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Ann Thorac Surg 2006;81:460-466
© 2006 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
b Department of Thoracic Anaesthesia, Sahlgrenska University Hospital, Gothenburg, Sweden
c Department of Cardiothoracic Surgery, Lund University Hospital, Lund, Sweden
Accepted for publication August 15, 2005.
* Address correspondence to Dr Wierup, Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, SE-413 85 Göteborg, Sweden (Email: pwi{at}sks.aaa.dk).
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Abstract |
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METHODS: The lungs are perfused ex vivo with Steen solution, a lung evaluation–preservation solution, mixed with red blood cells to a hematocrit of 15%. This extracellular solution is designed to have an optimal colloid osmotic pressure so that physiologic pressure and flow can be maintained without development of pulmonary edema. An oxygenator connected to the extracorporeal circuit maintains a normal mixed venous blood gas level in the perfusate. The lungs are ventilated and evaluated through analyses of pulmonary vascular resistance, oxygenation capacity, and arterial carbon dioxide pressure minus end-tidal carbon dioxide difference.
RESULTS: The arterial oxygen pressure (inspired oxygen fraction, 1.0) increased from 27 kPa (range, 17 to 34 kPa) in situ in the organ donor at the referring hospital to 57 kPa (range, 39 to 66 kPa) during the ex vivo evaluation. The pulmonary vascular resistance varied from 3.2 to 5.7 Wood units, and the arterial carbon dioxide pressure minus end-tidal carbon dioxide difference was in the range of 1 to 2.5 kPa.
CONCLUSIONS: The arterial oxygen pressure improves significantly in this model. This ex vivo evaluation model is a valuable addition to the armamentarium in finding acceptable lungs in a donor population with inferior arterial oxygen pressure values.
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Introduction |
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A new method for ex vivo lung evaluation was developed and used for the first time in humans when a lung from a non–heart-beating donor was transplanted by Steen and colleagues in Lund, Sweden, in 2000 [3]. The method, which has been described in detail elsewhere [4], can also be used for reconditioning of marginal and nonacceptable donor lungs. This is the result from our initial evaluation of six donor lungs that were found nonacceptable for transplantation by the Scandiatransplant, Eurotransplant, and UK transplant organizations.
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Material and Methods |
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Lung Donors
From February through May 2004 nonacceptable lungs from six organ donors (3 men, 3 women) from western Sweden were evaluated (Table 1). The donor ages varied from 44 to 66 years. Five died of a spontaneous intracerebral bleeding and 1 of a traumatic intracranial bleeding. All donors were rejected for lung donation because of arterial oxygen partial pressure (PaO
2) values less than 40 kPa measured after 5 minutes with an inspired oxygen fraction (FIO
2 of 1.0 and a positive end-expiratory pressure (PEEP) of 5 cm H2O. All lungs were found nonacceptable for transplantation by the Scandiatransplant, Eurotransplant and UK transplant organizations. Three of the donors had a heavy smoking history. Immediately before harvest, epoprostenol (Flolan 20 ng/kg; GlaxoSmithKlein UK, Middlesex, UK) was given until an arterial blood pressure reduction of 30% was obtained. At harvest, the lungs were perfused through the pulmonary trunk with cold Perfadex (Vitrolife, Gothenburg, Sweden; 60 mL/kg) and subsequently stored at 4°C in Perfadex during transport and preparation of the ex vivo evaluation model. In five of the donors the heart and lung package was taken out en bloc and in one case the heart was used for transplantation.
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The pulmonary artery cannula was connected to the corresponding tube of the extracorporeal circuit, the air was removed, and the shunt of the circuit was clamped (Fig 1). A low-flow perfusion (100 mL/min) at 25°C was initiated through the lungs. The first 200 mL of blood coming out of the cannula in the left atrium was discarded, and then the cannula was connected to the circuit.
Ex Vivo Assessment of Donor Lung Function
The lungs were gradually warmed by increasing the temperature of the evaluation solution, and when the temperature of the solution coming out of the left atrium was 32°C, careful ventilation (1 L/min) was started. The pump flow was gradually increased, but the pulmonary artery pressure was never allowed to exceed 20 mm Hg. Experiments in 60-kg pigs have shown that if the pulmonary artery pressure is kept at 20 mm Hg or less, perfusion with Steen solution can be done at 4 L/min for 8 hours without edema formation (unpublished data). If a flow of 4 L/min was reached before the pulmonary artery pressure reached 20 mm Hg, it was fixed at that rate. When the temperature of the solution coming out of the left atrium was 37°C, normal ventilation (100 mL · kg–1
· min–1) was given, and the PEEP was temporarily increased to get rid of atelectases. Then the ventilation was fixed at 100 mL · kg–1
· min–1, with a PEEP of 5 cm H2O and a rate of 16 breaths/min. When steady state was reached, blood gases and hemodynamics were registered. Blood gases were taken at FIO
2 of 0.5, 1.0, and 0.21. If the arterial carbon dioxide partial pressure (PaCO
2) minus the end-tidal carbon dioxide (ETCO
2) difference exceeded 1.0 and the pulmonary artery pressure was less than 20 mm Hg, hypoperfusion of the lungs was suspected, and the perfusion flow was gradually increased until the pulmonary artery pressure reached 20 mm Hg, after which new measurements were made. Finally, the FIO
2 was set to 0.5, and after new steady-state values had been registered, nitric oxide (NO) was administered by inhalation at 40 ppm, and new measurements were made at steady state.
The following variables were assessed: PaO 2, PaCO 2 PaCO 2 – ETCO 2, pulmonary vascular resistance (PVR), and PVR response to NO inhalation. Pulmonary vascular resistance was calculated as the mean pulmonary arterial pressure minus left atrial pressure divided by the pulmonary blood flow.
Histology and Cultures
After ex vivo evaluation the lungs were subjected to a standard histologic examination. Samples were taken for bacterial and fungal culture from the transportation medium, the solution in the evaluation box, and the donor lung bronchus.
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Results |
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TopAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Gas-Exchange Capacity
The median PaO
2 obtained in situ in the organ donor at the referring hospital was 27 kPa (range, 17 to 34 kPa) at an FIO
2 of 1.0 with a PEEP of 5 cm H2O. At steady state, during the ex vivo evaluation the median PaO
2 was 56 kPa (range, 39 to 66 kPa) at an FIO
2 of 1.0. (See Table 2
for individual changes in PaO
2 values at different FIO
2). The median PaCO
2 was 4.8 kPa (range, 4.1 to 5.4 kPa). The PaCO
2 – ETCO
2 difference ranged from 1 to 2.5 kPa (Table 3).
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Effect of NO Inhalation
Inhalation of NO did not affect the PVR significantly (Table 3). The mean PVR changed from 4.79 to 4.97 Wood units after administration of NO at 40 ppm.
Histology
Five of the six lungs showed varying degrees of focal bronchopneumonia.
Cultures
Bronchial cultures were positive for microorganisms in all donors, and five of six transportation medium cultures were positive. However, only one culture from the ex vivo evaluation box was positive (see Table 4).
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Comment |
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All the lungs in this study were rejected for transplantation because of inadequate blood gas values. All lungs had been subjected to extensive donor optimization, including airway and alveolar recruitment procedures and optimal fluid management, before being turned down for transplantation. With the ex vivo evaluation model used in the present study, all but one of these lungs met the blood gas criteria for acceptance, and the model therefore has the potential to increase lung donor availability.
It is important to be able to evaluate lungs ex vivo without edema formation. As mentioned above, the high colloid osmotic pressure of the evaluation solution allows it to be used for at least 8 hours without edema formation, and in fact the solution may have the potential to "dry up" wet lungs. The prerequisite is that the perfusion is done at normothermia with an adequate perfusion solution and a perfusion pressure of less than 20 mmHg. Cold perfusion creates a high PVR, which should be avoided. Similarly, it is of utmost importance that reperfusion after an ischemic period is carefully controlled [6]. Sudden uncontrolled reperfusion with an increased microvascular hydrostatic pressure may result in additional mechanical trauma to the already damaged vascular endothelium, and furthermore may lead to hydrostatic edema [7, 8]. With the ex vivo evaluation model we can gradually and gently rewarm and reperfuse the lungs. It also enables us to have a perfect inspection of the whole lungs, and consequently to reexpand persistent atelectases by means of manual ventilation and manipulation. Furthermore, antibiotics can be added to the evaluation solution to treat any infection without the risk of secondary organ dysfunction.
The PaO 2 showed a significant improvement already after 10 minutes of normothermic ex vivo reperfusion, compared with the best values measured in situ in the donor. This can be explained by removal of persistent atelectases and mobilization and removal of interstitial and alveolar fluid by the high colloid osmotic pressure of the evaluation solution. It is true that the normal physiologic shunt from the bronchial circulation is not present ex vivo, but this cannot explain the significant improvement in oxygenation. In a pig model in which exactly the same system was used as in the present study, the difference in PaO 2 in situ versus ex vivo was only 3 mm Hg, and there is no reason to believe that a human lung should behave differently [4].
Besides the blood gases and PVR, a valuable measurement to follow during ex vivo evaluation is the difference between PaCO 2 and ETCO 2 [9, 10]. In vivo, this is a sensitive test for obstructive pulmonary artery disease, eg, pulmonary embolism. With a good perfusion of the lungs ex vivo, this difference should not be very large. If the difference is greater than 1 kPa, the PEEP should be temporarily increased to get rid of possible atelectases, a perfusion flow creating a perfusion pressure of 20 mm Hg should be used, and the ventilation should be adjusted to match the flow. If the gradient is not reduced by this procedure, and the PVR is high, pulmonary artery emboli should be suspected and ruled out. The gradient between PaCO 2 and ETCO 2 was relatively high in most cases, which suggests a ventilation–perfusion mismatch. There is a possibility that this was because the perfusion was too low, or that it was the result of vasoconstriction of intermediate or small diameter pulmonary arterial branches in some areas of the lungs, even though prostacyclin was given before harvesting of the lungs. The minimal effect of NO ventilation on PVR argues against selective vasoconstriction, and furthermore, all the donor lungs were fully heparinized. Another explanation could be technical difficulties with the gas mixture delivery to the oxygenator, particularly with regard to carbon dioxide. To overcome this problem, the carbon dioxide can be administered from a gas tube with a constant concentration of carbon dioxide in nitrogen, eg, 6%. The first patient who received a lung from a non–heart-beating donor had a gradient between PaCO 2 and ETCO 2 of 1.45 with an FIO 2 of 0.5 and 2.63 with an FIO 2 of 1.0 during the ex vivo functional evaluation of the donor lungs; the mean pulmonary arterial pressure was only 12 mm Hg, and the left atrial pressure was –1 mm Hg with a flow of 4.0 L/min, giving a PVR of 3 Wood units. This donor lung was transplanted and had an excellent function from the very beginning of reperfusion [3]. Thus, a high gradient between PaCO 2 and ETCO 2 combined with a PVR of 4 to 5 Wood units or lower does not necessarily mean that lungs should not be accepted for transplantation.
The same ventilatory settings should be used when comparing blood gas values in situ and ex vivo, and the ETCO 2 value should be noted when the in situ blood gases are obtained. If these values are not known, a ventilation volume of 100 mL/kg body weight of the donor and a perfusion flow of 70 mL · kg–1 · min–1 may be used as a standard. If such a perfusion flow cannot be achieved with a mean pulmonary pressure of approximately 20 mm Hg, the PVR should be evaluated in the donor lungs, ensuring that the perfusion is done at normothermia, and the hematocrit in the evaluation solution is kept at approximately 15% ± 3%. If one lung looks bad, the better-looking lung can be tested alone by clamping the main bronchus, the pulmonary artery, and the veins of the bad lung, thereby excluding it from the circulation. In this case the ventilatory settings and perfusion flow should be reduced in proportion to the excluded lung volume. If both lungs look good but the PaO 2 is borderline for acceptance (<40 kPa), each lung should be tested separately in the above-mentioned way.
The PVR is dependent on the hematocrit of the solution, and on the temperature at which the perfusion is run. Cold perfusion with a high hematocrit gives a high PVR. Because the perfusion is given with a continuous flow, a higher mean pulmonary arterial pressure is obtained than if a physiologic pulsatile flow had been used. In fresh porcine lungs from 60-kg animals, the PVR in vivo at normothermia with a hematocrit of 30% is approximately 2 Wood units. When the same lungs are perfused ex vivo at normothermia with a hematocrit of approximately 15%, the PVR is around 4 Wood units, ie, it doubles in spite of the reduction in hematocrit [4]. Thus, the PVR values obtained in this study should be interpreted as within normal range.
Five of the six lungs showed varying degrees of focal bronchopneumonia on histologic examination. Interpretation and quantification of histologic changes in lung parenchyma are difficult and should always be correlated to the gas exchange capacity, as it is questionable whether the parts of the lung examined (in each case) are representative of the whole lung. Moreover, the histopathologic appearance of donor lungs at the time of retrieval has not been well studied. Interestingly, in a small study by Sole-Violan and associates [11] of nine brain-dead organ donors without clinical evidence of pulmonary infection and not on antibiotic therapy, histologic features of bronchopneumonia were seen in open-lung biopsy specimens in 7 patients (78%).
All bronchial cultures were positive for a variety of microbes. The clinical significance of a positive bronchial culture in the donor is unclear. Avlonitis and coworkers from the Newcastle group [12] found bacterial colonization of the lower airways of the donor lung to be a predictor of poor outcome, whereas several other studies found no such correlation [13–15].
Steen and colleagues [4] have performed large animal studies using this evaluation procedure and subsequently transplanted the left lung followed by contralateral pneumonectomy. All transplanted animals were in excellent condition throughout the postoperative period. We believe that this technique is safe enough to allow progression toward clinical transplantation of reconditioned lungs. The method used in this study to evaluate the lung function ex vivo was used clinically for the first time when a lung was transplanted from a non–heart-beating donor patient [3].
In normal clinical lung transplantation, poor posttransplantation function remains a major problem, with significantly impaired function in 10% to 20% of cases [16]. It is of utmost importance to identify these lungs in advance, especially when using marginal donors. This model may be a tool in the evaluation process for marginal donors as well as lungs from non–heart-beating donors. Furthermore, with this evaluation model it is possible to increase the time between harvest and transplantation and thereby improve the possibility to select a convenient time for the transplantation. Among other things this will allow optimization of donor-recipient matching, for example with HLA.
We believe that this ex vivo evaluation model is a valuable addition to the armamentarium in finding acceptable lungs in a donor population with inferior PaO 2 values. As always, donor selection comes down to good clinical judgment based on all available data. On the basis of this study, we now intend to proceed with transplantation of suitable reconditioned donor lungs in humans.
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