Wound Healing Complications with De Novo Sirolimus Versus Mycophenolate Mofetil-Based Regimen in Cardiac Transplant Recipients

Transcription

1 American Journal of Transplantation 2006; 6: Blackwell Munksgaard C 2006 The Authors Journal compilation C 2006 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x Wound Healing Complications with De Novo Sirolimus Versus Mycophenolate Mofetil-Based Regimen in Cardiac Transplant Recipients S. Kuppahally a,, A. Al-Khaldi b, D. Weisshaar c, H. A. Valantine a, P. Oyer b, R. C. Robbins b and S. A. Hunt a a Departments of Cardiac Transplant and b Cardiothoracic Surgery, c Stanford University Medical Center & Northern California Kaiser Permanente Heart Transplant Program, Stanford, CA, USA Corresponding author: S. Kuppahally, sumans@yahoo.com Sirolimus was introduced in de novo immunosuppression at Stanford University in view of its favorable effects on reduced rejection and cardiac allograft vasculopathy. After an apparent increase in the incidence of post-surgical wound complications as well as symptomatic pleural and pericardial effusions, we reverted to a mycophenolate mofetil (MMF)-based regimen. This retrospective study compared the outcome in heart transplant recipients on sirolimus (48 patients) with those on MMF (46 patients) in de novo immunosuppressive regimen. The incidence of any post-surgical wound complication (52% vs. 28%, p = 0.019) and deep surgical wound complication (35% vs. 13%, p = 0.012) was significantly higher in patients on sirolimus than on MMF. More patients on sirolimus also had symptomatic pleural (p = 0.035) and large pericardial effusions (p = 0.033) requiring intervention. Logistic regression analysis showed sirolimus (p = 0.027) and longer cardiac bypass time (OR = 1.011; p = 0.048) as risk factors for any wound complication. Sirolimus in de novo immunosuppression after cardiac transplantation was associated with a significant increase in the incidence of post-surgical wound healing complications as well as symptomatic pleural and pericardial effusions. Key words: Sirolimus, mycophenolate mofetil, wound healing, pleural, pericardial, effusion Received 24 September 2005, revised and accepted for publication 07 January 2006 Introduction Sirolimus is a novel immunosuppressive drug introduced in the field of solid-organ transplantation in 1999, initially for kidney transplant recipients. Since then it has been used increasingly as a denovo immunosuppressive drug after kidney, liver, lung and heart transplantations (1 4). In heart transplant recipients, de novo use of sirolimus has proven to reduce the incidence of acute rejection and allograft vasculopathy with comparable patient survival (4). However, its potent anti-proliferative action has been associated with poor wound healing in liver, small intestine, kidney and lung transplant recipients (1,5 8). In kidney transplant recipients, both prospective and retrospective studies have shown an increased rate of post-surgical wound healing complications when sirolimus was used in de novo immunosuppressive regimen (1,8). Sirolimus has also been implicated in the development of significant pleural and pericardial effusions, and leg edema when used in liver transplant recipients (5). At Stanford University Medical Center (SUMC), sirolimus was introduced in de novo immunosuppressive regimen with daclizumab induction between June 2002 and December 2003 after becoming aware of a reduction in the incidence of acute rejection, graft loss and death with sirolimus in kidney transplant recipients (9,10). Also, everolimus was shown to be efficacious in heart transplant recipients in reducing the incidence of allograft vasculopathy (11). We subsequently perceived a significant delay in surgical wound healing and serious wound complications as well as symptomatic pleural and pericardial effusions that led to a clinical decision to revert to our prior immunosuppressive regimen with MMF. The objective of this study was to review our data in detail to observe whether the use of sirolimus was associated with more surgical wound healing complications as well as symptomatic pleural and pericardial effusions than MMF when used as part of the primary immunosuppressive protocol after heart transplant at SUMC. Materials and Methods Patient population This was a retrospective study of adult heart transplant recipients whose transplant procedures were performed at a single center. Characteristics of the patients are shown in Table 1. Of 54 adult heart transplant patients with surgery performed between June 2002 and Dec 2003, 48 recipients received sirolimus as part of the de novo immunosuppressive regimen and formed our study group. Multiple or repeat organ transplants constituted the primary reason for exclusion of six patients in the sirolimus group from the analysis. Of the six patients excluded, two underwent multiple organ transplants (heart + liver and heart + kidney); three underwent second heart 986

2 Wound Healing Complications in Cardiac Transplant Recipients Table 1: Characteristics of heart transplant recipients Sirolimus MMF Characteristic (n = 48) (n = 46) p-value Recipient- 39/9 37/9 Male/Female Donor-Male/Female 40/8 40/6 Recipient age 51.5 ± ± 11.9 (years) Donor age (years) 31.6 ± ± 12.3 Recipient race Caucasian 33 (68.8) 37 (80.4) African American 9 (18.8) 5 (10.9) Hispanic 4 (8.3) 1 (2.2) Asian/Others 2 (4.2) 3 (6.5) Recipient BMI 27.1 ± ± 3.9 Recipient BMI categories < (29.2) 15 (32.6) (29.2) 18 (39.1) (22.9) 9 (19.6) >32 9 (18.8) 4 (8.7) Diabetes mellitus 17 (35.4) 9 (19.6) Pre-transplant 3.5 ± ± serum albumin (g/dl) g/dl (% of patients) Pre-transplant 1.5 (0.5) 1.5 (0.4) - >1.4 mg/dl (% of patients) Post-transplant 1.52 (0.58) 1.33 (0.39) at 6 months Post-transplant 1.50 (0.70) 1.52 (0.46) at 12 months Pre-transplant diagnosis (%) Dilated cardiomyopathy Ischemic cardiomyopathy Congenital heart disease Other Pre-transplant 16 (33.3) 20 (43.5) cardiac support Previous cardiac 17 (35.4) 16 (34.8) surgery Recipient CMV 25 (52.1) 34 (73.9) 0.05 positive Donor CMV positive 31 (64.6) 37 (80.4) Type of CNI (% of patients) Cyclosporine Tacrolimus None Cyclosporine level at 6 months (ng/ml) (51.70) ± Table 1: Continued Sirolimus MMF Characteristic (n = 48) (n = 46) p-value Cyclosporine level (27.37) ± at 12 months (ng/ml) Tacrolimus level at ± ± 2.47 months (ng/ml) Tacrolimus level at 6.58 ± ± months (ng/ml) Allograft ischemia 226 ± ± 57 time (min) Cardiopulmonary 157 ± ± 44 bypass time (min) Intubation (days) 1 (1, 3) 1.5 (1, 3) Initial hospital stay 14 (11, 20) 15 (11, 22) 30-day survival 48 (100) 44 (95.7) 1-year survival 46 (95.8) 39 (84.8) Using Fisher s test. CNI = calcineurin inhibitor, CMV = cytomegalovirus. transplant and therefore represent a group that may have been at increased risk for wound healing complications as a consequence of the long-term immunosuppression. One patient died immediately after the surgery. The control group was chosen from non-consecutive heart transplant recipients, with similar immunosuppressive regimen to have a larger control group, with procedures performed before (April 2001 June 2002, 36 patients) and after (Dec Feb. 2004, 10 patients) the above period, who were treated with a MMF-based regimen. Pediatric patients, multiple organ recipients, re-do heart transplant recipients and patients on both sirolimus and MMF were excluded from the study. Early deaths (within the first 10 days after transplant) and patients in whom sirolimus was discontinued in the first week after transplant were also excluded. Demographics of all patients, as well as pre- and post-transplant data were available from the patients medical records and computer database. Approval from the investigational review boards of Stanford University and Kaiser Foundation was obtained. Immunosuppression All patients received induction therapy with interleukin-2 receptor monoclonal antibody (daclizumab 1mg/kg) immediately after transplant and then every 2 weeks for a total of five doses. Intravenous methylprednisolone was administered as a single bolus dose of 500 mg in the immediate postoperative period, followed by three doses of 125 mg every 8 h, then changed to oral prednisone 1 mg/kg/day for 13 days and then tapered to be discontinued when possible by 6 9 months post-operatively. Cyclosporine was started as early as possible after transplantation and adjusted to keep a 12-h trough level between ng/ml during the first 6 months and ng/ml between 6 and 12 months in the MMF group. In the sirolimus group, lower serum levels of cyclosporine were targeted to keep a 12-h trough between ng/ml in the first 6 months and ng/ml between 6 12 months (Table 1). Patients who were changed to tacrolimus because of complications related to cyclosporine such as seizures or severe headaches or gingival hyperplasia were noted. In the MMF group, tacrolimus level was targeted to a 12-h trough level of ng/ml (8 12 ng/ml in sirolimus group) during the first 6 months and 7 10 ng/ml (6 8 ng/ml in sirolimus group) between 6 12 months post-operatively American Journal of Transplantation 2006; 6:

3 Kuppahally et al. (Table 1). Sirolimus was started at a dose of 1 3 mg daily, without a loading dose and targeted to achieve a 24-h trough level of 5 10 ng/ml. The average dose of MMF ranged between 500 mg 1000 mg twice a day. The occasional patient had a dose of 250 mg twice a day due to leucopenia or 1500 mg twice a day for recurrent moderate rejections. Intravenous gancyclovir was given as prophylaxis against cytomegalovirus (CMV) if the donor or recipient were CMV seropositive. Oral trimethoprimsulfamethoxazole was started for prophylaxis against pneumocystis-carinii infection. Rejection was treated with intravenous methylprednisolone. In case of persistent rejection or hemodynamic compromise, rabbit antithymocyte globulin was administered. For presumed or documented humoral rejection, plasmapheresis was performed. Follow-up After discharge from the hospital following heart transplantation at SUMC, patients were followed in the post-transplant clinic at Stanford hospital (80% of patients) or at Kaiser Permanente hospital (20% of patients). A thorough examination of the surgical wound for any signs of infection and sternal instability was done during each clinic visit. Surveillance endomyocardial biopsies and echocardiograms were performed weekly for the first 4 weeks, every 2 weeks until the third month and then monthly up to 6 months. After 6 months, if the patients had no complications, follow-up surveillance was reduced to every 3 months until the annual evaluation when a coronary angiogram was also performed. End points The end points of this study were the incidence of post-surgical wound healing complications as well as the incidence of symptomatic pleural or pericardial effusion. Definitions 1. Post-cardiac transplant surgical wound healing complications Superficial: Deficiency of surgical wound healing limited to skin and subcutaneous tissue, classified as one of the following: sterile dehiscence or persistent drainage requiring prolonged dressing changes; or treatment with antibiotics for clinical suspicion or microbiological evidence of cellulitis; or skin/subcutaneous tissue necrosis requiring debridement. Deep: Deficiency of surgical wound healing involving sternum, mediastinum, abdominal wall or deep organs, was classified as one of the following: sterile sternal non-union/dehiscence; or sternal osteomyelitis (OM); or mediastinitis/deep organ involvement. 2. Fluid collection Pleural effusion was classified as prolonged chest tube drainage postoperatively for more than 1 week after heart transplant surgery or symptomatic persistent/recurrent pleural effusion requiring thoracentesis in the early post-transplant period. Pericardial effusion was classified as mildmoderate effusion not requiring any intervention or symptomatic large effusion, with or without tamponade, requiring intervention such as pericardiocentesis or pericardial window in the early post-transplant period. Statistical Analysis Results are reported as counts (percentage), means ± standard deviation or median (inter-quartile range) as appropriate. Comparisons between groups were done using the independent samples Student s t-test or Analysis of Variance (ANOVA) method for continuous variables and the Chi-square method for categorical variables. Statistical significance was assumed when the p-value was <0.05. Logistic regression analysis was performed to determine factors associated with increased risk of any wound complication. In an intent-to-treat analysis the following factors were analyzed: donor and recipient factors including age, gender, race, CMV status and mismatch and allograft ischemic time; recipient factors including body mass index (BMI), presence or absence of diabetes, pre-transplant serum albumin and creatinine levels, United Network for Organ Sharing (UNOS status 1 vs. 2), prior cardiac surgery, pre-transplant circulatory support, underlying cardiac diagnosis, cardiopulmonary bypass time and immunosuppression protocol. We chose variables based on the initial univariate analysis to develop multivariate models. Spearman s rank test was used to evaluate relations between two variables prior to multivariate analysis and variables that correlated at >0.6 of the correlation coefficient were not used in the multivariate analysis at the same time. Cases with missing data were excluded when performing univariate or multivariate analyses. Selection of variables was performed by the backward stepwise method based on maximum likelihood estimation. Results are reported as odds ratio (OR) and 95% confidence interval (95% CI). All statistical analyses were performed using SPSS 10.0 (SPSS Inc.). Results Demographics Characteristics of the heart transplant recipients are shown in Table 1. The patients in both sirolimus and MMF groups were comparable in age, gender, BMI and pre-transplant serum creatinine. Although more patients on sirolimus had pre-transplant DM, this was not statistically significant. In the MMF group, the overall pre-transplant albumin was slightly lower (p = 0.03) and more recipients were cytomegalovirus positive pre-transplant (p = 0.05). Pre-transplant etiology of heart failure, need for cardiac support with inotropes/ intraaortic balloon pump or ventricular assist device (VAD), allograft ischemia time and posttransplant stay in the intensive care unit were not significantly different in the two groups. Twenty patients discontinued sirolimus and were switched to MMF over a period of 10 days at the earliest to 605 days for a variety of reasons, including poor surgical wound healing, pleural or pericardial effusions, recurrent oral ulcers, non-specific abdominal pain or bothersome peripheral edema. Some patients were switched back to sirolimus for allograft vasculopathy or recurrent rejections, once their wounds were healed. In the MMF group, 11 patients were switched from MMF to sirolimus later post-operatively, over a period of 110 to 795 days, 6 because of recurrent rejection, 4 because of the observation of allograft vasculopathy and 1 for unclear reasons. Two patients in the sirolimus group died. One died at 38 days due to sepsis after undergoing sternal rewiring for dehiscence and chest tube placement for symptomatic pleural effusion. The second patient, who died at 135 days due to severe rejection and graft failure, also had surgical wound dehiscence requiring rewiring of sternum. He also had symptomatic pleural and pericardial effusions prompting the discontinuation of sirolimus after 30 days. He was on MMF for 105 days before his death. In the MMF group, out of 10 total deaths, 6 died in the first year and survival 988 American Journal of Transplantation 2006; 6:

4 Wound Healing Complications in Cardiac Transplant Recipients days ranged from 18 to 346 days. The causes of death in the first year were, graft failure due to rejection (n = 3), accelerated allograft vasculopathy leading to cardiac arrest (n = 1), fungal myocarditis (n = 1) and sepsis (n = 1). Remaining four deaths occurred beyond 12 months; due to severe rejection (n = 1), progressive allograft vasculopathy leading to cardiac arrest (n = 2) and sepsis (n = 1). Wound healing complications The incidence of any wound complication was higher in the sirolimus group as compared to the MMF group (58% vs. 28%, p = 0.019, Table 2). A statistically significant higher incidence of deep wound complication was noted in the sirolimus group as compared to the MMF group (35% vs. 13%, p = 0.012). This included 3 with sterile sternal dehiscence and sternal instability, 1 with sternal osteomyelitis, 12 with mediastinitis and 1 with an infected intra and extracardiac thrombus at the atrial anastamosis and in the retrocardiac area, requiring surgical revision and long-term intravenous antibiotics. Ten patients underwent Table 2: Comparison of surgical wound healing complications, pleural and pericardial effusions between sirolimus and mycophenolate mofetil (MMF) Sirolimus MMF Complication (n = 48) (n = 46) p-value All wound 25 (52) 13 (28.2) complications (%) Superficial wound complication - Persistent 5 (10.4) 2 (4.3) drainage or sterile skin dehiscence - Cellulitis 3 (6.3) 5 (10.9) Deep wound complication - Sterile dehiscence 3 (6.3) 0 - Sternal 1 (2.1) 0 osteomyelitis - Mediastinitis/deep 13 (27) 6 (13) organ infection Pleural effusion 12 (25) 4 (8.7) Prolonged 5 (10.4) 1 (2.2) drainage (>1 week) after surgery - Persistent/ 7 (14.6) 3 (6.5) recurrent Pericardial effusion 22 (45.8) 21 (45.7) - Mild moderate 11 (22.9) 17 (37) effusion (no intervention) - Large effusion/ 11 (22.9) 4 (8.7) 0.06 tamponade (with intervention) Retrosternal fluid 7 (14.6) 4 (8.7) collection Need for surgical intervention 10 (20.8) 4 (8.7) repeat thoracic surgery, nine for osteomyelitis of sternum and/or mediastinitis with debridement and sternal rewiring and one for endocarditis with intracardiac infected thrombus. One patient had a prolonged, non-healing VAD site requiring debridement and wound-vac therapy. In the study group, the mean sirolimus level from post-operative day 7 to 90 ranged between 9.82 ng/ml ± 2.92 ng/ml. There were no significant differences in the mean sirolimus level comparing patients without any wound healing complication (9.87 ± 2.49 ng/dl), superficial wound healing complication (9.61 ± 1.93 ng/ml) and deep wound healing complication (9.85 ± 3.92 ng/ml). Univariate logistic regression analysis in all study subjects (n = 94) showed use of sirolimus (p = 0.020) and recipient BMI (p = 0.041) to be associated with any wound healing complication (Table 3). For every one-digit rise in BMI, the risk of wound healing complication increased by 10% (OR = 1.1). In sirolimus group, the mean BMI was higher in patients with serious deep wound complications as compared to patients without deep wound complications (25 ± 3.9 vs. 30 ± 5.6, p = 0.002) (Table 4). In MMF group, there was no significant difference in BMI of patients with or without deep wound complications (25.98 ± 3.69 vs ± 5.88, p = 0.712). Multivariate analysis in all study subjects identified sirolimus (p = 0.027) and prolonged cardiopulmonary bypass time (p = 0.048) as independent risk factors for surgical wound healing complications (Table 5). Pleural and pericardial effusions A significant number of patients in the sirolimus group had pleural effusions requiring prolonged chest tube posttransplant or recurrent/ persistent pleural effusion requiring Table 3: Univariate logistic regression analysis for any wound complication in heart transplant recipients in either sirolimus or MMF group (n = 94) 95% C.I. for OR OR Lower Upper Sig. Sirolimus Recipient age Female recipient Recipient BMI Diabetes mellitus Pre-transplant albumin Pre-transplant creatinine Tacrolimus Redo-sternotomy Recipient CMV positive Donor ischemia time Cardiopulmonary bypass Intubation days Pre-transplant inotropic support Pre-transplant IABP Pre-transplant VAD support Non-white recipient IABP = Intraaortic balloon pump; VAD = Ventricular assist device. American Journal of Transplantation 2006; 6:

5 Kuppahally et al. Table 4: Comparison of heart transplant recipients on sirolimus, with and without surgical deep wound complications No deep Deep wound wound complication complication (n = 31) (n = 17) p-value Recipient gender -Male/Female 18/5 21/4 Recipient BMI 25 ± ± Recipient BMI < > Recipient age 53 ± ± 10.4 (mean) Diabetic recipient 11 6 Pre-transplant 3.38 ± ± albumin (gm/dl) Pre-transplant 1.5 ± ± 0.6 Redo-sternotomy 11 6 Allograft ischemia 220 ± ± 45 time (min) Cardiopulmonary 144 ± ± bypass (min) Intubation (days) 2.2 ± ± 3.9 Length of ICU stay 6 ± ± 5.6 (days) Length of hospital 17 ± ± 24 stay (days) Mean sirolimus level (post-operative day 7 90) 9.80 ± ± 3.92 (min) = minutes. Table 5: Multivariate logistic regression analysis for any wound complication (backward likelihood ratio) 95% C.I. for OR Factor OR Lower Upper Sig. Sirolimus Cardiopulmonary bypass (per min) thoracentesis (25% vs. 8.7%, p = 0.035) (Table 2). Although it did not reach statistical significance, the sirolimus group had a higher incidence of large pericardial effusions requiring intervention than the MMF group. The mean sirolimus level from post-operative day 7 90 was not significantly different in patients with or without pleural or pericardial effusion. Discussion This is the first study comparing sirolimus and mycophenolate mofetil when used in a de novo immunosuppression regimen after heart transplantation. The study confirms our clinical suspicion of a higher incidence of surgical wound healing complications as well as recurrent, symptomatic pleural and pericardial effusions in cardiac transplant recipients on a sirolimus-based regimen as compared to MMF. In 2001, Radovancevic et al. conducted the pilot clinical trial evaluating sirolimus as de novo therapy in 11 heart transplant recipients and noticed fewer rejection rates without an increase in post-transplant infection rates (12). Another report described the use of sirolimus as a rescue therapy in heart transplant patients to salvage the kidney function, prevent graft failure or overcome neurotoxicity associated with calcineurin inhibitors (13). Sirolimus prevented further acute rejection episodes; however, an increased incidence of infection was reported. Keogh et al. compared sirolimus (92 patients) to azathioprine (44 patients) as de novo therapy after heart transplantation and noted only five cases of delayed sternal wound healing, presumed to be due to high sirolimus trough levels and an outbreak of mycoplasma hominis infection (4). In a recent pilot study by Meiser et al., using a calcineurin-inhibitor free immunosuppressive regimen in eight cardiac transplant recipients, an increased incidence of wound healing complications and effusions was reported, in accordance with the results of our study (14). Patients undergoing transplantation are at an elevated risk for poor wound healing and infection due to high-dose steroid treatment, immunosuppression, preexisting DM and/or poor nutrition. This risk may be exacerbated in patients receiving sirolimus due to its inhibitory action on platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bfgf), which are necessary for tissue healing and repair (15). The unique property of sirolimus to inhibit proliferation of both lymphocytic and non-lymphocytic cells including smooth muscle cells increases the risk of delayed wound healing at surgical sites. This property of sirolimus led to an increased incidence of airway dehiscence and reduced survival in lung transplant recipients leading to termination of the clinical trials with sirolimus (3,16). Similarly, delayed wound healing with sirolimus has also been documented in liver and kidney transplant recipients (1,6,8,17) We also noted significantly more symptomatic pleural and pericardial effusions requiring intervention in the sirolimus group than in the MMF group. The exact mechanism of increased pleural or pericardial effusions associated with sirolimus use is unclear. It cannot be explained on the same principle as the formation of lymphoceles post-renal transplantation, which occurs in the non-absorptive retroperitoneal space. After cardiac transplant surgeries, an incidence of 21% moderate to large pericardial effusion (18) and 6% pleural effusion (19) have been reported in the absence of immunosuppression with sirolimus. The pericardial effusion may be explained by post-operative bleeding, however, an imbalance in the production and absorption of the secretion by the epithelial lining of the pleural 990 American Journal of Transplantation 2006; 6:

6 Wound Healing Complications in Cardiac Transplant Recipients space cannot be explained. Of note, Montalbano et al. also reported an incidence of 16% pleural effusions and 5% pericardial effusions in 175 liver transplant recipients treated with sirolimus (5). In contrast to the other studies (1,8,17), despite maintaining relatively lower sirolimus levels, we noticed a higher rate of serious adverse postoperative outcomes as also reported in lung (3) and liver (5) transplant patients. The adverse post-operative outcomes noted do not seem to be dose related and may be due to the anti-proliferative actions of sirolimus. Higher recipient BMI was also correlated with an increased incidence of surgical wound healing complication. In the sirolimus group, patients with serious deep wound complications had a higher mean BMI. Higher BMI has been reported as a risk factor for surgical wound healing complications in several studies of kidney transplantation. In a prospective study involving kidney transplant recipients, wound healing complications with sirolimus were significantly higher with increasing BMI (>24 kg/m 2 ) (1). In another study involving kidney transplant patients, when retrospectively compared to MMF, significant wound complications were again noted with sirolimus in overweight patients with BMI > 30 kg/m 2 (8) as well as with lower serum albumin <3.5 g/dl. Although the serum albumin was significantly higher in patients experiencing wound healing, this finding cannot be explained and is unlikely to be clinically relevant. Limitations The limitations of our study are related to its retrospective, non-randomized study design. Specifically, we cannot exclude the possibility that some wound healing complications may have been missed. Another limitation is that we were unable to record reliable microbiological data for the patients with wound healing complications. Neither the exact type nor the duration of antibiotics before surgical intervention was available. Conclusion Sirolimus is associated with significant post-surgical deep wound healing complications as well as recurrent and symptomatic pleural and pericardial effusions, when used in de novo immunosuppression after heart transplantation as compared to MMF. Higher BMI and longer time on cardiopulmonary bypass is also associated with higher incidence of surgical wound healing complications. This finding suggests that we may best serve our patients by avoiding sirolimus in the initial 3 months post-operative period, but introducing it once the surgical wounds have healed. It is possible that by delaying the introduction of sirolimus until sternum is fully healed, we miss the most important time to address acute and chronic rejection. However, given the risk of sternal dehiscence and sepsis our limited data suggest that the risk benefit balance is likely tipped in favor of delayed initiation of sirolimus. Further study will be necessary to investigate whether the beneficial effect on rejection and mortality is maintained if the sirolimus is started 3 months post-transplant. References 1. Dean PG, Lund WJ, Larson TS et al. Wound-healing complications after kidney transplantation: A prospective, randomized comparison of sirolimus and tacrolimus. Transplantation 2004; 77: Dunkelberg JC, Trotter JF, Wachs M et al. Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications. Liver Transpl 2003; 9: Groetzner J, Kur F, Spelsberg F et al. Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression. J Heart Lung Transplant 2004; 23: Keogh A, Richardson M, Ruygrok P et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: A randomized clinical trial. Circulation 2004; 110: Montalbano M, Neff GW, Yamashiki N et al. A retrospective review of liver transplant patients treated with sirolimus from a single center: An analysis of sirolimus-related complications. Transplantation 2004; 78: Guilbeau JM. Delayed wound healing with sirolimus after liver transplant. Ann Pharmacother 2002; 36: Fishbein TM, Florman S, Gondolesi G et al. Intestinal transplantation before and after the introduction of sirolimus. Transplantation 2002; 73: Valente JF, Hricik D, Weigel K et al. Comparison of sirolimus vs. mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003; 3: Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: A randomised multicentre study. The Rapamune US Study Group. Lancet 2000; 356: MacDonald AS. A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001; 71: Eisen HJ, Tuzcu EM, Dorent R et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003; 349: Radovancevic B, El-Sabrout R, Thomas C, Radovancevic R, Frazier OH, Van Buren C. Rapamycin reduces rejection in heart transplant recipients. Transplant Proc 2001; 33: Snell GI, Levvey BJ, Chin W et al. Rescue therapy: A role for sirolimus in lung and heart transplant recipients. Transplant Proc 2001; 33: Meiser B, Reichart B, Adamidis I, Uberfuhr P, Kaczmarek I. First experience with de novo calcineurin-inhibitor-free immunosuppression following cardiac transplantation. Am J Transplant 2005; 5: Cao W, Mohacsi P, Shorthouse R, Pratt R, Morris RE. Effects of rapamycin on growth factor-stimulated vascular smooth muscle cell DNA synthesis. Inhibition of basic fibroblast growth factor and American Journal of Transplantation 2006; 6:

7 Kuppahally et al. platelet-derived growth factor action and antagonism of rapamycin by FK506. Transplantation 1995; 59: King-Biggs MB, Dunitz JM, Park SJ, Kay Savik S, Hertz MI. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003; 75: Troppmann C, Pierce JL, Gandhi MM, Gallay BJ, McVicar JP, Perez RV. Higher surgical wound complication rates with sirolimus immunosuppression after kidney transplantation: A matched-pair pilot study. Transplantation 2003; 76: Quin JA, Tauriainen MP, Huber LM et al. Predictors of pericardial effusion after orthotopic heart transplantation. J Thorac Cardiovasc Surg 2002; 124: Lenner R, Padilla ML, Teirstein AS, Gass A, Schilero GJ. Pulmonary complications in cardiac transplant recipients. Chest 2001; 120: American Journal of Transplantation 2006; 6: