Mediastinitis in Heart Transplantation Shreekanth V. Karwande, MD, Dale G. Renlund, MD, Stephanie L. Olsen, MD, William A. Gay, Jr, MD, Wayne E. Richenbacher, MD, John A. Hawkins, MD, Roger C. Millar, MD, and John D. Marks, PE Division of Cardiothoracic Surgery, University of Utah School of Medicine, and Utah Transplant Affiliated Hospitals Cardiac Transplant Program, Salt Lake City, Utah
Between March 1985 and December 1991, mediastinitis developed in 12 of 420 cardiac transplantation patients (2.8%). The mortality rate in this group of patients was 8.3% (1/12).Actuarial survival (1year, 75%; and 5 years, 65%) was not significantly different from that of the group without mediastinitis (1 year, 88%; and 5 years, 75%). A higher percentage of the patients in the group with mediastinitis were listed as UNOS status 1 (50% versus 35%) and had a history of previous sternotomies (58% versus 44%). The presentation of mediastinitis was typical. Computed tomographic scanning with or with-
out aspiration was a valuable adjunct in the diagnosis of mediastinitis. Induction immunotherapy with minimal steroids in the perioperative period was used in all patients. This may contribute to the patients' ability to mount an appropriate and effective response to infection, permitting earlier diagnosis. The debridement irrigation technique used in 8 of 12 patients had a low success rate of 33%, whereas the debridement muscle flap technique used in 4 of 12 was 100% successful in eliminating infection. (Ann Tkoruc Surg 2992;54:203945)
I
protocols, perioperative management protocols, and biopsy schedules were standardized. The operations were performed by surgeons at three different hospitals with comparable survival rates. The antibiotic regimen, skin preparation, and draping in the three hospitals were similar. The technical details of the recipient operation and the donor harvest were standardized, as were the donor heart transport and packaging techniques. A crystalloid cardioplegic solution was used. The sternum was closed with interrupted stainless steel wires. The fascia and the subcutaneous and subcuticular tissues were closed with continuous absorbable sutures. All patients received prophylactic antibiotics. Cefuroxime was given at least Ih hour before the skin incision. Antibiotics were added to the pump prime and were administered for 48 hours postoperatively. Reverse isolation was not used. Early rejection prophylaxis was based on equine antithymocyte globulin (polyclonal antibody) or murine monoclonal CD-3 antibody (OKT3). Our current immunosuppressive protocol involves a 14-day course of OKT3 beginning with a dose intraoperatively at the time of the pulmonary artery anastomosis. Intraoperative administration has the advantage of attenuating the first dose reaction and antigen recognition when the aortic crossclamp is removed. OKT3 levels and CD3 lymphocyte counts are monitored daily for 14 days. Cyclosporine administration is begun on the third or fourth postoperative day at an oral dosage of 6 mg * kg-' * day-' and is adjusted to a target trough level of 150 to 200 mg/mL. Azathioprine (2 to 4 mg/kg) is administered preoperatively, and the postoperative dosage is adjusted to maintain the white blood cell count between 4 and 6 x 109/L (4,000 and 6,OOO/pL). Methylprednisone is administered intraoperatively (500 mg intravenously). Corticosteroids
n the face of the rapid and continued growth of heart transplantation, it is essential to continuously scrutinize the results and complications of this procedure. Mediastinitis is one of the most serious complications after heart operations. It carries a high mortality and significant morbidity. Additionally, heart transplant recipients represent a group of patients in whom decreased immune defenses present a unique situation. Transplant literature is surprisingly sparse with regard to mediastinitis. Most reports have involved few patients [l-31 or examined patients in the preinduction therapy era [4]. We retrospectively studied mediastinitis in 420 consecutive patients undergoing orthotopic heart transplantation from March 1985 to December 1991. The term mediustinifis defines a retrosternal infectious process with or without sternal instability. This definition does not include a superficial infection or a subcutaneous process confined to the anterior aspect of the sternum. Patients included in this review fit the criteria described above. This study was designed to investigate several questions: (1)the incidence of mediastinitis in heart transplant patients and its attendant mortality and morbidity, (2) predisposing or risk factors, (3) clinical presentation, (4) diagnosis, and (5) surgical options. Material a n d Methods The Utah Transplant Affiliated Hospitals Cardiac Transplant Program is based in three hospitals in the Salt Lake City valley. The recipient criteria, immunosuppressive Presented at the Twenty-eighth Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Feb S 5 , 1992. Address reprint requests to Dr Karwande, Division of Cardiothoracic Surgery, University of Utah Medical Center, 50 North Medical Dr, Salt Lake City, UT 84132.
0 1992 by The Society of Thoracic Surgeons
0003-4975/92/$5.00
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Ann Thorac Surg 1992;54:1039-45
KARWANDE ET AL MEDIASTINITIS IN HEART TRANSPLANTATION
Table 1. Characteristics of Patients" Variable
Mediastinitis
Number
12 52 t 11 29 t 11
Age (Y) Donor age (y)
Male (%)
No Mediastinitis 408 13 11 82
49 t 27 t
100
Preoperative Diagnosis (%)
IDC CAD
Other UNOS status 1 (%) Transplant wait (d) Ischemic time (min) Redo operation (%) EF CI (L * min-' IABPNAD
. m-')
8
34
75 17
55 11 36 54 t 60 172 t 62 42 0.18 .+. 0.08 2.0 t 0.6 43 (12%)
50 88 2 107 167 t 45
58 0.18 t 0.09 2.0
-C
0.5
1(8%)
Values are reported as discrete, percentage, or mean tion.
a
?
standard devia-
EF = ejection C1 = cardiac index; CAD = coronary artery disease; fraction; IABP = intraaortic balloon pump; IDC = idiopathic dilated cardiomyopathy; UNOS = United Network for Organ Sharing; VAD = ventricular assist device.
(prednisone or equivalent) are then administered at 0.25 mg * kg-' * day-' until the completion of the OKT3 course, when the dosage is increased to 1mg kg-' * day-' for 7 days. A steroid taper is begun immediately and discontinued in the following 2 weeks; it is only reinstituted for episodes of rejection. Surveillance biopsies are performed as per standard protocol. Management of rejection episodes has been described in detail elsewhere [5]. Transplant patients were grouped by presence or absence of mediastinitis. Statistical differences between groups were analyzed using the ,$ or Fisher's exact test, as appropriate, for discrete variables, and unpaired Student's t tests for continuous variables. Odds ratios for risk factors were calculated from contingency tables and are reported with 95% confidence intervals. Multivariate analysis of risk factors was performed using a logistic stepwise regression model. Actuarial survival was determined by the Kaplan-Meier method, with significance of comparisons determined by the Tarone-Ware test. Statistical significance was considered for an a level of 0.05 ( p < 0.05).
-
Results A total of 12 mediastinal infections occurred in 420 patients for an overall incidence of 2.8%. One of these patients died, yielding a mortality rate of 8.3% (1112). There were three late deaths, which were unrelated to mediastinitis. Demographic and descriptive characteristics of transplant patients with and without mediastinitis are shown in Table 1. The following risk factors were analyzed for inclusion in a step-wise logistical regression model for prediction of mediastinitis: age, sex, time on wait list, ejection fraction,
pulmonary capillary wedge pressure, cardiac index, circulatory support, United Network for Organ Sharing (UNOS) status, donor heart ischemic time, cross match, cause of cardiac disease, previous sternotomy, year of transplantation, and immunosuppressive protocol. Risk factors identified in the model (criterion, p < 0.15) included year of transplantation, cause of cardiac disease, and UNOS status. Higher risk was associated with transplantation in earlier years, coronary artery disease as the cause of cardiac disease, and a pretransplantation UNOS status of 1. Knowledge of cause significantly improved the model ( p = 0.03). Differences were observed in terms of preoperative diagnosis and severity of illness before operation. Mediastinitis was 2.7 times (95%confidence interval 0.71-10.8) more likely to develop in patients listed for transplantation for ischemic cardiomyopathy than in other transplant patients. Seven of the 12 patients in whom mediastinitis developed had had prior sternotomy (58%).This is higher than the general transplant population, in which repeat operations comprise only 44% of the patients. Mediastinitis was 1.9 times (95% confidence interval, 0.566.03) more likely to develop in patients with one or more prior sternotomies. Six of the 12 recipients with mediastinitis (50%) had UNOS status 1 before their transplantation. These patients were in the intensive care unit for varying lengths of time receiving intravenous inotropes before transplantation. In comparison, pretransplantation inotropic support was required in 36% of the general transplant population. Mediastinitis was 1.9 times (95% confidence interval, 0.56-6.48) more likely to develop in patients listed as UNOS status 1 than in other transplant patients. One patient had an intraaortic balloon pump in place. Although it is customary for central lines to be inserted before transplantation in all patients, 6 of the 12 patients in whom mediastinitis developed had central line placement or Swan-Ganz monitoring performed for hemodynamic reasons. The average pretransplantation wait was 88 days and did not differ from the general transplant population. The average cross-clamp time was 81 minutes. The ischemic time was 167 minutes and the pump time was 122 minutes. These figures are not statistically different from those of the patients without mediastinitis. All patients were extubated within 24 hours. Blood loss and blood product requirements were reviewed. These were not found to be excessive. The average total chest tube drainage was 741 mL. All patients received fresh-frozen plasma preoperatively because all had been placed on full oral anticoagulation, which needed to be reversed at the time of transplantation. One of the 12 patients in whom mediastinitis developed (8%) was reexplored for mediastinal bleeding. The postoperative course of these patients after the development of mediastinitis was complicated. Four of the 12 patients required a variety of procedures to be performed (colonoscopy, suture ligation of bleeding duodenal ulcer, femoral embolectomy). Dialysis was required in 2 of 12 patients (17%). Postoperative opportunistic pneumonias were seen in 4 of 12 patients (enterococcus,
KARWANDE ET AL MEDIASTINITIS IN HEART TRANSPLANTATION
Ann Thorac Surg 1992;54103945
Table 2. Surqical Techniaue ~~
Procedure Debridement and irrigation Debridement and muscle flaps
No. of Patients
Success
8/12 (66%)
3/8 (37%)
4/12 (34%)
4 4 (100%)
Complications Bleeding (l), seroma (2) None
Legionella, and cytomegalovirus). Two of 12 patients (16%) had recognizable sepsis before transplantation and had been treated with appropriate antibiotics with resolution. The presentation of mediastinitis was quite typical. The usual presenting signs and symptoms were elevated white blood cell count (loo%), pain (66%), fever (66%), drainage, sternal instability, and shock (25%).The most common were fever and pain. Pain, seen in 8 of 12 patients (66%),was out of proportion with physical findings and often preceded other manifestations. Drainage, sternal instability, and fluctuance were less common. The average time of presentation was 9 days after operation, with a range of 5 to 17 days. Shock was the first presentation of mediastinitis in 3 patients. Two of these 3 required tracheal intubation and inotropic support. In spite of immunosuppression with azathioprine, all patients presented with an elevated white blood cell count, which ranged from 11 to 35 x 109/L(11,000 to 35,OOO/pL). Staphylococcus species was cultured from the majority of these wounds (11/12). There was one Legionella infection. No polymicrobial infections were seen. There was no relationship between the type of organism and outcome. Debridement, sternal closure, and irrigation was the most commonly used initial surgical procedure (8/12; 66%) (Table 2). This procedure, however, was unsuccessful in eliminating the infection in 5 of these patients (62%).All 5 eventually required muscle flaps to effect healing. The single death of this series was in this group. Debridement and muscle flap closure as a two-stage procedure was
1041
used as the initial surgical management in 4 of 12 patients (34%)with no failures and no mortality. The choice of the initial surgical procedure was based on surgeon preference. Debridement and muscle flap closure as a singlestage procedure was not used in this series. There were no significant differences in actuarial survival between patients with mediastinitis (75% at 1 year and 64% at 5 years) and the general transplant population (88% at 1 year and 75% at 5 years; p = 0.70). Morbidity and mortality after hospital discharge are significant in the nontransplant cardiac surgical population with mediastinitis. Survival of 86% at hospital discharge fell to 75% in 3 years in one series [6]. In this series of transplant patients discharged from the hospital after recovery from mediastinitis, the survival rate is similar to that of other transplant patients (Fig 1).
Comment Surgical Technique Deep infections of sternotomy wounds occur with a reported incidence of 0.3% to 5% in the general cardiac surgical population. Our incidence of sternal wound infection in the nontransplant population is less than 1%. In the transplant population this incidence is more than doubled at 2.8%. The pathogenesis of sternal infections is still unclear. Grossi and associates [7] postulate a localized area of osteomyelitis within the sternal marrow without external signs except for localized pain, a situation similar to an abscess in a bone in other locations. Such a localized area of osteomyelitis is not well penetrated by systemic antibiotics, and unless drained the infection spreads to adjacent costal cartilage and underlying mediastinum. Others believe that instability of sternal fragments is the cause of most sternal infections. Prolonged antibiotic treatment of mediastinitis as reported by Serry and colleagues [8] carries an unacceptable morbidity and mortality and has been abandoned. Sternal Fig I . Actuarial survival analysis of patients with and without mediastinitis. Statistically the difference was not significant (N.S.).
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2010
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Ann Thorac Surg 1992;541039-45
KARWANDE ET AL MEDIASTINITIS IN HEART TRANSPLANTATION
debridement, dressing changes, and closure by secondary intention with a mortality of about 30% [7] was the most widely used treatment until 1963. At that time, Shumacker and Mandelbaum [9] described a technique of closed catheter irrigation of the mediastinum after debridement and closure of the sternum. This technique was further modified in 1968 by Bryant and associates [lo]. Dilute antimicrobial solution was irrigated through the mediastinum until the wound infection clinically resolved or until cultures of the effluent were negative. The mortality of poststernotomy mediastinitis using this technique was reduced to 20%. Thurer and associates [ l l ] described the use of 0.5% povidone-iodine (Betadine) solution as a mediastinal irrigant and reported it to be an effective antimicrobial and nontoxic in the concentrations used. Since then, however, iodine toxicity has been reported and the use of this irrigant solution has been abandoned in some centers [12]. Lee and colleagues [13] in 1976 offered the first alternative to open granulation in those patients whose infection was not resolved by catheter irrigation. After wide debridement, omentum was transposed into the mediastinum. Jurkiewicz and co-workers [14] expanded on this concept and advocated the use of muscle flaps instead of omentum. Their report led to a dramatic increase in the use of muscle flaps and was accompanied by impressive results from different centers. Procedure mortality was largely eliminated and success rates climbed to more than 90%. The original technique [14] called for an interval period of open packing to prepare the mediastinal bed before swinging muscle flaps. Recently, however, a number of centers have reported a single-stage procedure involving debridement and muscle flap mobilization without compromising success [15, 161. Based on this experience a number of principles have evolved in the surgical management of mediastinal infections [17]: (1) Early recognition is crucial. (2) Adequate debridement and removal of all foreign bodies and devascularized bone is essential. (3) Obliteration of all mediastinal dead space with vascularized muscle flaps is preferred. Simple debridement and irrigation has been recommended in patients whose mediastinal structures are soft and pliable as opposed to those who have a thick fibrous peel that prevents obliteration of the mediastinal space [17]. In the transplant patient, however, the mediastinum is usually wide due to chronic cardiac dilatation, and suction obliteration of mediastinal space may be inadequate even if these tissues are pliable. Our own data reflect a high failure rate (66%) of the debridementirrigation technique. Muscle flaps most commonly used include one or both pectoralis major muscles and unilateral rectus abdominis muscle. The pectoralis may be based on the thoracoacromial or intercostal branches of the internal mammary artery. The rectus abdominis is based on the superior epigastric artery. Flap mobilization techniques have improved to reduce blood loss, decrease seroma formation, and maintain form and function [15, 181. Although respiratory mechanics are always a concern, none of our
patients had prolonged respiratory problems related to the sternal debridement and flaps. Other reports in the literature tend to support this observation [15, 191. Muscle flap treatment simplifies nursing care, helps ambulation, avoids psychological stress, and Simplifies immunosuppressive management in the event of a rejection episode. We currently favor the muscle flap technique in the management of these infections.
Presentation and Diagnosis In all cases reviewed, presentation of mediastinitis was fairly typical with an elevated white blood cell count, pain, and fever. These signs and symptoms appeared during the initial hospitalization. We believe that induction immunotherapy and a low dose of steroid therapy in the first 14 days enable the recipient to mount an appropriate clinical response to the infection. This is in contrast to the report by Trento and associates [4] on 6 patients with mediastinitis after transplantation, in which the use of triple-drug therapy masked signs and symptoms, resulting in frequent late diagnosis. In our series the diagnosis was fairly simple because of classic symptoms. Additionally, computed tomographic scanning of the mediastinum proved to be an extremely useful diagnostic tool. Coupled with aspiration, the accuracy of computed tomographic scanning for diagnosis of mediastinitis was 100%. There was one false-negative computed tomographic scan performed without aspiration in a patient with mediastinitis. Computed tomographic scanning also was useful in postoperative surveillance after surgical treatment of mediastinitis. The accuracy of computed tomographic scanning in this setting even without aspiration is 100%.
lrnmunosuppression Cardiac transplantation has evolved from a heroic sporadically successful clinical experiment in the late 1960s to a widely accepted therapeutic modality with a high degree of success. In the early years of cardiac transplantation, only nonselective immunosuppression with corticosteroids and antimetabolites such as azathioprine, cyclophosphamide, or actinomycin D was available. Rejection frequency and infection rates were high. The introduction of cyclosporine-based immunosuppression in the early 1980s led to dramatic increases in survival and quality of life [ 5 ] .Because of the selectivity of cyclosporine, rejection was more often a chronic smoldering process rather than an acute fulminant event. Triple therapy (cyclosporine, azathioprine, and corticosteroids) was rapidly adopted and became the standard immunosuppressive regimen used in cardiac transplantation. This in turn led to liberalization of recipient and donor criteria and a proliferation of centers offering cardiac transplantation. In recent years, therefore, patients with certain systemic diseases or end-organ dysfunction are being considered for cardiac transplantation. Immunosuppression in these patients has to be carefully regulated. The object is to develop a therapeutic window, wherein the degree of immunosuppression is sufficient to prevent allograft rejection but leaves the host sufficiently immunocompetent with regard to pathogenic
KARWANDE ET AL MEDIASTINITIS IN HEART TRANSPLANTATION
Ann Thorac Surg 1992;541039-45
-MHC
Class I & I1 Antigens Class I Antigens
-MHC
Interleukin 2
1043
Fig 2. Cascade of events leading to allograft destruction. Allograft rejection occurs when foreign antigen is processed by antigen-presenting cells and presented to mature helper or cytotoxic T lymphocytes. Processed antigen presented to helper T lymphocytes induces the formation of cytotoxic T lymphocytes by the synthesis and secretion of interleukin 2 . Once mature T lymphocytes have recognized foreign antigen, lymphocyte proliferation occurs, leading to cell killing, phagocytosis, and antibody formation. Left unchecked, allograft destruction ultimately occurs.
Cyclosporine Mono & Polyclonal Antibodies 4
Lymphocyte Activation
Lymphocyte Proliferation t
t
Azathioprine Cyclophosphamide Vicrisrine Methomxate
Mono & Polyclonal Antibodies
r-l
Cell Killing Phagocytosis Antibody Formation
I Allograft Destruction I 1
organisms or neoplastic processes. Our goal is to selectively and potently block the cascade of events leading to allograft destruction (Fig 2) with a combination of older and newer immunosuppressive agents. Table 3 lists future immunosuppressive agents and their mechanisms of action. Increased selectivity is the goal of future immunosuppressive protocols. It is generally established that greater immunosuppression is required earlier after organ transplantation rather than later. This lesser requirement with time is believed to develop as a result of the gradual emergence of suppressor mechanisms [20]. Aggressive early prophylaxis using cytolytic therapy delays the first episode of allograft rejection until the allograft has recovered from the ischemic insult and the surgical wounds have healed [21]. Whether early cytolytic therapy will enhance or hasten development of allograft tolerance is an unresolved issue. Nevertheless, routine administration of potent antilymphocyte preparations for early prophylaxis is used by almost 50% of the transplant centers [22]. This is in the hope of inducing the host to be more tolerant to the allograft, so-called “induction therapy.” Yacoub and associates in 1985 first suggested the use of early cytolytic therapy (polyclonal) leading to steroid withdrawal. When OKT3 became available for clinical trials, prophylactic administration in cardiac transplantation was pursued because of its predictable potency, easy availability, and lack of contamination with blood products.
OKT3 is a murine anti-CD3 monoclonal antibody. It was initially used to treat allograft rejection refractory to corticosteroids and polyclonal antilymphocytic prepara-
Table 3. Future Immunosuppressive Axents Agent FK-506
Mechanism of Action
Interferes with the production of interleukin 2 from helper T lymphocytes, blocking the induction of cytotoxic T lymphocytes RS-61443 Blocks the only pathyway, the de novo pathway, in lymphocytes for purine biosynthesis Rapamycin Suppresses interleukin 2 and interleukin 4-driven lymphocyte proliferation Blocks protein synthesis in CD-5 positive Anti-pan T lymphocyte lymphocytes by enzymatically cleaving antibody-Ricin A a specific adenosine linkage in chain ribosomal RNA immunoconjugate monoclonal antibody OKT4a Selectively reacts with and depletes CD-4 positive lymphocytes, suppressing the generation of primary cytotoxic responses Inhibits functional interleukin 2 to Anti-interleukin 2 receptor interleukin 2-receptor interaction monoclonal antibody
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KARWANDE ET AL MEDIASTINITIS IN HEART TRANSPLANTATION
tions [23]. OKT3 w a s introduced into early rejection prophylaxis protocols i n t h e hope of delaying rejection and t o block antigen recognition. This i n t u r n would result i n fewer rejection episodes. With this background, induction therapy was adopted by t h e U t a h Transplant Affiliated Hospitals Cardiac Transplant Program w i t h t h e following goals i n mind: (1)Delay t h e first rejection episode. (2) Decrease t h e severity and frequency of rejection episodes. (3) Establish a relatively drug free a n d rejection free interval immediately postoperatively to allow for wound healing. O u r own experience seems t o s u p p o r t these objectives [Zl].Data from o t h e r centers w i t h respect t o efficacy of OKT3 a r e quite varied [24-261. T h e large discrepancy i n comparative efficacy i s i n p a r t explained by differences i n t h e immunosuppressive protocols i n d e p e n d e n t of OKT3 administration. Recently, Prieto and co-workers [27] and Reid and associates [6] h a v e reported their experience w i t h high-risk patients managed by induction immunotherapy. They found that these patients required smaller doses of immunosuppressive d r u g s i n t h e early postoperative period a n d h a d fewer serious infections without compromising long-term survival. Clearly, i n high-risk p a t i e n t s i m m u n o s u p p r e s s i o n needs t o be individualized to reduce t h e risk of infection and assure allograft survival. With several new a n d potent immunosuppressive agents on t h e horizon (see Table 3), t h e hope that selective immunosuppression for highrisk patients will improve i n t h e years t o come is realistic.
Conclusions Mediastinitis after cardiac transplantation is twice as likely t o occur compared w i t h nontransplant cardiac operations. The major risk factor predisposing to mediastinitis is t h e patient’s preoperative condition. Patients i n t h e intensive care u n i t on intravenous inotropic support, those who are listed i n UNOS status 1, and those having had previous sternotomies h a v e a higher risk for development of mediastinitis. Elevation of t h e w h i t e blood cell count, incisional p a i n o u t of proportion w i t h physical findings, or unexplained shock in t h e first few weeks after transplantation s h o u l d be construed as mediastinitis unless proved otherwise. C o m p u t e d tomographic scanning w i t h aspiration is a valuable adjunct i n t h e diagnosis of mediastinitis, and its liberal use is recommended. Because of t h e high failure rate of t h e debridement-irrigation technique, a single- or two-stage application of t h e debridementmuscle flap technique is our current choice. Induction i m m u n o t h e r a p y and avoidance of high-dose steroids i n t h e perioperative period may allow the patient t o m o u n t an appropriate and effective response t o infection, either preventing mediastinitis or allowing it t o be diagnosed earlier.
References 1. Frimpong-Boakeng K, Warnecke H, Schuler S, Haverich A, Borst HG. Transposition of the greater omentum for management of mediastinal infection following orthotopic heart transplantation: a case report. J Heart Transplant 1986;5: 330-1. 2. Miller R, Ruder J, Karwande SV, Burton NA. Treatment of mediastinitis after heart transplantation. J Heart Transplant 1986;55:477-9.
Ann Thorac Surg 1992:54:103945
3. Pearl SN, Weiner MA, Dibbel DG. Sternal infection after cardiac transplantation. Successful salvage utilizing a variety of techniques. J Thorac Cardiovasc Surg 1982;83:6324. 4. Trento A, Dummer GS, Hardesty RL, Bahnson HT, Griffith BP. Mediastinitis following heart transplantation: incidence, treatment and results. Heart Transplant 1984;4:33640. 5. Renlund DG, OConnell JB, Bristow MR. Strategies of immunosuppression in cardiac transplantation. Semin Thorac Cardiovasc Surg 1990;2:181-8. 6. Reid KR, Menkis AH, Novick RJ, et al. Reduced incidence of severe infection after heart transplantation with lowintensity immunosuppression. J Heart Lung Transplant 1991; 103894-900. 7. Grossi EA, Culliford AT, Krieger KH. A survey of 77 major infectious complications of median sternotomy: a review of 7949 consecutive operative procedures. Ann Thorac Surg 1985;40:214-23. 8. Serry C, Bleck PC, Javid H, et al. Sternal wound complications: management and results. J Thorac Cardiovasc Surg 1980;80:861-7. 9. Shumacker HB Jr, Mandelbaum I. Continuous antibiotic irrigation in the treatment of infection. Arch Surg 1963;86: 384-7. 10. Bryant LR, Spencer FC, Trinkle JK. Treatment of median sternotomy infection by mediastinal irrigation with an antibiotic solution. Ann Surg 1969;169:914-20. 11. Thurer RJ, Bognolo D, Vargas A, Isch JH, Kaiser GA. The management of mediastinal infection following cardiac surgery. An experience utilizing continuous irrigation with povidone iodine. J Thorac Cardiovasc Surg 1974;68:962-8. 12. Glick PL, Guglielmo BJ, Tranbaugh RF, Turley K. Iodine toxicity in a patient treated by continuous povidone-iodine mediastinal irrigation. Ann Thorac Surg 1985;39:478-80. 13. Lee AB Jr, Schimert G, Shatkin S. Total incision of the sternum and thoracic pedicle transposition of the greater omentum: useful strategems in managing severe mediastinal infection following open heart surgery. Surgery 1976;80: 43M. 14. Jurkiewicz MJ, Bostwick J 111, Hester TR, Bishop JB, Craver J. Infected median sternotomy wound. Successful treatment by muscle flaps. Ann Surg 1980;191:738-43. 15. Jeevanandam V, Smith CR, Rose EA, Malm JR, Hugo NE. Single stage management of sternal wound infections. J Thorac Cardiovasc Surg 1990;99:256-63. 16. Nahai F, Rand RP, Hester TR, Bostwick J, Jurkiewicz MJ. Primary treatment of the infected sternotomy wound with muscle flaps. A review of 211 consecutive cases. Plast Reconstr Surg 1989;84:434-41. 17. Pairolero PC, Arnold PC. Management of infected median sternotomy wounds. Ann Thorac Surg 1986;42:1-2. 18. Nahai F, Morales L Jr, Bone DK, Bostwick J 111. Pectoralis major muscle turnover flaps for closure of the infected sternotomy wound with preservation of form and function. Plast Reconstr Surg 1982;70:4714. 19. Neale HW, Kreilein JG, Schreiber JT, Gregory RO. Complete sternotomy for chronic myelitis with reconstruction using a rectus abdominis myocutaneous island flap. Ann Plast Surg 1981;6305-14. 20. Lafferty KJ, Prowse SJ, Simeonlvic CJ. Immunobiology of tissue transplantation: a return of the passenger leukocytic concept. Annu Rev Immunol 1983;1:143-73. 21. Renlund DG, OConnell JB, Gilbert EM, et al. A prospective comparison of murine monoclonal CD-3 (OKT3) antibodybased and equine antithymocyte globulin-based rejection prophylaxis in cardiac transplantation. Decreased rejection and less corticosteroid use with OKT3. Transplantation 1989; 47:599-605. 22. A report of the working group of transplant cardiologists. Efficacyof induction and non-induction immunosuppression in cardiac transplantation [Abstract]. J Heart Transplant 1990;9:61. 23. Gilbert EM, DeWitt CW, Eisworth CE, et al. Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody. Am J Med 1987;82:202-6.
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24. Constanzo-Nordin MR, OSullivan EJ, Johnson MR, et al. Prospective randomized trial of OKT3 versus horse antithymocyte globulin-based immunosuppressive prophylaxis in heart transplantation. J Heart Transplant 1990;9:30&15. 25. Kirklin JK, Boulge RC, White-Williams C, et al. Prophylactic therapy for rejection after cardiac transplantation. J Thorac Cardiovasc Surg 1990;99:716-24. ~~
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26. Frist WH, Merrill WH, Eastburn TE, et al. Unique antithymocyte serum versus OKT3 for induction immunotherapy after heart transplantation. J Heart Transplant 1990;9:489-94. 27. Prieto M, Lake KD, Pritzker MR, et al. OKT3 induction and steroid-free maintenance immunosuppression for treatment of high risk heart transplant recipients. J Heart Lung Transplant 1991;10:901-11.
~
DISCUSSION D R THOMAS M. EGAN (Chapel Hill, NC): I would like to congratulate you for your success, and I had a question about your recommendation for muscle flaps as a primary procedure to deal with this very difficult problem. If 3 of 8 patients can be spared muscle flaps and then the balance subsequently salvaged, why d o you propose not going to the less aggressive procedure first? In your abstract you suggested that the death was related to acute rejection and not to failure of your muscle ffaps. DR KARWANDE: Well, first we have had a high failure rate with the debridement-irrigation technique. Muscle flap coverage makes the management of these patients after the surgical therapy simpler, ie, when rejection develops I think the treatment of rejection is simplified. You are not concerned about using steroids on these patients because you feel secure in the fact that their dead space has been obliterated with a viable muscle flap. The second reason is that patients who tend to fail debridement and irrigation, and their percentage is high in our series, have a prolonged hospital stay. The only fatal outcome we had was in a patient who had failed the debridement-irrigation technique; I believe we lost the window of opportunity and the subsequent cascade of events led to his death. DR RICHARD J. NOVICK (London, Ont, Canada): We have performed 294 heart transplantations and have had 10 cases of mediastinitis. All were treated with debridement, sternal reclosure, and mediastinal imgation for 10 to 14 days, and none had recurrent infection. I therefore believe that the conclusion that the primary mode of therapy should be a muscle flap is not correct. What were the reasons for failure of the sternal closure technique? Was there infection with methicillin-resistant Staphylococcus aureus? Was there any residual sternal instability? What factors could you identdy to indicate why those 4 or 5 patients failed? DR KARWANDE: I think the main reason why those 5 patients failed the debridement-irrigation technique was because the dead space was not obliterated by the suction technique. Some of these patients have a stiff, nonpliable mediastinum, and in spite of chest tube suction the mediastinum is not obliterated. Many of these patients, as you very well know, have large pericardial cavities, and these cavities are, generally speaking, occupied by a small donor heart. I presume that one of the reasons why the debridement-irrigation technique failed was because the cavity was not obliterated. DR H A N S G. BORST (Hannover, Germany): I thoroughly enjoyed your presentation because we are both in agreement on certain points and in disagreement on others. We certainly agree with you, and 1 think you have proved it, that mediastinitis is not as catastrophic an event in transplant patients as one would suppose on account of the fact that the patient is immunocompromised. We have had 6 such complications in a group about the size of
yours for an incidence of mediastinitis of about 1.5%; however, all 6 patients had an unstable sternum, and in fact we have never seen the discrete type of mediastinitis that you are describing. All 6 patients had omental pull-up and all of them healed per primam. There was no need of applying any more advanced plastic procedures. In addition, and more interestingly, we had 1 patient of 25 undergoing heart-lung transplantation who, on the 11th postoperative day, suddenly exsanguinated and was taken to the operating room where she was bleeding from the aortic cannulation site. During cardiac massage and mass transfusion, my co-worker, Dr Haverich, fixed the hole in the aorta and again did an omental pull-up, and this again resulted in primary healing. Lo and behold the causative agent was Candida! So I think we fully agree with you that one should be aggressive about these cases of mediastinitis with the aim of completely filling up the retrosternal space, and I think these patients should be treated promptly before any extensive osteomyelitis develops, because then you will wind up with all kinds of plastic procedures trying to fill holes. But it nevertheless is very interesting that you have these discrete forms that we have never seen. Now, if you do your plastic operations, d o you add an irrigation system or do you just leave it like it is? DR KARWANDE: I would like to compliment you on your low mediastinitis rate. I think what we are saying is basically the same thing. Instead of using omentum we have been using muscle. There is no irrigation involved when you use the pectoralis major muscle. You basically obliterate the dead space in the mediastinum using the muscle and then close the skin on top of it. D R BORST: Don’t you wind up with a big defect in the sternum then because you have to slip in the muscle somehow? DR KARWANDE: The sternum is left open. Fortunately we have not seen problems related to this, by way of respiratory embarrassment or cosmetic deformity. D R BORST Oh, I see; the sternum was always closed in our patients. D R EDWARD A. PASCOE (Winnipeg, Man, Canada): Coronary disease as the pretransplantation diagnosis I think also was an increased predictor of mediastinitis. Had many of those patients undergone myocardial revascularization with harvesting of internal mammary arteries, which might have made their chest walls relatively ischemic and more prone to infection? D R KARWANDE: That is a very good question. We looked at that specifically, and we found only 2 patients of 12 in whom mediastinitis developed had internal mammary artery revascuIarization, and of the 12 patients in whom mediastinitis developed, we could detect an unstable sternum in only 3 patients.
Between March 1985 and December 1991, mediastinitis developed in 12 of 420 cardiac transplantation patients (2.8%). The mortality rate in this group of patients was 8.3% (1/12).Actuarial survival (1year, 75%; and 5 years, 65%) was not significantly different from that of the group without mediastinitis (1 year, 88%; and 5 years, 75%). A higher percentage of the patients in the group with mediastinitis were listed as UNOS status 1 (50% versus 35%) and had a history of previous sternotomies (58% versus 44%). The presentation of mediastinitis was typical. Computed tomographic scanning with or with-
out aspiration was a valuable adjunct in the diagnosis of mediastinitis. Induction immunotherapy with minimal steroids in the perioperative period was used in all patients. This may contribute to the patients' ability to mount an appropriate and effective response to infection, permitting earlier diagnosis. The debridement irrigation technique used in 8 of 12 patients had a low success rate of 33%, whereas the debridement muscle flap technique used in 4 of 12 was 100% successful in eliminating infection. (Ann Tkoruc Surg 2992;54:203945)
I
protocols, perioperative management protocols, and biopsy schedules were standardized. The operations were performed by surgeons at three different hospitals with comparable survival rates. The antibiotic regimen, skin preparation, and draping in the three hospitals were similar. The technical details of the recipient operation and the donor harvest were standardized, as were the donor heart transport and packaging techniques. A crystalloid cardioplegic solution was used. The sternum was closed with interrupted stainless steel wires. The fascia and the subcutaneous and subcuticular tissues were closed with continuous absorbable sutures. All patients received prophylactic antibiotics. Cefuroxime was given at least Ih hour before the skin incision. Antibiotics were added to the pump prime and were administered for 48 hours postoperatively. Reverse isolation was not used. Early rejection prophylaxis was based on equine antithymocyte globulin (polyclonal antibody) or murine monoclonal CD-3 antibody (OKT3). Our current immunosuppressive protocol involves a 14-day course of OKT3 beginning with a dose intraoperatively at the time of the pulmonary artery anastomosis. Intraoperative administration has the advantage of attenuating the first dose reaction and antigen recognition when the aortic crossclamp is removed. OKT3 levels and CD3 lymphocyte counts are monitored daily for 14 days. Cyclosporine administration is begun on the third or fourth postoperative day at an oral dosage of 6 mg * kg-' * day-' and is adjusted to a target trough level of 150 to 200 mg/mL. Azathioprine (2 to 4 mg/kg) is administered preoperatively, and the postoperative dosage is adjusted to maintain the white blood cell count between 4 and 6 x 109/L (4,000 and 6,OOO/pL). Methylprednisone is administered intraoperatively (500 mg intravenously). Corticosteroids
n the face of the rapid and continued growth of heart transplantation, it is essential to continuously scrutinize the results and complications of this procedure. Mediastinitis is one of the most serious complications after heart operations. It carries a high mortality and significant morbidity. Additionally, heart transplant recipients represent a group of patients in whom decreased immune defenses present a unique situation. Transplant literature is surprisingly sparse with regard to mediastinitis. Most reports have involved few patients [l-31 or examined patients in the preinduction therapy era [4]. We retrospectively studied mediastinitis in 420 consecutive patients undergoing orthotopic heart transplantation from March 1985 to December 1991. The term mediustinifis defines a retrosternal infectious process with or without sternal instability. This definition does not include a superficial infection or a subcutaneous process confined to the anterior aspect of the sternum. Patients included in this review fit the criteria described above. This study was designed to investigate several questions: (1)the incidence of mediastinitis in heart transplant patients and its attendant mortality and morbidity, (2) predisposing or risk factors, (3) clinical presentation, (4) diagnosis, and (5) surgical options. Material a n d Methods The Utah Transplant Affiliated Hospitals Cardiac Transplant Program is based in three hospitals in the Salt Lake City valley. The recipient criteria, immunosuppressive Presented at the Twenty-eighth Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Feb S 5 , 1992. Address reprint requests to Dr Karwande, Division of Cardiothoracic Surgery, University of Utah Medical Center, 50 North Medical Dr, Salt Lake City, UT 84132.
0 1992 by The Society of Thoracic Surgeons
0003-4975/92/$5.00
1040
Ann Thorac Surg 1992;54:1039-45
KARWANDE ET AL MEDIASTINITIS IN HEART TRANSPLANTATION
Table 1. Characteristics of Patients" Variable
Mediastinitis
Number
12 52 t 11 29 t 11
Age (Y) Donor age (y)
Male (%)
No Mediastinitis 408 13 11 82
49 t 27 t
100
Preoperative Diagnosis (%)
IDC CAD
Other UNOS status 1 (%) Transplant wait (d) Ischemic time (min) Redo operation (%) EF CI (L * min-' IABPNAD
. m-')
8
34
75 17
55 11 36 54 t 60 172 t 62 42 0.18 .+. 0.08 2.0 t 0.6 43 (12%)
50 88 2 107 167 t 45
58 0.18 t 0.09 2.0
-C
0.5
1(8%)
Values are reported as discrete, percentage, or mean tion.
a
?
standard devia-
EF = ejection C1 = cardiac index; CAD = coronary artery disease; fraction; IABP = intraaortic balloon pump; IDC = idiopathic dilated cardiomyopathy; UNOS = United Network for Organ Sharing; VAD = ventricular assist device.
(prednisone or equivalent) are then administered at 0.25 mg * kg-' * day-' until the completion of the OKT3 course, when the dosage is increased to 1mg kg-' * day-' for 7 days. A steroid taper is begun immediately and discontinued in the following 2 weeks; it is only reinstituted for episodes of rejection. Surveillance biopsies are performed as per standard protocol. Management of rejection episodes has been described in detail elsewhere [5]. Transplant patients were grouped by presence or absence of mediastinitis. Statistical differences between groups were analyzed using the ,$ or Fisher's exact test, as appropriate, for discrete variables, and unpaired Student's t tests for continuous variables. Odds ratios for risk factors were calculated from contingency tables and are reported with 95% confidence intervals. Multivariate analysis of risk factors was performed using a logistic stepwise regression model. Actuarial survival was determined by the Kaplan-Meier method, with significance of comparisons determined by the Tarone-Ware test. Statistical significance was considered for an a level of 0.05 ( p < 0.05).
-
Results A total of 12 mediastinal infections occurred in 420 patients for an overall incidence of 2.8%. One of these patients died, yielding a mortality rate of 8.3% (1112). There were three late deaths, which were unrelated to mediastinitis. Demographic and descriptive characteristics of transplant patients with and without mediastinitis are shown in Table 1. The following risk factors were analyzed for inclusion in a step-wise logistical regression model for prediction of mediastinitis: age, sex, time on wait list, ejection fraction,
pulmonary capillary wedge pressure, cardiac index, circulatory support, United Network for Organ Sharing (UNOS) status, donor heart ischemic time, cross match, cause of cardiac disease, previous sternotomy, year of transplantation, and immunosuppressive protocol. Risk factors identified in the model (criterion, p < 0.15) included year of transplantation, cause of cardiac disease, and UNOS status. Higher risk was associated with transplantation in earlier years, coronary artery disease as the cause of cardiac disease, and a pretransplantation UNOS status of 1. Knowledge of cause significantly improved the model ( p = 0.03). Differences were observed in terms of preoperative diagnosis and severity of illness before operation. Mediastinitis was 2.7 times (95%confidence interval 0.71-10.8) more likely to develop in patients listed for transplantation for ischemic cardiomyopathy than in other transplant patients. Seven of the 12 patients in whom mediastinitis developed had had prior sternotomy (58%).This is higher than the general transplant population, in which repeat operations comprise only 44% of the patients. Mediastinitis was 1.9 times (95% confidence interval, 0.566.03) more likely to develop in patients with one or more prior sternotomies. Six of the 12 recipients with mediastinitis (50%) had UNOS status 1 before their transplantation. These patients were in the intensive care unit for varying lengths of time receiving intravenous inotropes before transplantation. In comparison, pretransplantation inotropic support was required in 36% of the general transplant population. Mediastinitis was 1.9 times (95% confidence interval, 0.56-6.48) more likely to develop in patients listed as UNOS status 1 than in other transplant patients. One patient had an intraaortic balloon pump in place. Although it is customary for central lines to be inserted before transplantation in all patients, 6 of the 12 patients in whom mediastinitis developed had central line placement or Swan-Ganz monitoring performed for hemodynamic reasons. The average pretransplantation wait was 88 days and did not differ from the general transplant population. The average cross-clamp time was 81 minutes. The ischemic time was 167 minutes and the pump time was 122 minutes. These figures are not statistically different from those of the patients without mediastinitis. All patients were extubated within 24 hours. Blood loss and blood product requirements were reviewed. These were not found to be excessive. The average total chest tube drainage was 741 mL. All patients received fresh-frozen plasma preoperatively because all had been placed on full oral anticoagulation, which needed to be reversed at the time of transplantation. One of the 12 patients in whom mediastinitis developed (8%) was reexplored for mediastinal bleeding. The postoperative course of these patients after the development of mediastinitis was complicated. Four of the 12 patients required a variety of procedures to be performed (colonoscopy, suture ligation of bleeding duodenal ulcer, femoral embolectomy). Dialysis was required in 2 of 12 patients (17%). Postoperative opportunistic pneumonias were seen in 4 of 12 patients (enterococcus,
KARWANDE ET AL MEDIASTINITIS IN HEART TRANSPLANTATION
Ann Thorac Surg 1992;54103945
Table 2. Surqical Techniaue ~~
Procedure Debridement and irrigation Debridement and muscle flaps
No. of Patients
Success
8/12 (66%)
3/8 (37%)
4/12 (34%)
4 4 (100%)
Complications Bleeding (l), seroma (2) None
Legionella, and cytomegalovirus). Two of 12 patients (16%) had recognizable sepsis before transplantation and had been treated with appropriate antibiotics with resolution. The presentation of mediastinitis was quite typical. The usual presenting signs and symptoms were elevated white blood cell count (loo%), pain (66%), fever (66%), drainage, sternal instability, and shock (25%).The most common were fever and pain. Pain, seen in 8 of 12 patients (66%),was out of proportion with physical findings and often preceded other manifestations. Drainage, sternal instability, and fluctuance were less common. The average time of presentation was 9 days after operation, with a range of 5 to 17 days. Shock was the first presentation of mediastinitis in 3 patients. Two of these 3 required tracheal intubation and inotropic support. In spite of immunosuppression with azathioprine, all patients presented with an elevated white blood cell count, which ranged from 11 to 35 x 109/L(11,000 to 35,OOO/pL). Staphylococcus species was cultured from the majority of these wounds (11/12). There was one Legionella infection. No polymicrobial infections were seen. There was no relationship between the type of organism and outcome. Debridement, sternal closure, and irrigation was the most commonly used initial surgical procedure (8/12; 66%) (Table 2). This procedure, however, was unsuccessful in eliminating the infection in 5 of these patients (62%).All 5 eventually required muscle flaps to effect healing. The single death of this series was in this group. Debridement and muscle flap closure as a two-stage procedure was
1041
used as the initial surgical management in 4 of 12 patients (34%)with no failures and no mortality. The choice of the initial surgical procedure was based on surgeon preference. Debridement and muscle flap closure as a singlestage procedure was not used in this series. There were no significant differences in actuarial survival between patients with mediastinitis (75% at 1 year and 64% at 5 years) and the general transplant population (88% at 1 year and 75% at 5 years; p = 0.70). Morbidity and mortality after hospital discharge are significant in the nontransplant cardiac surgical population with mediastinitis. Survival of 86% at hospital discharge fell to 75% in 3 years in one series [6]. In this series of transplant patients discharged from the hospital after recovery from mediastinitis, the survival rate is similar to that of other transplant patients (Fig 1).
Comment Surgical Technique Deep infections of sternotomy wounds occur with a reported incidence of 0.3% to 5% in the general cardiac surgical population. Our incidence of sternal wound infection in the nontransplant population is less than 1%. In the transplant population this incidence is more than doubled at 2.8%. The pathogenesis of sternal infections is still unclear. Grossi and associates [7] postulate a localized area of osteomyelitis within the sternal marrow without external signs except for localized pain, a situation similar to an abscess in a bone in other locations. Such a localized area of osteomyelitis is not well penetrated by systemic antibiotics, and unless drained the infection spreads to adjacent costal cartilage and underlying mediastinum. Others believe that instability of sternal fragments is the cause of most sternal infections. Prolonged antibiotic treatment of mediastinitis as reported by Serry and colleagues [8] carries an unacceptable morbidity and mortality and has been abandoned. Sternal Fig I . Actuarial survival analysis of patients with and without mediastinitis. Statistically the difference was not significant (N.S.).
h
70
-
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50-
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No mediastinitis
2010
64%
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Ann Thorac Surg 1992;541039-45
KARWANDE ET AL MEDIASTINITIS IN HEART TRANSPLANTATION
debridement, dressing changes, and closure by secondary intention with a mortality of about 30% [7] was the most widely used treatment until 1963. At that time, Shumacker and Mandelbaum [9] described a technique of closed catheter irrigation of the mediastinum after debridement and closure of the sternum. This technique was further modified in 1968 by Bryant and associates [lo]. Dilute antimicrobial solution was irrigated through the mediastinum until the wound infection clinically resolved or until cultures of the effluent were negative. The mortality of poststernotomy mediastinitis using this technique was reduced to 20%. Thurer and associates [ l l ] described the use of 0.5% povidone-iodine (Betadine) solution as a mediastinal irrigant and reported it to be an effective antimicrobial and nontoxic in the concentrations used. Since then, however, iodine toxicity has been reported and the use of this irrigant solution has been abandoned in some centers [12]. Lee and colleagues [13] in 1976 offered the first alternative to open granulation in those patients whose infection was not resolved by catheter irrigation. After wide debridement, omentum was transposed into the mediastinum. Jurkiewicz and co-workers [14] expanded on this concept and advocated the use of muscle flaps instead of omentum. Their report led to a dramatic increase in the use of muscle flaps and was accompanied by impressive results from different centers. Procedure mortality was largely eliminated and success rates climbed to more than 90%. The original technique [14] called for an interval period of open packing to prepare the mediastinal bed before swinging muscle flaps. Recently, however, a number of centers have reported a single-stage procedure involving debridement and muscle flap mobilization without compromising success [15, 161. Based on this experience a number of principles have evolved in the surgical management of mediastinal infections [17]: (1) Early recognition is crucial. (2) Adequate debridement and removal of all foreign bodies and devascularized bone is essential. (3) Obliteration of all mediastinal dead space with vascularized muscle flaps is preferred. Simple debridement and irrigation has been recommended in patients whose mediastinal structures are soft and pliable as opposed to those who have a thick fibrous peel that prevents obliteration of the mediastinal space [17]. In the transplant patient, however, the mediastinum is usually wide due to chronic cardiac dilatation, and suction obliteration of mediastinal space may be inadequate even if these tissues are pliable. Our own data reflect a high failure rate (66%) of the debridementirrigation technique. Muscle flaps most commonly used include one or both pectoralis major muscles and unilateral rectus abdominis muscle. The pectoralis may be based on the thoracoacromial or intercostal branches of the internal mammary artery. The rectus abdominis is based on the superior epigastric artery. Flap mobilization techniques have improved to reduce blood loss, decrease seroma formation, and maintain form and function [15, 181. Although respiratory mechanics are always a concern, none of our
patients had prolonged respiratory problems related to the sternal debridement and flaps. Other reports in the literature tend to support this observation [15, 191. Muscle flap treatment simplifies nursing care, helps ambulation, avoids psychological stress, and Simplifies immunosuppressive management in the event of a rejection episode. We currently favor the muscle flap technique in the management of these infections.
Presentation and Diagnosis In all cases reviewed, presentation of mediastinitis was fairly typical with an elevated white blood cell count, pain, and fever. These signs and symptoms appeared during the initial hospitalization. We believe that induction immunotherapy and a low dose of steroid therapy in the first 14 days enable the recipient to mount an appropriate clinical response to the infection. This is in contrast to the report by Trento and associates [4] on 6 patients with mediastinitis after transplantation, in which the use of triple-drug therapy masked signs and symptoms, resulting in frequent late diagnosis. In our series the diagnosis was fairly simple because of classic symptoms. Additionally, computed tomographic scanning of the mediastinum proved to be an extremely useful diagnostic tool. Coupled with aspiration, the accuracy of computed tomographic scanning for diagnosis of mediastinitis was 100%. There was one false-negative computed tomographic scan performed without aspiration in a patient with mediastinitis. Computed tomographic scanning also was useful in postoperative surveillance after surgical treatment of mediastinitis. The accuracy of computed tomographic scanning in this setting even without aspiration is 100%.
lrnmunosuppression Cardiac transplantation has evolved from a heroic sporadically successful clinical experiment in the late 1960s to a widely accepted therapeutic modality with a high degree of success. In the early years of cardiac transplantation, only nonselective immunosuppression with corticosteroids and antimetabolites such as azathioprine, cyclophosphamide, or actinomycin D was available. Rejection frequency and infection rates were high. The introduction of cyclosporine-based immunosuppression in the early 1980s led to dramatic increases in survival and quality of life [ 5 ] .Because of the selectivity of cyclosporine, rejection was more often a chronic smoldering process rather than an acute fulminant event. Triple therapy (cyclosporine, azathioprine, and corticosteroids) was rapidly adopted and became the standard immunosuppressive regimen used in cardiac transplantation. This in turn led to liberalization of recipient and donor criteria and a proliferation of centers offering cardiac transplantation. In recent years, therefore, patients with certain systemic diseases or end-organ dysfunction are being considered for cardiac transplantation. Immunosuppression in these patients has to be carefully regulated. The object is to develop a therapeutic window, wherein the degree of immunosuppression is sufficient to prevent allograft rejection but leaves the host sufficiently immunocompetent with regard to pathogenic
KARWANDE ET AL MEDIASTINITIS IN HEART TRANSPLANTATION
Ann Thorac Surg 1992;541039-45
-MHC
Class I & I1 Antigens Class I Antigens
-MHC
Interleukin 2
1043
Fig 2. Cascade of events leading to allograft destruction. Allograft rejection occurs when foreign antigen is processed by antigen-presenting cells and presented to mature helper or cytotoxic T lymphocytes. Processed antigen presented to helper T lymphocytes induces the formation of cytotoxic T lymphocytes by the synthesis and secretion of interleukin 2 . Once mature T lymphocytes have recognized foreign antigen, lymphocyte proliferation occurs, leading to cell killing, phagocytosis, and antibody formation. Left unchecked, allograft destruction ultimately occurs.
Cyclosporine Mono & Polyclonal Antibodies 4
Lymphocyte Activation
Lymphocyte Proliferation t
t
Azathioprine Cyclophosphamide Vicrisrine Methomxate
Mono & Polyclonal Antibodies
r-l
Cell Killing Phagocytosis Antibody Formation
I Allograft Destruction I 1
organisms or neoplastic processes. Our goal is to selectively and potently block the cascade of events leading to allograft destruction (Fig 2) with a combination of older and newer immunosuppressive agents. Table 3 lists future immunosuppressive agents and their mechanisms of action. Increased selectivity is the goal of future immunosuppressive protocols. It is generally established that greater immunosuppression is required earlier after organ transplantation rather than later. This lesser requirement with time is believed to develop as a result of the gradual emergence of suppressor mechanisms [20]. Aggressive early prophylaxis using cytolytic therapy delays the first episode of allograft rejection until the allograft has recovered from the ischemic insult and the surgical wounds have healed [21]. Whether early cytolytic therapy will enhance or hasten development of allograft tolerance is an unresolved issue. Nevertheless, routine administration of potent antilymphocyte preparations for early prophylaxis is used by almost 50% of the transplant centers [22]. This is in the hope of inducing the host to be more tolerant to the allograft, so-called “induction therapy.” Yacoub and associates in 1985 first suggested the use of early cytolytic therapy (polyclonal) leading to steroid withdrawal. When OKT3 became available for clinical trials, prophylactic administration in cardiac transplantation was pursued because of its predictable potency, easy availability, and lack of contamination with blood products.
OKT3 is a murine anti-CD3 monoclonal antibody. It was initially used to treat allograft rejection refractory to corticosteroids and polyclonal antilymphocytic prepara-
Table 3. Future Immunosuppressive Axents Agent FK-506
Mechanism of Action
Interferes with the production of interleukin 2 from helper T lymphocytes, blocking the induction of cytotoxic T lymphocytes RS-61443 Blocks the only pathyway, the de novo pathway, in lymphocytes for purine biosynthesis Rapamycin Suppresses interleukin 2 and interleukin 4-driven lymphocyte proliferation Blocks protein synthesis in CD-5 positive Anti-pan T lymphocyte lymphocytes by enzymatically cleaving antibody-Ricin A a specific adenosine linkage in chain ribosomal RNA immunoconjugate monoclonal antibody OKT4a Selectively reacts with and depletes CD-4 positive lymphocytes, suppressing the generation of primary cytotoxic responses Inhibits functional interleukin 2 to Anti-interleukin 2 receptor interleukin 2-receptor interaction monoclonal antibody
1044
KARWANDE ET AL MEDIASTINITIS IN HEART TRANSPLANTATION
tions [23]. OKT3 w a s introduced into early rejection prophylaxis protocols i n t h e hope of delaying rejection and t o block antigen recognition. This i n t u r n would result i n fewer rejection episodes. With this background, induction therapy was adopted by t h e U t a h Transplant Affiliated Hospitals Cardiac Transplant Program w i t h t h e following goals i n mind: (1)Delay t h e first rejection episode. (2) Decrease t h e severity and frequency of rejection episodes. (3) Establish a relatively drug free a n d rejection free interval immediately postoperatively to allow for wound healing. O u r own experience seems t o s u p p o r t these objectives [Zl].Data from o t h e r centers w i t h respect t o efficacy of OKT3 a r e quite varied [24-261. T h e large discrepancy i n comparative efficacy i s i n p a r t explained by differences i n t h e immunosuppressive protocols i n d e p e n d e n t of OKT3 administration. Recently, Prieto and co-workers [27] and Reid and associates [6] h a v e reported their experience w i t h high-risk patients managed by induction immunotherapy. They found that these patients required smaller doses of immunosuppressive d r u g s i n t h e early postoperative period a n d h a d fewer serious infections without compromising long-term survival. Clearly, i n high-risk p a t i e n t s i m m u n o s u p p r e s s i o n needs t o be individualized to reduce t h e risk of infection and assure allograft survival. With several new a n d potent immunosuppressive agents on t h e horizon (see Table 3), t h e hope that selective immunosuppression for highrisk patients will improve i n t h e years t o come is realistic.
Conclusions Mediastinitis after cardiac transplantation is twice as likely t o occur compared w i t h nontransplant cardiac operations. The major risk factor predisposing to mediastinitis is t h e patient’s preoperative condition. Patients i n t h e intensive care u n i t on intravenous inotropic support, those who are listed i n UNOS status 1, and those having had previous sternotomies h a v e a higher risk for development of mediastinitis. Elevation of t h e w h i t e blood cell count, incisional p a i n o u t of proportion w i t h physical findings, or unexplained shock in t h e first few weeks after transplantation s h o u l d be construed as mediastinitis unless proved otherwise. C o m p u t e d tomographic scanning w i t h aspiration is a valuable adjunct i n t h e diagnosis of mediastinitis, and its liberal use is recommended. Because of t h e high failure rate of t h e debridement-irrigation technique, a single- or two-stage application of t h e debridementmuscle flap technique is our current choice. Induction i m m u n o t h e r a p y and avoidance of high-dose steroids i n t h e perioperative period may allow the patient t o m o u n t an appropriate and effective response t o infection, either preventing mediastinitis or allowing it t o be diagnosed earlier.
References 1. Frimpong-Boakeng K, Warnecke H, Schuler S, Haverich A, Borst HG. Transposition of the greater omentum for management of mediastinal infection following orthotopic heart transplantation: a case report. J Heart Transplant 1986;5: 330-1. 2. Miller R, Ruder J, Karwande SV, Burton NA. Treatment of mediastinitis after heart transplantation. J Heart Transplant 1986;55:477-9.
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3. Pearl SN, Weiner MA, Dibbel DG. Sternal infection after cardiac transplantation. Successful salvage utilizing a variety of techniques. J Thorac Cardiovasc Surg 1982;83:6324. 4. Trento A, Dummer GS, Hardesty RL, Bahnson HT, Griffith BP. Mediastinitis following heart transplantation: incidence, treatment and results. Heart Transplant 1984;4:33640. 5. Renlund DG, OConnell JB, Bristow MR. Strategies of immunosuppression in cardiac transplantation. Semin Thorac Cardiovasc Surg 1990;2:181-8. 6. Reid KR, Menkis AH, Novick RJ, et al. Reduced incidence of severe infection after heart transplantation with lowintensity immunosuppression. J Heart Lung Transplant 1991; 103894-900. 7. Grossi EA, Culliford AT, Krieger KH. A survey of 77 major infectious complications of median sternotomy: a review of 7949 consecutive operative procedures. Ann Thorac Surg 1985;40:214-23. 8. Serry C, Bleck PC, Javid H, et al. Sternal wound complications: management and results. J Thorac Cardiovasc Surg 1980;80:861-7. 9. Shumacker HB Jr, Mandelbaum I. Continuous antibiotic irrigation in the treatment of infection. Arch Surg 1963;86: 384-7. 10. Bryant LR, Spencer FC, Trinkle JK. Treatment of median sternotomy infection by mediastinal irrigation with an antibiotic solution. Ann Surg 1969;169:914-20. 11. Thurer RJ, Bognolo D, Vargas A, Isch JH, Kaiser GA. The management of mediastinal infection following cardiac surgery. An experience utilizing continuous irrigation with povidone iodine. J Thorac Cardiovasc Surg 1974;68:962-8. 12. Glick PL, Guglielmo BJ, Tranbaugh RF, Turley K. Iodine toxicity in a patient treated by continuous povidone-iodine mediastinal irrigation. Ann Thorac Surg 1985;39:478-80. 13. Lee AB Jr, Schimert G, Shatkin S. Total incision of the sternum and thoracic pedicle transposition of the greater omentum: useful strategems in managing severe mediastinal infection following open heart surgery. Surgery 1976;80: 43M. 14. Jurkiewicz MJ, Bostwick J 111, Hester TR, Bishop JB, Craver J. Infected median sternotomy wound. Successful treatment by muscle flaps. Ann Surg 1980;191:738-43. 15. Jeevanandam V, Smith CR, Rose EA, Malm JR, Hugo NE. Single stage management of sternal wound infections. J Thorac Cardiovasc Surg 1990;99:256-63. 16. Nahai F, Rand RP, Hester TR, Bostwick J, Jurkiewicz MJ. Primary treatment of the infected sternotomy wound with muscle flaps. A review of 211 consecutive cases. Plast Reconstr Surg 1989;84:434-41. 17. Pairolero PC, Arnold PC. Management of infected median sternotomy wounds. Ann Thorac Surg 1986;42:1-2. 18. Nahai F, Morales L Jr, Bone DK, Bostwick J 111. Pectoralis major muscle turnover flaps for closure of the infected sternotomy wound with preservation of form and function. Plast Reconstr Surg 1982;70:4714. 19. Neale HW, Kreilein JG, Schreiber JT, Gregory RO. Complete sternotomy for chronic myelitis with reconstruction using a rectus abdominis myocutaneous island flap. Ann Plast Surg 1981;6305-14. 20. Lafferty KJ, Prowse SJ, Simeonlvic CJ. Immunobiology of tissue transplantation: a return of the passenger leukocytic concept. Annu Rev Immunol 1983;1:143-73. 21. Renlund DG, OConnell JB, Gilbert EM, et al. A prospective comparison of murine monoclonal CD-3 (OKT3) antibodybased and equine antithymocyte globulin-based rejection prophylaxis in cardiac transplantation. Decreased rejection and less corticosteroid use with OKT3. Transplantation 1989; 47:599-605. 22. A report of the working group of transplant cardiologists. Efficacyof induction and non-induction immunosuppression in cardiac transplantation [Abstract]. J Heart Transplant 1990;9:61. 23. Gilbert EM, DeWitt CW, Eisworth CE, et al. Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody. Am J Med 1987;82:202-6.
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24. Constanzo-Nordin MR, OSullivan EJ, Johnson MR, et al. Prospective randomized trial of OKT3 versus horse antithymocyte globulin-based immunosuppressive prophylaxis in heart transplantation. J Heart Transplant 1990;9:30&15. 25. Kirklin JK, Boulge RC, White-Williams C, et al. Prophylactic therapy for rejection after cardiac transplantation. J Thorac Cardiovasc Surg 1990;99:716-24. ~~
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26. Frist WH, Merrill WH, Eastburn TE, et al. Unique antithymocyte serum versus OKT3 for induction immunotherapy after heart transplantation. J Heart Transplant 1990;9:489-94. 27. Prieto M, Lake KD, Pritzker MR, et al. OKT3 induction and steroid-free maintenance immunosuppression for treatment of high risk heart transplant recipients. J Heart Lung Transplant 1991;10:901-11.
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DISCUSSION D R THOMAS M. EGAN (Chapel Hill, NC): I would like to congratulate you for your success, and I had a question about your recommendation for muscle flaps as a primary procedure to deal with this very difficult problem. If 3 of 8 patients can be spared muscle flaps and then the balance subsequently salvaged, why d o you propose not going to the less aggressive procedure first? In your abstract you suggested that the death was related to acute rejection and not to failure of your muscle ffaps. DR KARWANDE: Well, first we have had a high failure rate with the debridement-irrigation technique. Muscle flap coverage makes the management of these patients after the surgical therapy simpler, ie, when rejection develops I think the treatment of rejection is simplified. You are not concerned about using steroids on these patients because you feel secure in the fact that their dead space has been obliterated with a viable muscle flap. The second reason is that patients who tend to fail debridement and irrigation, and their percentage is high in our series, have a prolonged hospital stay. The only fatal outcome we had was in a patient who had failed the debridement-irrigation technique; I believe we lost the window of opportunity and the subsequent cascade of events led to his death. DR RICHARD J. NOVICK (London, Ont, Canada): We have performed 294 heart transplantations and have had 10 cases of mediastinitis. All were treated with debridement, sternal reclosure, and mediastinal imgation for 10 to 14 days, and none had recurrent infection. I therefore believe that the conclusion that the primary mode of therapy should be a muscle flap is not correct. What were the reasons for failure of the sternal closure technique? Was there infection with methicillin-resistant Staphylococcus aureus? Was there any residual sternal instability? What factors could you identdy to indicate why those 4 or 5 patients failed? DR KARWANDE: I think the main reason why those 5 patients failed the debridement-irrigation technique was because the dead space was not obliterated by the suction technique. Some of these patients have a stiff, nonpliable mediastinum, and in spite of chest tube suction the mediastinum is not obliterated. Many of these patients, as you very well know, have large pericardial cavities, and these cavities are, generally speaking, occupied by a small donor heart. I presume that one of the reasons why the debridement-irrigation technique failed was because the cavity was not obliterated. DR H A N S G. BORST (Hannover, Germany): I thoroughly enjoyed your presentation because we are both in agreement on certain points and in disagreement on others. We certainly agree with you, and 1 think you have proved it, that mediastinitis is not as catastrophic an event in transplant patients as one would suppose on account of the fact that the patient is immunocompromised. We have had 6 such complications in a group about the size of
yours for an incidence of mediastinitis of about 1.5%; however, all 6 patients had an unstable sternum, and in fact we have never seen the discrete type of mediastinitis that you are describing. All 6 patients had omental pull-up and all of them healed per primam. There was no need of applying any more advanced plastic procedures. In addition, and more interestingly, we had 1 patient of 25 undergoing heart-lung transplantation who, on the 11th postoperative day, suddenly exsanguinated and was taken to the operating room where she was bleeding from the aortic cannulation site. During cardiac massage and mass transfusion, my co-worker, Dr Haverich, fixed the hole in the aorta and again did an omental pull-up, and this again resulted in primary healing. Lo and behold the causative agent was Candida! So I think we fully agree with you that one should be aggressive about these cases of mediastinitis with the aim of completely filling up the retrosternal space, and I think these patients should be treated promptly before any extensive osteomyelitis develops, because then you will wind up with all kinds of plastic procedures trying to fill holes. But it nevertheless is very interesting that you have these discrete forms that we have never seen. Now, if you do your plastic operations, d o you add an irrigation system or do you just leave it like it is? DR KARWANDE: I would like to compliment you on your low mediastinitis rate. I think what we are saying is basically the same thing. Instead of using omentum we have been using muscle. There is no irrigation involved when you use the pectoralis major muscle. You basically obliterate the dead space in the mediastinum using the muscle and then close the skin on top of it. D R BORST: Don’t you wind up with a big defect in the sternum then because you have to slip in the muscle somehow? DR KARWANDE: The sternum is left open. Fortunately we have not seen problems related to this, by way of respiratory embarrassment or cosmetic deformity. D R BORST Oh, I see; the sternum was always closed in our patients. D R EDWARD A. PASCOE (Winnipeg, Man, Canada): Coronary disease as the pretransplantation diagnosis I think also was an increased predictor of mediastinitis. Had many of those patients undergone myocardial revascularization with harvesting of internal mammary arteries, which might have made their chest walls relatively ischemic and more prone to infection? D R KARWANDE: That is a very good question. We looked at that specifically, and we found only 2 patients of 12 in whom mediastinitis developed had internal mammary artery revascuIarization, and of the 12 patients in whom mediastinitis developed, we could detect an unstable sternum in only 3 patients.
