LIVER TRANSPLANTATION 20:46–53, 2014
ORIGINAL ARTICLE
Combined Lung and Liver Transplantation: Analysis of a Single-Center Experience Stephanie G. Yi,1 Sherilyn Gordon Burroughs,1 Matthias Loebe,2 Scott Scheinin,2 Harish Seethamraju,5 Soma Jyothula,3 Howard Monsour,4 Robert McFadden,4 Hemangshu Podder,1 Ashish Saharia,1 Emad H. Asham,1 Maha Boktour,1 A. Osama Gaber,1 R. Mark Ghobrial1 1 Department of Surgery, 2Department of Cardiovascular Surgery, 3Division of Lung Transplantation, Department of Medicine, and 4Division of Hepatology and Transplant Medicine, Department of Medicine, Methodist Hospital, Houston, TX; and 5Department of Internal Medicine, University of Kentucky, Lexington, KY
Patients with end-stage lung disease complicated by cirrhosis are not expected to survive lung transplantation alone. Such patients are potential candidates for combined lung-liver transplantation (CLLT), however few reports document the indications and outcomes after CLLT. This is a review of a large single-center CLLT series. Eight consecutive CLLT performed during 2009-2012 were retrospectively reviewed. One patient received a third simultaneous heart transplant. Mean age was 42.5 6 11.5 years. Pulmonary indications included cystic fibrosis (CF) (n 5 3), idiopathic pulmonary fibrosis (n 5 2), a1-antitrypsin deficiency (AATD) (n 5 1) and pulmonary hypertension (n 5 2). Liver indications were CF (n 5 3), hepatitis C (n 5 2), AATD (n 5 1), cryptogenic (n 5 1), and cardiac=congestive (n 5 1). Urgency was reflected by median lung allocation score (LAS) of 41 (36.0-89.0) and median predicted FEV1 of 25.7%. Median donor age was 25 (20-58) years with median cold ischemia times of 147 minutes and 6.1 hours for lung and liver, respectively. Overall patient survival at 30 days, 90 days and 1 year was 87.5%, 75.0% and 71.4% respectively. One patient had evidence of acute lung rejection, and no patients had liver allograft rejection. Early postoperative mortalities (90 days) were caused by sepsis in 2 recipients who exhibited the highest LAS of 69.9 and 89.0. The remaining recipients had a median LAS of 39.5 and 100% survival at 1-year. Median length of stay was 25 days (7-181). Complications requiring operative intervention included bile duct ischemia (n 5 1) and bile leak (n 5 1), ischemia of the bronchial anastomosis (n 5 1), and necrotizing pancreatitis with duodenal perforation (n 5 1). This series reflects a large single-center CLLT experience. Sepsis is the most common cause of death. The procedure should be considered for candidates with LAS < 50. Liver Transpl C 2013 AASLD. 20:46-53, 2014. V Received July 29, 2013; accepted September 29, 2013.
Combined lung and liver transplantation (CLLT) is a viable treatment option for patients with end-stage lung and liver disease who are not expected to survive with either transplant alone. Diseases that affect both the lungs and the liver, such as cystic fibrosis (CF)1,2 and alpha-1antitrypsin deficiency (AATD), have been previously described for CLLT.3,4 Putative benefits of multiorgan
transplantation with the inclusion of a liver graft include protection against rejection and survivability equivalent to that with single-organ transplantation.2,5 However, CLLT is not commonly performed, and the indications and the expected outcomes continue to be unclear. Because of the limited collective experience with CLLT, prior case series have reported variability in
Abbreviations: AATD, alpha-1-antitrypsin deficiency; BMI, body mass index; CF, cystic fibrosis; CLLT, combined lung and liver transplantation; FEV1, forced expiratory volume in 1 second; IPF, idiopathic pulmonary fibrosis; LAS, lung allocation score; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; OR, operating room; POD, postoperative day; UNOS, United Network for Organ Sharing. The authors have no grants, financial support, or conflicts of interest to report. Address reprint requests to Stephanie G. Yi, M.D., M.S., Department of Surgery, Methodist Hospital, 6565 Fannin Street, SM 1661 A, Houston, TX 77030. Telephone: 713-441-8085; FAX: 713-790-2872; E-mail: [email protected] DOI 10.1002/lt.23770 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2013 American Association for the Study of Liver Diseases. V
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patient populations, recipient selection criteria, and posttransplant management (eg, immunosuppression). Previously described recipient populations have ranged from pediatric patients with genetic diseases to patients with separate lung and liver disease who were on average 40 to 50 years old. Recently applied allocation schemes such as the Model for End-Stage Liver Disease (MELD) score and the lung allocation score (LAS) did not dictate patient selection in these series. Additionally, CLLT cases described in the literature were performed from 1986 to 2004, and this was an era before the most recent immunosuppressive agents and protocols for posttransplant care. The majority of single-center CLLT cases have been international, with data from the United States arising from multicenter institutions reflected in the United Network for Organ Sharing (UNOS) database. Currently, 58 cases have been published, and the 1-year mortality rate has ranged from 55.6% to 80%.1-4,6 Patient mortality has been attributed primarily to sepsis, with an earlier study reporting rejection.2,3 Most patients had previously known bacterial colonization,3 which may have placed these patients at a greater risk of death. More information is needed to determine which patients are at greatest risk for postoperative complications. Here we present our large singlecenter CLLT series and suggest criteria for patient selection for this combined procedure.
PATIENTS AND METHODS Data Collection Under an institutional review board–approved protocol, we performed a retrospective analysis of 8 consecutive patients greater than 18 years of age who underwent CLLT at our institution between February 3, 2009 and November 30, 2012. One patient underwent simultaneous heart, lung, and liver transplantation, whereas another patient received an islet cell transplant concomitantly with lung and liver transplantation. The following data were collected: the recipient age, sex, body mass index (BMI), albumin level, lung disease, liver disease, pulmonary function, and wait-list time; the donor age and BMI; the graft type, cold ischemia time, and warm ischemia time; and the 30-day, 90-day, and 1-year outcomes.
Patient Characteristics CLLT candidacy was determined with our center’s criteria for lung transplantation first, and approval for dual listing came after a multidisciplinary board review. Liver transplant candidacy for CLLT was based on the presence of biopsy-proven cirrhosis and a portal gradient 10 mm Hg. Candidates were listed according to the recipient LAS7 and the MELD score.8
Organ Allocation Transplant candidacy for patients with multiorgan disease was primarily based on the LAS, even in the
YI ET AL. 47
setting of heart, lung, and liver transplantation. Regional allocation protocols were based on Organ Procurement and Transplantation Network policy 3.9.3 for multiorgan allocation,9 which requires a candidate to be registered on each organ waiting list separately. If the candidate was eligible to receive a lung transplant from a local donor, the liver from the same donor was allocated to the multiorgan candidate. If the candidate was on the waiting list outside the local organ distribution unit, a mutual agreement among organizations within the regional setting was made to accommodate the aforementioned policy. Thus, the heart and the liver were allocated to the lung transplant recipient according to the LAS in all cases. Exclusion criteria for all wait lists included active infection, extrahepatic or extrapulmonary malignancy, history of noncompliance, evidence of substance abuse, and unavailability of social resources.
Donor Operation Donors were selected on the basis of standard criteria for lung and liver transplantation, and grafts were obtained by standard thoracoabdominal procurement techniques.10,11 All donors received intravenous heparin before procurement. Lung explants were infused with prostaglandin E1 and a preservation solution (Perfadex, XVIVO Perfusion AB, Gothenburg, Sweden). Liver explants were cooled and preserved in University of Wisconsin solution. The lung ischemia time was defined as the time between the clamping of donor vessels and the unclamping of recipient vessels.
Recipient Operation Lung and liver transplants were performed sequentially in the same operative setting. By 2011, patients were undergoing abdominal dissection before both lung and liver implantation in order to minimize the transfusion of blood products, fluid resuscitation, and pulmonary edema in the newly transplanted lung.
Lung Transplantation Bilateral thoracosternotomy or bilateral anterolateral thoracotomy through the fourth or fifth intercostal space was used for sequential double-lung transplantation. Cardiopulmonary bypass was not used during the lung transplantation procedure. Heart and lung transplantation was performed with a cardiopulmonary bypass.
Deceased Donor Whole Organ Liver Transplantation Whole organ orthotopic liver transplantation was performed in the normal, standard manner, as described previously.12 Venovenous bypass was used when the patient exhibited hemodynamic instability with test clamping of the portal vein. No livers were used for domino transplantation because all livers were cirrhotic.
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TABLE 1. Recipient Demographics Patient
Age
BMI
FEV1
MELD
(Years)
Sex
(kg/m2)
LAS
(% Predicted)
Lung Diagnosis
Score
Liver Diagnosis
1
54
Female
21.5
41.3
25.4
10
Hepatitis C
2 3 4 5
52 28 42 52
Female Female Male Female
29.6 16.0 18.0 20.1
37.9 69.9 41.0 89.0
14 14 24 36
Pulmonary hypertension AATD CF CF IPF
7 8 8 11
6 7
49 39
Male Male
22.0 16.5
44.2 37.8
36 34
9 14
8
24
Female
17.8
36.0
26
IPF Secondary pulmonary hypertension (congestive heart failure) CF
AATD CF CF Cryptogenic cirrhosis Hepatitis C Congestive
12
CF
Number
Islet Cell Transplantation
RESULTS
Islet cell transplantation was performed via portal vein cannulation after the completion of both the lung and liver transplants under the same anesthesia.
Patient Demographics
Immunosuppression Immunosuppression was administered according to the pulmonary transplant protocol. Recipients received methylprednisolone induction with or without daclizumab or basiliximab. Maintenance immunosuppression consisted of mycophenolate mofetil (MMF), a steroid taper, and tacrolimus, which was started on postoperative day 4 (POD4) after an evaluation of each patient’s renal function. The postoperative methylprednisolone dosing was as follows: 2 mg/ kg/day on POD1, 1 mg/kg/day on POD2, 0.5 mg/kg/ day from POD3 until tacrolimus was therapeutic, and then 10 mg of oral prednisone daily. Tacrolimus levels were titrated for a target trough level of 10 to 12 ng/ mL for 3 months, and this was reduced to 5 to 8 ng/ mL thereafter. On the basis of clinical suspicion or graft function, additional high-dose steroids were used at the discretion of the pulmonary transplant team. Starting on POD0, surveillance bronchoscopy was used to evaluate all patients for possible rejection. Bronchoscopy was performed weekly until 1 month after the operation and then every 2 weeks for 3 months, and this was followed by every month for a year. Postoperative liver function tests were used to monitor liver allograft function.
Twenty-one patients at our institution were placed on the CLLT waiting list. All patients had severe pulmonary disease with cirrhosis. Eight of these patients underwent CLLT, with 1 patient undergoing combined heart, lung, and liver transplantation and another undergoing combined islet cell, lung, and liver transplantation. Demographic information and disease severity are summarized in Table 1. The mean age of the patients at the time of transplantation was 42.5 6 11.5 years. Three patients (37.5%) were male, and 5 (62.5%) were female. The median BMI was 19.1 kg/m2 (range 5 16.0-29.6 kg/m2), and the median albumin level was 3.5 g/dL (range 5 2.4-3.9 g/dL) before the operation.
Indications for Transplantation The pulmonary indications included CF (n 5 3), idiopathic pulmonary fibrosis (IPF; n 5 2), AATD (n 5 1), and pulmonary hypertension (n 5 2). The biopsy-proven causes of cirrhosis were CF (n 5 3), hepatitis C (n 5 2), AATD (n 5 1), cryptogenic cirrhosis (n 5 1), and cardiac/ congestive (n 5 1). Urgency was reflected by a median LAS of 41 (range 5 36.0-89.0) and by a median predicted forced expiratory volume in 1 second (FEV1) of 25.7% (range 5 14%-36%). All patients required supplemental oxygen before transplantation; 2 patients (25%) were on mechanical ventilation (patients 3 and 5). The median MELD score was 9.5 (range 5 7-14). All patients receiving CLLT exhibited biopsy-proven cirrhosis with portal hypertension. The median wait-list time for transplantation was 116 days (range 5 40-709 days).
Statistics The statistical analysis was performed with Stata 12.1 (StataCorp, College Station, TX). Descriptive statistics are presented as medians and ranges.
Donor Details Donor characteristics and ischemia times are summarized in Table 2. All were ABO-identical, cadaveric,
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YI ET AL. 49
TABLE 2. Donor and Graft Characteristics Donor Patient Number
Donor
Liver Cold
Liver Warm
Age
Donor
BMI
Lung Ischemia
Ischemia
Ischemia
(Years)
Sex
(kg/m2)
Time (Minutes)*
Time (Hours)
Time (Minutes)
34 58 23 21 27 40 20 20
Male Male Female Male Male Male Female Male
22.7 22.3 18.3 20.9 19.7 29.1 29.0 20.2
213† (right) (right) (right) (right) (right) (right) (right)
6.4 6.2 7.0 5.9 7.8 4.7 3.8 5.4
19 20 27 11 36 23 36 34
1 2 3 4 5 6 7 8
193 (left) 136 147 (left) 198 229 (left) 182 193 (left) 260 126 (left) 81 72 (left)‡ 72 77 (left) 147
*Including donor clamping and recipient unclamping. Single-lung transplant only. ‡ En bloc heart and double-lung transplants. †
brain-dead donors. The median donor age was 25 years (range 5 20-58 years), and the median BMI was 21.6 kg/m2 (range 5 18.3-29.1 kg/m2). The median lung ischemia time was 147 minutes (range 5 72-260 minutes). The median cold and warm liver ischemia times were 6.1 hours (range 5 3.8-7.8 hours) and 25 minutes (range 5 11-36 minutes), respectively.
Operative Details All but 1 patient underwent bilateral lung transplantation (patient 1). Whole livers were used for all liver transplants. One patient (patient 3) received a simultaneous third transplant of pancreatic islet cells, and another patient (patient 7) underwent simultaneous lung, liver, and heart transplantation. All recipients underwent 2-stage sequential transplantation (lung and then liver) under the same anesthesia. Two patients required delayed biliary reconstruction after hemodynamic optimization (patients 5 and 6). Four patients (50%) required venovenous bypass during liver transplantation. The median values for intraoperative blood product use were 8 U of packed red blood cells, 8.5 U of fresh frozen plasma, and 1.5 U of platelets. The mean transplant operating room (OR) time was 8.6 6 1.2 hours for both procedures.
One patient required extracorporeal membrane oxygenation in the immediate postoperative period and subsequently died (patient 3).
Immunosuppression Specific immunosuppression regimens are summarized in Table 3. Immunoprophylaxis consisted of a regimen of corticosteroids, MMF, and tacrolimus. Four patients received daclizumab or basiliximab with induction. Tacrolimus levels were dosed according to the protocol described in the Patients and Methods section. Corticosteroids were dosed and tapered on the basis of weight as described in the Patients and Methods section. All patients underwent surveillance bronchoscopy as described in the Patients and Methods section, and postoperative liver function tests were performed to monitor liver allograft function. One of the 8 patients exhibited bronchoscopic evidence of early acute rejection on POD2 and received high-dose steroids. This patient did not exhibit any additional bronchoscopic signs of rejection after treatment and was subsequently discharged from the hospital by POD11. No evidence of liver allograft rejection was detected in any patient.
Surgical Complications Postoperative Management Immediate postoperative management combined fluid restriction and vasopressor support titrated for a mean arterial pressure 65 mm Hg. Postoperatively, patients had a median central venous pressure of 8.5 mm Hg (range 5 4-17 mm Hg) and a median pulmonary artery pressure of 22.3 mm Hg (range 5 14.3-27 mm Hg). Fifty percent of the patients were extubated (patients 1, 4, 7, and 8), whereas the remaining patients could not be weaned from the ventilator and underwent tracheostomy (50%). The patients who were extubated had a median LAS of 39.4 (range 5 36.0-41.3), whereas those requiring tracheostomy had a median LAS of 57 (range 5 37.9-89.0).
No primary nonfunction of the hepatic graft was reported in this series. Additionally, there was no incidence of hepatic artery thrombosis or portal vein thrombosis. Because of hemodynamic instability or marginal oxygenation during transplantation, 2 patients returned to the OR for delayed biliary reconstruction or closure of the abdomen and chest. Four patients (50%) had unplanned returns to the OR. Three patients had multiple (>1) returns to the OR after the initial transplant. Patients who had unplanned returns to the OR had a median LAS of 53.9 (range 5 37.8-89.0), whereas those who did not return to the OR had a median LAS of 41.2 (range 5 36.0-44.2).
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TABLE 3. Immunosuppression Patient Number 1 2 3 4 5 6 7 8
Induction Methylprednisolone Methylprednisolone, daclizumab Methylprednisolone Methylprednisolone Methylprednisolone, basiliximab Methylprednisolone, basiliximab Methylprednisolone Methylprednisolone, basiliximab
Two of the 4 patients with unplanned returns to the OR developed septic shock in the postoperative period. The first patient, who had a history of CF, had an LAS of 69.9 and developed a bile duct leak requiring exploratory laparotomy on POD2 for the revision of the biliary anastomosis with T-tube placement. This patient went into septic shock, required multiple vasopressors, and on POD7 was placed on extracorporeal membrane oxygenation and expired. The second patient, who had a history of IPF and cryptogenic cirrhosis, had an LAS of 89.0 and developed a bronchopleural fistula from ischemia of the bronchial anastomosis. This patient was on multiple high-dose vasopressors immediately after transplantation. Despite bronchial stent placement on POD15, the patient became septic, returned to the OR on POD58 for muscle flap coverage over the bronchopleural fistula, underwent exploratory laparotomy for an evaluation for possible bowel ischemia (which was not seen), and subsequently expired on POD59. The third patient, who had an LAS of 37.9, was taken to the OR on POD3 for re-exploration of a bile duct leak, which was found to be bile duct ischemia from hepatic arterial compression due to arcuate ligament syndrome. This was resolved by the surgical release of the arcuate ligament with no further complications. The fourth patient, who underwent combined lung, liver, and heart transplantation, had an LAS of 37.8, and he developed necrotizing pancreatitis by POD23 and required several visits to the OR for pancreatic debridement. He again returned to the OR on POD30 for a repair of a duodenal perforation. After a prolonged hospital course, the patient expired because of a failure to thrive and sepsis on POD468.
Infectious Complications All patients were placed on broad-spectrum antibiotics (vancomycin, piperacillin/tazobactam, or imipenem/cilastatin) and antifungal agents (voriconazole or micafungin) prophylactically. Chronic colonization of the bronchial tree was present preoperatively in 4 of the 8 recipients (50%) and consisted of Pseudomonas aeruginosa, Klebsiella, and extended-spectrum betalactamase species. All 3 of the patients with CF had
Maintenance MMF, MMF, MMF, MMF, MMF, MMF, MMF, MMF,
tacrolimus, tacrolimus, tacrolimus, tacrolimus, tacrolimus, tacrolimus, tacrolimus, tacrolimus,
prednisone prednisone prednisone prednisone prednisone prednisone prednisone prednisone
(steroid (steroid (steroid (steroid (steroid (steroid (steroid (steroid
taper) taper) taper) taper) taper) taper) taper) taper)
prior colonization. One of the 8 patients had a known history of multidrug-resistant P. aeruginosa susceptible to polymyxin E, which was used for antibiotic prophylaxis before transplantation. This patient did not experience any complications. Two of the 4 patients with prior bacterial colonization (50%) died after CLLT. These 2 patients had the highest LASs (69.9 and 89.0), and they developed sepsis from cultureproven gram-negative bacteremia in the immediate postoperative period.
Patient Outcomes and Graft Survival Patient outcomes are summarized in Table 4. No patients underwent retransplantation. The median postoperative length of stay was 24.5 days (range 5 7181 days). The median follow-up was 505.5 days (range 5 7-1355 days). The patient and graft survival rates at 30 days, 90 days, and 1 year were 87.5% (7/8), 75.0% (6/8), and 71.4% (5/7) respectively. Two patients died within 90 days of CLLT: they had experienced acute respiratory failure requiring ventilator support before the operation and had the highest recipient LASs of 69.9 and 89.0. The remaining recipients had a median LAS of 39.5 and 100% survival at 1 year. Fifty percent of the deaths occurred beyond the 90-day postoperative period, and they were due to decompensated liver disease from recurrent hepatitis C on POD627 and to gram-negative sepsis with respiratory failure on POD468. The causes of sepsis included bacteremia with P. aeruginosa and pneumonia with multidrug resistant P. aeruginosa.
DISCUSSION CLLT is an important option for patients with endstage lung disease secondarily compromised by liver disease. Although multiorgan transplantation has gained increasing acceptance, the procedure still faces multiple challenges. More importantly, the identification of outcomes is needed to justify dual allocation to a single recipient. Here we analyze one of the largest US single-center reports on CLLT. Because of the complexity of the procedure, CLLT is not frequently performed, and there is limited
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YI ET AL. 51
TABLE 4. Patient Outcomes Acute Patient
Length of
Follow-Up
Postoperative
Cellular
Stay (Days)
(Days)*
Complications
Rejection
Outcome
Cause of Death
1
11
627
None
No
Expired (POD627)
Liver failure (recurrent hepatitis C)
2 3
54 7
1355 7
No No
Survived Expired (POD7)
Sepsis
4 5
15 59
876 59
No No
Survived Expired (POD59)
Sepsis
6 7
35 181
543 468
Bile duct ischemia (POD3) Bile duct leak (POD2), extracorporeal membrane oxygenation (POD7), sepsis, multiorgan failure None Ischemic necrosis of bronchial anastomosis (POD15), bronchopleural fistula (POD58), sepsis None Necrotizing pancreatitis (POD23), duodenal perforation (POD30), sepsis
No No
Survived Expired (POD468)
8
11
275
Acute lung rejection (grade A1 or minimal)
Lung: Yes Liver: No
Survived
Number
Sepsis, respiratory failure, failure to thrive
*To date (September 1, 2013).
information regarding patient characteristics and outcomes. The largest published single-center series comes from Germany: Grannas et al.3 described 13 patients with a median age of 35 years (range 5 19-55 years) who underwent CLLT from 1999 to 2003. Similarly to our study, the indications for CLLT encompassed a wide range of diseases, including treatmentresistant pulmonary hypertension (n 5 5), CF (n 5 5), AATD (n 5 2), and sarcoidosis (n 5 1). The overall patient survival rates at 1, 3, and 5 years were 69%, 62%, and 49%, respectively. Fifty percent of the deaths were due to sepsis. Interestingly, 76.9% of their recipients (10/13) were colonized with bacteria before their procedure, and despite prophylactic antibiotics, 5 patients developed pneumonia postoperatively. However, recipient selection criteria for achieving improved outcomes were not clearly defined. In the United States, the largest published report on CLLT came from Arnon et al.,1 who reviewed the UNOS database from 1987 to 2008 and identified 7 children and 8 adults with CF who underwent CLLT. The average recipient age was 14.8 6 8.2 years, which is less than the average age of previous case reports and our series. In this young cohort, the 1-year graft and patient survival rates were 80%, and patients who were 11 to 18 years old had the highest 1-year survival rate of 88.3%. Adults in this study had a lower 1-year survival rate, and this suggests greater lung and liver disease severity. The LAS was available for only 4 patients and was on average 41.9 6 6.1 (range 5 35-50).
The adoption of the LAS in 2005 changed organ allocation, wait-list status, and expected outcomes.1,3,4 In lung-only transplant patients, a higher LAS confers a worse prognosis. Merlo et al.13 showed that the risk of death was significantly increased among patients with an LAS > 46. Horai et al.14 showed that recipients with an LAS > 50 were associated with significantly decreased survival and increased complications in comparison with patients with an LAS < 50. Recipients with IPF in a higher LAS group had a significantly lower survival rate than recipients with IPF in a lower LAS group.15 Patients with CF did not show any significant differences in survival when they underwent transplantation with a high LAS versus a low LAS.13 Furthermore, national and regional data from 2011 showed 1-year survival rates for double-lung–only transplants of 82.6% and 78.1%, respectively.16 Seventy-one percent of these recipients had an LAS < 50, and this demonstrated that patients with an LAS < 50 achieved superior survival outcomes in comparison with patients with a higher LAS.16 Our CLLT patients achieved an overall survival rate of 71.4% at 1 year. However, the patients in our series with an LAS < 50 exhibited 100% 1-year survival, and this rivals rates achieved with single- or double-lung transplants with an equivalent LAS. This argues for the continued application of the combined procedure with careful recipient selection. Although it may be difficult to define futility at the present time, our data currently argue against the application of CLLT for ventilated patients or patients with an LAS > 50. Although nutrition is of paramount
52 YI ET AL.
importance, the utilization of BMI alone as a predictor of survivability may not be adequate. Patient selection for CLLT is complicated by increased wait-list times for all organs, and this prompts the need to justify the use of multiple organs in a single recipient. In 2011, there were 1753 and 15,376 patients nationally on the lung and liver wait lists, respectively.16,17 Only 52% and 36.1% of those listed after 1 year underwent lung transplantation and liver transplantation, respectively.16,17 At our center, liver patients were selected for CLLT on the basis of biopsy-proven cirrhosis and a portal pressure gradient. This selection was based on previous demonstrations of increased perioperative mortality in patients with cirrhosis and elevated portal pressures.18 The MELD scores of these patients ranged from 7 to 14. These scores seemed low because the primary indication for CLLT was the severity of lung disease in all cases. Currently, there is no MELD score above which we have not performed the procedure. Nevertheless, caution is warranted for patients with high MELD scores, which may synergize with a high LAS to increase the complexity of the procedure and reduce outcomes. At the onset of our experience, liver transplantation was performed after implantation of the lungs. This sequence resulted in the majority of intraoperative fluid resuscitations and blood transfusions after transplantation of the new lungs and thereby contributed to lung injury. To minimize this possibility of injury from excessive fluid administration, we have implemented a protocol to perform abdominal dissection of the liver and product administration while the old lungs are in place. This is followed by the lung transplant procedure and completion of the liver transplant. We believe that this approach may reduce injury to the new lungs. Challenges in the immediate postprocedural period for CLLT include the desire to restrict fluid intake and blood pressure support by vasopressors on the part of the pulmonary transplant team. Although this may be beneficial to the lungs, it may compromise liver and abdominal organ perfusion. We encountered severe pancreatitis in 1 patient and a bile duct leak in 2 other recipients. We have, therefore, newly adopted a strategy of allowing more liberal fluid intake for a central venous pressure of 8 to 10 mm Hg and reduced vasopressor support. With increasing experience, clinical pathways will be better developed to facilitate the optimal postoperative management of CLLT patients. Infectious complications are the most common cause of death for patients undergoing CLLT. Deaths in the first 90 days were all attributed to sepsis. Patients with CF appear to be the most susceptible. Colonization with P. aeruginosa19 or Burkholderia cepacia20 has been shown to confer a worse prognosis for patients undergoing transplantation for CF. It has been estimated that approximately 80% of patients with CF are colonized with P. aeruginosa.21 The recurrent use of antibiotics for a recurring infection before transplantation may result in drug-resistant bacteria.22 Although
LIVER TRANSPLANTATION, January 2014
the exact pathway for de novo allograft colonization is unclear, therapies targeted at preventing de novo allograft colonization or early aggressive treatment may confer a survival benefit to these patients. Currently, we have not denied CLLT on the basis of preoperative colonization. Although 2 patients died of sepsis, these recipients exhibited high LASs 70. In contrast, 2 of the 3 CF patients who exhibited colonization but a low LAS achieved excellent outcomes. We strongly recommend continued antibiotic therapy for all colonized organisms in the 3 months after CLLT; this is akin to the principle of antifungal prophylaxis for our liver recipients. Thus, our data and others argue against denying a combined procedure on the basis of bacterial colonization.23 Immunosuppression may also be adjusted to reduce the infectious risk. Sepsis—not rejection—was the primary cause of mortality for our patients. Currently, our immunosuppression protocol is targeted toward the lung allograft. Tacrolimus levels are titrated at 10 to 12 ng/mL, whereas levels for liver-only grafts are maintained at a lower level of 7 to 8 ng/mL. The utilization of antibody induction is aimed to delay the introduction of calcineurin inhibitors to confer renal protection. Liver allografts have been postulated to be immunoprotective for other cotransplanted allografts. This theory is based on the ability of the liver to reduce the level of lymphocytotoxic antibiotics and release class I antigens.24,25 Additionally, the transplanted liver may also result in improved immune properties previously not seen because of the diseased organ.5 In a retrospective review of the UNOS database, Rana et al.5 showed that rejection rates were significantly lower for patients who underwent multiorgan transplants (including the liver) versus patients with only 1 allograft. Despite the low number of rejection episodes in our study, it may be too early to conclude that the liver confers a protective advantage to the lung allograft. We currently decrease the tacrolimus dose to 5 to 8 ng/mL at 3 months, taper the prednisone dose to 0.1 mg/kg/day, and monitor MMF in the first year. Continued follow-up for such patients may provide further insights into immunosuppression utilization. The identification of suitable candidates for multiorgan transplantation is complex and may require the evaluation of multiple factors in comparison with single-organ transplantation. Additionally, appropriate candidate selection is necessary to ensure proper utility for the limited organs allocated to patients on growing transplant wait lists. Therefore, outcomes research such as the outcomes data presented in this study helps us to improve our prognostic abilities and enable more effective allocation decisions that are consistent with utility.
ACKNOWLEDGMENTS The authors acknowledge Courtenay R. Bruce, J.D., M.A. (consultant for medical ethics and health policy); Kristine Dahl, R.N. (quality transplant
LIVER TRANSPLANTATION, Vol. 20, No. 1, 2014
coordinator and pulmonary database administrator); and Samir Patel, Pharm.D. (clinical transplant pharmacist).
REFERENCES 1. Arnon R, Annunziato RA, Miloh T, Padilla M, Sogawa H, Batemarco L, et al. Liver and combined lung and liver transplantation for cystic fibrosis: analysis of the UNOS database. Pediatr Transplant 2011;15:254-264. 2. Barshes NR, DiBardino DJ, McKenzie ED, Lee TC, Stayer SA, Mallory GB, et al. Combined lung and liver transplantation: the United States experience. Transplantation 2005;80:1161-1167. 3. Grannas G, Neipp M, Hoeper MM, Gottlieb J, L€ uck R, Becker T, et al. Indications for and outcomes after combined lung and liver transplantation: a single-center experience on 13 consecutive cases. Transplantation 2008;85:524-531. 4. Couetil JP, Houssin DP, Soubrane O, Chevalier PG, Dousset BE, Loulmet D, et al. Combined lung and liver transplantation in patients with cystic fibrosis: a 4 1/2year experience. J Thorac Cardiovasc Surg 1995;110: 1415-1422. 5. Rana A, Robles S, Russo MJ, Halazun KJ, Woodland DC, Witkowski P, et al. The combined organ effect: protection against rejection? Ann Surg 2008;248:871-879. 6. Praseedom RK, McNeil KD, Watson CJ, Alexander GJ, Calne RY, Wallwork J, Friend PJ. Combined transplantation of the heart, lung, and liver. Lancet 2001;358:812813. 7. United Network for Organ Sharing. A guide to calculating the lung allocation score. http://www.unos.org/docs/ lung_allocation_score.pdf. Accessed May 2013. 8. United Network for Organ Sharing. Questions & answers for transplant candidates about liver allocation policy. http://www.unos.org/docs/Liver_patient.pdf. Accessed May 2013. 9. Organ Procurement and Transplantation Network. Policy 3.93. Organ allocation to multiple organ transplant candidates. http://optn.transplant.hrsa.gov/PoliciesandBylaws2/policies/pdfs/policy_11.pdf. Accessed August 2013. 10. Sundaresan S, Trachiotis GD, Aoe M, Patterson GA, Cooper JD. Donor lung procurement: assessment and operative technique. Ann Thorac Surg 1993;56:14091413. 11. Abu-Elmagd K, Fung J, Bueno J, Martin D, Madariaga JR, Mazariegos G, et al. Logistics and technique for procurement of intestinal, pancreatic, and hepatic grafts from the same donor. Ann Surg 2000;232:680-687. 12. Busuttil RW, Colonna JO II, Hiatt JR, Brems JJ, el Khoury G, Goldstein LI, et al. The first 100 liver transplants at UCLA. Ann Surg 1987;206:387-402.
YI ET AL. 53
13. Merlo CA, Weiss ES, Orens JB, Borja MC, Diener-West M, Conte JV, Shah AS. Impact of U.S. lung allocation score on survival after lung transplantation. J Heart Lung Transplant 2009;28:769-775. 14. Horai T, Shigemura N, Gries C, Pilewski J, Bhama JK, Bermudez CA, et al. Lung transplantation for patients with high lung allocation score: single-center experience. Ann Thorac Surg 2012;93:1592-1597. 15. Weiss ES, Allen JG, Merlo CA, Conte JV, Shah AS. Lung allocation score predicts survival in lung transplantation patients with pulmonary fibrosis. Ann Thorac Surg 2009; 88:1757-1764. 16. Scientific Registry of Transplant Recipients. OPTN/SRTR 2011 annual data report: lung. http://srtr.transplant. hrsa.gov/annual_reports/2011/pdf/06_lung_12.pdf. Accessed May 2013. 17. Scientific Registry of Transplant Recipients. OPTN/SRTR 2011 annual data report: liver. http://srtr.transplant. hrsa.gov/annual_reports/2011/pdf/03_%20liver_12.pdf. Accessed May 2013. 18. Bruix J, Castells A, Bosch J, Feu F, Fuster J, GarciaPagan JC, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:10181022. 19. Botha P, Archer L, Anderson RL, Lordan J, Dark JH, Corris PA, et al. Pseudomonas aeruginosa colonization of the allograft after lung transplantation and the risk of bronchiolitis obliterans syndrome. Transplantation 2008; 85:771-774. 20. Boussaud V, Guillemain R, Grenet D, Coley N, Souilamas R, Bonnette P, Stern M. Clinical outcome following lung transplantation in patients with cystic fibrosis colonised with Burkholderia cepacia complex: results from two French centres. Thorax 2008;63:732-737. 21. Tramper-Stranders GA, van der Ent CK, Slieker MG, Terheggen-Lagro SW, Teding van Berkhout F, Kimpen JL, Wolfs TF. Diagnostic value of serological tests against Pseudomonas aeruginosa in a large cystic fibrosis population. Thorax 2006;61:689-693. 22. Chaparro C, Kesten S. Infections in lung transplant recipients. Clin Chest Med 1997;18:339-351. 23. Aris RM, Gilligan PH, Neuringer IP, Gott KK, Rea J, Yankaskas JR. The effects of panresistant bacteria in cystic fibrosis patients on lung transplant outcome. Am J Respir Crit Care Med 1997;155:1699-1704. 24. Cr eput C, Durrbach A, Menier C, Guettier C, Samuel D, Dausset J, et al. Human leukocyte antigen-G (HLA-G) expression in biliary epithelial cells is associated with allograft acceptance in liver-kidney transplantation. J Hepatol 2003;39:587-594. 25. Gugenheim J, Le Thai B, Rouger P, Gigou M, Gane P, Vial MC, et al. Relationship between the liver and lymphocytotoxic alloantibodies in inbred rats. Specific absorption by nonparenchymal liver cells. Transplantation 1988;45:474-478.
ORIGINAL ARTICLE
Combined Lung and Liver Transplantation: Analysis of a Single-Center Experience Stephanie G. Yi,1 Sherilyn Gordon Burroughs,1 Matthias Loebe,2 Scott Scheinin,2 Harish Seethamraju,5 Soma Jyothula,3 Howard Monsour,4 Robert McFadden,4 Hemangshu Podder,1 Ashish Saharia,1 Emad H. Asham,1 Maha Boktour,1 A. Osama Gaber,1 R. Mark Ghobrial1 1 Department of Surgery, 2Department of Cardiovascular Surgery, 3Division of Lung Transplantation, Department of Medicine, and 4Division of Hepatology and Transplant Medicine, Department of Medicine, Methodist Hospital, Houston, TX; and 5Department of Internal Medicine, University of Kentucky, Lexington, KY
Patients with end-stage lung disease complicated by cirrhosis are not expected to survive lung transplantation alone. Such patients are potential candidates for combined lung-liver transplantation (CLLT), however few reports document the indications and outcomes after CLLT. This is a review of a large single-center CLLT series. Eight consecutive CLLT performed during 2009-2012 were retrospectively reviewed. One patient received a third simultaneous heart transplant. Mean age was 42.5 6 11.5 years. Pulmonary indications included cystic fibrosis (CF) (n 5 3), idiopathic pulmonary fibrosis (n 5 2), a1-antitrypsin deficiency (AATD) (n 5 1) and pulmonary hypertension (n 5 2). Liver indications were CF (n 5 3), hepatitis C (n 5 2), AATD (n 5 1), cryptogenic (n 5 1), and cardiac=congestive (n 5 1). Urgency was reflected by median lung allocation score (LAS) of 41 (36.0-89.0) and median predicted FEV1 of 25.7%. Median donor age was 25 (20-58) years with median cold ischemia times of 147 minutes and 6.1 hours for lung and liver, respectively. Overall patient survival at 30 days, 90 days and 1 year was 87.5%, 75.0% and 71.4% respectively. One patient had evidence of acute lung rejection, and no patients had liver allograft rejection. Early postoperative mortalities (90 days) were caused by sepsis in 2 recipients who exhibited the highest LAS of 69.9 and 89.0. The remaining recipients had a median LAS of 39.5 and 100% survival at 1-year. Median length of stay was 25 days (7-181). Complications requiring operative intervention included bile duct ischemia (n 5 1) and bile leak (n 5 1), ischemia of the bronchial anastomosis (n 5 1), and necrotizing pancreatitis with duodenal perforation (n 5 1). This series reflects a large single-center CLLT experience. Sepsis is the most common cause of death. The procedure should be considered for candidates with LAS < 50. Liver Transpl C 2013 AASLD. 20:46-53, 2014. V Received July 29, 2013; accepted September 29, 2013.
Combined lung and liver transplantation (CLLT) is a viable treatment option for patients with end-stage lung and liver disease who are not expected to survive with either transplant alone. Diseases that affect both the lungs and the liver, such as cystic fibrosis (CF)1,2 and alpha-1antitrypsin deficiency (AATD), have been previously described for CLLT.3,4 Putative benefits of multiorgan
transplantation with the inclusion of a liver graft include protection against rejection and survivability equivalent to that with single-organ transplantation.2,5 However, CLLT is not commonly performed, and the indications and the expected outcomes continue to be unclear. Because of the limited collective experience with CLLT, prior case series have reported variability in
Abbreviations: AATD, alpha-1-antitrypsin deficiency; BMI, body mass index; CF, cystic fibrosis; CLLT, combined lung and liver transplantation; FEV1, forced expiratory volume in 1 second; IPF, idiopathic pulmonary fibrosis; LAS, lung allocation score; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; OR, operating room; POD, postoperative day; UNOS, United Network for Organ Sharing. The authors have no grants, financial support, or conflicts of interest to report. Address reprint requests to Stephanie G. Yi, M.D., M.S., Department of Surgery, Methodist Hospital, 6565 Fannin Street, SM 1661 A, Houston, TX 77030. Telephone: 713-441-8085; FAX: 713-790-2872; E-mail: [email protected] DOI 10.1002/lt.23770 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2013 American Association for the Study of Liver Diseases. V
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patient populations, recipient selection criteria, and posttransplant management (eg, immunosuppression). Previously described recipient populations have ranged from pediatric patients with genetic diseases to patients with separate lung and liver disease who were on average 40 to 50 years old. Recently applied allocation schemes such as the Model for End-Stage Liver Disease (MELD) score and the lung allocation score (LAS) did not dictate patient selection in these series. Additionally, CLLT cases described in the literature were performed from 1986 to 2004, and this was an era before the most recent immunosuppressive agents and protocols for posttransplant care. The majority of single-center CLLT cases have been international, with data from the United States arising from multicenter institutions reflected in the United Network for Organ Sharing (UNOS) database. Currently, 58 cases have been published, and the 1-year mortality rate has ranged from 55.6% to 80%.1-4,6 Patient mortality has been attributed primarily to sepsis, with an earlier study reporting rejection.2,3 Most patients had previously known bacterial colonization,3 which may have placed these patients at a greater risk of death. More information is needed to determine which patients are at greatest risk for postoperative complications. Here we present our large singlecenter CLLT series and suggest criteria for patient selection for this combined procedure.
PATIENTS AND METHODS Data Collection Under an institutional review board–approved protocol, we performed a retrospective analysis of 8 consecutive patients greater than 18 years of age who underwent CLLT at our institution between February 3, 2009 and November 30, 2012. One patient underwent simultaneous heart, lung, and liver transplantation, whereas another patient received an islet cell transplant concomitantly with lung and liver transplantation. The following data were collected: the recipient age, sex, body mass index (BMI), albumin level, lung disease, liver disease, pulmonary function, and wait-list time; the donor age and BMI; the graft type, cold ischemia time, and warm ischemia time; and the 30-day, 90-day, and 1-year outcomes.
Patient Characteristics CLLT candidacy was determined with our center’s criteria for lung transplantation first, and approval for dual listing came after a multidisciplinary board review. Liver transplant candidacy for CLLT was based on the presence of biopsy-proven cirrhosis and a portal gradient 10 mm Hg. Candidates were listed according to the recipient LAS7 and the MELD score.8
Organ Allocation Transplant candidacy for patients with multiorgan disease was primarily based on the LAS, even in the
YI ET AL. 47
setting of heart, lung, and liver transplantation. Regional allocation protocols were based on Organ Procurement and Transplantation Network policy 3.9.3 for multiorgan allocation,9 which requires a candidate to be registered on each organ waiting list separately. If the candidate was eligible to receive a lung transplant from a local donor, the liver from the same donor was allocated to the multiorgan candidate. If the candidate was on the waiting list outside the local organ distribution unit, a mutual agreement among organizations within the regional setting was made to accommodate the aforementioned policy. Thus, the heart and the liver were allocated to the lung transplant recipient according to the LAS in all cases. Exclusion criteria for all wait lists included active infection, extrahepatic or extrapulmonary malignancy, history of noncompliance, evidence of substance abuse, and unavailability of social resources.
Donor Operation Donors were selected on the basis of standard criteria for lung and liver transplantation, and grafts were obtained by standard thoracoabdominal procurement techniques.10,11 All donors received intravenous heparin before procurement. Lung explants were infused with prostaglandin E1 and a preservation solution (Perfadex, XVIVO Perfusion AB, Gothenburg, Sweden). Liver explants were cooled and preserved in University of Wisconsin solution. The lung ischemia time was defined as the time between the clamping of donor vessels and the unclamping of recipient vessels.
Recipient Operation Lung and liver transplants were performed sequentially in the same operative setting. By 2011, patients were undergoing abdominal dissection before both lung and liver implantation in order to minimize the transfusion of blood products, fluid resuscitation, and pulmonary edema in the newly transplanted lung.
Lung Transplantation Bilateral thoracosternotomy or bilateral anterolateral thoracotomy through the fourth or fifth intercostal space was used for sequential double-lung transplantation. Cardiopulmonary bypass was not used during the lung transplantation procedure. Heart and lung transplantation was performed with a cardiopulmonary bypass.
Deceased Donor Whole Organ Liver Transplantation Whole organ orthotopic liver transplantation was performed in the normal, standard manner, as described previously.12 Venovenous bypass was used when the patient exhibited hemodynamic instability with test clamping of the portal vein. No livers were used for domino transplantation because all livers were cirrhotic.
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LIVER TRANSPLANTATION, January 2014
TABLE 1. Recipient Demographics Patient
Age
BMI
FEV1
MELD
(Years)
Sex
(kg/m2)
LAS
(% Predicted)
Lung Diagnosis
Score
Liver Diagnosis
1
54
Female
21.5
41.3
25.4
10
Hepatitis C
2 3 4 5
52 28 42 52
Female Female Male Female
29.6 16.0 18.0 20.1
37.9 69.9 41.0 89.0
14 14 24 36
Pulmonary hypertension AATD CF CF IPF
7 8 8 11
6 7
49 39
Male Male
22.0 16.5
44.2 37.8
36 34
9 14
8
24
Female
17.8
36.0
26
IPF Secondary pulmonary hypertension (congestive heart failure) CF
AATD CF CF Cryptogenic cirrhosis Hepatitis C Congestive
12
CF
Number
Islet Cell Transplantation
RESULTS
Islet cell transplantation was performed via portal vein cannulation after the completion of both the lung and liver transplants under the same anesthesia.
Patient Demographics
Immunosuppression Immunosuppression was administered according to the pulmonary transplant protocol. Recipients received methylprednisolone induction with or without daclizumab or basiliximab. Maintenance immunosuppression consisted of mycophenolate mofetil (MMF), a steroid taper, and tacrolimus, which was started on postoperative day 4 (POD4) after an evaluation of each patient’s renal function. The postoperative methylprednisolone dosing was as follows: 2 mg/ kg/day on POD1, 1 mg/kg/day on POD2, 0.5 mg/kg/ day from POD3 until tacrolimus was therapeutic, and then 10 mg of oral prednisone daily. Tacrolimus levels were titrated for a target trough level of 10 to 12 ng/ mL for 3 months, and this was reduced to 5 to 8 ng/ mL thereafter. On the basis of clinical suspicion or graft function, additional high-dose steroids were used at the discretion of the pulmonary transplant team. Starting on POD0, surveillance bronchoscopy was used to evaluate all patients for possible rejection. Bronchoscopy was performed weekly until 1 month after the operation and then every 2 weeks for 3 months, and this was followed by every month for a year. Postoperative liver function tests were used to monitor liver allograft function.
Twenty-one patients at our institution were placed on the CLLT waiting list. All patients had severe pulmonary disease with cirrhosis. Eight of these patients underwent CLLT, with 1 patient undergoing combined heart, lung, and liver transplantation and another undergoing combined islet cell, lung, and liver transplantation. Demographic information and disease severity are summarized in Table 1. The mean age of the patients at the time of transplantation was 42.5 6 11.5 years. Three patients (37.5%) were male, and 5 (62.5%) were female. The median BMI was 19.1 kg/m2 (range 5 16.0-29.6 kg/m2), and the median albumin level was 3.5 g/dL (range 5 2.4-3.9 g/dL) before the operation.
Indications for Transplantation The pulmonary indications included CF (n 5 3), idiopathic pulmonary fibrosis (IPF; n 5 2), AATD (n 5 1), and pulmonary hypertension (n 5 2). The biopsy-proven causes of cirrhosis were CF (n 5 3), hepatitis C (n 5 2), AATD (n 5 1), cryptogenic cirrhosis (n 5 1), and cardiac/ congestive (n 5 1). Urgency was reflected by a median LAS of 41 (range 5 36.0-89.0) and by a median predicted forced expiratory volume in 1 second (FEV1) of 25.7% (range 5 14%-36%). All patients required supplemental oxygen before transplantation; 2 patients (25%) were on mechanical ventilation (patients 3 and 5). The median MELD score was 9.5 (range 5 7-14). All patients receiving CLLT exhibited biopsy-proven cirrhosis with portal hypertension. The median wait-list time for transplantation was 116 days (range 5 40-709 days).
Statistics The statistical analysis was performed with Stata 12.1 (StataCorp, College Station, TX). Descriptive statistics are presented as medians and ranges.
Donor Details Donor characteristics and ischemia times are summarized in Table 2. All were ABO-identical, cadaveric,
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YI ET AL. 49
TABLE 2. Donor and Graft Characteristics Donor Patient Number
Donor
Liver Cold
Liver Warm
Age
Donor
BMI
Lung Ischemia
Ischemia
Ischemia
(Years)
Sex
(kg/m2)
Time (Minutes)*
Time (Hours)
Time (Minutes)
34 58 23 21 27 40 20 20
Male Male Female Male Male Male Female Male
22.7 22.3 18.3 20.9 19.7 29.1 29.0 20.2
213† (right) (right) (right) (right) (right) (right) (right)
6.4 6.2 7.0 5.9 7.8 4.7 3.8 5.4
19 20 27 11 36 23 36 34
1 2 3 4 5 6 7 8
193 (left) 136 147 (left) 198 229 (left) 182 193 (left) 260 126 (left) 81 72 (left)‡ 72 77 (left) 147
*Including donor clamping and recipient unclamping. Single-lung transplant only. ‡ En bloc heart and double-lung transplants. †
brain-dead donors. The median donor age was 25 years (range 5 20-58 years), and the median BMI was 21.6 kg/m2 (range 5 18.3-29.1 kg/m2). The median lung ischemia time was 147 minutes (range 5 72-260 minutes). The median cold and warm liver ischemia times were 6.1 hours (range 5 3.8-7.8 hours) and 25 minutes (range 5 11-36 minutes), respectively.
Operative Details All but 1 patient underwent bilateral lung transplantation (patient 1). Whole livers were used for all liver transplants. One patient (patient 3) received a simultaneous third transplant of pancreatic islet cells, and another patient (patient 7) underwent simultaneous lung, liver, and heart transplantation. All recipients underwent 2-stage sequential transplantation (lung and then liver) under the same anesthesia. Two patients required delayed biliary reconstruction after hemodynamic optimization (patients 5 and 6). Four patients (50%) required venovenous bypass during liver transplantation. The median values for intraoperative blood product use were 8 U of packed red blood cells, 8.5 U of fresh frozen plasma, and 1.5 U of platelets. The mean transplant operating room (OR) time was 8.6 6 1.2 hours for both procedures.
One patient required extracorporeal membrane oxygenation in the immediate postoperative period and subsequently died (patient 3).
Immunosuppression Specific immunosuppression regimens are summarized in Table 3. Immunoprophylaxis consisted of a regimen of corticosteroids, MMF, and tacrolimus. Four patients received daclizumab or basiliximab with induction. Tacrolimus levels were dosed according to the protocol described in the Patients and Methods section. Corticosteroids were dosed and tapered on the basis of weight as described in the Patients and Methods section. All patients underwent surveillance bronchoscopy as described in the Patients and Methods section, and postoperative liver function tests were performed to monitor liver allograft function. One of the 8 patients exhibited bronchoscopic evidence of early acute rejection on POD2 and received high-dose steroids. This patient did not exhibit any additional bronchoscopic signs of rejection after treatment and was subsequently discharged from the hospital by POD11. No evidence of liver allograft rejection was detected in any patient.
Surgical Complications Postoperative Management Immediate postoperative management combined fluid restriction and vasopressor support titrated for a mean arterial pressure 65 mm Hg. Postoperatively, patients had a median central venous pressure of 8.5 mm Hg (range 5 4-17 mm Hg) and a median pulmonary artery pressure of 22.3 mm Hg (range 5 14.3-27 mm Hg). Fifty percent of the patients were extubated (patients 1, 4, 7, and 8), whereas the remaining patients could not be weaned from the ventilator and underwent tracheostomy (50%). The patients who were extubated had a median LAS of 39.4 (range 5 36.0-41.3), whereas those requiring tracheostomy had a median LAS of 57 (range 5 37.9-89.0).
No primary nonfunction of the hepatic graft was reported in this series. Additionally, there was no incidence of hepatic artery thrombosis or portal vein thrombosis. Because of hemodynamic instability or marginal oxygenation during transplantation, 2 patients returned to the OR for delayed biliary reconstruction or closure of the abdomen and chest. Four patients (50%) had unplanned returns to the OR. Three patients had multiple (>1) returns to the OR after the initial transplant. Patients who had unplanned returns to the OR had a median LAS of 53.9 (range 5 37.8-89.0), whereas those who did not return to the OR had a median LAS of 41.2 (range 5 36.0-44.2).
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TABLE 3. Immunosuppression Patient Number 1 2 3 4 5 6 7 8
Induction Methylprednisolone Methylprednisolone, daclizumab Methylprednisolone Methylprednisolone Methylprednisolone, basiliximab Methylprednisolone, basiliximab Methylprednisolone Methylprednisolone, basiliximab
Two of the 4 patients with unplanned returns to the OR developed septic shock in the postoperative period. The first patient, who had a history of CF, had an LAS of 69.9 and developed a bile duct leak requiring exploratory laparotomy on POD2 for the revision of the biliary anastomosis with T-tube placement. This patient went into septic shock, required multiple vasopressors, and on POD7 was placed on extracorporeal membrane oxygenation and expired. The second patient, who had a history of IPF and cryptogenic cirrhosis, had an LAS of 89.0 and developed a bronchopleural fistula from ischemia of the bronchial anastomosis. This patient was on multiple high-dose vasopressors immediately after transplantation. Despite bronchial stent placement on POD15, the patient became septic, returned to the OR on POD58 for muscle flap coverage over the bronchopleural fistula, underwent exploratory laparotomy for an evaluation for possible bowel ischemia (which was not seen), and subsequently expired on POD59. The third patient, who had an LAS of 37.9, was taken to the OR on POD3 for re-exploration of a bile duct leak, which was found to be bile duct ischemia from hepatic arterial compression due to arcuate ligament syndrome. This was resolved by the surgical release of the arcuate ligament with no further complications. The fourth patient, who underwent combined lung, liver, and heart transplantation, had an LAS of 37.8, and he developed necrotizing pancreatitis by POD23 and required several visits to the OR for pancreatic debridement. He again returned to the OR on POD30 for a repair of a duodenal perforation. After a prolonged hospital course, the patient expired because of a failure to thrive and sepsis on POD468.
Infectious Complications All patients were placed on broad-spectrum antibiotics (vancomycin, piperacillin/tazobactam, or imipenem/cilastatin) and antifungal agents (voriconazole or micafungin) prophylactically. Chronic colonization of the bronchial tree was present preoperatively in 4 of the 8 recipients (50%) and consisted of Pseudomonas aeruginosa, Klebsiella, and extended-spectrum betalactamase species. All 3 of the patients with CF had
Maintenance MMF, MMF, MMF, MMF, MMF, MMF, MMF, MMF,
tacrolimus, tacrolimus, tacrolimus, tacrolimus, tacrolimus, tacrolimus, tacrolimus, tacrolimus,
prednisone prednisone prednisone prednisone prednisone prednisone prednisone prednisone
(steroid (steroid (steroid (steroid (steroid (steroid (steroid (steroid
taper) taper) taper) taper) taper) taper) taper) taper)
prior colonization. One of the 8 patients had a known history of multidrug-resistant P. aeruginosa susceptible to polymyxin E, which was used for antibiotic prophylaxis before transplantation. This patient did not experience any complications. Two of the 4 patients with prior bacterial colonization (50%) died after CLLT. These 2 patients had the highest LASs (69.9 and 89.0), and they developed sepsis from cultureproven gram-negative bacteremia in the immediate postoperative period.
Patient Outcomes and Graft Survival Patient outcomes are summarized in Table 4. No patients underwent retransplantation. The median postoperative length of stay was 24.5 days (range 5 7181 days). The median follow-up was 505.5 days (range 5 7-1355 days). The patient and graft survival rates at 30 days, 90 days, and 1 year were 87.5% (7/8), 75.0% (6/8), and 71.4% (5/7) respectively. Two patients died within 90 days of CLLT: they had experienced acute respiratory failure requiring ventilator support before the operation and had the highest recipient LASs of 69.9 and 89.0. The remaining recipients had a median LAS of 39.5 and 100% survival at 1 year. Fifty percent of the deaths occurred beyond the 90-day postoperative period, and they were due to decompensated liver disease from recurrent hepatitis C on POD627 and to gram-negative sepsis with respiratory failure on POD468. The causes of sepsis included bacteremia with P. aeruginosa and pneumonia with multidrug resistant P. aeruginosa.
DISCUSSION CLLT is an important option for patients with endstage lung disease secondarily compromised by liver disease. Although multiorgan transplantation has gained increasing acceptance, the procedure still faces multiple challenges. More importantly, the identification of outcomes is needed to justify dual allocation to a single recipient. Here we analyze one of the largest US single-center reports on CLLT. Because of the complexity of the procedure, CLLT is not frequently performed, and there is limited
LIVER TRANSPLANTATION, Vol. 20, No. 1, 2014
YI ET AL. 51
TABLE 4. Patient Outcomes Acute Patient
Length of
Follow-Up
Postoperative
Cellular
Stay (Days)
(Days)*
Complications
Rejection
Outcome
Cause of Death
1
11
627
None
No
Expired (POD627)
Liver failure (recurrent hepatitis C)
2 3
54 7
1355 7
No No
Survived Expired (POD7)
Sepsis
4 5
15 59
876 59
No No
Survived Expired (POD59)
Sepsis
6 7
35 181
543 468
Bile duct ischemia (POD3) Bile duct leak (POD2), extracorporeal membrane oxygenation (POD7), sepsis, multiorgan failure None Ischemic necrosis of bronchial anastomosis (POD15), bronchopleural fistula (POD58), sepsis None Necrotizing pancreatitis (POD23), duodenal perforation (POD30), sepsis
No No
Survived Expired (POD468)
8
11
275
Acute lung rejection (grade A1 or minimal)
Lung: Yes Liver: No
Survived
Number
Sepsis, respiratory failure, failure to thrive
*To date (September 1, 2013).
information regarding patient characteristics and outcomes. The largest published single-center series comes from Germany: Grannas et al.3 described 13 patients with a median age of 35 years (range 5 19-55 years) who underwent CLLT from 1999 to 2003. Similarly to our study, the indications for CLLT encompassed a wide range of diseases, including treatmentresistant pulmonary hypertension (n 5 5), CF (n 5 5), AATD (n 5 2), and sarcoidosis (n 5 1). The overall patient survival rates at 1, 3, and 5 years were 69%, 62%, and 49%, respectively. Fifty percent of the deaths were due to sepsis. Interestingly, 76.9% of their recipients (10/13) were colonized with bacteria before their procedure, and despite prophylactic antibiotics, 5 patients developed pneumonia postoperatively. However, recipient selection criteria for achieving improved outcomes were not clearly defined. In the United States, the largest published report on CLLT came from Arnon et al.,1 who reviewed the UNOS database from 1987 to 2008 and identified 7 children and 8 adults with CF who underwent CLLT. The average recipient age was 14.8 6 8.2 years, which is less than the average age of previous case reports and our series. In this young cohort, the 1-year graft and patient survival rates were 80%, and patients who were 11 to 18 years old had the highest 1-year survival rate of 88.3%. Adults in this study had a lower 1-year survival rate, and this suggests greater lung and liver disease severity. The LAS was available for only 4 patients and was on average 41.9 6 6.1 (range 5 35-50).
The adoption of the LAS in 2005 changed organ allocation, wait-list status, and expected outcomes.1,3,4 In lung-only transplant patients, a higher LAS confers a worse prognosis. Merlo et al.13 showed that the risk of death was significantly increased among patients with an LAS > 46. Horai et al.14 showed that recipients with an LAS > 50 were associated with significantly decreased survival and increased complications in comparison with patients with an LAS < 50. Recipients with IPF in a higher LAS group had a significantly lower survival rate than recipients with IPF in a lower LAS group.15 Patients with CF did not show any significant differences in survival when they underwent transplantation with a high LAS versus a low LAS.13 Furthermore, national and regional data from 2011 showed 1-year survival rates for double-lung–only transplants of 82.6% and 78.1%, respectively.16 Seventy-one percent of these recipients had an LAS < 50, and this demonstrated that patients with an LAS < 50 achieved superior survival outcomes in comparison with patients with a higher LAS.16 Our CLLT patients achieved an overall survival rate of 71.4% at 1 year. However, the patients in our series with an LAS < 50 exhibited 100% 1-year survival, and this rivals rates achieved with single- or double-lung transplants with an equivalent LAS. This argues for the continued application of the combined procedure with careful recipient selection. Although it may be difficult to define futility at the present time, our data currently argue against the application of CLLT for ventilated patients or patients with an LAS > 50. Although nutrition is of paramount
52 YI ET AL.
importance, the utilization of BMI alone as a predictor of survivability may not be adequate. Patient selection for CLLT is complicated by increased wait-list times for all organs, and this prompts the need to justify the use of multiple organs in a single recipient. In 2011, there were 1753 and 15,376 patients nationally on the lung and liver wait lists, respectively.16,17 Only 52% and 36.1% of those listed after 1 year underwent lung transplantation and liver transplantation, respectively.16,17 At our center, liver patients were selected for CLLT on the basis of biopsy-proven cirrhosis and a portal pressure gradient. This selection was based on previous demonstrations of increased perioperative mortality in patients with cirrhosis and elevated portal pressures.18 The MELD scores of these patients ranged from 7 to 14. These scores seemed low because the primary indication for CLLT was the severity of lung disease in all cases. Currently, there is no MELD score above which we have not performed the procedure. Nevertheless, caution is warranted for patients with high MELD scores, which may synergize with a high LAS to increase the complexity of the procedure and reduce outcomes. At the onset of our experience, liver transplantation was performed after implantation of the lungs. This sequence resulted in the majority of intraoperative fluid resuscitations and blood transfusions after transplantation of the new lungs and thereby contributed to lung injury. To minimize this possibility of injury from excessive fluid administration, we have implemented a protocol to perform abdominal dissection of the liver and product administration while the old lungs are in place. This is followed by the lung transplant procedure and completion of the liver transplant. We believe that this approach may reduce injury to the new lungs. Challenges in the immediate postprocedural period for CLLT include the desire to restrict fluid intake and blood pressure support by vasopressors on the part of the pulmonary transplant team. Although this may be beneficial to the lungs, it may compromise liver and abdominal organ perfusion. We encountered severe pancreatitis in 1 patient and a bile duct leak in 2 other recipients. We have, therefore, newly adopted a strategy of allowing more liberal fluid intake for a central venous pressure of 8 to 10 mm Hg and reduced vasopressor support. With increasing experience, clinical pathways will be better developed to facilitate the optimal postoperative management of CLLT patients. Infectious complications are the most common cause of death for patients undergoing CLLT. Deaths in the first 90 days were all attributed to sepsis. Patients with CF appear to be the most susceptible. Colonization with P. aeruginosa19 or Burkholderia cepacia20 has been shown to confer a worse prognosis for patients undergoing transplantation for CF. It has been estimated that approximately 80% of patients with CF are colonized with P. aeruginosa.21 The recurrent use of antibiotics for a recurring infection before transplantation may result in drug-resistant bacteria.22 Although
LIVER TRANSPLANTATION, January 2014
the exact pathway for de novo allograft colonization is unclear, therapies targeted at preventing de novo allograft colonization or early aggressive treatment may confer a survival benefit to these patients. Currently, we have not denied CLLT on the basis of preoperative colonization. Although 2 patients died of sepsis, these recipients exhibited high LASs 70. In contrast, 2 of the 3 CF patients who exhibited colonization but a low LAS achieved excellent outcomes. We strongly recommend continued antibiotic therapy for all colonized organisms in the 3 months after CLLT; this is akin to the principle of antifungal prophylaxis for our liver recipients. Thus, our data and others argue against denying a combined procedure on the basis of bacterial colonization.23 Immunosuppression may also be adjusted to reduce the infectious risk. Sepsis—not rejection—was the primary cause of mortality for our patients. Currently, our immunosuppression protocol is targeted toward the lung allograft. Tacrolimus levels are titrated at 10 to 12 ng/mL, whereas levels for liver-only grafts are maintained at a lower level of 7 to 8 ng/mL. The utilization of antibody induction is aimed to delay the introduction of calcineurin inhibitors to confer renal protection. Liver allografts have been postulated to be immunoprotective for other cotransplanted allografts. This theory is based on the ability of the liver to reduce the level of lymphocytotoxic antibiotics and release class I antigens.24,25 Additionally, the transplanted liver may also result in improved immune properties previously not seen because of the diseased organ.5 In a retrospective review of the UNOS database, Rana et al.5 showed that rejection rates were significantly lower for patients who underwent multiorgan transplants (including the liver) versus patients with only 1 allograft. Despite the low number of rejection episodes in our study, it may be too early to conclude that the liver confers a protective advantage to the lung allograft. We currently decrease the tacrolimus dose to 5 to 8 ng/mL at 3 months, taper the prednisone dose to 0.1 mg/kg/day, and monitor MMF in the first year. Continued follow-up for such patients may provide further insights into immunosuppression utilization. The identification of suitable candidates for multiorgan transplantation is complex and may require the evaluation of multiple factors in comparison with single-organ transplantation. Additionally, appropriate candidate selection is necessary to ensure proper utility for the limited organs allocated to patients on growing transplant wait lists. Therefore, outcomes research such as the outcomes data presented in this study helps us to improve our prognostic abilities and enable more effective allocation decisions that are consistent with utility.
ACKNOWLEDGMENTS The authors acknowledge Courtenay R. Bruce, J.D., M.A. (consultant for medical ethics and health policy); Kristine Dahl, R.N. (quality transplant
LIVER TRANSPLANTATION, Vol. 20, No. 1, 2014
coordinator and pulmonary database administrator); and Samir Patel, Pharm.D. (clinical transplant pharmacist).
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