Christof Schmid

Cerebral and Systemic Embolization During Left Ventricular Support With the Novacor N100 Device

BACKGROUND Patients undergoing implantation of left ventricular assist systems (LVAS) are prone to thromboembolic complications. We analyzed the incidence, clinical findings, and outcome of neurologic and systemic thromboembolic events (TE) in patients with the Novacor N100 LVAS. In a subset of patients, transcranial Doppler sonography was used to detect microembolic signals. METHODS Thirty-six patients underwent implantation of a Novacor N100 LVAS for various reasons. The surgical procedure was elective in 18 patients and scheduled on an urgent or emergency basis in another 18 patients. The assist period lasted from 17 to 336 days (109 +/- 88 days); 22 patients were forwarded to heart transplantation after being supported for 140 +/- 87 days. RESULTS Clinical cerebral embolism was evident in 17 patients (47%). Thromboembolic events were singular in 8 and multiple in 9 patients; in the latter up to 10 TE occurred (mean +/- SD, 1.4 +/- 2 TE). Leading neurologic symptoms were unilateral hemiplegia in 11, as well as ocular symptoms and aphasia in 12 patients each. Noncerebral TE were detected in 4 patients, 2 of whom underwent an emergency operation for intestinal and iliac artery occlusion. The incidence of TE did not correlate strongly with the interval of LVAS support. Cerebral computed tomography confirmed lesions in 58% of patients. Transcranial Doppler sonography detected microembolic signals on 67% of all recordings, with the microembolic signals being more frequent on days with clinically manifest TE. The outcomes were good, as only 2 patients suffer from neurologic sequelae. CONCLUSIONS Thromboembolism is still a major threat for patients with LVAS implantation. Neurologic sequelae are frequent but have a favorable prognosis, and systemic complications occur considerably less often. Patient selection, adequate anticoagulation, and transcranial Doppler sonography may help to reduce the incidence of TE.

Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172.

BACKGROUND In patients with heparin-induced thrombocytopenia undergoing cardiac operations, anticoagulation with heparin should be avoided. The low-molecular-weight glycosaminoglycan Orgaran has been used as an alternative, but the overall experience is limited. METHODS Two patients with heparin-induced thrombocytopenia underwent cardiopulmonary bypass using Orgaran for anticoagulation. A 30-year-old woman suffered from emboli to her brain through a secondary atrial septal defect, a 14-year-old boy from ischemia of his left leg due to recurrent embolism originating from the mitral valve. In both cases, cardiopulmonary bypass was performed in a routine manner, except for using low-dose Orgaran instead of heparin. Anticoagulation was monitored during cardiopulmonary bypass by measuring Orgaran plasma levels and activated clotting time. RESULTS No thromboembolic or bleeding complications occurred during and after atrial septal defect repair and mitral valve replacement, respectively. In the former case, thrombotic material from the inferior vena cava was removed during hypothermic circulatory arrest within the same procedure. Activated clotting time did not correlate with plasma levels of Orgaran. CONCLUSIONS Orgaran might be a useful alternative for anticoagulation during extracorporeal circulation. Adequate dosages and measurement of plasma levels are recommended for its use in cardiopulmonary bypass.

Cardiac Pacemaker Infection: Surgical Management With and Without Extracorporeal Circulation

BACKGROUND Pacemaker infections are rare, but serious complications of pacemaker therapy. The generator pocket, the pacing leads, or both may be involved. METHODS We report on 12 patients with infected pacemaker systems. Four patients suffered from localized generator pocket infections, 6 had infected leads, and 2 patients had both. Pacemaker systems were completely removed in all patients. When the infection was limited to the generator pocket, the pacemaker system was removed at the original implantation site. Extracorporeal circulation was employed for the explantation of infected pacing leads. RESULTS No complications occurred in patients with localized generator pocket infections. One patient with infected leads who was preoperatively already in a serious clinical condition died of septic shock in the early postoperative period; another patient died of pulmonary complications after tricuspid valve replacement 14 months after pacemaker explantation. No recurrent infections were observed. CONCLUSIONS Explantation of the complete pacemaker system has proved a reliable method to eradicate infection. Complications have been rare, except in patients in a critically ill state who undergo cardiopulmonary bypass.

Clinical Relevance of Intracranial Microembolic Signals in Patients With Left Ventricular Assist Devices: A Prospective Study

BACKGROUND AND PURPOSE The use of left ventricular assist devices has become an established method in bridging patients with end-stage cardiac failure to heart transplantation. Since thromboembolism is one of the major complications, we undertook this study to evaluate the clinical significance of Doppler microembolic signals (MES) in patients with left ventricular assist devices. METHODS Six patients with left ventricular assist devices were monitored for MES with transcranial Doppler ultrasonography during the first 30 postoperative days. Additionally, repeated (10 per day and patient) and prolonged (3 hours per patient) monitorings were performed to assess the adequacy of the 30-minute recordings. Three observers evaluated 30 randomly assigned monitorings in a blinded fashion to assess the interobserver variability. The relation between MES counts and clinical, radiological, hemostaseological, and pump flow parameters and the predictive value of MES counts regarding the occurrence of embolic events was evaluated. RESULTS Ten ischemic cerebrovascular accidents and 2 peripheral thromboembolic events occurred during the observation period of 177 days (total incidence, 6.8%). MES were found in 143 of 170 monitorings (84.1%). Their counts were significantly higher on days with clinically manifest embolic events as compared with event-free days (18.5 [3-74] versus 4 [0-52], respectively, median and 95% CI; P < .001, Mann-Whitney). The predictive value of MES counts above 7 per 30 minutes was high (75%). Significant differences in the incidence and counts of MES as well as in the incidence of clinically manifest embolic events were noted among the six patients (all P < .01) without equal differences in anticoagulant treatment or pump flow. Interobserver agreement was high (p = .78 to .89, unpaired Students t test). Considerable short- and long-term intrapatient variations of MES counts, without consistent pattern, were noted. CONCLUSIONS Serial monitoring for MES is prognostically superior to single monitorings in patients with left ventricular assist devices. In the future, this new application mode may individually guide anticoagulation strategies and even influence the decision regarding early cardiac transplantation versus long-term use of the assist devices.

Reversal of metallothionein expression is different throughout the human myocardium after prolonged left-ventricular mechanical support

OBJECTIVES We examined the distribution of metallothionein (MT), a stress-inducible protein, and the cardiomyocyte diameter in human hearts after left-ventricular assist device (LVAD) support. BACKGROUND Remodeling in end-stage heart failure is characterized by myocyte hypertrophy and alterations of several inducible proteins. LVADs used as a bridge to cardiac transplantation unload the left ventricle and may lead to a reversal of the remodeling, but little is known about the pathophysiology of this process. METHODS The immunoreactivity for MT and the cardiomyocyte diameter was analyzed in left-ventricular tissue specimens of 17 patients with end-stage heart failure before and after LVAD support. RESULTS MT positive cells were mainly located sub-endocardially in vacuolized cardiomyocytes and in small vessels throughout the myocardium. During LVAD support, MT-positive myocytes decreased in the sub-endocardial (p < 0.008) and sub-epicardial region (p < 0.003), MT-positive vessels decreased similarly (p < 0.003). Cardiomyocyte diameter decreased significantly only in the sub-endocardium (p < 0.03). Hearts of patients supported longer than 88 days (= median) showed substantially lower MT reactivity at the time of LVAD explantation as compared to patients supported less than 88 days. CONCLUSION Our results suggest that unloading of the left ventricle during prolonged LVAD support leads to regression of cellular hypertrophy and a decrease of MT expression. The preferential reduction of MT-positive vacuolized cardiomyocytes in the sub-endocardium is comparable with the concept of greatest reduction of wall stress in this area of the myocardium and may be due to the improvement of myocardial blood flow and the energy balance.

The impact of anti-endotoxin core antibodies on endotoxin and cytokine release and ventilation time after cardiac surgery☆

OBJECTIVES We hypothesized that a temporary cardiopulmonary bypass (CPB)-induced reduction of endotoxin antibody levels contributes to elevated endotoxin levels and the associated inflammatory consequences, with a significant influence on the postoperative ventilation time period. BACKGROUND Cardiac surgery using CPB induces a systemic inflammatory response syndrome with an associated risk of increased postoperative morbidity and mortality. METHODS A total of 100 consecutive patients undergoing elective coronary artery bypass graft surgery using CPB were prospectively investigated. Endotoxin core antibodies (immunoglobulin [Ig] M/IgG against lipid A and lipopolysaccharide), endotoxin, interleukin (IL)-1-beta, IL-6, IL-8 and tumor necrosis factor-alpha were measured serially from 24 h preoperatively until 72 h postoperatively. RESULTS Eighty-five patients had no complications (group 1), whereas 15 patients required prolonged ventilation (group 2). In both groups, there was a decrease of all antibodies 5 min after CPB onset, compared with baseline values (p < 0.001), an increase of endotoxin and IL-8 peaking at 30 min postoperatively (p < 0.001) and an increase of IL-6 peaking 3 h postoperatively (p < 0.001). In group 2, preoperative antibody levels were lower (p < 0.01)--specifically, the decrease in IgM was significantly stronger and of longer duration (p < 0.002)--and levels of endotoxin (p < 0.001) and IL-8 (p < 0.001) were higher at 30 min postoperatively. CONCLUSIONS We conclude that an CPB-associated temporary reduction of anti-endotoxin core antibody levels contributes to elevated endotoxin and IL-8 release. Furthermore, lower levels of IgM anti-endotoxin core antibodies were associated with a greater rise in endotoxin and IL-8, as well as prolonged respirator dependence.

Reduction of hypoxia‐inducible heme oxygenase‐1 in the myocardium after left ventricular mechanical support

Left ventricular assist devices (LVAD) may improve cardiac function. The pathogenesis of this phenomenon, called ‘reverse remodelling’, is not completely elucidated. To examine the hypothesis that LVAD support eliminates tissue stress by reducing local hypoxia, the distribution of heme oxygenase‐1 (HO‐1), a stress protein inducible by hypoxia, was examined in vivo and in vitro. The immunoreactivity for HO‐1 was semi‐quantitatively analysed in left ventricular tissue of 23patients (14 dilated cardiomyopathy (DCM), six ischaemic heart disease (IHD), three myocarditis/congenital heart disease) with end‐stage heart failure before and after LVAD support, while two unused donor hearts served as controls. Control hearts stained almost negative for HO‐1, while failing hearts showed immunoreactivity mainly in cardiomyocytes, but also in endothelial cells, some smooth muscle cells and fibroblasts. Hearts with IHD showed significantly higher HO‐1 immunoreactivity than hearts with DCM or myocarditis/congenital heart disease. After LVAD support, the HO‐1 content decreased significantly in the DCM and IHD group and was significantly higher in the subendocardium than in the subepicardium. In vitro, under hypoxic conditions, neonatal rat cardiomyocytes showed an increase of HO‐1 protein content up to sixfold above the normal level, which returned to normal values after normoxic cultivation. Mechanical support reduces the HO‐1 content of the failing heart and HO‐1 is inducible in vitro under hypoxia and is reversible under normoxia. This supports the concept that restoration of cardiac normoxia by mechanical unloading, particularly in the subendocardium, may be in part responsible for the phenomenon of ‘reverse remodelling’. Copyright

The impact of the pro‐ and anti‐inflammatory immune response on ventilation time after cardiac surgery

Cardiac surgery using cardiopulmonary bypass (CPB) may induce a systemic inflammatory response syndrome (SIRS), which is associated with an increased risk of postoperative morbidity and mortality. The intention of this pilot study was to investigate the influence of the pro‐ and anti‐inflammatory cytokine responses as well as of released adhesion molecules and endotoxin on the time requirements for assisted postoperative respiration following CPB surgery.

Doppler microembolic load predicts risk of thromboembolic complications in Novacor patients

OBJECTIVE Left ventricular assist devices have become an established method to bridge patients with end-stage cardiac failure to heart transplantation. Besides infection and bleeding, thromboembolism represents one of the most serious complications. We evaluated the value of microembolic signals in predicting thromboembolic events for individual patients and distinctive left ventricular assist device periods. METHODS Twenty patients (14 male) aged 23-57 years supported with the Novacor N100 left ventricular assist device were enrolled in this study. All patients were on effective anticoagulation, 12 patients additionally received antiplatelet therapy. Unilateral detection of microembolic signals was performed once weekly by insonation of the middle cerebral artery using transcranial Doppler sonography for 30 minutes duration. Evidence of clinically manifest thromboembolic events was based on regular questionnaires, clinical examinations, and results of diagnostic procedures. RESULTS During a cumulative follow-up of 3876 left ventricular assist device days, 44 thromboembolic complications occurred (incidence, 1.1%) in 15 out of 20 patients. A total of 360 transcranial Doppler sonography monitorings (range, 5-34 per patient) were performed with an overall microembolic signals prevalence of 35.3% and a microembolic signal mean of 2.3 +/- 9.2 per examination. There was a highly significant correlation between the individual microembolic signal activity and the respective incidence of clinical thromboembolism (r = 0.61-0.9; P <.01). Patients with additional antiplatelet treatment had significantly less thromboembolic complications (0.7%) and lower microembolic signal prevalence (18.3%) than those without (2.8% and 65.4%, respectively). Individual patients and left ventricular assist device months with clinical thromboembolization could be identified using the microembolic signal activity with moderate positive (0.37-0.7) and high negative predictive values (0.82-1.0). CONCLUSIONS The amount of microembolic signals, serially detected in patients with the Novacor left ventricular assist device, is significantly associated with their incidence of embolic complications. The high negative predictive value of microembolic signals enables to identify those patients and left ventricular assist device periods with particularly low risk of clinical thromboembolization.

Early proliferative changes in hearts of hypertensive Goldblatt rats: an immunohistochemical and flow-cytometrical study

Hyperplasia of myocytes in cardiac adaptation is a rare event in the mammalian cardiac muscle. Recent findings support the concept that proliferation of myocytes in the adult mammalian heart may be induced after a prolonged increase in pressure load on the myocardium. To determine whether short-term hypertension leads to hyperplasia of myocyte nuclei in the rat heart renal hypertension was produced in 12 Wistar rats. As soon as hypertension occurred, bromodeoxyuridine (BrdU) (50 mg/kg/day) was injected intraperitoneally on three subsequent days. Twelve sham-operated rats served as controls. After 3 days, the left cardiac ventricle was excised and double-staining with anti-BrdU antibody and propidium iodide was performed to determine the phase of cell-cycle of the BrdU-positive cells by flow-cytometry. Immunohistochemical double-staining with desmin, smooth muscle actin, vimentin, and BrdU was done to classify the BrdU-positive cells.Most of the BrdU-positive cells were in the G0/G1-phase of the cellcycle, suggesting cell proliferation or DNA-repair have taken place; polyploidy was not observed. In the hypertensive group (4.62%±2.36) significantly more cells incorporated BrdU than in the control group (1.46%±0.96). Immunohistochemically, the majority of the BrdU-positive cells consisted of fibrocytes, smooth muscle cells, and endothelial cells. Only 0.35%±0.26 of cardiac myocytes in the normotensive group showed positive BrdU-staining compared to 0.48%±0.32 in the hypertensive group. This difference was statistically not significant.This study showed that early after onset of hypertension proliferation of non-myocytes, but not of myocytes occurred. DNA synthesis is limited almost completely to the interstitial cells and does not occur in any significant extent in cardiac myocytes. In conclusion, hyperplasia of cardiac myocytes is not observed at carly stages of hypertension, but it may develop at a late stage of cardiac adaptation.