Ann Thorac Surg 2007;84:271-272
© 2007 The Society of Thoracic Surgeons
Case Reports
Uneventful Thoracic Healing With Everolimus After Aortic Valve Replacement
Julio Pascual, MDa,*,
Cristina Galeano, MDa,
Daniel Celemín, MDb,
Maria C. Alarcón, MDa,
Roberto Marcén, MDa,
Ana M. Fernández, MDa,
Francisco J. Burgos, MDc,
Joaquin Ortuño, MDa
a Department of Nephrology, Hospital Ramón y Cajal, Madrid, Spain
b Department of Cardiac Surgery, Hospital Ramón y Cajal, Madrid, Spain
c Department of Urology, Hospital Ramón y Cajal, Madrid, Spain
Accepted for publication February 20, 2007.
* Address correspondence to Dr Pascual, Department of Nephrology, Hospital Ramón y Cajal, Carretera de Colmenar km 9,100, Madrid, 28034, Spain (Email: julpascual{at}gmail.com).
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Abstract
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Impaired wound healing problems constitute a frequent severe adverse event associated to de novo use of proliferation signal inhibitors sirolimus or everolimus in kidney, heart, and lung transplantation. No published experience on the best practice to manage these drugs in patients scheduled for elective thoracic surgery is available. Herein we present a renal allograft recipient with recurrent cutaneous neoplasia who was maintained on everolimus plus prednisone undergoing aortic valve replacement. Although the most advisable practice may be everolimus withdrawal during the perioperative period, everolimus was maintained with transient dose decrease without any wound healing problem.
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Introduction
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The proliferation signal inhibitor (PSI) everolimus is used in de novo kidney and heart transplant recipients in combination with cyclosporine (CsA) to avoid allograft rejection [1, 2]. In addition, conversion from CsA to a PSI has recently been suggested as a potential method of treating malignancies in transplant recipients without increasing the risk of graft rejection. Impaired wound healing problems constitute frequent adverse events associated with de novo use of PSIs in the kidney [2, 3], heart [4], and lung [5] transplantations. Delayed introduction of sirolimus [5], or even avoidance of sirolimus and use of mycophenolate mofetil instead of a PSI [4] have been proposed measures. However, no published experience on the best practice to manage PSIs in patients scheduled for elective thoracic surgery is available. Herein we present a renal allograft recipient undergoing aortic valve replacement. Reduced dose everolimus was maintained during the whole operative and postoperative period without any wound healing problem.
A non-obese, nondiabetic 69-year-old man had skin carcinoma develop 2 years after receiving a deceased, donor kidney transplantation while receiving tacrolimus (Prograft, Astellas Pharma Inc, Staines, UK) (target levels, 7 to 10 ng/mL) and prednisone (Prograft). The tumor was resected. Three years later he was admitted with heart failure, with three further readmissions. His graft function was not optimal, and he remained stable in serum creatinine (2.2 to 2.5 mg/dL) for 4 years, despite tacrolimus dose reduction to 5 to 6 ng/mL. He was diagnosed with severe aortic valve stenosis with moderate aortic valve insufficiency and moderate left ventricular dysfunction, with a left ventricular ejection fraction of 40%. No significant lesions were detected on coronariography. A second epidermoid skin carcinoma of 2 x 2 cm was again resected in his parietal region and after excision, a conversion from tacrolimus to everolimus was planned. Due to underlying renal vasculitis as the original disease, it was decided to perform a progressive (not abrupt) conversion, so tacrolimus reduction from 3 mg twice a day (blood level, 5.2 ng/mL) to 2 mg twice a day, plus everolimus 0.75 mg twice a day was started for target levels of 5 to 8 ng/mL. Three weeks later, everolimus trough levels were 4.2 ng/mL, the dose was increased to 1.5 mg twice a day, and tacrolimus was withdrawn. He remained on everolimus (1.5 mg twice a day) and prednisone (5 mg per day) until November 25, 2005, when he was admitted for aortic valve replacement. He had a functional class IV of the New York Heart Association; therefore quick valve replacement was scheduled. Everolimus level at admission was 7.1 ng/mL, and 2 days before surgery his everolimus dose was halved to 0.75 mg twice a day as a preventive measure to avoid wound healing problems and suture dehiscence (Fig 1). His valve replacement took place on December 1, 2005 after antibiotic prophylaxis with cefazolin (2 g intravenously). The everolimus blood level was 4.5 ng/mL. A calcified, stenotic aortic valve was replaced with a Carbomedics prosthesis (Carbomedics Inc, Austin, TX) through a median sternotomy under cardiopulmonary bypass and hypothermic (28°C) cardioplegic arrest. The valve was sutured in place with interrupted, pledgetted 2-0 Tycron sutures (Davis & Geck, Danbury, CT). At the conclusion of the operation, the incision was closed with surgical staples. On December 9, 2005, 8 days after the operation, the everolimus dose was again at 1.5 mg twice a day, and the patient was discharged. During the following year, his wound healing was excellent, without delay, dehiscence, or any other adverse event.
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Fig 1. Immunosuppressive drug treatment 4 months before and 1 year after conversion to everolimus in a tacrolimus-treated patient. Eight months after conversion, scheduled aortic valve replacement was undertaken and a temporary (10 day) everolimus dose decrease but not discontinuation was performed (asterisk and arrow). (bid = twice a day; SCr = serum creatinine; solid line = tacrolimus blood level; dotted line = everolimus blood level.)
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Comment
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Conversion from CsA to a PSI (such as sirolimus or everolimus) has recently been suggested as a potential method of treating malignancies in transplant recipients without increasing the risk of graft rejection. For example, beneficial effects on Kaposi’s sarcoma have been explored in a prospective study in 15 renal transplant recipients who were switched from CsA to sirolimus [6]. Three months after conversion, all Kaposi’s sarcoma lesions had disappeared, and remission was confirmed by histopathology at 6 months. Everolimus has a mode of action that is distinct from calcineurin inhibitors, which inhibit the transcription of early T-cell specific genes, thus reducing the production of T-cell growth factors such as interleukin-2 [7]. Everolimus acts at a later stage of the cell cycle, blocking the proliferation signal provided by these growth factors, and preventing cells from entering the S-phase [7]. The antiproliferative actions of everolimus are not limited to the immune system; it also inhibits growth factor-driven cell proliferation in general (eg, reducing vascular smooth muscle cell proliferation) [7]. Everolimus and sirolimus interrupt the phosphatidylinositide 3,4,5-triphosphate kinase (PI3K)/protein kinase B (Akt) signaling pathway, which plays a critical role in regulating cell proliferation, survival, mobility, and angiogenesis. Therefore, tumors that rely on overactivity of the phosphatidylinositide 3,4,5-triphosphate kinase (PI3K)/protein kinase B (Akt) pathway for growth may be susceptible to this class of agent.
In maintenance renal transplant recipients, use of everolimus may allow minimization or elimination of CsA from treatment regimens [2]. In clinical trials of sirolimus, CsA has been reduced or withdrawn in progressive steps of approximately 25% within a 4-week period, although abrupt cessation of CsA has been used in clinical practice outside of the trial setting [2].
The antiproliferative effects of PSIs have been associated with a high incidence of wound healing problems [2, 3–5]. Potential risk factors for delayed healing include recipient age, high body mass index, the presence of diabetes, and living versus cadaveric donors [2, 8]. Our patient was 69 year old; otherwise he did not meet any other risk factor. Excellent surgical technique, such as meticulous ligation of transected lymphatic channels, delayed removal of skin clips, and the use of nonabsorbable sutures, may reduce wound complications.
After a recent conversion from tacrolimus-based treatment to everolimus-based treatment, a major thoracic surgery was undertaken in our renal allograft recipient. Although PSIs should probably be temporarily withdrawn in patients scheduled for elective thoracic surgery, no published experience on the best practice is available. We had two possibilities to prevent the possible suture problems: (1) to change main immunosuppressive drugs again (tacrolimus substitution for everolimus) or (2) minimize everolimus exposure. We decided to maintain low-dose everolimus plus low-dose prednisone as the basic drug treatment because of two main reasons: (1) the background of malignant neoplasia and (2) tacrolimus potential nephrotoxicity in a chronic allograft nephropathy patient suffering a major cardiovascular surgical procedure. Minimizing everolimus exposure and surgeon awareness of potent stitches and meticulous technique allowed successful evolution.
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References
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- 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;349:847-858.[Abstract/Free Full Text]
- Pascual J, Boletis IN, Campistol JM. Everolimus in renal transplantation: a review of clinical trial data, current usage and future directions Transplant Rev 2006;20:1-18.[Medline]
- Dean PG, Lund WJ, Larson TS, et al. Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus Transplantation 2004;77:1555-1561.[Medline]
- Kuppahally S, Al-Khaldi A, Weisshaar D, et al. Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients Am J Transplant 2006;6:986-992.[Medline]
- Groetzner J, Kur F, Spelsberg F, et al. Airway anatomosis complications in de novo lung transplantation with sirolimus-based immunosuppression J Heart Lung Transplant 2004;23:632-638.[Medline]
- Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients N Engl J Med 2005;352:1317-1323.[Abstract/Free Full Text]
- Schuler W, Sedrani R, Cottens S, et al. SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo Transplantation 1997;64:36-42.[Medline]
- Flechner SM, Zhou L, Derweesh I, et al. The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients Transplantation 2003;76:1729-1734.[Medline]
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Abstract
Introduction
