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Ann Thorac Surg 2007;83:1684-1690
© 2007 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri
b Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri
Accepted for publication December 11, 2006.
* Address correspondence to Dr Moazami, Division of Cardiothoracic Surgery, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8234, St. Louis, MO62236 (Email: moazamin{at}wustl.edu).
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Abstract |
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Methods: Between 1996 and 2005, 200 patients (64% men; mean age, 49 ± 12 years) underwent heart transplantation at our institution. Overall, 46 patients (23%) showed a wide spectra of early neurologic complications.
Results: Cause of ischemic complications was stroke in 11 patients (7 had concomitant epileptic seizures) and transient ischemic attack (TIA) in 7. Encephalopathy (n = 10), epileptic seizures unrelated to focal cerebral lesions (n = 7), severe headache (n = 6), cerebral infection (n = 3), and peripheral nervous system injuries (n = 2) completed the spectra of adverse neurologic outcomes. Multivariate analysis identified advanced age (p = 0.03), preoperative left ventricular assist device support (p = 0.02), preoperative intraaortic balloon pump support (p < 0.001), prolonged cardiopulmonary bypass time (p < 0.001), and postoperative hepatic failure (p = 0.04) as independent predictors of early neurologic complications. Postoperative morbidities associated with neurologic complications included longer ventilation time (p < 0.001), longer stay in the intensive care unit (p < 0.001), and higher incidence of pneumonia (p < 0.001) and sepsis (p = 0.01) compared with patients without neurologic events. There was a trend toward higher in-hospital mortality (15% versus 6%, p = 0.07), but there was no difference in long-term survival (65% versus 78%, p = 0.15).
Conclusions: Despite rigorous pretransplantation screening, neurologic complications were common after cardiac transplantation. Most frequently, these complications were not the actual cause of death, but they significantly contributed to increased morbidity. Preoperative mechanical circulatory support requirement was the strongest predictor for adverse neurologic outcome.
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Introduction |
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The complicated physiologic states and interplay associated with cardiac transplantation, including preoperative hemodynamic instability, iatrogenic coagulopathies, cardiopulmonary bypass (CPB) with cardiectomy, and atrial arrhythmias should, in theory, contribute to considerable risk for cerebral infarction or hemorrhage. The literature in this topic, however, is controversial. Historical reports have shown a wide variation in the incidence of neurologic complications after cardiac transplantation. This variation reflects that these studies have used various neuropathologic and clinical diagnostic criteria, as well as inclusion of various spectra of neurologic complications [1–5].
Although early neuropathologic studies have reported cerebral lesions in up to 94% of cardiac transplant patients [6–8], registries of the International Society for Heart Transplantation in the late 1980s did not mention stroke as a cause of death after transplantation [9, 10]. More recently, however, the International Society for Heart and Lung Transplantation has changed its position, stating that cerebrovascular accidents are responsible for 7% of early postoperative deaths after cardiac transplantation [11]. This article reports our investigation of the incidence, clinical impact, and risk factors of early neurologic complications in a current series of 200 heart transplant recipients.
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Patients and Methods |
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The study cohort comprised 128 (64%) men and 72 (36%) women with a mean age of 49 ± 12 years, and overall, 46 patients (23%) were diagnosed with early neurologic complications. Selected demographic patient characteristics are summarized in Table 1. Comorbidities were equally distributed among all patients, but the need for preoperative pharmacologic or mechanical circulatory support was significantly higher in patients who had early posttransplantation neurologic complications.
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Data collected on all patients included postoperative hemodynamics, complete blood count with differential, chemistry panel, coagulation times, and cyclosporine and tacrolimus level. Acute renal failure was defined by a twofold increase in serum creatinine from baseline [12]. The clinical diagnosis of hepatic failure was determined by liver function indices, including aspartate aminotransferase, alanine aminotransferase, total and bound bilirubin, albumin and prealbumin, factors V and VII, 
-fetal protein, and other coagulation tests (prothrombin time, activated partial thromboplastin time, international normalized ratio, and antithrombin III). The mean follow up was 4.1 ± 3 years and was 100% complete.
Transplantation Protocol
Cardiac transplantations were performed according to the technical description by Lower and Shumway [13], or modified to involve bicaval anastomosis. All operations were performed with moderate hypothermia (28° to 32°C). The perfusion pressure was maintained between 50 and 80 mm Hg during the cross-clamp period. All patients were treated with a standardized three-drug immunosuppressive protocol consisting of a calcineurin inhibitor, an antimetabolite (either azathioprine or mycophenolate mofetil), and steroids.
Neurologic Evaluation
Pretransplant work-up included a detailed evaluation of any prior neurologic events. All patients with a positive history were evaluated by an institutional neurologist, and any prior residual deficits were documented. Extracerebral vasculature was studied in all patients by carotid ultrasonography before transplantation. Patients with significant carotid artery stenosis (symptomatic >50% or asymptomatic >80%) were excluded from transplantation or had a preoperative carotid endarterectomy (CEA) if no other major comorbidities were present. Only one patient in this group had CEA before transplantation.
During the 10-year period assessed in the study, all early neurologic complications were diagnosed by the attending physician, confirmed by an institutional neurologist, and prospectively entered into our database. All patients evaluated for posttransplant onset of neurologic deficit underwent cranial computed tomography (CT), magnetic resonance imaging, or both, to diagnose acute focal cerebral lesions and to further separate embolic events from cerebral hemorrhage.
If clinical symptoms of a stroke persisted, but noninvasive studies provided inadequate information, patients underwent cerebral angiography to exclude an acute embolic event. An electroencephalogram (EEG) was performed to document epileptic seizure activity.
Patients with fever and neurologic symptoms underwent lumbar puncture to determine if an infection of the CNS was present. Encephalopathy was defined as a spectrum of neuropsychiatric abnormalities characterized by personality changes, intellectual impairment, and a depressed level of consciousness. Transient ischemic attacks (TIA) were defined as any ischemic deficits with resolution of symptoms within 24 hours after diagnosis. For each new postoperative neurologic complication, the time of appearance and duration of symptoms were recorded. Transitory neurologic symptoms (resolution within 4 months with no lingering effects) were separated from persistent neurologic symptoms (duration exceeding 4 months or with no resolution). Four-month follow-up for persistence of neurologic symptoms was performed by our institutional neurologists and was 100% complete.
Data Analysis
Operative mortality included any death during the initial hospitalization or within 30 days of operation for discharged patients. Cumulative survival rates were calculated using Kaplan-Meier analysis, and survival curves were compared using the log-rank test. Continuous data were reported as mean ± one standard deviation or median with intraquartile range (IQR) where appropriate and compared using the Student t test. Categoric variables were analyzed using the 
2 test or the Fisher exact test, as appropriate. Odds ratios (OR) were reported with 95% confidence intervals (CI). Multivariate analysis (stepwise backward regression) was used to determine preoperative, intraoperative, and postoperative risk factors that were significant independent predictors of early neurologic complications. The statistical software Stata (StataCorp, College Station, TX) was used for the calculations.
We analyzed 19 variables: age, gender, history of tobacco use, diabetes, chronic renal insufficiency, previous cerebrovascular disease, previous cardiac intervention, preoperative atrial fibrillation, etiology of heart failure, New York Heart Association functional classification, preoperative left ventricular assist device (LVAD) support requirement, preoperative IABP support requirement, year of transplantation, CPB time, number of red blood cell (RBC) units given in the operating room, postoperative atrial fibrillation, cyclosporine level, postoperative renal failure, and postoperative hepatic failure.
These variables were initially screened by performing univariate logistic regression on all possible explanatory variables with the dependent variable of neurologic complication of any kind. This was screened to include any variable with a p < 0.20 for further examination. The variables that remained then underwent cross-tab analysis to look for any strong correlations between pairs of variables, and none were found. These variables were then forced into a logistic regression model, and this model was bootstrapped with 1000 repetitions; each repetition used a sample size of 200 with replacement. In an attempt to identify postoperative morbidities that were actually the initiating cause of neurologic complications, we strictly correlated their onset to the time of diagnosis of neurologic impairment. Only factors that were clearly documented before neurologic events were included in the multivariate analysis. Statistical differences were considered significant at p < 0.05.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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0.02). Operative mortality for the entire series was 8% (17/200), but was 15% (7/46) in patients with neurologic complications (p = 0.07). Early neurologic complications were diagnosed in 46 patients (23%). The cause of ischemic neurologic complications was stroke in 11 patients and TIA in 7 patients. An embolic event caused seven of the diagnosed strokes, and a cerebral hemorrhage caused 4. Concomitant epileptic seizures developed in 7 of these stroke patients, all of which had EEGs revealing that these seizures were symptoms directly attributable to the focal cerebral lesion. In our series, 3 of the 4 patients with cerebral hemorrhage had coagulopathy and thrombocytopenia owing to multisystem organ failure. Hypertensive postoperative episodes were recorded in all 4 patients. Encephalopathy (n = 10), epileptic seizures not related to ischemic cerebral lesions (n = 7), severe headache (n = 6), cerebral infection (n = 3), and peripheral nervous system injury (n = 2) completed the broad spectra of neurologic events.
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The remaining 2 patients with persistent symptoms died after CNS infections developed. In one patient, abrupt right arm paralysis occurred in the setting of fever, and a chest roentgenogram revealed a right lower lobe infiltrate. Parenteral amphotericin B therapy was initiated after sputum cultures grew Aspergillus and Candida species. Cranial CT demonstrated a 3-cm hypodense area in the left frontal region. The patient died 1 week later from multisystem organ failure. A neuropathologic work-up confirmed invasive Aspergillus involving multiple organs, including the brain. The second patient was diagnosed with a cerebral abscess, which was located in the anterior putamen and the left thalamus. Histologic determination of Toxoplasma gondii from a stereotaxic brain biopsy specimen provided a definitive diagnosis. Despite maximum treatment, the patient died within 3 days after the diagnosis.
Postoperative morbidities were unequally distributed among patients with and without neurologic events (Table 3). Longer ventilation time (p < 0.001), longer stay in the intensive care unit (p < 0.001), and higher incidence of pneumonia (p < 0.001) and sepsis (p = 0.01), were consistent with a complicated postoperative recovery in patients with adverse neurologic outcome.
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Comment |
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The higher incidence of stroke and TIA in the cardiac transplantation population can be attributed to multiple factors. Coagulation function varies widely as the anticoagulated patient is rapidly reversed before thoracotomy, re-anticoagulated during CPB, and then reversed again at the end of the procedure. Multiple suture lines also create intracardiac sites along which platelets aggregate and fibrin forms.
Mechanical circulatory support before transplantation was the most significant determining factor of postoperative stroke or TIA in this study. In particular, preoperative IABP use was the strongest independent predictor of ischemic and hemorrhagic events. Another interesting finding is the steady increase in the requirement of preoperative mechanical circulatory support during the 10-year period in our series. This probably reflects that the cardiac transplantation population has steadily shifted toward higher-risk patients. Thus, the fact that incidence of postoperative stroke and TIA has remained steady over the 10-year period likely represents a continuous improvement in the surgical management of these patients.
Intraoperative hypotensive episodes during cardiac operations in general are widely feared. Stockard and colleagues [15] observed a significant correlation between CPB pressures of 50 mm Hg or less during cardiac operations with the development of postoperative neurologic symptoms. The median CPB pressure in our series was 66 ± 8 mm Hg and was similar in the patients who had neurologic complications and in those that did not. The CPB and cross-clamp times, however, were significantly longer in patients who had neurologic complications after transplantation, as were the numbers of RBC units given perioperatively. Longer CPB and cross-clamp times and higher numbers of RBC units transfused indicate a more complicated and challenging intraoperative course, which clearly put the patients at higher risk of cerebral hypoperfusion.
Hemodynamic instability—both preoperatively and postoperatively—may obviously directly cause cerebral hypoperfusion, and is therefore aggressively managed. Although it may sound paradoxical, improved cardiac function after transplantation may also lead to cerebral damage. Hypertensive episodes can cause a relative postoperative hyperperfusion. This seems particularly dangerous, because postoperative hypertensive episodes were present in all 4 patients with cerebral hemorrhage in our series.
Although it is difficult to prove, cardiac transplant recipients may modify their cerebral autoregulation toward lower pressure to adapt to the progressive systemic hypotension over extended periods before transplantation. The range of systemic blood pressure they can tolerate may therefore be limited, requiring an extremely sensitive hemodynamic management after transplantation to avoid both hypotensive and hypertensive episodes.
Chronic atrial fibrillation (AF) has long been identified as a risk factor for embolic stroke in the general population, as the Framingham study reported a fivefold increase in the risk of stroke in patients with AF [16]. Although atrial arrhythmias including AF have been reported to occur in 18% to 65% of cardiac transplant recipients, the association of postoperative AF and postcardiac transplantation neurologic events remains controversial [17–19].
Almassi and colleagues [20] reported a 5.3% incidence of stroke in transplantation patients with episodes of postoperative AF compared with 2.4% in patients without postoperative AF (p = 0.001). Other authors have reported similar findings [21–23]. In contrast, Keogh and colleagues [24] observed that AF was not associated with systemic embolism in patients undergoing cardiac transplantation. In the current series, preoperative AF was equally distributed between both groups. Although posttransplantation AF was detected more frequently in patients with adverse neurologic outcome, multivariate analysis did not identify it as an independent predictor of early neurologic complications.
The incidence of epileptic seizures in cardiac transplant recipients has previously been reported to be between 15% to 39%, with cyclosporine A neurotoxicity being described as the principal cause [7, 25, 26]. In addition to epileptic seizures, other central nervous system toxicity of cyclosporine A has included tremor in 21% to 55%, and headaches in 2% to 15% of transplant recipients [27]. The overall incidence of epileptic seizures in our series was only 7%, which is substantially lower compared with these previous reports. Epileptic seizures occurred in 7 patients that were directly related to focal ischemic cerebral lesions; another 7 were diagnosed with seizure activity after transplantation that was unrelated to any focal morphologic changes. Only 2 patients experienced a toxic reaction directly related to high doses of cyclosporine, consisting of myoclonus and seizures, all of which resolved after tapering the dosage.
CNS infections in patients undergoing cardiac surgery are extremely rare, and are almost exclusively diagnosed in transplant recipients or in patients with infective endocarditis [28, 29]. Immunosuppression after transplantation clearly puts these patients at a high risk for opportunistic infections. In the early days of cardiac transplantation, the reported incidence of cerebral infections was as high as 24% [1]. With the use of improved immunosuppressive regimens that combine cyclosporine, azathioprine, and corticosteroids, the risk of CNS infections has steadily decreased to 14%, and more recently dropped to 5% [2]. The incidence of cerebral infections in the current report was even as low as 1.5% (3/200), also reflecting the encouraging progress in the medical management of transplant recipients. It should be noted, however, that 2 of the 3 patients who sustained cerebral infections in our series died despite maximal treatment. Consistent with previous studies [30], Toxoplasma gondii and Aspergillus infections were responsible for these two deaths in the early posttransplantation period.
Two other spectra of neurologic complications were lower trunk brachial plexopathy in 2 patients attributed to stretching during intraoperative chest wall retraction and severe headache in 6. Vascular headache in the first week after transplantation week may be related to relative cerebral hyperperfusion in recipients with smaller body surface area compared with their donors [30]. Although unpleasant, symptoms resolved within 1 week in all 6 patients. It is important to note that an immediate detailed neurologic work-up was performed if symptoms persisted despite standard analgesic treatment, because severe headache in cardiac transplant recipients can be associated with a variety of life-threatening neurologic complications.
In summary, our series found neurologic complications were common after cardiac transplantation, affecting nearly a quarter of recipients. These complications were most frequently transitory and not the principle cause of death. Fundamental contributing factors to the neurologic complications were hemodynamic instability before transplantation, prolonged CPB times, and metabolic derangement secondary to postoperative hepatic failure.
Our series showed substantially lower incidence of immunosuppressive agent neurotoxicity and cerebral infections compared with historical reports, reflecting improved modern medical management and pharmacological surveillance. Unfortunately, the incidence of stroke and TIA was consistent with older reports. Despite improved surgical experience and medical postoperative management, this may be because during this 10-year period, we observed a trend in cardiac transplantation toward higher-risk patients, as evidenced in an increased incidence of preoperative circulatory support requirement.
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Acknowledgments |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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References |
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