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Ann Thorac Surg 1996;62:1-7
© 1996 The Society of Thoracic Surgeons
Departments of Surgery and Pediatrics, Loma Linda University School of Medicine, and Children's Hospital, Loma Linda, California
Abstract
Background. Hypoplastic left heart syndrome is a lethal malformation. For the last 10 years, orthotopic cardiac transplantation has been our preferred treatment for infants with hypoplastic left heart syndrome.
Methods. One hundred seventy-six infants with hypoplastic left heart syndrome were entered into a cardiac transplant protocol between November 1985 and November 1995. Interventional procedures to stent the ductus arteriosus or enlarge the interatrial communication were performed in 8 and 35 patients, respectively. Thirty-four patients (19%) died during the waiting period, and 142 infants underwent cardiac transplantation. Age at cardiac transplantation ranged from 1.5 hours to 6 months (median, 29 days). The majority of grafts were oversized, and the median graft ischemic time was 273 minutes (range, 60 to 576 minutes). The implantation procedure used a period of hypothermic circulatory arrest ranging from 23 to 110 minutes (median, 53 minutes). Repair of other significant defects included interrupted aortic arch (5) and total or partial anomalous pulmonary venous connection (7).
Results. There were 13 early and 22 late deaths. Patient actuarial survival at 1 month and at 1, 5, and 7 years was 91%, 84%, 76%, and 70% respectively. Half of the late deaths were due to rejection. Severe graft vasculopathy was confirmed in 8 patients. Retransplantation was performed in 5 patients for graft vasculopathy (4) and rejection (1). Lymphoblastic leukemia developed in 1 patient 3 years after cardiac transplantation.
Conclusions. Cardiac transplantation can be performed in infants with hypoplastic left heart syndrome with good operative and intermediate-term results. Improved survival can be achieved with increased donor availability, better management of rejection, and control of graft vasculopathy.
Hypoplastic left heart syndrome (HLHS) is one of the more common congenital heart defects diagnosed during neonatal life. It is the most common cardiac anomaly with one functional ventricle. Prior to the 1980s, this complex malformation was uniformly fatal, with 95% of untreated patients dying within the first month of life. The pioneering efforts of Norwood and associates [1] and Bailey and colleagues [2] during the past decade introduced two surgical approaches to the newborn with HLHS, namely staged reconstruction and cardiac transplantation (CTx). For the last 10 years the preferred primary treatment for infants with HLHS at Loma Linda University Medical Center has been orthotopic cardiac transplantation. This approach was initially based on the successful results of neonatal heart transplantation in the goat model. The unpredictable outcome with open repair techniques for HLHS and the encouraging early results of cardiac allotransplantation in infancy from other institutions [3] prompted us to continue with the policy of offering CTx to those infants. Cardiac transplantation offers the potential of a normal cardiovascular physiology as compared with the limitations of a single-ventricle physiology achieved after multistaged reconstruction. The purpose of this report is to review the entire 10-year experience at Loma Linda University Medical Center with CTx for hypoplastic left heart syndrome, analyze the intermediate-term results, and discuss the major issues of this therapy.
Material and Methods
Hospital records and the heart transplant computer data base at Loma Linda University Medical Center were reviewed to identify all infants with HLHS who were evaluated between November 1985 and November 1995. During that period, a total of 190 infants with the diagnosis of HLHS were initially registered for CTx with the United Network for Organ Sharing. Fourteen patients were subsequently unlisted due to medical contraindications to transplantation (7) or to parents choosing alternative therapy (7). The remaining 176 infants were entered into a pediatric cardiac transplant protocol. Thirty-four patients (group I) died during the waiting period (median, 28 days; range, 1 to 127 days). Nearly half of those who died (16 of 34 patients) were hospitalized outside our facility. Group II consisted of 142 infants who completed the transplant protocol by undergoing orthotopic CTx (Fig 1
). Patient age at transplantation ranged from 1.5 hours to 183 days (mean, 40 ± 33 days; median, 29 days). More than half of those patients who received transplants (74 of 142 patients) were less than 30 days of age. Thirty-eight patients in this series had fetal diagnosis of HLHS, and twenty-five were registered for transplantation in-utero. Twenty of those infants underwent CTx; 2 fetuses were delivered by cesarian section when a donor heart became available and received transplants at 1.5 hours and 3 hours of life. The waiting period for group II patients, not including the in-utero time, ranged from 0 to 171 days (mean, 27 ± 27 days; median, 19 days). The diagnosis of HLHS was made by echocardiography in all patients; 14 patients had additional cardiac anatomic variations (Table 1). Pathologic examination of explanted hearts revealed aortic atresia in 52, mitral atresia in 21, both aortic and mitral atresia in 35, and other morphologic findings in 34 specimens.
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Organ Procurement and Operative Technique
Donors and recipients were matched according to ABO blood group compatibility; preoperative serum cytotoxicity assays and tissue-typing were not routinely performed. Donors from all over North America including Alaska provided viable cardiac grafts for Loma Linda's recipients located in southern California. Donor:recipient weight ratio ranged from 0.6 to 4.2 with a median of 1.8. The longest graft ischemic time was 576 minutes. Donor organ preservation consisted of a single dose of crystalloid cardioplegia and cold storage at 4°C. Three transplant surgeons performed the donor procurement and recipient operations in this series. The operative technique used a period of hypothermic circulatory arrest as was originally described by Bailey and colleagues [4]. The donor aorta was used to reconstruct the recipient's hypoplastic aortic arch well beyond the ductal tissue. Modification of the transplantation technique was necessary when repair of other complex cardiovascular defects was also performed.
Immunosuppression
Cyclosporine has been the major immunosuppressive agent for all patients. Recipients were started on an intravenous cyclosporine infusion (0.1 mg•kg-1•h-1) when a donor was identified. Subsequently, cyclosporine was given orally (10 to 20 mg•kg-1•day-1 in three divided doses) when oral intake was well established. Initial cyclosporine target levels were 250 to 300 ng/mL then were adjusted to 100 to 150 ng/mL at 12 months. Azathioprine administration was started immediately after transplantation at 3 mg•kg-1•day-1 and by 1 year was reduced to 1 mg•kg-1•day-1. Azathioprine was further adjusted to maintain the white blood cell count at greater than 4,000 cells/µL. Methylprednisolone was administered intravenously during the transplant operation (25 mg/kg) and postoperatively every 12 hours for four doses only. Chronic oral steroid therapy was not part of the routine immunosuppressive regimen. The induction protocol for infant heart transplantation has gradually evolved over time. Early in our experience, murine monoclonal antibody (OKT-3 at 0.1 mg•kg-1•day-1) was used occasionally as an induction agent. However, since 1990, a polyclonal antithymocyte serum (AMR, Inc, Nashville, TN) has been administered to all recipients older than 30 days at the time of transplantation. Antithymocyte serum was given intravenously (0.5 mL•kg-1•day-1) on the day of transplantation, and the dose was repeated for a total of 5 days.
Surveillance and Follow-up
All surviving recipients were followed up closely at Loma Linda University Medical Center for the first 6 months after transplantation. Afterwards, close communication was maintained with the referring cardiologist and primary pediatrician. Transplant clinic visits initially took place twice a week, and then at 3 months, evaluations were done weekly. Close monitoring included serial echocardiography with Doppler/color flow mapping, electrocardiography, physical examination, and measurement of cyclosporine levels. Cardiac catheterization and coronary angiography were performed 1 year after transplantation and every 2 years thereafter unless otherwise indicated. Cumulative follow-up has been complete as of December 1995 and includes 532 patient-years with a mean follow-up of 3.8 ± 2.6 years. The diagnosis of cardiac graft rejection was based on a set of echocardiographic and clinical parameters that have been previously described in detail [5]. Endomyocardial biopsy was not performed routinely but was reserved for clinically confusing situations when the diagnosis of rejection could not be made noninvasively. The diagnosis of graft coronary artery disease was based on coronary angiography, gross and histologic examination of explanted grafts (after retransplantation) or autopsy specimens, or a combination of angiography and examination. Graft coronary artery disease was considered severe when luminal obliteration was greater than 50%. Data regarding other transplantation related events have been progressively collected and entered into the Transplant Center database.
Statistical Methods
Survival and freedom from event probability curves were generated using the Kaplan-Meier method. Multivariate logistic regression analysis was used to determine which recipient- or donor-related variables were significant predictors of operative mortality (defined as death within 30 days of operation or death in the hospital before discharge after transplantation). For continuous data, variability was reflected by ± standard deviation.
Results
Survival
Pretransplantation mortality for this series was 19% (34/176). The most common cause of death among those who died waiting for a donor heart was cardiac failure in 14 patients. Other causes of death in this group included necrotizing enterocolitis or sepsis in 5 patients, restrictive atrial septal communication in 5 patients, and other miscellaneous causes in 10 patients. In the group that came to CTx, there were 13 early deaths with an operative mortality of 9.2%. Four of those deaths were due to technical issues, 3 to acute graft failure, 2 to acute rejection, 2 to pneumonia, 1 to pulmonary hypertension, and 1 to a perforated duodenal ulcer. Of the variables analyzed as possible risk factors for operative death, none was significant when multivariate analysis was performed:
Twenty-two deaths occurred late in this series. Causes of late death included rejection (acute or chronic) in 11 patients, infection in 5 patients, graft coronary artery disease in 2 patients, and 1 death each due to toxic epidermal necrolysis, hemorrhagic shock after circumcision, smoke inhalation, and abdominal aortic thrombosis. Currently 107 patients are alive. Actuarial survival estimates at 1, 5, and 7 years are 84%, 76%, and 70% respectively (Fig 2).
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). Two early deaths and 11 late deaths were directly attributed to rejection.
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Lymphoproliferative Disease
Acute lymphocytic leukemia developed in only 1 patient in this series 3 years after transplantation. He was managed by reduction of immunosuppression as well as chemotherapy. He is still alive 1 year after the diagnosis, but mucormycosis has developed in him.
Renal Status
Perioperative peritoneal dialysis was instituted in 17 infants after transplantation. The duration of peritoneal dialysis ranged from 1 to 11 days. None of the survivors has required chronic dialysis. The mean serum creatinine level of survivors is 0.68 ± 0.23 mg/dL (range, 0.4 to 1.5 mg/dL) and the mean glomerular filtration rate is 78 ± 26 mL•min-1•1.7 m-2 (range, 25 to 146 mL•min-1•1.7 m-2). Twenty patients (18.7%) are currently receiving antihypertensive therapy.
Reoperations
Five patients in this series underwent retransplantation with one operative death due to severe rejection. The indication for retransplantation was GV in 4 patients and severe acute rejection in 1 patient. Freedom from retransplantation at 1, 5, and 7 years was 99%, 98%, and 95%, respectively (Fig 5). Residual or recurrent coarctation was detected in 29 patients after transplantation; 4 patients required surgical coarctectomy and 25 patients were treated with balloon angioplasty without any mortality. Sick sinus syndrome and intermittent heart block warranted the placement of a permanent pacemaker in 2 children at 8 months and 4.5 years after transplantation. Both patients are alive, and 1 of them is no longer pacemaker dependent. Two patients required plication of the left hemidiaphragm, and 1 patient underwent 3 reoperations for recurrent pulmonary venous obstruction before he died of infection. Freedom from reoperation, including retransplantation, at 1, 5, and 7 years was 94%, 90%, and 87%, respectively (Fig 6).
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Comment
Nearly 1,500 to 2,000 babies born in the United States and Canada each year have HLHS. Current management of those infants varies from supportive care only, concluding in death, to staged palliative reconstruction and cardiac transplantation. Successful repair of HLHS by staged reconstruction was first reported by Norwood and associates in 1983 [1]. Since then there have been various modifications of this approach. Currently reconstructive repair consists of three carefully planned operations that culminate in the separation of the systemic and pulmonary circulations by the application of the Fontan procedure. Although Iannettoni and associates [6] reported in recent years improved results of first-stage palliation for HLHS with 85% hospital survival, cumulative experience with first-stage operation from other institutions reflects a 30% to 40% operative mortality [7, 8]. Moreover, the cumulative risk associated with multistage reconstruction and interstage attrition remains high. Newborns with HLHS and significant tricuspid valve regurgitation have been known to be poor candidates for palliative reconstruction. Moreover, Boston Children's Hospital's 10-year experience with palliative operations for HLHS indicated that infants with certain anatomic subtypes (eg, mitral atresia or aortic atresia) face significant early mortality after reconstruction and perhaps are best treated with cardiac transplantation [8]. Early attempts to treat HLHS patients with transplantation were made in 1984 by Yacoub in London (unreported case) and Bailey and associates [9], who implanted a baboon heart in the case of Baby Fae. Successful neonatal cardiac allotransplantation for HLHS was first performed by Bailey in November 1985; the recipient is now 10 years old and currently the oldest survivor of such therapy.
One of the major issues with transplantation is the shortage of heart donors. The management of HLHS infants during the waiting period can be extremely challenging. They are prone to the development of intractable heart failure or systemic organ dysfunction as the waiting period lengthens. Prostaglandin E1 infusion is maintained at the minimal dose to avoid the potential side effects of its prolonged administration. Infants with a restrictive foramen ovale tend to experience progressive hypoxemia during the waiting period and therefore require appropriate intervention to enlarge the interatrial communication and reduce pulmonary venous congestion. Although some restriction in blood shunting at the atrial level is desirable in infants with HLHS to prevent pulmonary overcirculation, a severely restrictive atrial septal communication has been shown to be a significant negative risk factor for death before transplantation [10]. As institutions, neonatologists, and cardiologists develop more experience in caring for these infants, the pretransplantation mortality, which now ranges from 20% to 40%, can be reduced significantly [11–14].
The short-term results of CTx for HLHS have been excellent and the operative mortality, in our experience, has remained around 10% over the 10-year period. Backer and colleagues [15] reported a 15% operative mortality in their early experience but no in-hospital deaths in their later series of 10 HLHS patients who received transplants. Others, whose reports included a smaller group of patients, had an 18% to 37% operative mortality [12, 13].
Early death is usually related to technical issues, graft failure, infection, or rejection. Management and technical failures can be minimized as the experience of the transplant team grows and the learning curve flattens. Four operative deaths in this series were related to surgical technique or an error in judgement. Patchy ischemic necrosis of the myocardium developed in one donor heart and led to the recipient's death 5 days after CTx. At autopsy, the small vessels as well as the major coronary arteries were clear. There was no apparent cause of necrosis, but perhaps myocardial preservation may not have been adequate. Another patient was discovered at the time of transplantation to have anomalous drainage of the right pulmonary veins and a persistent left superior vena cava. The right pulmonary venous connection was ambiguous and could not be clearly identified. The infant died a day later with marked congestion of the right pulmonary vasculature. When other complex cardiovascular defects are associated with HLHS, echocardiography alone may not be sufficient to define the anatomy properly. In these instances pretransplantation cardiac catheterization may be prudent. One neonate with HLHS and interrupted aortic arch received an oversized heart from a 13-month-old child (donor:recipient weight ratio greater than 4). The baby died a day later. Autopsy revealed a hypoplastic native descending aorta and a restrictive anastomosis between donor and recipient aorta. The combination of interrupted aortic arch, small descending aorta, and an oversized graft proved lethal in that case. The fourth management-related death was due to a mural thrombus of the distal aorta in a 9-day-old baby. The thrombus formed along an umbilical artery catheter and occluded the renal arteries.
It has also been proposed that some neonates with HLHS may have pulmonary vascular disease at birth negatively influencing survival. In fact, Turrentine and associates' series [12] of 13 transplants for HLHS had two operative deaths secondary to pulmonary hypertension, and 1 of those 2 patients demonstrated Heath-Edwards grade 4 pulmonary vascular changes on postmortem examination. The only death in our series directly related to pulmonary hypertension occurred early in our experience when a 3-month-old infant died on the second day after transplantation. However, neither he nor any of the other patients who had early death showed significant pulmonary vascular disease on postmortem histologic examination. For the last 5 years, it has been our protocol to maintain all HLHS recipients on a prostaglandin E1 regimen after transplantation and gradually wean them from the drug over a 1-week period. Perhaps this practice, along with our tendency to accept oversized donor hearts, has contributed to the low incidence of postoperative complications related to pulmonary hypertension.
Size matching of the pediatric donor heart to the infant recipient can be a complex issue because of the severe shortage of donors. Undersized donor hearts can be problematic, especially in the presence of pulmonary hypertension. Our data regarding oversized grafts did not support suggestions by Turrentine and associates [12] that a donor-to-recipient weight ratio of greater than 1.9 had an adverse effect on survival. In our series, grafts from donors up to four times the weight of the recipient have been well tolerated with minimal morbidity. In cases of oversized grafts, the pericardium along the left pleural cavity was excised to the level of the left phrenic nerve. On occasion, the sternum was kept open and delayed primary sternotomy closure was done a few days later. This approach was used in 16 patients in this series with no increase in morbidity. Excessive cardiac output and systemic hypertension seen with larger donor hearts may contribute to cerebral edema and visceral and renal vasospasm. In such cases, inotropic agents are usually avoided after transplantation and vasodilator drugs are used instead to control hypertension.
Rejection is a major cause of death in pediatric heart transplant recipients, partly because early diagnosis of rejection is often challenging. The routine use of surveillance endomyocardial biopsy in infants is not very practical and, in the absence of cardiac symptoms, has not been helpful in detecting rejection early [16]. Half of the late deaths in the present series were directly related to graft rejection. In a collected series of 151 children who underwent CTx at different institutions, 80% of late deaths were due to rejection [15]. The rate of rejection in the present series is very similar to that reported by others (1.6 to 1.95 episodes per patient), despite avoidance of chronic steroids [12, 13, 15]. Turrentine and associates [12] noted a lower frequency of rejection among neonate recipients, and 40% of their HLHS patients were not treated for rejection. In our series, more infants than newborns had a long-term rejection-free history, and the freedom from rejection at 5 years was only 20%. This finding may be related to antithymocyte serum induction immunotherapy in our older infants and the longer period of follow-up. Accelerated graft vasculopathy is a major limitation of long-term survival of patients after CTx. The incidence of GV among pediatric heart transplant recipients has ranged from 2% to 40% at 3 years [17]. The earliest documentation of GV in our series was 18 months after CTx. Backer and colleagues [15] reported histologic evidence of intimal proliferation at 13 months and severe GV at 15 months after CTx in 2 separate children. Graft coronary vasculopathy was identified as the immediate cause of two late deaths in our series. It was also a major contributing factor to one late death due to severe rejection. Although we have previously noted an association between multiple rejection episodes and GV, the etiology of this lesion is probably multifactorial [18]. It is not known yet whether all pediatric heart recipients are at risk of having GV develop if they live long enough. Therefore, close and long-term follow-up of all patients is indicated. Coronary angiography, dobutamine stress echocardiography, and intracoronary ultrasound imaging may have complementary roles in detecting this lesion. Graft coronary artery disease affects the major epicardial vessels and branches along their entire length, and the only effective treatment, therefore, is retransplantation.
Another major issue with CTx in infants has been the side effects of life-long immunosuppressive therapy. The incidence of hypertension in this group of patients has varied from 20% to 50% [12, 15, 19]. Backer and associates [15] reported severe renal insult from combination cyclosporine and amphotericin in 1 neonate who required continuous ambulatory peritoneal dialysis. The other 10 infants in that report had good renal function with a mean serum creatinine level of 0.73 ± 0.14 mg/dL. Ninety percent of survivors in our population had a creatinine level less than 1 mg/dL at an average period of 4.6 ± 1.7 years after CTx. Lymphoproliferative disease in children is usually associated with Epstein-Barr virus infection and with a more intense immunosuppressive therapy. We strongly believe that avoiding the use of chronic steroids in infants and maintaining a level of immunosuppression as low as is compatible with good allograft function will reduce the incidence of neoplasms, hypertension, and renal dysfunction.
Concerns have been raised regarding the growth potential and the quality of life of children surviving CTx. We had observed delayed bone age maturation and growth impairment in children taking prednisone. However, when steroid therapy was discontinued, growth velocity normalized and the majority of infants have ultimately shown normal growth. The Bayley scales of infant development used for cognitive assessment found the majority of our infants with a normal mental developmental index and psychomotor developmental index. Neurologic abnormalities occurred in 10% of our patients, with dystonia being the most common disability. Numerous factors may contribute to poor neurologic outcome, including pretransplantation hypoxic ischemic brain injury and low output state, preexisting central nervous system abnormalities, intraoperative cerebral insults, cyclosporine neurotoxicity, and other metabolic and fluid derangements. A study by Rogers and associates [20] evaluated the neurodevelopmental outcome of 20 infants with HLHS who underwent staged surgical repair at three different Children's Hospitals. Of 11 survivors, 7 patients (64%) had varying degrees of mental retardation and 2 patients (18%) had severe cerebral palsy. Eight of 9 children with cognitive delays had acquired microcephaly.
In conclusion, CTx in infants is associated with a 70% survival at 7 years of patients who receive transplants. The majority of recipients enjoy a good quality of life. Older survivors attend school and participate in age-appropriate activities. It is our belief that passive euthanasia for babies with HLHS is seldom acceptable. Surgical therapy, either staged reconstruction or CTx, provides hope for survival and is a better alternative to death. Although the long-term prognosis of CTx in this age group is unknown, we believe that CTx can be performed with good operative and intermediate-term results and an acceptable quality of life. Expansion of the donor pool, improvements in the diagnosis and treatment of rejection, advances in immunomodulations, and control of graft vasculopathy can make CTx a more available and durable therapy and thus positively affect the survival of infants with HLHS.
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We acknowledge the important contributions of the neonatologists, pediatric cardiologists, cardiac surgical fellows, intensive care unit nurses, transplant coordinators, infectious disease specialists, and cardiac anesthesiologists at Loma Linda University Medical Center, Loma Linda, California.
Footnotes
Presented at the Thirty-second Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 29–31, 1996.
Address reprint requests to Dr Razzouk, Division of Cardiothoracic Surgery, Loma Linda University Medical Center, 11234 Anderson St, Loma Linda, CA 92354.
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R. L. Larsen, P. M. Applegate, D. A. Dyar, P. A. Ribeiro, S. D. Fritzsche, N. F. Mulla, G. S. Shirali, M. A. Kuhn, R. E. Chinnock, and P. M. Shah Dobutamine stress echocardiography for assessing coronary artery disease after transplantation in children J. Am. Coll. Cardiol., August 1, 1998; 32(2): 515 - 520. [Abstract] [Full Text] [PDF]
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M. B. Mitchell, D. N. Campbell, D. R. Clarke, D. A. Fullerton, F. L. Grover, M. M. Boucek, B. Pietra, M. Luna, A. L. Shroyer, J. R. Coll, et al. Infant heart transplantation: improved intermediate results J. Thorac. Cardiovasc. Surg., August 1, 1998; 116(2): 242 - 246. [Abstract] [Full Text] [PDF]
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 A. J. Razzouk, R. E. Chinnock, J. A. Dearani, S. R. Gundry, and L. L. Bailey Cardiac Retransplantation for Graft Vasculopathy in Children: Should We Continue to Do It? Arch Surg, August 1, 1998; 133(8): 881 - 885. [Abstract] [Full Text] [PDF]
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F. Dapper, J. Bauer, J. Kroll, B. Zickmann, R. M. Bohle, K. J. Hagel, and D. Schranz Clinical experience with heart transplantation in infants Eur J Cardiothorac Surg, July 1, 1998; 14(1): 1 - 6. [Abstract] [Full Text] [PDF]
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 L D Allan, H D Apfel, and B F Printz Outcome after prenatal diagnosis of the hypoplastic left heart syndrome Heart, April 1, 1998; 79(4): 371 - 373. [Abstract] [Full Text]
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 J. J Sistino Foetal bypass: concepts and controversies Perfusion, March 1, 1998; 13(2): 111 - 117. [Abstract] [PDF]
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A. H Stammers Monitoring controversies during cardiopulmonary bypass: how far have we come? Perfusion, January 1, 1998; 13(1): 35 - 43. [PDF]
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 J. F. Dashe, M. S. Pessin, R. E. Murphy, and D. D. Payne Carotid occlusive disease and stroke risk in coronary artery bypass graft surgery Neurology, September 1, 1997; 49(3): 678 - 686. [Abstract] [Full Text] [PDF]
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A. Jaretzki III Thymectomy for myasthenia gravis: Analysis of the controversies regarding technique and results Neurology, April 1, 1997; 48(Suppl_5): 52S - 63S. [Full Text] [PDF]
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