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Ann Thorac Surg 1995;59:336-341
© 1995 The Society of Thoracic Surgeons

Successful Canine Bilateral Single-Lung Transplantation After 21-Hour Lung Preservation

Department of Surgery II, Okayama University Medical School, Okayama, Japan

Accepted for publication September 13, 1994.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
A canine bilateral single-lung transplantation model was used to evaluate 21-hour lung preservation with low-potassium dextran glucose solution. Donor lungs were flushed with low-potassium dextran glucose solution (50 mL/kg), inflated with 100% oxygen (35 mL/kg), and preserved at 8°C. Bilateral single-lung transplantation was performed without using cardiopulmonary bypass. The ischemic times to the right and left lungs were designed to be 3 and 6 hours, respectively, in group 1 (n = 5) and 18 and 21 hours in group 2 (n = 6). After bilateral single-lung transplantation, animals were maintained on a ventilator for 12 hours and lung function, including arterial blood gas and pulmonary hemodynamics, was measured. All 5 dogs in group 1 and 5 of 6 dogs in group 2 completed bilateral single-lung transplantation successfully and survived for 12 hours with excellent lung function. Arterial oxygen tension and mean pulmonary artery pressure were stable during the 12-hour assessment period in both groups and did not differ significantly from donor values. Twelve hours after reperfusion, mean arterial oxygen tension (inspired oxygen fraction = 1.0) was 590 ± 18 mm Hg in group 1 and 604 ± 8 mm Hg in group 2. After the 12-hour assessment period, the animals were extubated and immunosuppressed. Two dogs in group 2 survived for 7 and 8 days, respectively, with a mean arterial oxygen tension of 74 mm Hg on room air at 5 days. These results lead us to conclude that lungs flushed with low-potassium dextran glucose solution, inflated with 100% oxygen, and preserved at 8°C for 21 hours provides excellent lung function in a canine bilateral single-lung transplantation model in which the animal is totally dependent on the function of transplanted lung tissue.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Numerous studies on lung preservation have been published using ex vivo models or in vivo single-lung transplantation models. Most of these models are useful to compare different preservation conditions. However, the safe preservation time that is applicable for clinical use is difficult to determine.

In this study, a canine bilateral single-lung transplantation (BSLT) model was used to evaluate 21-hour lung preservation with the method that had been proved to provide safe preservation for up to 24 hours in a canine single-lung transplantation model [1]. The postoperative survival of the recipient is totally dependent on the function of transplanted lung tissue over the entire postoperative period in BSLT and therefore attests to the safe preservation time in question.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Eleven bilateral single-lung allotransplantation procedures were performed in weight-matched pairs of mongrel dogs (7.8 to 17.5 kg). The dogs were assigned randomly to one of the two study groups. The mean weights of donor and recipient were 12.4 ± 0.6 kg and 13.4 ± 1.2 kg, respectively, in group 1 (n = 5) and 13.6 ± 1.9 kg and 13.6 ± 1.7 kg, respectively, in group 2 (n = 6). The animals were treated identically except that in group 1, the ischemic times to the right and left lungs were designed to be 3 and 6 hours, respectively (currently accepted ischemic intervals in human lung transplantation) [2–4], and in group 2, the ischemic times were 18 and 21 hours, respectively.

The donors were premedicated with subcutaneous atropine sulfate (0.5 mg) and ketamine hydrochloride (20 mg/kg) and anesthetized with intravenous thiamylal sodium (15 mg/kg). They then were intubated and placed on a mechanical ventilator using a tidal volume of 20 mL/kg, positive end-expiratory pressure of 5 cm H₂O, a respiratory rate of 15 breaths per minute, and an inspired oxygen fraction of 1.0. A femoral arterial monitoring line was inserted and a 5F Swan-Ganz catheter (Baxter Healthcare Corporation, Edwards Division, Irvine, CA) was positioned into the main pulmonary artery through the femoral vein. Systemic, pulmonary artery, and central venous pressures were recorded. Cardiac output was determined in triplicate by the thermodilution method. Arterial blood gas analysis was made.

After the assessment of donor lung and cardiac function, median sternotomy was made. The donor lung excision was performed by means of previously described techniques [5]. Before the excision, the tidal volume was increased to 35 mL/kg and the positive end-expiratory pressure was decreased to 0 cm H₂O. Both donor lungs were then flushed in situ with low-potassium dextran glucose solution [1] (4°C, 50 mL/kg) by means of a cannula placed in the main pulmonary artery while the flushing pressure was continuously monitored from a side arm of the cannula. Simultaneous topical cooling was achieved by immersing the lungs in cold saline (1° to 4°C). At the completion of the flush, the trachea was stapled, leaving the lungs well-inflated with 100% oxygen (35 mL/kg). The double-lung block was excised and placed in a sterile plastic bag containing cold low-potassium dextran glucose solution, then preserved at 8°C for a designed preservation period.

The recipient animals were sedated, anesthetized, intubated, and ventilated as were the donors, with the exception that anesthesia was maintained during the subsequent procedure with a 40:60 mixture of nitrous oxide/oxygen and 0.5% to 1.0% halothane. Percutaneous insertion of a femoral artery catheter and a pulmonary artery catheter (5F Swan-Ganz catheter) through the femoral vein was then performed for monitoring during the procedure.

With the animals in the left decubitus position, the right pneumonectomy was performed through a lateral thoracotomy in the right fifth intercostal space. The interatrial groove was dissected to create a left atrial cuff for subsequent anastomosis. On a separate surgical table, the right and left donor lungs were separated and prepared for implantation. Because the right lung was implanted first, the left lung was returned to 8°C storage until it was required for implantation. The right lung implantation was performed with the order of anastomoses as follows: left atrium, pulmonary artery, bronchus. A chest drain was inserted and the chest was closed. The recipient dog then was turned from the left to right lateral decubitus position, and the left lung transplantation was performed in essentially the same fashion as was right lung transplantation. Because cardiopulmonary bypass was not used in this study, the recipient was totally dependent on the right transplanted lung during the left lung implantation. After closure of the left chest, the recipient animals were placed in the spine position and maintained on a ventilator for 12 hours, during which time arterial blood gas analysis and full hemodynamic assessment (systemic, pulmonary, and central venous pressures, along with cardiac output) were repeatedly made at intervals with the same setting of the ventilator as for the donor assessment. After the 12-hour period of posttransplantation assessment, they were weaned from the ventilator support and the chest tubes were removed. Once the animals showed satisfactory spontaneous ventilation, they were extubated.

The surviving recipients received FK506 (0.1 mg/kg) intramuscularly and prednisone (0.5 mg/kg) orally every day for immunosuppression. Penicillin G (1,200,000 U) and gentamicin (40 mg) were given intramuscularly every day. Arterial blood gases on room air and chest roentgenograms were obtained daily, and suspected rejection was treated with 250 mg of intravenous methylprednisolone. After death of each recipient, the transplanted lungs were examined macroscopically and histologically.

All results are presented as the mean ± 1 standard error of the mean. One-way analysis of variance with repeated measures was used to determine whether an overall difference existed in lung function between the two groups during the assessment period. When a difference was obtained, contrast was performed to determine where significant differences arose. Paired Student's t test was used to compare the results of donor and recipient. Statistical significance was accepted at the 95% confidence level, p less than 0.05.

All animals received 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'' published by the National Institutes of Health (NIH Publication 85-23, revised 1985).

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
For the two groups, the flushing time (group 1, 95 ± 14; group 2, 92 ± 8 seconds), flushing pressure (23.0 ± 1.1 and 20.8 ± 1.4 mm Hg), excision time (6.6 ± 0.3 and 7.6 ± 0.8 minutes), right lung implantation time (66.6 ± 4.8 and 60.8 ± 2.3 minutes), and left lung implantation time (64.6 ± 4.1 and 58.0 ± 2.9 minutes) were similar (p = not significant). In group 1, the mean ischemic time of the right lung was 3 hours, 9 minutes ± 28 minutes, and for the left lung it was 6 hours, 2 minutes ± 33 minutes. In group 2, they were 18 hours, 11 minutes ± 28 minutes and 21 hours, 6 minutes ± 21 minutes, respectively.

All 5 dogs (100%) in group 1 had successful BSLT without cardiopulmonary bypass. Five of 6 dogs (83%) in group 2 completed BSLT successfully; 1 dog died of lung edema during the left lung transplantation. Results from the 5 operative survivors in each group form the basis of this report.

Lung Function During the 12-hour Assessment Period
All 5 of the operative survivors in each group completed the 12-hour assessment with excellent lung function. The results of gas exchange and hemodynamics of the donor animals and surviving recipients during the 12-hour assessment period are shown in Table 1. Arterial oxygen tension (PaO₂) was not different between the two groups except at 6 hours and did not differ significantly from the donor value in both groups. Arterial carbon dioxide tension (PaCO₂) was stable in group 1, but it increased significantly in group 2 after 2 hours of reperfusion. However, PaCO₂ was not significantly different between the two groups except at 6 hours. Mean pulmonary artery pressure and mean central venous pressure were stable during the assessment period in both groups and did not differ significantly from the donor values. Mean arterial pressure and cardiac output were significantly lower in recipient than in donor; however, both mAP and CO were stable during the assessment period in both groups.

View larger version (133K): [in this window] [in a new window]   Fig 1. . Photomicrograph of the lung allograft of a dog in group 2 that died of unknown cause 12 hours after extubation. No overt sign of lung injury was seen. (Hematoxylin and eosin; original magnification, x100.)

View larger version (167K): [in this window] [in a new window]   Fig 2. . Chest roentgenogram of a recipient in group 2 3 days after bilateral single lung transplantation. No significant abnormalities are seen in lungs.

View larger version (16K): [in this window] [in a new window]   Fig 3. . Arterial oxygen tension (PaO2) on room air, arterial carbon dioxide tension (PaCO2), and respiratory rate (RR) of 2 recipients in group 2 after extubation. The 2 dogs survived for 7 and 8 days, respectively.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

We maintained the animal on a ventilator for 12 hours after BSLT and focused on the immediate graft function, as this period reflects the effects of preservation without any superimposed effects of rejection or infection. Five of 6 dogs (83%) in the 21-hour preservation group survived the BSLT procedure and showed excellent PaO₂ and stable pulmonary hemodynamics throughout the 12-hour assessment period. In particular, mean PaO₂ (the gold standard in terms of lung preservation quality) [9] of the 5 survivors was 604 ± 8 mm Hg at 12 hours. We lost 1 dog because of severe lung edema during the left lung implantation. However, none of the other 5 dogs showed PaO₂ levels of less than 550 mm Hg during the entire assessment period. It is difficult to explain why this large difference occurred in the same group. We suspect that we made an undetectable technical mistake in this particular 1 animal experiment. A significant increase of PaCO₂ was observed in the 21-hour preservation group. Because the PaCO₂ was measured with a fixed respiratory setting, the increase in PaCO₂ represented the decrease of transplanted lung compliance. However, the decrease of lung compliance did not seem to be fatal, as the survivors showed normal PaCO₂ after extubation.

Despite the fact that several parameters suggested excellent early graft function, the survival of the animals after extubation was modest. It is well known that dogs can rarely survive bilateral lung transplantation [10, 11] because of the dependence of their respiratory control on vagal innervation [12]. It is for this reason that primates have been used for heart-lung [13] and bilateral lung [14] experiments. About half of the dogs in this experiment died of unknown causes in an early postoperative period without any overt signs of lung injury macroscopically or histologically. We suspect that causes of death in these animals were related not to poor lung preservation, but rather to other factors such as extensive magnitude of operation, effects of denervation, and prolonged anesthesia (over 18 hours) because of the postoperative assessment. Survivors after extubation showed a stereotyped deep and slow respiratory pattern with a forceful expiratory effort due to the absence of reflexes normally originating in the lungs. However, we were fortunate to have 2 animals in the 21-hour preservation group survive more than a week, which allowed us to measure the graft function further. These 2 animals showed good arterial blood gases on room air until death, with a mean PaO₂ of 74 mm Hg and PaCO₂ of 35.9 mm Hg, respectively, at 5 days. Although the survival rate was relatively low, these results suggested that the present preservation method could provide good long-term graft function.

The lung is the only organ that can be preserved with a ready supply of oxygen through the airway. It has been demonstrated that lung cells are able to maintain aerobic metabolism utilizing the oxygen in the alveoli [15]. Based upon previous studies, our basic strategy for lung preservation was to maintain a minimum and optimal level of aerobic metabolism. For this reason, the present method consisted of three important elements: preservation solution (low-potassium dextrose glucose), inflation gas (100% oxygen 35 mL/kg), and preservation temperature (8°C).

Low-potassium dextran glucose solution is an extracellular fluid-type solution that contains phosphate buffer, glucose, and dextran. Several investigators have reported extracellular fluid-type solution to be superior to intracellular fluid-type solution for lung preservation [16, 17], although Puskas and co-workers [18] reported that there was no difference when prostaglandin E₁ was administered before pulmonary artery flush. A high concentration of phosphate buffer would show effective buffer action for carbon dioxide produced as a product of oxygen consumed. Glucose in the preservation solution is actively metabolized in the glycolytic pathway as well as in the citric acid cycle, and it improves lung preservation [1]. Dextran would function as an oncotic agent, tending to keep water in the intravascular compartment, thereby decreasing interstitial edema formation [19].

The oxygen concentration in the inflation gas and the degree of inflation are very important. Weder and co-workers [20] reported that preservation with 100% oxygen inflation appeared superior to inflation with room air and much superior to inflation with 100% nitrogen. There is recent evidence that the uses of large tidal volume during harvesting and hyperinflation during preservation provide superior preservation, although the mechanism of the beneficial effect has not been clearly demonstrated yet [21, 22]. Lungs were ventilated and hyperinflated with 100% oxygen at a volume of 35 mL/kg in the present study.

Optimal temperature for lung preservation has been demonstrated to be in the vicinity of 10°C [5, 23]. We preserved lungs at 8°C in the present study because we thought that metabolic rate was too fast at 10°C when the preservation time was more than 24 hours, according to the analysis of metabolites in the preserved lung tissue (unpublished data). Nakamoto and co-workers [24] reported optimal temperature to be at 8° to 9°C in a rabbit lung model.

We recognize that other methods of preservation [16, 21, 25] may be able to accomplish the same goal, and believe that the importance of this work is the demonstration that consistent, excellent, 21-hour lung preservation is achievable.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We gratefully acknowledge the advice received from Dr Joel D. Cooper, Barnes Hospital, St. Louis, MO. We are grateful to Tetsuo Kawakami for his expert technical assistance.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Date, Department of Surgery II, Okayama University Medical School, 2-5-1 Shikata cho, Okayama 700, Japan.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract 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): Nobuyoshi Shimizu Shigeru Teramoto Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Date, H. Articles by Teramoto, S. Search for Related Content PubMed PubMed Citation Articles by Date, H. Articles by Teramoto, S.