C failure recalcitrant to medical or surgical therapy has

Transcription

1 Prolonged Extracorporeal Life Support of Pediatric and Adolescent Cardiac Transplant Patients Ralph E. Delius, MD, Joseph B. Zwischenberger, MD, Robert Cilley, MD, Douglas M. Behrendt, MD, Edward L. Bove, MD, G. Michael Deeb, MD, Dennis Crowley, MD, Kathleen P. Heidelberger, MD, and Robert H. Bartlett, MD Section of Thoracic Surgery, Department of Surgery, Department of Pediatrics, and Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan Options for mechanical support of pediatric patients with severe heart failure who are awaiting transplantation or have undergone transplantation are limited. This report examines 3 patients placed on extracorporeal life support (ECLS) while awaiting transplantation and 3 patients who underwent transplantation and suffered subsequent heart failure due to rejection or postoperative myocardial dysfunction. The overall survival rate was 2 of 6. The 2 surviving patients had a failing transplanted heart. There were no survivors among the patients placed on ECLS as a bridge to transplantation. In each case a contraindication to transplantation developed before a donor heart could be obtained. The mean time of ECLS support was hours (range, 70 to 370 hours). The ECLS circuit did not affect cyclosporin levels or antirejection therapy. Extracorporeal life support can be used to support pediatric cardiac transplant patients with biventricular failure due to acute rejection or postoperative dysfunction. Although the results have been discouraging, ECLS may still have a role as a bridge to transplantation. However, complications can develop during ECLS that may preclude transplantation. (Ann Thoruc Surg 2990;50:792-5) ardiac transplantation in pediatric patients with heart C failure recalcitrant to medical or surgical therapy has become increasingly common [l]. Deterioration of patients with severe heart failure is often rapid, with death or irreversible organ failure occurring before procurement of a donor organ. This problem has prompted interest in developing mechanical circulatory support devices to maintain patients until a suitable donor heart becomes available. Several mechanical support devices have been developed, including univentricular and biventricular assist devices, the total artificial heart, and the intraaortic balloon pump [2-4]. All have been used successfully in maintaining adult patients with life-threatening heart failure who are awaiting transplantation. A biventricular support device has also been used to support an adult patient with a failing transplanted heart [5]. Options for mechanical support of pediatric patients awaiting heart transplantation or with a failing transplanted heart are limited, however, owing to the size of the patients and the need for biventricular support. Intraaortic balloon pumps have been used in infants as small as 2 kg, but only partial circulatory support is offered by this device [6]. To date, ventricular assist devices and the total artificial heart are not available in appropriate sizes for pediatric patients. Venoarterial cardiopulmonary bypass via external catheters has been used to support neonatal and pediatric patients with cardiac Accepted for publication July 26, Address reprint requests to Dr Bartlett, University of Michigan Medical Center, 2920 Taubman Center, Box 0331, 1500 East Medical Center Dr, Ann Arbor, MI and respiratory failure due to a variety of causes [ This procedure has been called extracorporeal membrane oxygenation; extracorporeal life support (ECLS) is a better term which will be used in this report. This is a report of our experience with ECLS in pediatric patients with heart failure who were awaiting transplantation or needed support of a failing transplanted heart. Material and Methods Pa tien t Population The charts were reviewed of 3 patients with a failing transplanted heart who required ECLS for circulatory support and 3 patients with heart failure who were placed on ECLS while waiting for a donor heart. All patients were on the Pediatric Cardiac Surgery service at C.S. Mott Children s Hospital. There were 4 boys and 2 girls, aged 7 months to 18 years. Weights ranged from 4 to 70 kg. Diagnoses are listed in Table 1. In each case venoarterial ECLS was initiated for cardiogenic shock that was refractory to optimum medical management. The 3 patients placed on ECLS before anticipated transplantation had no contraindications to transplantation before the initiation of circulatory support. The patients who had received a cardiac transplant were on an immunosuppression regimen consisting of steroids, cyclosporin, and azathioprine. Two transplant recipients were supported for heart failure during a rejection episode, and right ventricular failure developed in 1 patient shortly after transplantation. In both cases of rejection the diagnosis was confirmed by biopsy demonstrating severe rejection. Treatment of rejection consisted of three meth by The Society of Thoracic Surgeons /90/$3.50

2 792 DELIUS ET AL Table 1. Summary of Patient Data Time on Weight ECLS Patient Age Sex 0%) Diagnosis (h) Hemofilter Complications Outcome LQ 7mo F 4 RV failure of 64 Y Bleeding Survived transplanted heart JG 3 Y F 14 Tx rejection 73 Y None Survived MC 17 Y M 70 Tx rejection 112 Y Neurological injury Died CG 15 Y M 38 Tx bridge 70 N B 1 e e d i n g, Died (cardiomyopathy) p u 1 m o n a ry edema RS 6Y M 22 Tx bridge (double- 196 N Hernothorax Died BF 18 Y M 44 outlet right ventricle; after Fontan) Tx bridge (situs 370 Y Bleeding, sacral Died inversus, single decubitus ulcer ventricle) ECLS = extracorporeal life support; RV = right ventricular; Tx = transplantation. ylprednisolone pulses (15 mg - kg-' - day-') followed by antithymocyte globulin (15 mg kg-' - day-') in 1 patient and three methylprednisolone pulses followed by OKT3 in the other patient. The adequacy of OKT3 therapy was followed by flow cytometry. Lack of T cells indicated a therapeutic response to OKT3. Extracorporeal Life Support Technique The ECLS circuits used in this report were identical to those described in prior reports [7]. The circuit consisted of a membrane lung (SciMed Life Systems, Inc), a servoregulated roller pump, and a heat exchanger. The circuit was primed with blood. Cannulation was performed under local anesthesia and intravenous sedation. The patient was paralyzed with succinylcholine and systemically anticoagulated with heparin (100 to 200 unitdkg). The right internal jugular vein or femoral vein was cannulated for venous drainage. Oxygenated blood was reinfused through the axillary, carotid, or femoral arteries. Anticoagulation was maintained by constant heparin infusion to keep the activated clotting time between 200 and 240 seconds (between 180 and 200 seconds since 1988). Platelet counts were maintained at greater than 50 X 109/L (50,00O/pL) (greater than 100 x 109/L since 1988). Blood was transfused as needed to keep the hematocrit above Bypass flow was initiated at 75 to 100 ml - kg-' min-'. Inotropes were weaned as tolerated. During ECLS the ventilator settings were placed at an inspired oxygen fraction of 0.30 to 0.40, peak inspiratory pressure of less than 30 cm H,O, and a rate of 10 cycles/minute. Antibiotics and parenteral nutrition were administered throughout the ECLS course. Diuretics were given as needed to maintain urine output. When necessary, hemofiltration was instituted by placing a filter in the ECLS circuit. Recovery of cardiac function was followed up by serial echocardiograms. Brief trial periods off ECLS and trends in the mixed venous oxygen saturation were used to determine when weaning of circulatory support could be initiated. Flows were gradually decreased to less than 50 ml * kg-' - min-'. Ventilatory support and inotropes were added as needed. When a longer trial off ECLS indicated that mechanical support was no longer necessary the cannulas were removed. Results Overall, 2 of 6 patients survived. Two of the 3 patients with a failing transplanted heart improved and were weaned off ECLS. There were no survivors among the patients placed on ECLS as a bridge to transplantation. In one survivor with pulmonary hypertension right-sided heart failure developed 30 hours after transplantation. She was supported for 64 hours on ECLS. She is alive with normal cardiac function 60 months later. The other survivor was on ECLS for 72 hours while being treated for a severe rejection episode. A photomicrograph of the cardiac biopsy specimen is shown in Figure 1. She subsequently survived for 8 months before dying suddenly of marked, diffuse coronary artery narrowing (Fig 2). One adult-sized patient with rejection initially had an intraaortic balloon pump placed but was converted to ECLS when shock persisted despite support with the balloon pump. He was maintained on ECLS for 112 hours while being treated for rejection. Cardiac function did improve, but he was electively removed from ECLS after sustaining a severe, irreversible neurological injury. There were no survivors among the 3 patients placed on ECLS as a bridge to transplantation. The mean time of ECLS support for these patients was hours, with a range of 79 to 370 hours. In each case ECLS was electively discontinued after contraindications to transplantation developed before a donor heart could be obtained. In one 15-year-old patient with familial cardiomyopathy, severe

3 Fig 1. Biopsy specimen with ser~ererejertion shoroing diffirse foci of infiltration by polymorphoiiuclear leukorytes and lymphocytes. Necrotic myofibers "dead end" in collections of inf7ammatory cells. (Hematoxylin and eosin, x3.30 before 29% reditrtion.) pulmonary edema developed after complete left ventricular failure developed during ECLS. Transatrial blade and balloon septostomy was performed 36 hours later in an effort to decompress the left atrium. This procedure failed to improve the pulmonary edema. Extracorporeal life support was discontinued when transplantation was no longer possible. The second patient, an 18-year-old with situs inversus, levocardia, single ventricle, and a common atrioventricular valve was taken to the operating room for transplantation. However, the donor heart was found to be unsatisfactory. During anesthesia the patient's heart failure worsened despite inotropic support and FCLS was initiated. He was relisted for transplantation, but another Fig 2. Representatiae area of left anterior desrending coronary artery showing almost complete occlusion of the lumen by intimal proliferation. Focal lipid droplets are noted closest to the internal elastic lamina. (Hematoxylin and eosin, x83 before 29% reduction.) DELIUS ET AL EC1.S FOR YOUNG CARDIAC TRANSPLANT PATIENTS 793 heart did not become available. A sacral decubitus ulcer developed, along with an elevated white blood cell count and mild renal failure. He was no longer believed to be a good transplant candidate and ECLS was discontinued after 370 hours. The third patient, a 6-year-old with tricuspid atresia and double-outlet right ventricle, was listed for transplantation and placed on ECLS after severe heart failure developed 6 weeks after a Fontan procedure. A chest tube in the right pleural space was removed during ECLS in an attempt to prevent any infectious complications that could preclude transplantation. Within 36 hours a right hemothorax developed, necessitating placement of another chest tube. Bleeding continued, and a thoracotomy was performed. The patient's respiratory and renal function deteriorated shortly thereafter, and the child was removed from the transplant list and ECLS was discontinued. For all patients, flows ranged from 45 to 120 ml kg-' * min-' (mean, 70.4 ml * kg-' * min-') and were maintained to provide adequate perfusion as demonstrated by mean arterial pressure, resolution of acidosis, increased urine output, and diminished need for inotropic support. All patients were on multiple inotropes before initiating ECLS The most commonly used inotropes included isoproterenol, dopamine, dobutamine, amrinone, and epinephrine. In 4 patients, including both survivors, all inotropes except low-dose dopamine were discontinued. In the other 2 patients the infusion rates were decreased substantially and at least one inotrope was discontinued. Both patients who were weaned from ECLS required inotropic support for 7 to 11 days after ECLS was discontinued. In the 2 largest patients (>40 kg) the femoral artery and vein were cannulated. The remaining 4 patients had the right internal jugular vein cannulated for venous drainage. In 2 patients (weights, 37.5 and 22 kg) the oxygenated blood was infused through the femoral artery. Of the remaining patients 1 (14 kg) was cannulated through the right axillary artery and the smaller patient (4 kg) was cannulated through the right common carotid artery. The patients who were weaned from ECLS had their right internal jugular vein repaired. One survivor had the axillary artery repaired. The other surviving patient had her right carotid artery ligated, with no apparent neurological complications. Hemofiltration was initiated for 4 patients, including both survivors, to facilitate additional fluid removal (see Table 1). No patient required hemodialysis. Two patients received cyclosporin while on ECLS. The other transplant recipient was taken off cyclosporin while receiving OKT3. Cyclosporin doses ranged from 4 to 7 mg/kg. The cyclosporin levels did not appear to be affected by the ECLS circuit. The OKT3 level was also unaffected by the ECLS circuit, as evidenced by a lack of T cells on flow cytometry. Mechanical complications included 1 case of hemolysis that resolved after a centrifugal pump was changed to a roller pump. Roller pumps were used for all other patients and no other episodes of hemolysis occurred. Two oxy- -

4 794 DELIUS ET AL genators were replaced owing to leakage of blood at the gas outlet. Both oxygenators were changed without incident. Major physiological complications are listed in Table 1. The complications of pulmonary edema, sacral decubitus ulcer, and hemothorax after chest tube removal have been mentioned. Three patients had bleeding at the cannulation sites and required exploration. In each case a minor subcutaneous vessel was cauterized and no further bleeding developed. One patient sustained an irreversible neurological injury that developed 100 hours after ECLS was started. The cause of the injury was unknown. Permission for autopsy was denied. The patient was removed from circulatory support after neurological examination and electroencephalogram confirmed the absence of brainstem activity. Comment Mechanical circulatory support has been used to support patients with end-stage heart failure while a donor heart is sought [2-4]. Temporary mechanical support of the failing transplanted heart has also been described [5, 101. At the present time mechanical support of pediatric patients is limited to intraaortic balloon pumping or ECLS. Intraaortic balloon pumping supports approximately 40% of left ventricular function. The access is simple and the cost moderate. Intraaortic balloon pumping is useful for moderate cardiac failure isolated to the left ventricle, but provides no right ventricular or pulmonary support. Extracorporeal life support can support 100% of cardiac and pulmonary function. Access is usually through extrathoracic vessels. Hemofiltration, if necessary, is easy to insert in the ECLS circuit and can allow full parenteral nutrition without fear of fluid overload. The disadvantages of ECLS include the need for anticoagulation, cost, and labor intensity. This report suggests that ECLS may be useful for support of the transplanted heart with right ventricular failure shortly after implantation. Patients with an increased pulmonary vascular resistance greater than 8 Wood units are not usually considered candidates for orthotopic cardiac transplantation because it is expected that the right ventricle of the transplanted heart cannot respond to the sudden increase in afterload, especially after the ischemic period imposed by the transplant procedure [12]. Extracorporeal life support can temporarily provide cardiopulmonary support while the transplanted right ventricle recovers in patients with borderline elevation of pulmonary vascular resistance. This report also suggests that a patient with biventricular failure due to severe acute rejection can be supported with ECLS to allow time for the antirejection therapy to become effective. Hemodynamic symptoms as a manifestation of rejection often do not develop in cardiac transplant patients receiving cyclosporin and prednisone until the hemodynamic status is so compromised that survival is in doubt. When rejection does not respond promptly to high-dose steroids, antithymocyte globulin, or OKT3, retransplantation has been thought to be the only effective option because antirejection therapy may require several days to effectively reverse rejection [ 131. Extracorporeal life support may provide another option for managing the cardiac transplant patient with heart failure due to rejection. Rogers and associates [ll] have described the successful use of ECLS as a bridge to transplantation in a pediatric patient. Extracorporeal life support has also been used as a bridge to transplantation in adults, but the results have been disappointing [ 101. In our experience a contraindication to transplantation developed during ECLS while waiting for a donor heart to become available. The difficulty in finding a pediatric donor heart resulted in a protracted length of time on ECLS. However, in all 3 cases an error in judgment or management may have contributed in part to the development of contraindications to transplantation. It may be illustrative to examine these points. In 1 patient (BF) a sacral decubitus ulcer and subsequent leukocytosis developed. Turning the patient more frequently may have prevented this complication. Another case (patient RS) was complicated by bleeding that developed after chest tube removal. A thoracotomy was required to control the bleeding and the patient was subsequently removed from the transplant list. In a patient awaiting transplantation the risk of infection from a chest tube in the pleural space must be weighed against the risk of manipulating a chest tube while the patient is anticoagulated. In the remaining patient (CG) complete cessation of left ventricular function developed within 12 hours after starting ECLS. Left-sided decompression by transatrial balloon and blade septostomy was not attempted until 36 hours later, by which time severe pulmonary edema had developed. Pulmonary edema resulting from a nonfunctioning left ventricle can pose a difficult problem. Extracorporeal life support does not completely decompress the left side of the heart in patients with an intact septum. Decompression procedures such as blade or balloon septostomy have been used with varying degrees of success. Transsternal placement of ECLS cannulas can allow better decompression, but this may also lead to bacterial contamination or infection of the mediastinum, making the patient an unacceptable candidate for transplantation. Despite our discouraging experience, ECLS may still have a role as a bridge to transplantation. However, complications may develop that could make the patient a poor transplant candidate. Ethical questions have been raised regarding the use of ECLS or other mechanical support devices in conjunction with transplantation [14]. One author [15] has questioned whether transplantation (or retransplantation) should be performed in a suboptimal recipient given the scarcity of donor hearts. Answers to this and other difficult questions are not readily available. Nevertheless, this report suggests that ECLS can support the pediatric transplant patient with right ventricle failure due to pulmonary hypertension or biventricular failure due to rejection. Furthermore, it may be possible to provide cardiopulmonary support for pediatric transplantation. However, complications from ECLS may preclude subsequent transplantation.

5 DELIUS ET AL 795 Supported in part by a grant from the National Institutes of Health. References Starnes VA, Bernstein D, Oyer PE, et al. Heart transplantation in children. J Heart Transplant 1989;8:20-6. Farrar DJ, Hill JD, Gray LA Jr, et al. Heterotopic prosthetic ventricles as a bridge to cardiac transplantation. N Engl J Med 1988;318:33-0. Oaks TE, Wisman CB, Pae WE, Pennock JL, Burg J, Pierce WJ. Results of mechanical circulatory assistance before heart transplantation. J Heart Transplant 1989;8: Pennington DG, McBride LR, Kanter KR, et al. Bridging to heart transplantation with circulatory support devices. J Heart Transplant 1989;8: Icenogle TB, Williams RJ, Smith RG, et al. Extracorporeal pulsatile biventricular support after cardiac transplantation. 1989; del Nido PJ, Swan PR, Benson LN, et al. Successful use of intraaortic balloon pumping in a 2-kilogram infant. Ann Thorac Surg 1988;46: Anderson HL 111, Attori RJ, Custer JR, Chapman RA, Bartlett RH. Extracorporeal membrane oxygenation for pediatric cardiopulmonary failure. J Thorac Cardiovasc Surg 1990;99: Bartlett RH, Gazzaniga AB, Fong SW, Jeffries MR, Roohk HV, Haiduc N. Extracorporeal membrane oxygenator support for cardiopulmonary failure: experience in 28 cases. J Thorac Cardiovasc Surg 1977;73: Kanter KR, Pennington DG, Weber TR, Zambie MA, Braun P, Martychenko V. Extracorporeal membrane oxygenation.- for postoperative cardiac support in children. J Thorac Cardiovasc Surg 1987;93: Pennington DG, Merjevy JP, Codd JE, Swartz MT, Miller LL, Williams GA. Extracorporeal membrane oxygenation for patients with cardiogenic shock. Circulation 1984;7O(Suppl l): Rogers AJ, Trento A, Siewers RD, et al. Extracorporeal membrane oxygenation for postcardiotomy cardiogenic shock in children. 1989;47: Frazier OH, Cooley DA. Cardiac transplantation. Surg Clin North Am 1986;66:3: Copeland JG, Griepp RB, Bieber CP, et al. Successful retransplantation of the human heart. J Thorac Cardiovasc Surg 1977;73:2: Hill JD, Farrar DJ, Hershon JJ, et al. Use of a prosthetic ventricle as a bridge to transplantation for postinfarction cardiogenic shock. N Engl J Med 1986;314: Annas GJ. No cheers for temporary artificial hearts. Hastings Cen Rep 1985;314:64&5.