Comparative outcome of double lung transplantation using ...

ARTICLE IN PRESS doi:10.1510/icvts.2010.244830

Interactive CardioVascular and Thoracic Surgery 12 (2011) 162–165 www.icvts.org

Institutional report - Transplantation

Comparative outcome of double lung transplantation using conventional donor lungs and non-acceptable donor lungs reconditioned ex vivo Sandra Lindstedta,*, Joanna Hlebowiczb, Bansi Koula, Per Wierupa, Johan Sjo ¨grena, Ronny Gustafssona, Stig Steena, Richard Ingemanssona Department of Cardiothoracic Surgery, Heart and Lung Centre, Lund University Hospital, SE-221 85 Lund, Sweden b Department of Medicine, Malmo ¨ University Hospital, Malmo ¨, Sweden

a

Received 30 June 2010; received in revised form 1 November 2010; accepted 4 November 2010

Abstract A method to evaluate and recondition lungs ex vivo has been tested on donor lungs that have been rejected for transplantation. In the present paper, we compare early postoperative course between the six patients who received reconditioned lungs and the patients who received conventional donor lungs during the same period of time. During 2006 and 2007, a total of 21 patients underwent double sequential lung transplantation at the University Hospital of Lund. Six of those patients received reconditioned lungs. The other 15 patients received conventional donor lungs for transplantation without reconditioning ex vivo. The results are presented as median and interquartile range. Time in intensive care unit (days) between recipients of reconditioned lungs w13 (5–24) daysx, and recipients of conventional donor lungs w7 (5–12) daysx, Ps0.44. Total hospital stay after transplantation (days) between recipients of reconditioned lungs w52 (47–60) daysx and recipients of conventional donor lungs w44 (37–48) daysx, Ps0.9. Ex vivo lung evaluation and reconditioning might not prolong early postoperative course in double lung transplantation. However, given the small number of patients, there might be a failure to detect a difference between the two groups. 䊚 2011 Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Double lung transplantation; Reconditioned lungs; Clinical outcome

1. Introduction Steen and colleagues have developed a new method for ex vivo lung evaluation, which was used successfully for the first time in humans, when a lung from a non-heartbeating donor was transplanted by the same team at the cardiothoracic surgery department at Lund University Hospital, Sweden, in 2000. The method has earlier been described in detail w1, 2x, and can also be used for reconditioning of marginal and non-acceptable donor lungs. The method increases the number of potential lungs for transplantation. We have recently reported the results of the first six double lung transplantations performed with donor lungs reconditioned ex vivo that were rejected for transplantation by the Scandia-transplant, Euro-transplant, and UKtransplant organizations. The six patients were transplanted between 2006 and 2007. Three-month survival was 100%. One patient has since died from sepsis after 95 days, and one from rejection after nine months. Four patients are alive and well without any sign of bronchiolitis obliterans syndrome two years after transplantation w3x. *Corresponding author. Tel.: q46 46 173803; fax: q46 46 158635. E-mail address: [email protected] (S. Lindstedt). 䊚 2011 Published by European Association for Cardio-Thoracic Surgery

During 2006 and 2007, a total of 21 patients underwent double sequential lung transplantation at the University Hospital of Lund. Six of those patients received initially rejected donor lungs after reconditioning ex vivo (referred to as reconditioned lungs), as reported above. The other 15 patients received conventional donor lungs for transplantation without reconditioning ex vivo (referred to as conventional donor lungs). It has been proposed that patients who received reconditioned lungs require more time on the ventilator, more days in the intensive care unit (ICU), and a significantly longer hospital-stay postoperatively compared to patients who receive conventional donor lungs. In the present paper, we compare early postoperative course between the patients who received reconditioned lungs and the patients who received conventional donor lungs during 2006 and 2007. 2. Materials and methods 2.1. Ex vivo lung reconditioning Fig. 1 shows the perfusion circuit. A 28-Fr venous cannula was placed with its tip in the proximal left pulmonary artery through the proximal part of the right pulmonary artery. The stump of the pulmonary trunk was over-sewn.

ARTICLE IN PRESS S. Lindstedt et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) 162–165

ESCVS Article Proposal for Bailout Procedure Negative Results Follow-up Paper State-of-the-art Best Evidence Topic Nomenclature Historical Pages Brief Case Report Communication

2.3.1. Patients transplanted with initially rejected donor lungs after reconditioning ex vivo All double lungs had -40 kPa during ventilation at 100% oxygen, and end-expiratory pressure at 5 cm H2O. The criteria for lungs chosen to undergo reconditioning were the same as for ordinary donor lungs except that lungs with lower partial pressure of oxygen in arterial blood (PaO2) values were accepted. To be accepted for transplantation,

Institutional Report

2.3. Transplantation

Protocol

When reconditioning and evaluation were completed, the temperature of the ingoing perfusate was reduced to 25 8C, and when temperature had stabilized, the perfusion was stopped. The pulmonary artery cannula and the trachea were clamped with the lungs in a semi-inflated state (FiO2s1.0). The lungs were then immersed in the perfusate, to which a buffered Perfadex solution was added. The extracorporeal circuit was then used to perfuse the solution in the box containing the immersed lungs, keeping that medium oxygenated and cooled to 8 8C w3x.

Work in Progress Report

2.2. Topical extracorporeal membrane oxygenation (ECMO)

New Ideas

A baby feeding catheter was placed in the pulmonary artery to measure the perfusion pressure. During the reconditioning, the perfusion solution flowed directly out into the lung reconditioning box. Therefore, left atrium pressure was always zero. The extracorporeal perfusion circuit (Ex Vivo Lung Evaluation Set) was delivered by Medtronic (Medtronic Nederland, Kerkrade, The Netherlands). The system was primed with 2 l of STEEN solution (Vitrolife AB, Lund, Sweden), mixed with two units of ABO-compatible erythrocyte concentrate that had been irradiated, leukocytefiltered and washed. STEEN solution is a physiological electrolyte solution containing human serum albumin and dextran to keep a high-colloid osmotic pressure. Imipenem (0.5 g, Tienam, Merck Sharp & Dohme, Sollentuna, Sweden), insulin (20 IU, Actrapid, Novo Nordisk, Bagsvaerd, Denmark), and heparin (10,000 IU, Leo Pharma, Malmo ¨, Sweden) were added, and isotonic trometamol (AddexTham, Kabi, Sweden) was used to buffer the mixed solution to a temperature-adjusted pH of 7.4. Gas was supplied to the membrane oxygenator, first oxygen and CO2 during the reconditioning phase, and then 93% N2 and 7% CO2 during the testing phase, mimicking a normal venous blood gas in the perfusate to the pulmonary artery (i.e. the oxygenator is used to deoxygenate the perfusate). Before the perfusion was started, 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). After removing the air from the pulmo-

nary artery, a slow perfusion (perfusion pressure -20 mmHg) was started at 25 8C. The initial perfusion flow was approximately 100 mlymin. The flow was slowly increased, and the pulmonary pressure was kept at 15– 20 mmHg. The temperature in the perfusate was gradually increased to 37 8C during the next 15 min. The gases to the oxygenator were mixed to get perfusate gas values (temperature corrected) of PO2f15 kPa and PCO2f5 kPa. After 20 min, the temperature of the perfusate from the lung was 37 8C. The end-expiratory pressure was kept at 5 cm H2O, except when it was increased temporarily to 10 cm H2O, then the atelectasis in the mediobasal segment disappeared. Ten minutes later, the ventilation was fixed at 3.5 lymin (i.e. half of 100 mlykg, the estimated optimum for two lungs, 12 breathsymin) and the perfusion flow was kept at 2.5 lymin (fhalf of 70 mlykg). During the next 20 min, with stable ventilator settings and perfusion flow, the pulmonary artery pressure decreased from 12 mmHg to 7 mmHg, where it stabilized. The gas mixture to the oxygenator was now shifted to 7% CO2 and 93% N2. The ventilation was regulated according to PCO2, kept between 4.0 kPa and 4.5 kPa. At this point, the flow was kept at 5.5 l. Blood gases of the perfusate were taken before and after passing through the lung after 10 min exposure of FiO2 of 0.5, 1.0, and 0.21, respectively. Then a collapse test was done, which consists of observing the lung after a sudden disconnection of the endotracheal tube from the ventilator. In a normal lung, the whole lung should collapse (global atelectasis). We deemed the collapse test to be normal and judged the lung acceptable for transplantation in spite of the bleeding spots still present in the lower lobe w1–4x. This method has been approved by the Ethics Committee at Lund University. The duration of reconditioning in ex vivo circuit was between 1.5 h and 2.0 h. Evaluation was stopped when the lungs reached 37 8C, and PCO2 was between 4.0 kPa and 4.5 kPa.

Editorial

Fig. 1. The figure shows a schematic drawing of the ex vivo lung reconditioning system. The cannulation is performed through a piece of aorta (A) harvested from the donor and used to elongate the pulmonary artery. The blood coming out from the remaining dorsal part of the left atrium (LA) runs freely out in the box. Pulmonary arterial pressure (PAP) is measured continuously.

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Table 1. The recipients of reconditioned lungs (ns6)

1 2 3 4 5 6

Sex

Age (years)

Diagnosis

ECMO preoperative (min)

ECC perioperative (days)

ECMO postoperative (days)

Reintubation (occasions)

Female Male Male Female Female Male

54 53 55 64 35 63

COPD Lung fibrosis

– – – – – –

– 31 – – 365 –

– – – – – 42

– 3 – 2 2 –

COPD CF COPD

ECMO, extracorporeal membrane oxygenation; ECC, extracorporal circulation; COPD, chronic obstructive pulmonary disease; CF, cystic fibrosis. Table 2. The recipients of traditionally accepted lungs (ns15) Sex

Age (years)

Diagnosis

ECMO preoperative (min)

ECC perioperative (days)

ECMO postoperative (days)

Reintubation (occasions)

1 2

Female Female

62 59

– –

– Yes

– 2

– –

3 4 5 6 7 8 9 10 11 12 13 14 15

Male Male Male Female Male Female Female Female Female Female Male Female Male

47 36 34 29 22 52 66 55 53 41 37 24 23

COPD Pulmonary hypertension Lung fibrosis CF CF CF CF COPD COPD COPD COPD Emphysema CF CF CF

Yes – – – – – – – – – – – –

327 Yes 331 259 – – – – 81 – 134 287 –

9 16 – – – – – – – – 28 – –

– – – – – 2 – – – – 2 – –

ECMO, extracorporeal membrane oxygenation; ECC, extracorporal circulation; COPD, chronic obstructive pulmonary disease; CF, cystic fibrosis.

the PaO2 on fraction of inspired oxygen (FiO2 )s1.0 had to be 50 kPa or higher after reconditioning. The method is described in detail elsewhere w1, 2x. All relevant data of the recipients are given in Table 1. 2.3.2. Patients transplanted with conventional donor lungs without reconditioning ex vivo Fifteen patients underwent double sequential lung transplantation with conventional donor lungs without reconditioning ex vivo. All relevant data of the recipients are given in Table 2.

initially, but on postoperative day 2 developed septicemia. He never recovered but died after 95 days because of multiorgan failure. He was on ECMO for 42 days, postoperatively. He had a remarkably long total ischemic time on the donor lungs (right lung 17 h and 18 min and left lung 21 h and 26 min), which may have affected the results.

3. Calculations and statistics Calculations and statistical analysis were performed using GraphPad 4.0 software (San Diego, CA, USA). Statistical analysis was performed using Mann–Whitney test. A level of P-0.05 was considered statistically significant, and P)0.05 was considered not significant (n.s.). Values are shown as median (50th percentile) and the interquartile range (25th and 75th percentiles). 4. Results All recipients of double lung transplantation during the year 2006 and 2007 at Lund University Hospital, despite the diagnosis of the recipients of reconditioned lungs (ns6), and recipients of conventional donor lungs (ns15). Early postoperative data are shown in Figs. 2 and 3. Tables 1 and 2 show data of all the recipients. Recipient no. 6 in Table 1 was a man who had good lung function

Fig. 2. The figure shows total cold ischemic time for all donors. The boxes show the median and the interquartile range.


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Negative Results Follow-up Paper State-of-the-art Best Evidence Topic Nomenclature

w1x Steen S, Sjo ¨berg T, Pierre L, Liao Q, Eriksson L, Algotsson L. Transplantation of lungs from a non-heart-beating donor. Lancet 2001;357:825– 829. ˚ , Nilsson F, Pierre L, Scherste w2x Wierup P, Haraldsson A ´n H, Silverborn M, Sjo ¨berg T, Westfeldt U, Steen S. Ex vivo evaluation of nonacceptable donor lungs. Ann Thorac Surg 2006;81:460–466. w3x Ingemansson R, Eyjolfsson A, Mared L, Pierre L, Algotsson L, Ekmehag B, Gustafsson R, Johnsson P, Koul B, Lindstedt S, Lu ¨hrs C, Sjo ¨berg T, Steen S. Clinical transplantation of initially rejected donor lungs after reconditioning ex vivo. Ann Thorac Surg 2009;87:255–260. w4x Steen S, Ingemansson R, Eriksson L, Pierre L, Algotsson L, Wierup P, Liao Q, Eyjolfsson A, Gustafsson R, Sjo ¨berg T. First human transplantation of a nonacceptable donor lung after reconditioning ex vivo. Ann Thorac Surg 2007;83:2191–2194.

Proposal for Bailout Procedure

A new method for ex vivo lung evaluation has been developed by Steen and colleagues, which was used successfully for the first time in humans at Lund University Hospital, Sweden, in 2000. Further progress has been made since w1, 2x, and the method is now used for reconditioning of marginal and non-acceptable donor lungs. We have recently reported the results of the first six double lung transplantations performed with donor lungs reconditioned ex vivo that were rejected for transplantation because of insufficient arterial oxygen tension by the Scandia-transplant, Euro-transplant, and UK-transplant organizations. Three-month survival was 100% w3x.

References

ESCVS Article

5. Discussion

Institutional Report

Fig. 3. The figure shows the results for all the recipients for double lung transplantation during the year 2006 and 2007 at Lund University Hospital, Sweden. (a) Shows ventilator time, (b) shows intensive care unit (ICU) time, (c) represents the values for in-ward time, (d) represents the values for the total hospital stay. The boxes show the median and the interquartile range.

There was no difference between time on a ventilator, ICU time, in-ward time, and total hospital stay between the recipients of reconditioned lungs and recipients of conventional donor lungs. However, a longer study period in a larger number of patients is needed before the method of reconditioning donor lungs ex vivo becomes routine.

Protocol

7. Conclusion

Work in Progress Report

The present study shows a relatively small number of patients. There were no statistical differences between the two groups. However, given the small numbers of patients and the wide interquartile range, there might be a failure to detect a difference between the two groups.

New Ideas

6. Study limitations

Editorial

In the present study, we compared the results between recipients of reconditioned donor lungs and recipients of conventional donor lungs during 2006 and 2007 at Lund University Hospital, Sweden. No difference could be observed between the two groups in respect to the time they were on a ventilator. The recipients of reconditioned lungs required slightly more reintubations because of postoperative respiratory failure than the recipients of conventional donor lungs. From clinical experience during the study, we learned that it was necessary for the recipients of reconditioned lungs to lose half the excessive fluid gained during surgery before they could be extubated successfully. Interestingly, there was no difference between the two groups in respect to the time they spent in the ICU and in the ward after the transplantation.

Historical Pages Brief Case Report Communication