperfused. Arterial blood samples were taken, and hemodynamic and respiratory variables recorded every 30 min after circumflex reperfusion until 120 min. Successful coronary occlusion was checked, by observing the immediate colour change of the tissues perfused by the corresponding arteries. Reperfusion was checked by the return of the bright red colour of the tissues. After the completion of the experiment, suture snares were checked to see if they completely circled coronary arteries, to ensure that occlusion of the corresponding coronary arteries was complete in each animal.
Statistical analysis
The significance of differences within the same group was determined by repeated measures ANOVA, with Dunnett’s multiple comparison test and Tukey’s multiple comparison test as appropriate. Statistical significance between the two groups was determined using unpaired Student’s t test with Welch’s correction. All data are presented as mean ± standard deviation (SD) and P < 0.05 was considered significant. Power calculations comparing the two groups were performed for the observed values obtained after 120 min of reperfusion (the final measurement) for the major outcomes concerning pulmonary function: this gives for PAP ß = 0.83, PVR ß = 0.91, PAP-LAP ß = 0.92, PaO2 ß = 0.77, PaO2/FIO2 ß = 0.85. The power calculations were performed using the online power calculators from the UCLA Department of Statistics (http://calculators.stat.ucla.edu/powercalc/).
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Results |
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). As shown in Table II, hemodynamic variables were comparable in both groups at baseline. RPC immediately decreased the PVR. Mean PAP and PVR in Group-C increased gradually during reperfusion and after 120 min of reperfusion were higher than the corresponding baseline values. RPC prevented this increase in mean PAP and PVR. An increase of the transpulmonary pressure gradient, calculated as the pressure difference between the mean PAP and LAP, was observed in Group-C after reperfusion. This transpulmonary pressure gradient was higher in the control group than that in Group-RPC after 90 and 120 min of reperfusion. Repeated coronary occlusion and reperfusion was associated with a decrease in systemic arterial pressure and CO in both Group-C and Group-RPC. After 120 min reperfusion, the mean systemic arterial pressure and CO was lower in Group C than in Group RPC. Heart rate, LAP and central venous pressure did not change significantly over time in either group.
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). However, no significant changes of PaO2 and PaO2/FIO2 were observed in Group-RPC throughout the procedure. After 120 min of reperfusion, PaO2 and PaO2/FIO2 in Group-C were lower than that in Group-RPC (P < 0.05). Concomitantly, PaCO2 in Group-C increased after 90 min reperfusion and was higher than that in Group-RPC (Table III). In Group-RPC, PaCO2 and pH values remained within the normal range after reperfusion.
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depicts the negative correlation between PVR and PaO2 as well as PaO2/FIO2 after 120 min reperfusion (P < 0.01). As shown in Figure 2, changes of PVR 30 min after reperfusion were correlated with impaired PaO2 and PaO2/FIO2 after 120 min of reperfusion.
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Discussion |
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Postoperative pulmonary dysfunction, a potentially lethal syndrome, has been reported to occur after OPCAB surgery,2,4 vascular surgery11 and after CPB.12,13 It is associated with a significant decrease in PaO2 and PaO2/FIO2. OPCAB surgery implies one or more coronary arteries to undergo occlusion and reperfusion. During reperfusion, specific myocardial enzymes (presumably leaked from damaged or necrotic tissue) and inflammatory cytokines14 are being washed out and reach the lungs,15 which might lead to lung injury. A series of acute experimental studies5,16–18 has demonstrated that coronary artery occlusion and reperfusion resulted in pulmonary edema, evidenced by an increase in extra-vascular lung water. Increased pulmonary microvascular permeability is suggested as one of the possible mechanisms. Although the mediators of the rise in pulmonary permeability have not been clearly identified, increasing evidence suggests that IL-6, IL-814 and prostaglandins19 are among the potential contributors. Infusing indomethacin19 reduced extra-vascular lung water after coronary artery occlusion in dogs. In a sheep model, Stamler et al.20 and Friedman et al.21 showed that myocardial ischemia and reperfusion was associated with an increase in PVR, which was accompanied by an increase in plasma thromboxane. Inhibition of thromboxane synthesis eliminated the lung injury seen in this model.21 Extra-vascular lung water was not measured in our model. Given the increase of PAP and PVR in Group-C, combined with a continuous decrease of PaO2 and PaO2/FIO2 as well as an increase in PaCO2, pulmonary edema may be one of the major contributors to the deterioration of pulmonary function in our model.
Recently, Fehrenbach et al.19 reported that the extent of lung epithelial injury increased with PVR using an isolated heart-lung ischemia-reperfusion model, suggesting PVR is a reliable indirect indicator of lung injury. The fact that PVR increased after coronary artery occlusion-reperfusion in Group-C, and that PaO2 and PaO2/FIO2 after 120 min reperfusion were negatively correlated with this early rise in PVR further supports this finding (Figure 2
). This suggests that changes in PVR could serve as a sensitive predictor for pulmonary function deterioration after coronary occlusion/reperfusion in this model. Acute postoperative pulmonary hypertension and elevated PVR may cause morbidity and mortality in patients undergoing cardiac surgery involving CPB.22 Recently, Li et al.10 reported that two cycles of three minutes of aortic cross clamping and two minutes of reperfusion (cardiac ischemic preconditioning) before cardioplegic arrest improves lung function in patients undergoing valve replacement operations. In their observations, two cycles of brief cardiac ischemic preconditioning were associated with a reduced PVR index and mean pulmonary artery pressure, which was accompanied by improved cardiac index as well as enhanced PaO2 after reperfusion. Also, histological findings confirmed a reduced alveolar injury in the cardiac ischemic preconditioned group.10 However, the method of global ischemic cardiac preconditioning is not applicable when OPCAB surgery is performed, since no aortic cross-clamping is possible during beating heart surgery. Furthermore, this method carries the risk of neurological damage by embolism of atheromatous material in the aorta during the cross-clamping. Therefore preconditioning by a short occlusion of a peripheral region or organ as performed in our experiments might clinically be far more relevant.
We report that sheep, submitted to a clinically relevant model mimicking OPCAB surgery, show an increase in PVR and jeopardized lung gas exchange. RPC induced by short ischemia of a non-vital organ completely prevented the increase of PVR and preserved lung gas exchange following coronary artery occlusion and reperfusion in our model. The underlying mechanism of the observations described in this experiment and in that of Li et al.10 needs to be further elucidated. It is not clear whether the same underlying mechanism is responsible for both observations. It is tempting, although speculative, to attribute a role to the KATP channel, since: 1) activation of this channel causes pulmonary vascular vasodilatation;23,24 and 2) the end effector of myocardial protection by ischemic preconditioning is at least in part the KATP channel.25,26 Further studies are warranted to unravel the underlying mechanism.
One may argue that the improvement in pulmonary function seen in Group-RPC might be attributable to the improvement in cardiac function as evidenced by increased CO and systemic arterial pressure in our experiment. We cannot completely exclude this possibility but think that this is not likely the major mechanism for the improvement in pulmonary function after repeated coronary occlusion and reperfusion in our model. Significant differences in CO and systemic arterial pressure between the groups were not observed until after 120 min reperfusion, while PaO2/FIO2 was already significantly lower and PaCO2 significantly higher in Group-C than in Group-RPC after 90 min of reperfusion (Tables II and III). Furthermore, there was no correlation between CO or systemic arterial pressure and pulmonary function described by PaO2/FIO2 and PaO2.
A weakness of our study is the fact that no control group was included without RPC and without coronary occlusions. Addition of this group might have clearly demonstrated the effect of the consecutive episodes of myocardial ischemia and reperfusion in itself. We had chosen to start with a model that mimics clinical OPCAB surgery, and then to try to reduce the pulmonary functional deterioration in this model by RPC.
In conclusion, the present study shows that in this sheep model, brief periods of ischemia followed by reperfusion in a remote peripheral non-vital organ can prevent pulmonary dysfunction following myocardial ischemia and reperfusion. This study may have clinical implications in OPCAB surgery. It might be of particular importance to those patients who have preexisting high PVR and pulmonary hypertension.
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Footnotes |
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Revision received February 12, 2003. Accepted for publication October 22, 2002.
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