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Ann Thorac Surg 2000;69:198-203
© 2000 The Society of Thoracic Surgeons

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Original Articles

Lowering reperfusion pressure reduces the injury after pulmonary ischemia

^a Division of Cardiothoracic Surgery, Heart Institute for Children, Hope Children’s Hospital, Oak Lawn, and The University of Illinois at Chicago, Chicago, Illinois, USA

Address reprint requests to Dr Allen, Heart Institute for Children, Hope Children’s Hospital, 4440 W 95th St, Oak Lawn, IL 60453
e-mail: brad{at}thic.com

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Controlled reperfusion with a modified solution limits pulmonary injury following ischemia. Our initial studies infused this modified reperfusate at a pressure of 40 to 50 mm Hg to insure distribution. However, perhaps a lower pressure, which is closer to the normal physiologic pressure in the lung, would improve results by decreasing sheer stress.

Methods. Fifteen adult pigs underwent 2 hours of lung ischemia by clamping the left bronchus and pulmonary artery. Five (group 1) then underwent uncontrolled reperfusion by removing the vascular clamps and allowing unmodified blood to reperfuse the lung at a pulmonary artery pressure of 20 to 30 mm Hg. The other 10 pigs underwent controlled reperfusion by mixing blood from the femoral artery with a crystalloid solution, and infusing this modified reperfusate into the ischemic lung through the pulmonary artery for 10 minutes before removing the arterial clamp. In 5 (group 2), the modified solution was infused at a pressure of 40 to 50 mm Hg, and in 5 (group 3) 20 to 30 mm Hg. Lung function was assessed 60 minutes after reperfusion and expressed as percentage of control.

Results. Compared to uncontrolled reperfusion (group 1), controlled reperfusion at a pressure of 40 to 50 mm Hg (group 2) significantly improved postreperfusion pulmonary compliance (77% versus 86%; p < 0.001 versus group 1), and arterial/alveolar ratio (a/A) ratio (27% versus 52%; p < 0.001 versus group 1); as well as decreased pulmonary vascular resistance (PVR) (198% versus 154%; p < 0.001 versus group 1), lung water (84.3% versus 83.5%; p < 0.001 versus group 1), and myeloperoxidase (0.35 versus 0.23 optical density/min/mg protein). Reducing the pressure of the modified reperfusate to 20 to 30 mm Hg further improved postreperfusion compliance (92% ± 1%; p < 0.001 versus groups 1 and 2) and a/A ratio (76% ± 1%; p < 0.001 versus groups 1 and 2); and lowered PVR (133% ± 2%; p < 0.001 versus groups 1 and 2), lung water (82.7% ± 0.1%; p < 0.001 versus groups 1 and 2), and myeloperoxidase (0.16% ± 0.01%; p < 0.001 versus groups 1 and 2).

Conclusions. After 2 hours of pulmonary ischemia, a severe lung injury occurs following uncontrolled reperfusion, controlled reperfusion with a modified solution reduces this reperfusion injury, and lowering the pressure of the modified reperfusate to more physiologic levels (20 to 30 mm Hg) further reduces the reperfusion injury improving pulmonary function.

	Introduction

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The lungs are the most vulnerable solid organs currently being transplanted [1, 2]. With most centers using strict criteria for donor selection, only 15% to 20% of lungs from multiorgan donors are suitable for transplantation [1, 2]. Despite these conservative practices, reperfusion injury remains a significant cause of morbidity and mortality after transplantation [2, 3]. In recent years, however, our understanding of the reperfusion injury has increased dramatically. We have shown that the reperfusion injury in cardiac tissue can be avoided by controlling the composition of the initial reperfusate, as well as the conditions (pressure) of reperfusion [4–6]. Based on these principles, we recently demonstrated that controlled reperfusion using a leukodepleted modified blood solution, delivered at a pressure of 40 to 50 mm Hg, limited pulmonary reperfusion damage and restored lung function [7]. This pressure was chosen in our initial study to insure adequate distribution to all areas of the lung, as well as because studies in the ischemic heart demonstrated that this lower reperfusion pressure decreased myocardial damage [4, 5, 8]. Although a pressure of 40 to 50 mm Hg is less than the normal arterial pressure in the heart, it is significantly higher than the normal arterial pressure in the lung. Because endothelial damage can occur as a result of increased sheer stress, this supra physiologic pressure may have increased pulmonary reperfusion injury. This study therefore investigates whether lowering the initial reperfusion pressure to a more normal physiologic pressure of 20 to 30 mm Hg decreases the reperfusion injury after pulmonary ischemia, and improves pulmonary function.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Fifteen healthy mature Duroc-Yorkshire pigs (25 to 35 kg) were sedated with intramuscular ketamine (20 mg/kg), anesthetized with intravenous phenobarbital (25 mg/kg), and maintained by intermittent intravenous phenobarbital. Mechanical ventilation was achieved with a tracheostomy using a Servo 900-B volume-controlled ventilator (Siemens-Elema, Solna, Sweden). All animals received 1 g of cefazolin intravenously preoperatively, as well as humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and "The Guide for the Care and Use of Laboratory Animals," prepared by the National Academy of Science and published by the National Institutes of Health (NIH publication 96-03, revised 1996).

The left femoral artery and vein were cannulated for continuous monitoring of arterial blood pressure, blood gas determinations, and intravenous infusions. Body temperature was monitored using esophageal temperature probe (Mon-A-Therm 400H, Mallinckrodt, St. Louis, MO) and maintained at 36° to 38°C with a heating blanket. Periodic arterial blood samples were drawn and analyzed for blood gas, potassium, ionized calcium, glucose, and hemoglobin (Ciba-Corning, Blood Gas System 288, Medfield, MA). Electrolytes were kept within normal limits, and all animals had an initial hemoglobin higher than 10.0 g/dL.

After a median sternotomy, the pericardium and both pleural spaces were entered. A 7F balloon-tipped thermodilution catheter (Baxter Healthcare Corp, Deerfield, IL) was placed through the right internal jugular vein into the main pulmonary artery for determination of pressure and cardiac output. An 18-gauge catheter was placed in the left atrium for pressure measurements. The right and left hilar structures (pulmonary arteries, veins, and main bronchi) were dissected. Special attention was paid to skeletonizing the left bronchus for a length of approximately 1 cm, thereby obliterating the bronchial blood supply. Animals were then given 3 mg/kg heparin intravenously. In animals undergoing controlled reperfusion, the right femoral artery and left pulmonary artery were cannulated using an 8F DLP arterial cannula (DLP Inc, Grand Rapids, MI). This allowed blood to be withdrawn from the femoral artery, using a roller pump passed through a mixer and heater (BCD, Shiley Corp, Irvine, CA), and returned to the left pulmonary artery (Fig 1). A catheter was also placed to allow constant monitoring of pulmonary artery pressure during controlled reperfusion.

View larger version (34K): [in this window] [in a new window]   Fig 1. (A) Our experimental model of controlled pulmonary reperfusion. Blood is taken from the femoral artery and combined with a modified crystalloid solution using a BCD as a mixer, and then returned to the pulmonary artery. The pressure in the distal pulmonary artery is constantly measured. (B) The modified reperfusate is given into the left pulmonary artery distal to the clamp, and is able to return to the pig through the pulmonary veins.

Uncontrolled reperfusion (group 1)
The clamps were simply removed from the left pulmonary artery and bronchus, allowing unmodified blood to reperfuse the lung by restoring native pulmonary flow. This resulted in a reperfusion pressure of 20 to 30 mm Hg and simulates the usual clinical practice.

Controlled reperfusion-high pressure (group 2)
The left lung was reperfused by taking blood from the femoral artery, mixing it in a 4 to 1 ratio with a modified crystalloid solution (Table 1), and then infusing this solution into the left pulmonary artery distal to the arterial clamp for 10 minutes (Fig 1). The reperfusate was allowed to return to the pig through the pulmonary vein. Perfusion pressure was continuously monitored and kept between 40 and 50 mm Hg in the distal pulmonary artery. After 10 minutes, the controlled perfusion was stopped, and the pulmonary artery and bronchial clamps were removed, restoring native pulmonary circulation.

All animals were observed for 1 hour after reperfusion, and functional measurements were repeated. Lung biopsy specimens were then obtained for tissue edema and myeloperoxidase activity, and the animals euthanized.

Pulmonary functional measurements
Pulmonary functional measurements were obtained by transiently clamping the right bronchus and pulmonary artery so all blood flow and ventilation were directed through the left lung. All measurements were obtained before ischemia (baseline) and 60 minutes after reperfusion. Postreperfusion measurements are expressed as a percentage of baseline to allow each pig to act as its own control.

Arterial/alveolar ratio
With ventilation unchanged between preischemic and post reperfusion settings, the a/A oxygen ratio for each lung was calculated as previously described [7, 9].

Pulmonary vascular resistance
Cardiac output was measured using a Swan-Ganz catheter and a Edwards 9502 computer (Baxter Health-Care Corp, Edwards Division, Santa Ana, CA). Using the average from three measurements, PVR was calculated as previously described [7, 9].

Lung compliance
Peak airway pressure was measured using a tidal volume of 15 mL/kg without positive end expiratory pressure. Static compliance was calculated as change in volume over change in pressure (mL/cm H₂0).

Tissue measurements
A wedge biopsy was taken from the inferior portion of the left upper lobe at the end of the experiment for tissue water and myeloperoxidase activity.

Lung edema
A portion of each biopsy specimen was weighed and dried to a constant weight at 80°C, and lung water calculated as previously described [7, 9].

Myeloperoxidase activity
The other portion of each biopsy was immediately frozen and stored in liquid nitrogen. The frozen tissue was then crushed using a liquid nitrogen-cooled motor and pestle, and lyophilized (Savant Speed Vac Systems, Farmingdale, NY). Quantitative myeloperoxidase activity was determined, as previously described, using the modified procedures of Okabayashi and associates [7, 9, 10]. Enzyme activity is expressed as the change in optical density units per minute per milligram of tissue protein (OD/min/mg protein).

Statistical analysis
Data were analyzed using JMP V2.0 (SAS Institute Inc, Cary, NC) on a Macintosh IIVX Computer (Apple Inc, Cupertino, CA). All data are expressed as mean ± standard error of the mean. Paired Student’s t test and analysis of variance with interaction (factorial analysis) were used for comparison of variables among experimental groups. If analysis of variance revealed a significant interaction, pair-wise tests of individual group means were contrasted by way of multiple comparisons (Tukey’s test) using a level of significance of p less than 0.05, p less than 0.01, and p less than 0.001.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
No statistical difference was found in baseline (preischemic) measurements of compliance (14.3 ± 0.4 mL/cm H₂0), PVR (957 ± 19 dynes/s/cm), or a/A ratio (0.82 ± 0.04) between any of the groups. All animals remained stable throughout this experiment.

Pulmonary function
Results are summarized in Figures 2 to 4 and Table 2. All postoperative values are expressed as a percentage of baseline measurements to allow each pig to act as its own control. After 2 hours of warm ischemia, uncontrolled reperfusion (group 1) caused a significant pulmonary injury manifested by decreased compliance, elevated PVR, and decreased oxygenation (a/A ratio). In contrast, controlled reperfusion using a modified solution infused at a high pressure (group 2) significantly blunted this injury. However, infusing the modified reperfusate solution at a lower pressure (group 3), reduced this injury even further, resulting in almost complete recovery of pulmonary function.

View larger version (13K): [in this window] [in a new window]   Fig 2. Postreperfusion pulmonary compliance expressed as percent recovery compared to baseline values. Uncontrolled reperfusion with unmodified blood significantly lowered pulmonary compliance indicating a reperfusion injury. In contrast, controlled reperfusion using a modified blood solution, given at a low pressure, resulted in almost full recovery of pulmonary compliance, *p < 0.001.

View larger version (13K): [in this window] [in a new window]   Fig 3. Postreperfusion pulmonary vascular resistance expressed as a percent increase compared to baseline values. The pulmonary vascular resistance increased significantly when the lung was reperfused with unmodified blood in an uncontrolled fashion. Conversely, lungs undergoing controlled reperfusion with a modified reperfusate at a low pressure experienced minimal change in pulmonary vascular resistance, *p < 0.001.

View larger version (12K): [in this window] [in a new window]   Fig 4. Postreperfusion arterial/alveolar (a/A) ratio measured with the same ventilator settings used to make preischemic measurements. Uncontrolled reperfusion resulted in a very low posttransplant PO2 (a/A ratio), implying severe alveolar damage in this group. In contrast, the a/A ratio was almost normal in animals receiving low pressure controlled reperfusion implying very little alveolar injury, *p < 0.001.

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
These results support previous studies which demonstrated that the method of reperfusion is more important than the duration of ischemia in determining reperfusion damage [4–7, 9]. By controlling the composition of the initial reperfusate, using a modified solution, as well as the conditions of reperfusion, by lowering the pressure, the reperfusion injury was significantly reduced, resulting in improved biochemical and functional recovery.

In our initial study, we primarily investigated the composition of the reperfusate solution and found that complete functional recovery was possible by infusing a leukodepleted, modified blood solution into the pulmonary artery at a pressure of 40 to 50 mm Hg for 10 minutes before restoring normal blood flow [7]. This infusion pressure was chosen because it optimized recovery in studies of controlled reperfusion in the heart, as well as insuring adequate distribution of the modified solution to all pulmonary segments [4–6]. However, because arterial pressure is normally lower in the lung compared to the heart, reducing the infusion pressure might still provide adequate distribution while limiting any of the detrimental effects of pressure on ischemic tissue. The present study, therefore, was designed to specifically investigate the conditions of reperfusion (pressure), by infusing the identical reperfusate solution at different pressures. We did not use a white blood cell (WBC) filter because our initial study demonstrated complete functional recovery when a leukodepleted modified reperfusate solution was delivered at a pressure of 40 to 50 mm Hg [7]. Therefore, a WBC filter would have made it difficult to identify any improvement provided by lowering the reperfusate pressure. We continue to believe however, that leukodepletion is extremely important in limiting the reperfusion injury, and strongly advocate its use as part of a comprehensive reperfusate strategy.

Although controlled reperfusion, with a modified solution delivered at a pressure of 40 to 50 mm Hg, improved functional recovery compared to uncontrolled reperfusion, recovery was significantly better if the pressure of the modified reperfusate was reduced to 20 to 30 mm Hg. However, pigs undergoing uncontrolled reperfusion with unmodified blood were also reperfused at a pressure of 20 to 30 mm Hg. In contrast to controlled reperfusion, these pigs sustained a substantial reperfusion injury resulting in markedly reduced pulmonary function. This implies that both the composition of the reperfusate (modified solution) as well as the conditions of reperfusion (pressure) are important in reducing reperfusion damage, and that the maximal benefits of controlled reperfusion are only achieved when all aspects of reperfusion are combined. This is further supported by previous studies in the heart, as well a recent investigation in pigs undergoing lung transplantation following 24 hours of cold ischemic storage [4–6, 9]. In this study, all pigs receiving uncontrolled reperfusion with unmodified blood died as a result of posttransplant pulmonary dysfunction, whereas animals receiving controlled reperfusion with a leukodepleted modified solution delivered at a pressure of 20 to 30 mm Hg survived, and had almost complete recovery of pulmonary function in the transplanted lung.

It remains speculative why a slightly higher reperfusion pressure causes increased damage after ischemia, but considerable evidence suggest that it is primarily a result of an endothelial cell injury [11–16]. Mills and associates demonstrated that endothelial continuity was maintained after hypothermic storage, but 5 minutes after reperfusion, there was denudation of the endothelium with loss of continuity between cells, as well as perivascular edema [17]. Pickford showed that this endothelial detachment increased the damaging effects of sheer stress seen with high pressure reperfusion [15]. Besides causing direct cellular damage, sheer stress also releases cytokines as well as activates vascular endothelial cells [14, 18–20]. This leads to attachment of WBC, which then release proteases and oxygen free radicals resulting in further endothelial and cellular damage [12, 19–21]. Indeed, studies using endothelial cell culture have shown that high hydrostatic pressure alone activates cytokines causing cellular injury independent of sheer stress [20]. High reperfusion pressure also increases release of vasoactive substances such as endothelin which causes vasoconstriction and hypoperfusion [18, 22]. Finally, high pressure may increase myocardial edema.

The present study was done using a large animal model in which the lungs were subjected to 2 hours of normothermic (37°C) ischemia. We have previously used this model to investigate various components of the reperfusate solution, and have confirmed its validity in 24 hour lung transplant studies [7, 9]. Besides being less expensive, this model has all the benefits and clinical parallels of a large animal study that imulates the real transplant experience, while eliminating confounding variables, such as rejection, and complex surgical techniques experienced in a true transplant model. We therefore believe the results from these studies are transferable to the clinical situation. Furthermore, this study and our previous studies used a simple reperfusate system that can be used clinically without the need for blood transfusions [7, 9]. The only difference is that, in patients, blood would be taken directly from the aorta instead of the femoral artery, as the chest would be open.

Although this study implies that a lower (physiologic) reperfusion pressure is beneficial following lung ischemia, the optimal pressure, as well as length of a modified infusion, remains uncertain. It is possible that lowering the pressure of the initial reperfusate even further to subphysiologic levels would improve recovery. However, it must be remembered that the pressure must be high enough to insure adequate distribution of the modified reperfusate, and because there is improved recovery of pulmonary function using a pressure of 20 to 30 mm Hg, this pressure achieves this goal. Whether the same holds true for a lower reperfusion pressure remains unknown. Further complicating this issue is the fact that hydrostatic pressure can also release beneficial substances like nitric oxide and prostacyclin, which in addition to their vasodilatory effects, have a wide range of cellular protective actions [15, 20, 21]. Another question is, how long does controlled reperfusate need to be continued? We have previously demonstrated in the heart that 20 minutes of controlled reperfusion was superior to 10 minutes [5, 6]. In contrast, Babra and associates demonstrated in the lung that controlled reperfusion for less than 10 minutes is not as effective, and that extending the period of controlled reperfusion to 30 minutes had no further preventive action [23]. Although the ideal length of controlled reperfusion, as well as the optimal pressure remains uncertain, these and other data suggest that the first minutes of reperfusion are critical, and that by using controlled reperfusion, subsequent tissue edema, WBC adherence, and cellular injury is kept to a minimum [4–7, 9, 24]. This allows the ischemic endothelial and myocardial cells to recover so that after a period of controlled reperfusion the transplanted lung can tolerate native pulmonary perfusion with normal blood.

In conclusion, this study reaffirms our previous findings that reperfusion damage is determined primarily by the method of reperfusion. Because the transplant surgeon is in the unique position of being able to precisely control all aspects of reperfusion, we believe it is incumbent upon that person to utilize controlled reperfusion to limit the pulmonary reperfusion injury and insure optimal graft function. Based on this, as well as previous data, we believe that this is best accomplished by infusing a leukodepleted modified blood solution for 10 minutes at a pressure of 20 to 30 mm Hg [7, 9]. Utilizing this approach may not only improve postoperative recovery but, because there is less graft damage, may allow less than perfect lungs to be harvested, thereby expanding the donor pool.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Ari O. Halldorsson Michael T. Kronon Bradley S. Allen Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Halldorsson, A. O. Articles by Wang, T. Search for Related Content PubMed PubMed Citation Articles by Halldorsson, A. O. Articles by Wang, T.