Combined lung and liver transplantation: Analysis of a single-center experience

Authors


  • The authors have no grants, financial support, or conflicts of interest to report.

Abstract

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 ± 11.5 years. Pulmonary indications included cystic fibrosis (CF) (n = 3), idiopathic pulmonary fibrosis (n = 2), α1-antitrypsin deficiency (AATD) (n = 1) and pulmonary hypertension (n = 2). Liver indications were CF (n = 3), hepatitis C (n = 2), AATD (n = 1), cryptogenic (n = 1), and cardiac/congestive (n = 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 = 1) and bile leak (n = 1), ischemia of the bronchial anastomosis (n = 1), and necrotizing pancreatitis with duodenal perforation (n = 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 20:46–53, 2014. © 2013 AASLD.

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

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-1-antitrypsin 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 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 single-center 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 LAS[7] and the MELD score.[8]

Organ Allocation

Transplant candidacy for patients with multiorgan disease was primarily based on the LAS, even in the 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.

Islet Cell Transplantation

Islet cell transplantation was performed via portal vein cannulation after the completion of both the lung and liver transplants under the same anesthesia.

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.

Statistics

The statistical analysis was performed with Stata 12.1 (StataCorp, College Station, TX). Descriptive statistics are presented as medians and ranges.

RESULTS

Patient Demographics

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 ± 11.5 years. Three patients (37.5%) were male, and 5 (62.5%) were female. The median BMI was 19.1 kg/m2 (range = 16.0-29.6 kg/m2), and the median albumin level was 3.5 g/dL (range = 2.4-3.9 g/dL) before the operation.

Table 1. Recipient Demographics
Patient NumberAge (Years)SexBMI (kg/m2)LASFEV1 (% Predicted)Lung DiagnosisMELD ScoreLiver Diagnosis
154Female21.541.325.4Pulmonary hypertension10Hepatitis C
252Female29.637.914AATD7AATD
328Female16.069.914CF8CF
442Male18.041.024CF8CF
552Female20.189.036IPF11Cryptogenic cirrhosis
649Male22.044.236IPF9Hepatitis C
739Male16.537.834Secondary pulmonary hypertension (congestive heart failure)14Congestive
824Female17.836.026CF12CF

Indications for Transplantation

The pulmonary indications included CF (n = 3), idiopathic pulmonary fibrosis (IPF; n = 2), AATD (n = 1), and pulmonary hypertension (n = 2). The biopsy-proven causes of cirrhosis were CF (n = 3), hepatitis C (n = 2), AATD (n = 1), cryptogenic cirrhosis (n = 1), and cardiac/congestive (n = 1). Urgency was reflected by a median LAS of 41 (range = 36.0-89.0) and by a median predicted forced expiratory volume in 1 second (FEV1) of 25.7% (range = 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 = 7-14). All patients receiving CLLT exhibited biopsy-proven cirrhosis with portal hypertension. The median wait-list time for transplantation was 116 days (range = 40-709 days).

Donor Details

Donor characteristics and ischemia times are summarized in Table 2. All were ABO-identical, cadaveric, brain-dead donors. The median donor age was 25 years (range = 20-58 years), and the median BMI was 21.6 kg/m2 (range = 18.3-29.1 kg/m2). The median lung ischemia time was 147 minutes (range = 72-260 minutes). The median cold and warm liver ischemia times were 6.1 hours (range = 3.8-7.8 hours) and 25 minutes (range = 11-36 minutes), respectively.

Table 2. Donor and Graft Characteristics
Patient NumberDonor Age (Years)Donor SexDonor BMI (kg/m2)Lung Ischemia Time (Minutes)aLiver Cold Ischemia Time (Hours)Liver Warm Ischemia Time (Minutes)
  1. a

    Including donor clamping and recipient unclamping.

  2. b

    Single-lung transplant only.

  3. c

    En bloc heart and double-lung transplants.

134Male22.7213b6.419
258Male22.3193 (left) 136 (right)6.220
323Female18.3147 (left) 198 (right)7.027
421Male20.9229 (left) 182 (right)5.911
527Male19.7193 (left) 260 (right)7.836
640Male29.1126 (left) 81 (right)4.723
720Female29.072 (left)c 72 (right)3.836
820Male20.277 (left) 147 (right)5.434

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 ± 1.2 hours for both procedures.

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 = 4-17 mm Hg) and a median pulmonary artery pressure of 22.3 mm Hg (range = 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 = 36.0-41.3), whereas those requiring tracheostomy had a median LAS of 57 (range = 37.9-89.0). 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.

Table 3. Immunosuppression
Patient NumberInductionMaintenance
1MethylprednisoloneMMF, tacrolimus, prednisone (steroid taper)
2Methylprednisolone, daclizumabMMF, tacrolimus, prednisone (steroid taper)
3MethylprednisoloneMMF, tacrolimus, prednisone (steroid taper)
4MethylprednisoloneMMF, tacrolimus, prednisone (steroid taper)
5Methylprednisolone, basiliximabMMF, tacrolimus, prednisone (steroid taper)
6Methylprednisolone, basiliximabMMF, tacrolimus, prednisone (steroid taper)
7MethylprednisoloneMMF, tacrolimus, prednisone (steroid taper)
8Methylprednisolone, basiliximabMMF, tacrolimus, prednisone (steroid taper)

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

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 = 37.8-89.0), whereas those who did not return to the OR had a median LAS of 41.2 (range = 36.0-44.2).

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 beta-lactamase species. All 3 of the patients with CF had 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 culture-proven 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 = 7-181 days). The median follow-up was 505.5 days (range = 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.

Table 4. Patient Outcomes
Patient NumberLength of Stay (Days)Follow-Up (Days)aPostoperative ComplicationsAcute Cellular RejectionOutcomeCause of Death
  1. a

    To date (September 1, 2013).

111627NoneNoExpired (POD627)Liver failure (recurrent hepatitis C)
2541355Bile duct ischemia (POD3)NoSurvived 
377Bile duct leak (POD2), extracorporeal membrane oxygenation (POD7), sepsis, multiorgan failureNoExpired (POD7)Sepsis
415876NoneNoSurvived 
55959Ischemic necrosis of bronchial anastomosis (POD15), bronchopleural fistula (POD58), sepsisNoExpired (POD59)Sepsis
635543NoneNoSurvived 
7181468Necrotizing pancreatitis (POD23), duodenal perforation (POD30), sepsisNoExpired (POD468)Sepsis, respiratory failure, failure to thrive
811275Acute lung rejection (grade A1 or minimal)Lung: Yes Liver: NoSurvived 

DISCUSSION

CLLT is an important option for patients with end-stage 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 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 = 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 treatment-resistant pulmonary hypertension (n = 5), CF (n = 5), AATD (n = 2), and sarcoidosis (n = 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 ± 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 ± 6.1 (range = 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 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. aeruginosa[19] or Burkholderia cepacia[20] 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 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 coordinator and pulmonary database administrator); and Samir Patel, Pharm.D. (clinical transplant pharmacist).

Ancillary