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Use of Extracorporeal Membrane Oxygenation as a Bridge to Primary Lung Transplant: 3 Consecutive, Successful Cases and a Review of the Literature
BEAUTY OF BREVITY
Use of Extracorporeal Membrane Oxygenation as a Bridge to Primary Lung Transplant: 3 Consecutive, Successful Cases and a Review of the Literature Andrew Jackson, MBBS, Jonathan Cropper, MSc, Roger Pye, MBBS, Frank Junius, MBBS, Monique Malouf, MBBS, and Allan Glanville, MBBS, MD Many transplant centers have considered extracorporeal membrane oxygenation (ECMO) to be a contraindication to lung transplantation, due to historically poor outcomes. However, recent advances in the technical aspects of ECMO have enabled patients to be supported with relative safety for several weeks until a donor lung becomes available. We present 3 young patients with acute (in 1 case, acute on chronic), severe respiratory failure that was refractory to conventional ventilation, who were placed on venovenous ECMO. In each case, a clinical decision was made that the patient’s respiratory failure was irreversible and they were successfully managed with urgent lung transplantation. J Heart Lung Transplant 2008;27:348 –52. Copyright © 2008 by the International Society for Heart and Lung Transplantation.
Extracorporeal membrane oxygenation (ECMO) is an increasingly utilized therapy for adults with acute, severe respiratory failure that is refractory to conventional ventilation. ECMO is now a recognized rescue therapy for severe primary graft dysfunction after lung transplantation.1 A recent review of the Extracorporeal Life Support Organization registry showed 151 cases with a 42% survival to hospital discharge.2 However, reports on the use of ECMO as a bridge to lung transplant are isolated, and the outcomes remain mixed. Many centers have considered ECMO to be a contraindication to lung transplantation. However, considering recent technological advances, we have found that patients can now be maintained on ECMO with relative safety for up to 4 to 6 weeks. This allows a reasonable time period for a donor lung to become available should the patient be listed for lung transplantation. We present 3 consecutive, successful cases in which ECMO was used as a bridge to primary lung transplant. CASE REPORTS Over the last 5 years there have been approximately 45 patients in our transplant center’s catchment area with From the Department of Anaesthetics, St Vincent’s Hospital, Sydney, Australia. Submitted September 15, 2007; revised December 18, 2007; accepted December 18, 2007. Reprint requests: Andrew Jackson, MBBS, Department of Anaesthetics, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, Sydney 2010, Australia. Telephone: 006-102-9713-6473. Fax: 006-1028382-3981. E-mail: [email protected] Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2007.12.006
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acute, severe respiratory failure who were treated with ECMO. Our lung transplant physicians were asked by the referring hospitals to consider listing 7 of these patients for lung transplantation. Of these, 3 were not listed due to medical contraindications and 4 were listed for urgent lung transplantation. One of the patients was later de-listed due to recovery of lung function. The remaining 3 patients underwent urgent lung transplantation at the referring hospital. In each case, our hospital’s transplant team traveled to the referring hospital to perform the operation as it was not possible to transport patients on ECMO at that time. Case 1 A previously well 15-year-old boy presented with influenza B complicated by severe Staphylococcus aureus pneumonia. After 6 days of conventional ventilation, the patient remained severely hypoxic, with PaO2/FIO2 (P/F) ratios of 35 to 40, and he was placed on venovenous (VV) ECMO. The use of ECMO corrected the hypoxia and his condition stabilized. His severe respiratory failure persisted while on ECMO, but he did not develop failure of other organ systems. After 17 days of ECMO, a clinical decision was made that the patient’s respiratory failure was irreversible and he was listed for an urgent lung transplant. After 28 days of ECMO, he underwent bilateral sequential lung transplantation (BSLTx). The early post-operative course was complicated by severe bleeding, requiring re-operation and massive transfusion. He was slow to wean from the ventilator due to a profound myopathy, requiring a tracheostomy and 34 days of ventilation after transplant. Further complications included several seizures in the early post-operative period and a transient cranial nerve III palsy. He was discharged from the hospital 104
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days after initial admission. At 12 months, he had near-normal exercise tolerance and no long-term complications. He remains alive at 5 years 2 months. Case 2 A previously well 18-year-old man presented with influenza complicated by severe Candida albicans pneumonia. Conventional ventilatory techniques were able to prevent hypoxia but progressive hypercarbia developed. After 7 days of conventional ventilation, PaCO2 reached 165 mm Hg and he was placed on VV ECMO. The use of ECMO corrected the hypercarbia and his condition stabilized. The patient required hemodialysis while on ECMO to correct acute hyperkalemia, but no other organ dysfunction occurred. The patient was listed for an urgent lung transplant after 5 days of ECMO when a clinical assessment was made that his respiratory failure was irreversible. After 10 days of ECMO the patient underwent BSLTx. The early post-operative course was complicated by moderate primary graft dysfunction (requiring an FIO2 up to 0.7), and severe bleeding, requiring re-operation and massive transfusion. He was slow to wean from the ventilator, requiring a tracheostomy and 26 days of ventilation after the transplant. He also had several seizures in the early post-operative period that were most likely due to cyclosporine. He was discharged from the hospital 65 days after admission. At 12 months, he had normal exercise tolerance and no long-term complications. He remains alive at 3 years 11 months. Case 3 A 26-year-old man with a background of end-stage, non-specific interstitial lung disease awaiting lung transplantation presented with an acute decompensation due to acute respiratory distress syndrome (ARDS) from urinary tract sepsis. After 24 hours of conventional ventilation he developed severe hypoxia, with a P/F ratio of 40, and he was placed on VV ECMO. This corrected the hypoxia and his condition stabilized. There was no improvement in respiratory failure while on ECMO, but he did not develop failure of other organ systems. As the patient was already listed for lung transplantation, and weaning from ECMO was considered very unlikely, his status was increased to urgent. After 14 days of ECMO the patient underwent BSLTx. The early post-operative course was complicated by severe bleeding requiring multiple re-operations and massive transfusion. He was slow to wean from the ventilator, requiring a tracheostomy and 23 days of ventilation after the transplant. He was discharged from the hospital 59 days after his initial admission. At 7 months he was progressing well, with markedly improved exercise tolerance.
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DISCUSSION The reporting of the use of ECMO as a bridge to primary or re-do lung transplant is limited to a handful of case reports and very small case series spread over some 30 years. In 1975, the first case of ECMO as a bridge to lung transplant was performed for post-traumatic respiratory failure.3 The patient was successfully weaned from ECMO after the transplant. However, he died 10 days post-transplant from a combination of sepsis, bronchial leak and size mismatch. Interestingly, this was only the 37th lung transplant ever attempted and it is noteworthy that none of these patients were alive at 12 months. Prior to 1975, 6 other patients on ECMO were considered for lung transplantation but all died before donor lungs became available. In 1982, a further case of ECMO as a bridge to lung transplant was attempted in a patient with severe paraquat poisoning.4 After the transplant the patient was successfully weaned from ECMO, but paraquat poisoning recurred and ECMO was re-instituted. The patient remained on ECMO for a further 19 days until a second lung transplant was performed. This was the first report on the use of ECMO as a bridge to re-do lung transplant. The patient eventually died 93 days after the initial transplant from complications of a tracheal-innominate artery fistula. In the early series of lung transplants ischemic breakdown of the bronchial anastomosis was a common cause of death.3 Thus, healing of the bronchial anastomosis was seen as a key to long-term patient survival. Many centers came to view ECMO, and endotracheal intubation, as contraindications to lung transplantation as it was believed that both compromised bronchial healing.5 This view was supported by the poor outcomes for the initial lung transplants attempted from ECMO.3,4 In addition, the use of adult ECMO for respiratory failure declined in the 1980s after the publication of a negative randomized, controlled trial.6 This combination of factors resulted in the concept of using ECMO as a bridge to lung transplant being largely discounted. The era of successful lung transplantation was ushered in by the publication of the first series of long-term survivors (⬎12 months) by the Toronto group in 1987.7 Four years later, the Hannover group published the first report of long-term survival after using ECMO as a bridge to re-do lung transplant.8 The report detailed 2 patients with severe primary graft dysfunction who were treated with venoarterial (VA) ECMO and then re-transplantation. One of these patients died 5 months after surgery due to chronic graft rejection but the other was alive and well 42 months after re-transplantation. In 1992, the same group reported the first long-
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term survivor (⬎12 months) after using ECMO as a bridge to primary transplant.9 In 1993, this report was incorporated into a series of 3 cases where acute, severe respiratory failure was managed with VV ECMO.5 After 4, 5 and 9 days of ECMO, a clinical decision was made that in each case the respiratory failure was irreversible and the patients were listed for lung transplantation. Lung transplantation was then performed after 5, 6 and 13 days of ECMO. One patient died intra-operatively but the other 2 were alive and well 12 months after surgery. Today, lung transplantation is an established treatment for end-stage respiratory failure, with 23,716 lung transplant recipients reported up to 2006.10 However, despite the early cases detailed previously, reports on the use of ECMO as a bridge to transplant have remained isolated, and the results mixed.11,12 In 2002, the Vienna group reported 2 cases in which VA ECMO was used as a bridge to primary lung transplant in patients with decompensated primary pulmonary hypertension.11 One patient died 5 months post-operatively from complications of a severe hypoxic brain injury, and the outcome of the other was not specified. In 2007, the Vienna group also reported 2 cases of VA ECMO as a bridge to primary lung transplant in patients with decompensated cystic fibrosis.12 One patient died 2 months post-operatively of sepsis and the other was a long-term survivor. The report also stated that 3 patients were bridged to re-do transplantation but did not detail the outcome. Unfortunately, there are no accurate data on the outcomes of patients in whom ECMO was used as a bridge to lung transplant. Combining all reported cases in which the outcome was specified, the 12-month survival would be 40% (4 of 10).3–5,8,11,12 If the cases reported prior to the era of successful lung transplantation are excluded, then the 12-month survival would be 50% (4 of 8).5,8,11,12 This compares with the current benchmark 12-month survival of 78%.10 In recent years there have been three major advances in the technical aspects of the ECMO circuit (Figure 1). The development of polymethylpentene (PMP) oxygenators is probably the single most important advance. Before 2000, the majority of adult ECMO circuits used silicone membrane oxygenators and the remainder used polypropylene microporous oxygenators.13 Both these oxygenators had major drawbacks. In comparison with silicone membrane oxygenators, the PMP oxygenator has reduced red blood cell and platelet transfusion requirements, better gas exchange, lower resistance, lower priming volume and an incorporated heat exchanger.14 In comparison with polypropylene microporous oxygenators, the PMP oxygenator has a greatly reduced rate of oxygenator failure. The introduction of heparin-coated circuits has led to reduced platelet activation, reduced complement acti-
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vation, reduced granulocyte activation, and greatly reduced heparin requirements.15,16 Importantly, PMP oxygenators can be readily heparin coated, whereas the silicone membrane oxygenators cannot. Thus, a modern ECMO circuit can be entirely heparin coated and requires minimal systemic heparinization. By contrast, the early ECMO circuits required full heparinization and, accordingly, the daily blood product requirement was 1,000 to 2,500 ml.6 The third important technical advance was the development of the new generation of centrifugal pumps. In comparison with traditional roller pumps, the centrifugal pump has virtually no risk of tubing rupture or spallation; it has a smaller priming volume, it does not require the use of a reservoir, and the new generation of centrifugal pumps have an equivalent incidence of hemolysis.17 Several large series now report survival of ⬎50% for VV ECMO in acute, severe respiratory failure.18,19 Currently, there are no randomized, controlled trials to support the use of the new ECMO circuits in the management of severe, acute respiratory failure, but such a trial (the CESAR trial) is nearing completion in the UK.20 Although recent case series suggest that the outcome of patients managed with ECMO for acute, severe respiratory disease has improved, there remains a subset of patients in whom there is no significant recovery of lung function. Our center will consider listing for urgent lung transplantation those patients on ECMO who have acute, irreversible respiratory failure without multi-system organ failure. The 3 patients described earlier in this report all met the standard criteria for lung transplantation,21 and had good rehabilitation potential due the acute nature of their illness. The key clinical decision is to determine when the respiratory failure has become irreversible. Unfortunately, there is only limited evidence on which to base this decision. In the 1970s, reports suggested that, if lung recovery had not occurred after 5 days of ECMO, then the outcome was uniformly fatal.3 Today, many patients can recover after 5 days of ECMO, but there are no recent, accurate data on which to base the decision and, thus, it remains a question of clinical judgment. In all 3 of our cases, pathology of the explanted lungs showed grossly abnormal lung architecture, suggesting that recovery was unlikely. In considering a patient with acute respiratory failure requiring ECMO for lung transplantation it is important to consider the long-term outcomes of lung transplantation and ECMO. In 2006, the worldwide benchmark 5- and 10-year survival rates after lung transplantation were 50% and 26%, respectively.10 For comparison, the current 5and 10-year survival rates at our institution are 71% and 43%. Survival will almost certainly be lower for transplants
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Figure 1. Current ECMO circuit showing three technical advances: 1—polymethylpentene oxygenator; 2— heparin-coated tubing; 3— centrifugal pump.
performed from ECMO. Although there is a significantly smaller quantity of accurate data, the long-term outcome for survivors of ECMO (not requiring transplantation) appears good.18,19 For example, one large series reported on long-term outcome of 82 respiratory failure patients treated with ECMO who survived to hospital discharge (a further 64 patients died prior to discharge). They found no cases of residual respiratory disability and only 2 late deaths.18 This suggests that transplantation should only be offered to patients who cannot be weaned from ECMO. Further research is required to define which subset of patients on ECMO may benefit from lung transplantation. Although the use of ECMO as a bridge to lung transplant has remained limited, alternative extracorporeal circuits are currently being evaluated. The Han-
nover group has recently reported on the use of a novel, pumpless lung assist device (NovaLung) as a bridge to lung transplant.22 The NovaLung was used in 12 patients who developed severe ventilation-refractory hypercapnia while awaiting lung transplant. Ten patients were successfully bridged to transplant and 8 of these were alive at 1 year. In this study, use of the lung assist device was limited to cases of severe hypercapnia without severe hypoxia. Resource allocation is an important consideration in any transplant program, and it is clear that the patients in this report were resource-intensive. Although the patients had good long-term outcomes, all had prolonged intensive-care admissions, re-operations for bleeding, massive transfusion requirements, prolonged
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hospital admissions, and extended periods of rehabilitation. Also, 2 of the 3 patients had seizures in the early post-transplant period and it is possible that this group of patients may have a lower seizure threshold due to critical illness, poor nutrition, hypomagnesemia, and the associated milieu of a prolonged intensive-care stay. Given this level of resource utilization, and the scarcity of donor organs, careful patient selection is clearly needed. No specific criteria for this group of patients can be suggested due to the small number of cases, but, in addition to the standard criteria, young age, absence of multiple-organ dysfunction and good prospects for rehabilitation may be considered. Nevertheless, it remains that the 3 patients presented herein provide evidence that patients with acute, isolated, respiratory failure that is refractory to conventional ventilation can be successfully bridged to lung transplant using the current ECMO circuits. REFERENCES 1. Wigfield C, Lindsey J, Steffens T, Edwards N, Love R. Early institution of extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation improves outcome. J Heart Lung Transplant 2007;26:331– 8. 2. Fischer S, Bohn D, Rycus P, et al. Extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation: analysis of the Extracorporeal Life Support Organization (ELSO) registry. J Heart Lung Transplant 2007;26:472–7. 3. Veith F. Lung transplantation. Transplant Proc 1977;9:203– 8. 4. Saunders N, Alpert H, Cooper J. Sequential bilateral lung transplantation for paraquat poisoning. J Thorac Cardiovasc Surg 1985;89:734 – 42. 5. Jurmann M, Schaefers H-J, Demertzis S, et al. Emergency lung transplantation after extracorporeal membrane oxygenation. ASAIO J 1993;39:M448 –52. 6. Zapol W, Snider M, Hill J, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. JAMA 1979;242: 2193– 6. 7. Cooper J, Pearson F, Patterson G, et al. Technique of successful lung transplantation in humans. J Thorac Cardiovasc Surg 1987; 93:173– 81. 8. Jurmann M, Haverich A, Demertzis S, et al. Extracorporeal membrane oxygenation as a bridge to lung transplantation. Eur J Cardio-thorac Surg 1991;5:94 – 8.
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9. Demertzis S, Haverich A, Ziemer G, et al. Successful lung transplantation for posttraumatic adult respiratory distress syndrome after extracorporeal membrane oxygenation support. J Heart Lung Transplant 1992;11:1005–7. 10. Trulock E, Christie J, Edwards L, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart–lung transplantation report—2007. J Heart Lung Transplant 2007;26:782–95. 11. Pereszlenyi A, Lang G, Steltzer H, et al. Bilateral lung transplantation with intra- and postoperatively prolonged ECMO support in patients with pulmonary hypertension. Eur J Cardio-thorac Surg 2002;21:858 – 63. 12. Aigner C, Wisser W, Taghavi S, et al. Institutional experience with extracorporeal membrane oxygenation in lung transplantation. Eur J Cardio-thorac Surg 2007;31:468 –74. 13. Peek G, Killer H, Reeves R, et al. Early experience with a polymethyl pentene oxygenator for adult extracorporeal life support. ASAIO J 2002;48:480 –2. 14. Khoshbin E, Roberts N, Harvey C, et al. Poly-methyl pentene oxygenators have improved gas exchange capability and reduced transfusion requirements in adult extracorporeal membrane oxygenation. ASAIO J 2005;51:281–7. 15. Moen O, Fosse E, Dregelid E, et al. Centrifugal pump and heparin coating improves cardiopulmonary bypass compatibility. Ann Thorac Surg 1996;62:1134 – 40. 16. Fosse E, Moen O, Johnson E, et al. Reduced complement and granulocyte activation with heparin-coated cardiopulmonary bypass. Ann Thorac Surg 1994;58:472–7. 17. Lawson D, Richard I, Cheifetz I, et al. Hemolytic characteristics of three commercially available centrifugal blood pumps. Pediatr Crit Care Med 2005;6:573–7. 18. Bartlett R, Roloff D, Custer J, Younger J, Hirschl R. Extracorporeal life support: the University of Michigan experience. JAMA 2000; 283:904 – 8. 19. Peek G, Moore H, Moore N, Sosnowski A, Firmin R. Extracorporeal membrane oxygenation for adult respiratory failure. Chest 1997;112:759 – 64. 20. Peek G, Clemens F, Elbourne D, et al. CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure. BMC Health Serv Res 2006;6:163–75. 21. Orens J, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745–55. 22. Fischer S, Simon A, Welte T, et al. Bridge to lung transplantation with the novel pumpless interventional lung assist device NovaLung. J Thorac Cardiovasc Surg 2006;131:719 –23.
Use of Extracorporeal Membrane Oxygenation as a Bridge to Primary Lung Transplant: 3 Consecutive, Successful Cases and a Review of the Literature Andrew Jackson, MBBS, Jonathan Cropper, MSc, Roger Pye, MBBS, Frank Junius, MBBS, Monique Malouf, MBBS, and Allan Glanville, MBBS, MD Many transplant centers have considered extracorporeal membrane oxygenation (ECMO) to be a contraindication to lung transplantation, due to historically poor outcomes. However, recent advances in the technical aspects of ECMO have enabled patients to be supported with relative safety for several weeks until a donor lung becomes available. We present 3 young patients with acute (in 1 case, acute on chronic), severe respiratory failure that was refractory to conventional ventilation, who were placed on venovenous ECMO. In each case, a clinical decision was made that the patient’s respiratory failure was irreversible and they were successfully managed with urgent lung transplantation. J Heart Lung Transplant 2008;27:348 –52. Copyright © 2008 by the International Society for Heart and Lung Transplantation.
Extracorporeal membrane oxygenation (ECMO) is an increasingly utilized therapy for adults with acute, severe respiratory failure that is refractory to conventional ventilation. ECMO is now a recognized rescue therapy for severe primary graft dysfunction after lung transplantation.1 A recent review of the Extracorporeal Life Support Organization registry showed 151 cases with a 42% survival to hospital discharge.2 However, reports on the use of ECMO as a bridge to lung transplant are isolated, and the outcomes remain mixed. Many centers have considered ECMO to be a contraindication to lung transplantation. However, considering recent technological advances, we have found that patients can now be maintained on ECMO with relative safety for up to 4 to 6 weeks. This allows a reasonable time period for a donor lung to become available should the patient be listed for lung transplantation. We present 3 consecutive, successful cases in which ECMO was used as a bridge to primary lung transplant. CASE REPORTS Over the last 5 years there have been approximately 45 patients in our transplant center’s catchment area with From the Department of Anaesthetics, St Vincent’s Hospital, Sydney, Australia. Submitted September 15, 2007; revised December 18, 2007; accepted December 18, 2007. Reprint requests: Andrew Jackson, MBBS, Department of Anaesthetics, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, Sydney 2010, Australia. Telephone: 006-102-9713-6473. Fax: 006-1028382-3981. E-mail: [email protected] Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2007.12.006
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acute, severe respiratory failure who were treated with ECMO. Our lung transplant physicians were asked by the referring hospitals to consider listing 7 of these patients for lung transplantation. Of these, 3 were not listed due to medical contraindications and 4 were listed for urgent lung transplantation. One of the patients was later de-listed due to recovery of lung function. The remaining 3 patients underwent urgent lung transplantation at the referring hospital. In each case, our hospital’s transplant team traveled to the referring hospital to perform the operation as it was not possible to transport patients on ECMO at that time. Case 1 A previously well 15-year-old boy presented with influenza B complicated by severe Staphylococcus aureus pneumonia. After 6 days of conventional ventilation, the patient remained severely hypoxic, with PaO2/FIO2 (P/F) ratios of 35 to 40, and he was placed on venovenous (VV) ECMO. The use of ECMO corrected the hypoxia and his condition stabilized. His severe respiratory failure persisted while on ECMO, but he did not develop failure of other organ systems. After 17 days of ECMO, a clinical decision was made that the patient’s respiratory failure was irreversible and he was listed for an urgent lung transplant. After 28 days of ECMO, he underwent bilateral sequential lung transplantation (BSLTx). The early post-operative course was complicated by severe bleeding, requiring re-operation and massive transfusion. He was slow to wean from the ventilator due to a profound myopathy, requiring a tracheostomy and 34 days of ventilation after transplant. Further complications included several seizures in the early post-operative period and a transient cranial nerve III palsy. He was discharged from the hospital 104
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days after initial admission. At 12 months, he had near-normal exercise tolerance and no long-term complications. He remains alive at 5 years 2 months. Case 2 A previously well 18-year-old man presented with influenza complicated by severe Candida albicans pneumonia. Conventional ventilatory techniques were able to prevent hypoxia but progressive hypercarbia developed. After 7 days of conventional ventilation, PaCO2 reached 165 mm Hg and he was placed on VV ECMO. The use of ECMO corrected the hypercarbia and his condition stabilized. The patient required hemodialysis while on ECMO to correct acute hyperkalemia, but no other organ dysfunction occurred. The patient was listed for an urgent lung transplant after 5 days of ECMO when a clinical assessment was made that his respiratory failure was irreversible. After 10 days of ECMO the patient underwent BSLTx. The early post-operative course was complicated by moderate primary graft dysfunction (requiring an FIO2 up to 0.7), and severe bleeding, requiring re-operation and massive transfusion. He was slow to wean from the ventilator, requiring a tracheostomy and 26 days of ventilation after the transplant. He also had several seizures in the early post-operative period that were most likely due to cyclosporine. He was discharged from the hospital 65 days after admission. At 12 months, he had normal exercise tolerance and no long-term complications. He remains alive at 3 years 11 months. Case 3 A 26-year-old man with a background of end-stage, non-specific interstitial lung disease awaiting lung transplantation presented with an acute decompensation due to acute respiratory distress syndrome (ARDS) from urinary tract sepsis. After 24 hours of conventional ventilation he developed severe hypoxia, with a P/F ratio of 40, and he was placed on VV ECMO. This corrected the hypoxia and his condition stabilized. There was no improvement in respiratory failure while on ECMO, but he did not develop failure of other organ systems. As the patient was already listed for lung transplantation, and weaning from ECMO was considered very unlikely, his status was increased to urgent. After 14 days of ECMO the patient underwent BSLTx. The early post-operative course was complicated by severe bleeding requiring multiple re-operations and massive transfusion. He was slow to wean from the ventilator, requiring a tracheostomy and 23 days of ventilation after the transplant. He was discharged from the hospital 59 days after his initial admission. At 7 months he was progressing well, with markedly improved exercise tolerance.
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DISCUSSION The reporting of the use of ECMO as a bridge to primary or re-do lung transplant is limited to a handful of case reports and very small case series spread over some 30 years. In 1975, the first case of ECMO as a bridge to lung transplant was performed for post-traumatic respiratory failure.3 The patient was successfully weaned from ECMO after the transplant. However, he died 10 days post-transplant from a combination of sepsis, bronchial leak and size mismatch. Interestingly, this was only the 37th lung transplant ever attempted and it is noteworthy that none of these patients were alive at 12 months. Prior to 1975, 6 other patients on ECMO were considered for lung transplantation but all died before donor lungs became available. In 1982, a further case of ECMO as a bridge to lung transplant was attempted in a patient with severe paraquat poisoning.4 After the transplant the patient was successfully weaned from ECMO, but paraquat poisoning recurred and ECMO was re-instituted. The patient remained on ECMO for a further 19 days until a second lung transplant was performed. This was the first report on the use of ECMO as a bridge to re-do lung transplant. The patient eventually died 93 days after the initial transplant from complications of a tracheal-innominate artery fistula. In the early series of lung transplants ischemic breakdown of the bronchial anastomosis was a common cause of death.3 Thus, healing of the bronchial anastomosis was seen as a key to long-term patient survival. Many centers came to view ECMO, and endotracheal intubation, as contraindications to lung transplantation as it was believed that both compromised bronchial healing.5 This view was supported by the poor outcomes for the initial lung transplants attempted from ECMO.3,4 In addition, the use of adult ECMO for respiratory failure declined in the 1980s after the publication of a negative randomized, controlled trial.6 This combination of factors resulted in the concept of using ECMO as a bridge to lung transplant being largely discounted. The era of successful lung transplantation was ushered in by the publication of the first series of long-term survivors (⬎12 months) by the Toronto group in 1987.7 Four years later, the Hannover group published the first report of long-term survival after using ECMO as a bridge to re-do lung transplant.8 The report detailed 2 patients with severe primary graft dysfunction who were treated with venoarterial (VA) ECMO and then re-transplantation. One of these patients died 5 months after surgery due to chronic graft rejection but the other was alive and well 42 months after re-transplantation. In 1992, the same group reported the first long-
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term survivor (⬎12 months) after using ECMO as a bridge to primary transplant.9 In 1993, this report was incorporated into a series of 3 cases where acute, severe respiratory failure was managed with VV ECMO.5 After 4, 5 and 9 days of ECMO, a clinical decision was made that in each case the respiratory failure was irreversible and the patients were listed for lung transplantation. Lung transplantation was then performed after 5, 6 and 13 days of ECMO. One patient died intra-operatively but the other 2 were alive and well 12 months after surgery. Today, lung transplantation is an established treatment for end-stage respiratory failure, with 23,716 lung transplant recipients reported up to 2006.10 However, despite the early cases detailed previously, reports on the use of ECMO as a bridge to transplant have remained isolated, and the results mixed.11,12 In 2002, the Vienna group reported 2 cases in which VA ECMO was used as a bridge to primary lung transplant in patients with decompensated primary pulmonary hypertension.11 One patient died 5 months post-operatively from complications of a severe hypoxic brain injury, and the outcome of the other was not specified. In 2007, the Vienna group also reported 2 cases of VA ECMO as a bridge to primary lung transplant in patients with decompensated cystic fibrosis.12 One patient died 2 months post-operatively of sepsis and the other was a long-term survivor. The report also stated that 3 patients were bridged to re-do transplantation but did not detail the outcome. Unfortunately, there are no accurate data on the outcomes of patients in whom ECMO was used as a bridge to lung transplant. Combining all reported cases in which the outcome was specified, the 12-month survival would be 40% (4 of 10).3–5,8,11,12 If the cases reported prior to the era of successful lung transplantation are excluded, then the 12-month survival would be 50% (4 of 8).5,8,11,12 This compares with the current benchmark 12-month survival of 78%.10 In recent years there have been three major advances in the technical aspects of the ECMO circuit (Figure 1). The development of polymethylpentene (PMP) oxygenators is probably the single most important advance. Before 2000, the majority of adult ECMO circuits used silicone membrane oxygenators and the remainder used polypropylene microporous oxygenators.13 Both these oxygenators had major drawbacks. In comparison with silicone membrane oxygenators, the PMP oxygenator has reduced red blood cell and platelet transfusion requirements, better gas exchange, lower resistance, lower priming volume and an incorporated heat exchanger.14 In comparison with polypropylene microporous oxygenators, the PMP oxygenator has a greatly reduced rate of oxygenator failure. The introduction of heparin-coated circuits has led to reduced platelet activation, reduced complement acti-
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vation, reduced granulocyte activation, and greatly reduced heparin requirements.15,16 Importantly, PMP oxygenators can be readily heparin coated, whereas the silicone membrane oxygenators cannot. Thus, a modern ECMO circuit can be entirely heparin coated and requires minimal systemic heparinization. By contrast, the early ECMO circuits required full heparinization and, accordingly, the daily blood product requirement was 1,000 to 2,500 ml.6 The third important technical advance was the development of the new generation of centrifugal pumps. In comparison with traditional roller pumps, the centrifugal pump has virtually no risk of tubing rupture or spallation; it has a smaller priming volume, it does not require the use of a reservoir, and the new generation of centrifugal pumps have an equivalent incidence of hemolysis.17 Several large series now report survival of ⬎50% for VV ECMO in acute, severe respiratory failure.18,19 Currently, there are no randomized, controlled trials to support the use of the new ECMO circuits in the management of severe, acute respiratory failure, but such a trial (the CESAR trial) is nearing completion in the UK.20 Although recent case series suggest that the outcome of patients managed with ECMO for acute, severe respiratory disease has improved, there remains a subset of patients in whom there is no significant recovery of lung function. Our center will consider listing for urgent lung transplantation those patients on ECMO who have acute, irreversible respiratory failure without multi-system organ failure. The 3 patients described earlier in this report all met the standard criteria for lung transplantation,21 and had good rehabilitation potential due the acute nature of their illness. The key clinical decision is to determine when the respiratory failure has become irreversible. Unfortunately, there is only limited evidence on which to base this decision. In the 1970s, reports suggested that, if lung recovery had not occurred after 5 days of ECMO, then the outcome was uniformly fatal.3 Today, many patients can recover after 5 days of ECMO, but there are no recent, accurate data on which to base the decision and, thus, it remains a question of clinical judgment. In all 3 of our cases, pathology of the explanted lungs showed grossly abnormal lung architecture, suggesting that recovery was unlikely. In considering a patient with acute respiratory failure requiring ECMO for lung transplantation it is important to consider the long-term outcomes of lung transplantation and ECMO. In 2006, the worldwide benchmark 5- and 10-year survival rates after lung transplantation were 50% and 26%, respectively.10 For comparison, the current 5and 10-year survival rates at our institution are 71% and 43%. Survival will almost certainly be lower for transplants
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Figure 1. Current ECMO circuit showing three technical advances: 1—polymethylpentene oxygenator; 2— heparin-coated tubing; 3— centrifugal pump.
performed from ECMO. Although there is a significantly smaller quantity of accurate data, the long-term outcome for survivors of ECMO (not requiring transplantation) appears good.18,19 For example, one large series reported on long-term outcome of 82 respiratory failure patients treated with ECMO who survived to hospital discharge (a further 64 patients died prior to discharge). They found no cases of residual respiratory disability and only 2 late deaths.18 This suggests that transplantation should only be offered to patients who cannot be weaned from ECMO. Further research is required to define which subset of patients on ECMO may benefit from lung transplantation. Although the use of ECMO as a bridge to lung transplant has remained limited, alternative extracorporeal circuits are currently being evaluated. The Han-
nover group has recently reported on the use of a novel, pumpless lung assist device (NovaLung) as a bridge to lung transplant.22 The NovaLung was used in 12 patients who developed severe ventilation-refractory hypercapnia while awaiting lung transplant. Ten patients were successfully bridged to transplant and 8 of these were alive at 1 year. In this study, use of the lung assist device was limited to cases of severe hypercapnia without severe hypoxia. Resource allocation is an important consideration in any transplant program, and it is clear that the patients in this report were resource-intensive. Although the patients had good long-term outcomes, all had prolonged intensive-care admissions, re-operations for bleeding, massive transfusion requirements, prolonged
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hospital admissions, and extended periods of rehabilitation. Also, 2 of the 3 patients had seizures in the early post-transplant period and it is possible that this group of patients may have a lower seizure threshold due to critical illness, poor nutrition, hypomagnesemia, and the associated milieu of a prolonged intensive-care stay. Given this level of resource utilization, and the scarcity of donor organs, careful patient selection is clearly needed. No specific criteria for this group of patients can be suggested due to the small number of cases, but, in addition to the standard criteria, young age, absence of multiple-organ dysfunction and good prospects for rehabilitation may be considered. Nevertheless, it remains that the 3 patients presented herein provide evidence that patients with acute, isolated, respiratory failure that is refractory to conventional ventilation can be successfully bridged to lung transplant using the current ECMO circuits. REFERENCES 1. Wigfield C, Lindsey J, Steffens T, Edwards N, Love R. Early institution of extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation improves outcome. J Heart Lung Transplant 2007;26:331– 8. 2. Fischer S, Bohn D, Rycus P, et al. Extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation: analysis of the Extracorporeal Life Support Organization (ELSO) registry. J Heart Lung Transplant 2007;26:472–7. 3. Veith F. Lung transplantation. Transplant Proc 1977;9:203– 8. 4. Saunders N, Alpert H, Cooper J. Sequential bilateral lung transplantation for paraquat poisoning. J Thorac Cardiovasc Surg 1985;89:734 – 42. 5. Jurmann M, Schaefers H-J, Demertzis S, et al. Emergency lung transplantation after extracorporeal membrane oxygenation. ASAIO J 1993;39:M448 –52. 6. Zapol W, Snider M, Hill J, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. JAMA 1979;242: 2193– 6. 7. Cooper J, Pearson F, Patterson G, et al. Technique of successful lung transplantation in humans. J Thorac Cardiovasc Surg 1987; 93:173– 81. 8. Jurmann M, Haverich A, Demertzis S, et al. Extracorporeal membrane oxygenation as a bridge to lung transplantation. Eur J Cardio-thorac Surg 1991;5:94 – 8.
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9. Demertzis S, Haverich A, Ziemer G, et al. Successful lung transplantation for posttraumatic adult respiratory distress syndrome after extracorporeal membrane oxygenation support. J Heart Lung Transplant 1992;11:1005–7. 10. Trulock E, Christie J, Edwards L, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart–lung transplantation report—2007. J Heart Lung Transplant 2007;26:782–95. 11. Pereszlenyi A, Lang G, Steltzer H, et al. Bilateral lung transplantation with intra- and postoperatively prolonged ECMO support in patients with pulmonary hypertension. Eur J Cardio-thorac Surg 2002;21:858 – 63. 12. Aigner C, Wisser W, Taghavi S, et al. Institutional experience with extracorporeal membrane oxygenation in lung transplantation. Eur J Cardio-thorac Surg 2007;31:468 –74. 13. Peek G, Killer H, Reeves R, et al. Early experience with a polymethyl pentene oxygenator for adult extracorporeal life support. ASAIO J 2002;48:480 –2. 14. Khoshbin E, Roberts N, Harvey C, et al. Poly-methyl pentene oxygenators have improved gas exchange capability and reduced transfusion requirements in adult extracorporeal membrane oxygenation. ASAIO J 2005;51:281–7. 15. Moen O, Fosse E, Dregelid E, et al. Centrifugal pump and heparin coating improves cardiopulmonary bypass compatibility. Ann Thorac Surg 1996;62:1134 – 40. 16. Fosse E, Moen O, Johnson E, et al. Reduced complement and granulocyte activation with heparin-coated cardiopulmonary bypass. Ann Thorac Surg 1994;58:472–7. 17. Lawson D, Richard I, Cheifetz I, et al. Hemolytic characteristics of three commercially available centrifugal blood pumps. Pediatr Crit Care Med 2005;6:573–7. 18. Bartlett R, Roloff D, Custer J, Younger J, Hirschl R. Extracorporeal life support: the University of Michigan experience. JAMA 2000; 283:904 – 8. 19. Peek G, Moore H, Moore N, Sosnowski A, Firmin R. Extracorporeal membrane oxygenation for adult respiratory failure. Chest 1997;112:759 – 64. 20. Peek G, Clemens F, Elbourne D, et al. CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure. BMC Health Serv Res 2006;6:163–75. 21. Orens J, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745–55. 22. Fischer S, Simon A, Welte T, et al. Bridge to lung transplantation with the novel pumpless interventional lung assist device NovaLung. J Thorac Cardiovasc Surg 2006;131:719 –23.