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Clinic of Anesthesiology and Intensive Care Medicine, University Clinic Carl Gustav Carus, Technical University Dresden, Dresden, Germany
Address correspondence and reprint requests to Marcelo Gama de Abreu, MD, MSc, Clinic of Anesthesiology and Intensive Care Medicine, University Clinic Carl Gustav Carus, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany. Address e-mail to mgabreu{at}aol.com
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Abstract |
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IMPLICATIONS: One-lung ventilation with high tidal volumes and zero positive end-expiratory pressure (PEEP) is injurious in the isolated rabbit lung model. A ventilatory strategy with tidal volumes and PEEP set to avoid lung overdistension and collapse minimizes lung injury during one-lung ventilation in this model.
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Introduction |
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Different studies have shown that mechanical ventilation may initiate or worsen lung injury (5,6). Also, it has been demonstrated that cyclic collapse and reopening of alveoli at lower PEEP levels may lead to the development of shear-stress forces and lung injury (7). Those studies, however, were performed with ventilation of both lungs. The OLV situation may differ from the previous settings in two respects: first, the ventilated lung is usually not previously injured. Second, extreme overdistension, as used to achieve lung injury in other studies (5), is usually not present, but the distribution of ventilation could theoretically lead to similar degrees of mechanical stress in some lung zones. However, no study has addressed the development of ventilator-induced lung injury (VILI) during OLV and the use of protective respiratory strategies under such conditions.
In this work, we investigated whether a nonprotective mechanical ventilatory strategy for OLV with high VT values and zero PEEP may cause VILI in the isolated rabbit lung model. Also, we tested the hypothesis that the titration of VT and PEEP to avoid lung overdistension and collapse would have a protective effect, minimizing VILI during OLV.
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Methods |
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After a median sternotomy, the pulmonary artery was cannulated, and the heart was opened to permit the exsanguination of the lungs with Krebs-Henseleit hydroxyethyl starch buffer solution (perfusate), which was pumped with a roller pump at 50 mL/min (Masterflex L/S; Cole-Parmer, Mfg. Barnant, Barrington, IL). The lungs and trachea were carefully dissected, removed en bloc, and suspended from a weight transducer (Hottinger Baldwin Meßtechnik, Darmstadt, Germany) in a temperature-controlled (37°C) double-walled chamber. The lung perfusate dropping from the lungs into the chamber was collected into a reservoir and redirected to the roller pump as a closed recirculation system. The total volume of perfusate in the system was 200 mL. The temperature of the perfusate was maintained at 37°C with a water bath, and the pH was maintained between 7.35 and 7.45 by means of the inflow of CO2 into the inspiratory air, achieving a concentration of approximately 4% CO2. The perfusate flow rate was increased to 100 mL/min, and the whole volume was exchanged two times before measurements began.
Mean pulmonary artery pressure (MPAP) was monitored continuously by means of a pressure difference transducer with the CMS Monitor (Agilent Technologies, Böblingen, Germany). The MPAP was zero-referenced at the hilus height. Because the perfusion was held constant, alterations of the perfusion pressure were directly related to the total pulmonary vascular resistance. The weight transducer was also connected to the CMS Monitor, and both weight and MPAP were recorded each minute by means of a microcomputer. Weight gain (WG) was defined as the weight of the trachea-lung bloc measured in a given moment minus the weight measured at the beginning of the experiment.
Airway opening pressure was monitored at the connection between the intratracheal catheter and the Y-piece of the mechanical ventilator by using a differential pressure transducer referenced to the atmospheric pressure (PasCal; Hoffrichter GmbH, Schwerin, Germany). Because the chamber containing the trachea-lung bloc was open to the atmosphere, airway opening pressure was identical to the transpulmonary pressure (PL). The PL signal was digitized at 200 Hz by an analog-digital board (DAQ-Pad 1200; National Instruments, Austin, TX) with 10 bits and acquired by a laptop by using a special routine developed for LabView (National Instruments).
Dynamic pressure-time (P-vs-t) curves were recorded during constant flow inflation over three consecutive respiratory cycles. The relationship between pressure and time can be described according to a power equation (9):
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where coefficient a is a constant that represents the slope of the P-vs-t relation at t = 1, and coefficient c is the pressure at t = 0. The coefficient b is a dimensionless constant that describes the concavity of the P-vs-t curve. For b values >1, the dynamic P-vs-t curve has an upward concavity, indicating that the compliance decreases with time, as, for instance, when the lungs are being overdistended. For b values <1, the dynamic P-vs-t curve has a downward concavity, indicating that the compliance increases with time, as, for instance, when the lungs are being inflated from collapse. For b = 1, the dynamic P-vs-t curve is a straight line, indicating a constant lung compliance without collapse or overdistension. Unfortunately, Equation 1 cannot be used to describe a P-vs-t curve with concavities in both the lower and upper ranges (sigmoidal shape) appropriately (10). Therefore, in this work, we divided the P-vs-t curve into two portions. The first lower third and the upper two thirds of the dynamic P-vs-t curve were described according to Equations 2 and 3, respectively. These ranges were arbitrarily defined after careful analysis of the P-vs-t curve.
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where the coefficients blower and bupper describe the concavity of the lower and upper portions of the P-vs-t curve, respectively, in the same way as described for Equation 1.
The P-vs-t curves were processed off-line to identify the beginning and end of inspiration. Because the PL increase has a characteristic spike when the inspiratory flow starts, flow curves were not necessary to identify the beginning of inspiration. To ensure that on- and off-flow transients generated by the mechanical ventilator did not skew the results, the first and last 50 ms of the inspiratory cycle were excluded from the analysis. These values have been derived from preliminary experiments and are virtually the same as those used by Ranieri et al. (10) in a similar procedure. The curve-fitting procedures for the lower and upper portions of the P-vs-t curve were performed with the remaining data, and blower and bupper were calculated according to the experimental protocol.
Perfusate samples were taken with 2-mL syringes containing 13.6 µg of diclofenac (Rewodina; ASTA Medica AWD, Frankfurt, Germany) and immediately centrifuged at 14,000 U/min for 10 min. By using a calibrated pipette, 1000 µL of the samples was drawn and frozen at -20°C. Afterward, samples were allowed to thaw, and thromboxane B2 (TXB2) concentrations were measured in a blinded fashion with enzyme-linked immunosorbent assay (Institute of Biochemistry, University Clinic Carl Gustav Carus, Dresden, Germany).
Initially, PEEP was increased until a straight line was achieved in the lower part of the dynamic P-vs-t curve (blower 
1). After that, a sustained inflation with 30 cm H2O was performed for 30 s (recruitment maneuver), and VT was set at 6 to 8 mL/kg to obtain a straight line also in the upper portion of the dynamic P-vs-t curve (bupper 1). All other ventilator settings were kept constant, and the lungs were randomized to one of three groups:
The entire procedure to achieve adequate ventilation of one isolated lung lasted approximately 5 min. Animals were excluded from the study if 1) an air leak was identified during recruitment procedures, 2) ventilation of the right lung was observed at any time after the beginning of OLV, or 3) ventilation of the upper left lobe was absent.
Measurements of respiratory mechanics were performed before randomization (baseline) and at 0, 60, and 90 min after OLV ventilation was established or under two-lung ventilation (control group). To compensate for the delay needed to achieve OLV in the other groups, the first measurement after randomization in the control group (time 0) was also delayed by 5 min. Perfusate samples were drawn at baseline and at 0, 30, 60, and 90 min in all groups.
All results are expressed as mean ± SEM. Changes in ventilatory settings were assessed with paired Student’s t-tests. Comparison among groups was performed with two-way analysis of variance with two-way entry (group and time; general linear model). Multiple comparisons were performed with the Student-Newman-Keuls correction. One-way analysis of variance was used where appropriate. A P value <0.05 was considered to be statistically significant in all tests performed.
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Results |
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The peak inspiratory pressure (PIP) levels achieved in the nonprotective OLV group were higher than those in the protective OLV and control groups (P < 0.001) (Fig. 2). In addition, the PIP level increased significantly with time in the nonprotective OLV group, as compared with Time 0 (P < 0.01). No statistically significant differences were observed between the protective OLV and control groups. Also, there was no significant increase of PIP with time in the protective OLV and control groups.
We found no statistically significant differences in mean MPAP at baseline among animals (Fig. 3). A slight but significant increase in MPAP (2 and 1 mm Hg on average, respectively) was observed in both the nonprotective and protective OLV groups when OLV was initiated, compared with baseline. In the nonprotective OLV group, but not in the protective OLV group, MPAP increased further compared with the control group, achieving levels as high as 90 mm Hg at 90 min. There were no statistically significant differences in MPAP between the protective OLV and control groups at the end of experiments.
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The concentration of TXB2 in the perfusate was comparable among groups at baseline (Fig. 3). During the observation period, a significant increase of TXB2 concentration was observed in the nonprotective OLV group as compared with the protective OLV and control groups. In the protective OLV and control groups, no statistically significant increase of the concentrations of TXB2 could be observed. The pH of the perfusate did not differ significantly among the experimental groups during the observation period.
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Discussion |
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In recent years, there has been major interest in ventilatory strategies aimed at protecting the lungs from overdistension and collapse. In patients with acute respiratory distress syndrome (ARDS), the titration of VT and PEEP according to respiratory mechanics has been suggested to be effective in improving lung function and even mortality (11,12). A multicenter clinical trial on a protective ventilatory strategy for ARDS patients demonstrated that the use of reduced VT values with PEEP set according to an arterial oxygenation protocol could significantly reduce the number of ventilator-free days and hospital mortality of a group of 861 patients compared with a ventilatory strategy with high VT values (13).
Wrigge et al. (14) investigated the effect of one hour of ventilation with the protective ventilatory approach compared with a ventilatory strategy with higher VT values on the release of cytokines and pulmonary function in patients without preexisting lung injury. Those authors were not able to show a difference in the release of tumor necrosis factor (TNF)-
, interleukin (IL)-10, IL-6, or IL-1 among groups. In addition, the pulmonary function did not deteriorate in the group with nonprotective ventilation. Those findings, however, may not be valid if ventilation is performed for longer periods of time or the distribution of ventilation is importantly altered, as may be observed during OLV.
The best way to set an optimal mechanical ventilatory strategy to minimize the risk of ventilator-associated lung injury has been subject of intense debate (15). In this study, the mechanical ventilator settings were defined by using the dynamic characteristic of the P-vs-t curve of the respiratory system. This method can predict a minimally injurious ventilatory strategy in an ARDS model (10) and also in patients with ARDS (16), and it seems to be useful for the purpose of defining individual mechanical ventilatory settings. Because the P-vs-t curve had a sigmoidal shape in our study, we analyzed both the lower and the upper portions by means of the power equation: PL = a x tb + c. Therefore, we implicitly assumed that PL should vary linearly with time (volume) during the entire inspiratory cycle if collapse and overdistension could be avoided. Using the targets recommended by Ranieri et al. (10), we defined the ventilatory settings of the protective OLV and control groups to obtain blower and bupper coefficients approximately equal to the unit and were able to minimize VILI in those groups. Conversely, in the nonprotective OLV group, blower coefficients were much less than one, whereas bupper coefficients were much higher than the unit. Whereas blower coefficients <0.9 are associated with collapse, bupper coefficients >1.1 are associated with overdistension of alveoli (10).
The development of VILI in the nonprotective OLV group was mirrored by a significant increase in MPAP and WG. The increase of pulmonary vascular resistance is one of the hallmarks of lung injury of different causes (17). In the in vivo situation, the increase of MPAP usually correlates with the degree of hypoxemia and the protective hypoxic vasoconstrictory effect (18). In the isolated rabbit lung model, the partial pressure of oxygen in the perfusate is practically the same as in the atmosphere, and there is virtually no exchange in the alveoli. Thus, the MPAP increase is most probably explained by the release of inflammatory mediators. Indeed, the concentration of TXB2, the stable metabolite of TXA2, was much larger in the nonprotective OLV group. TXA2 is an inflammatory mediator that has been implicated in the genesis of lung injury (19,20). Besides the potent pulmonary vasoconstrictory property, this metabolite may enhance the extravasation of fluid into the structurally damaged lung parenchyma, with a consequent increase of lung weight and stiffness. The increase in lung stiffness is usually accompanied by the increase in airway pressures needed to achieve a given volume. This phenomenon was also present in the nonprotective OLV group, as evidenced by a progressive increase of PIP over time.
Alveoli overdistension and shear stress disrupt the pulmonary epithelium, leading to microvascular leakage and pulmonary edema (7). In addition, structural lung disruption caused by the use of high VT values is associated with the inhibition of the Na,K-ATPase function of alveolar Type II cells and impairment of the ability to clear edema (21). A link between mechanical stress and release of inflammatory mediators has been demonstrated in different studies. Investigators showed that membrane stretch may lead to disruption, activation of ion channels, and conformational changes in the structure of integrins (22,23). All these mechanisms lead to an increase of gene expression, with production of cytokines and pro- and antiinflammatory molecules. Although these pathophysiological mechanisms are often associated with the presence of TNF- and IL-8 in the bronchial lavage and/or plasma or perfusate, Imanaka et al. (24) showed that TNF- is not necessarily increased in the course of severe VILI, suggesting that different proinflammatory reactions may be involved. We determined the perfusate concentration of TNF- and IL-8 in 2 animals that had a dramatic development of VILI (nonprotective OLV) and another 2 that did not develop VILI (protective OLV and control groups) (data not shown). There was no increase of these cytokines in the course of VILI and also no difference among animals.
As expected, the presence of a nonventilated lung did not interfere with the protective effect of the ventilatory strategy with low VT and PEEP set to avoid lung collapse. In our study, a control group with ventilation of both lungs was included, and we did not observe any significant differences in the variables investigated, with the exception of MPAP, which increased only slightly when changing from two-lung ventilation to OLV in both the nonprotective and protective ventilation groups.
The isolated, perfused rabbit lung model permits the investigation of the effects of ventilatory strategies on the lungs without the influence of confounding factors, as, for instance, the metabolization of inflammatory mediators by other organ systems. However, the ventilation of one lung without the influence of the chest wall limits the extrapolation of our results to the clinical setting. When lung surgery is performed by means of thoracotomy, i.e., in the lateral decubitus position, the dependent lung is confined to a closed hemithorax, and the development of atelectasis is limited by the interaction between the lung and chest wall. Under such conditions, atelectasis may occur as the result of the paralysis of the diaphragm combined with increased intraabdominal pressure and the weight of the mediastinum and nondependent lung. Thus, the phenomenon of cycling collapse and reopening of lung zones probably occurs less with this approach. However, even if the expansion of the ventilated lung is limited in the closed hemithorax, the VT values used in the clinical setting are even greater than those used in our study. Consequently, the degree of lung expansion that can be achieved during thoracotomy is at least comparable to that we obtained experimentally, provided that end-expiratory lung volumes are also comparable between those situations. We did not measure end-expiratory lung volumes in our study, but we visually observed that lung collapse was almost complete at end-expiration in the nonprotective OLV group. The combination of overdistension and global atelectasis probably led to an exaggeration of the mechanical stress of ventilation in this study. Therefore, our results probably represent a "worst case" scenario of OLV during thoracotomy.
Another important approach used for lung surgery is the median sternotomy, which may be superior to the thoracotomy for certain procedures (25,26). This approach is frequently seen during lung volume reduction surgery (27,28) and may be advantageous for resection of lung metastases (29,30). Usually, both hemithoraxes are open to the atmosphere during lung surgery with the median sternotomy approach, and the ventilated lung may be able to expand and collapse with minimal interaction with the chest wall. Because the lung mechanics during such an approach are similar to those observed in our model, our results suggest that the conventional, nonprotective ventilatory strategy for OLV should be avoided during median sternotomy.
The reexpansion of the lungs after longer periods of collapse is associated with increased concentrations of inflammatory mediators in plasma (31), which may contribute to the development of postoperative lung injury and even infection. We were concerned about those issues when we performed our study. However, the nonprotective ventilatory strategy led to dramatic degrees of lung injury, which would have not allowed the investigation of the effects of reexpansion of the nonventilated lungs. Thus, interpretation of our findings must take into account that only the OLV phase was addressed. No controlled trials have been performed to investigate the possible harmful effects of the nonprotective ventilatory strategy with high VT values and zero PEEP during OLV under different surgical conditions. Thus, clinical studies are necessary to confirm our findings.
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Acknowledgments |
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We are indebted to Prof. P. Dieter, MD, PhD, and M. Kolada (Institute of Biochemistry, University Clinic Carl Gustav Carus, Dresden, Germany) for the measurement of TXB2. We also wish to thank E. Kuhlisch (Institute of Biometry, University Clinic Carl Gustav Carus, Dresden, Germany) for assistance in statistics.
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P < 0.01 versus Time 0.
P < 0.01 versus baseline.
