Effects of chronic amiodarone treatment on human myocardial beta adrenoceptor density and adenylate cyclase response.

STUDY OBJECTIVE: The aim of the study was to evaluate the effect of chronic treatment by amiodarone on beta adrenoceptor density and adenylate cyclase response in human myocardium. DESIGN: Density of beta 1 and beta 2 adrenoceptors was measured by radioligand binding assay. beta Adrenoceptor stimulated production of cAMP was measured by adenylate cyclase assay. EXPERIMENTAL MATERIAL: Right auricular tissue from five patients on chronic amiodarone treatment was compared with that from nine patients in similar clinical and haemodynamic state undergoing coronary bypass surgery. MEASUREMENTS AND MAIN RESULTS: beta 1 and beta 2 adrenoceptor subtypes were quantified using the highly beta 1 selective antagonist Sandoz 204 545. The total beta adrenoceptor density was 28% lower in the amiodarone treated group than in the controls (42.0 v 58.3 fmol.mg-1 protein, p less than 0.02), beta 1 adrenoceptors were 25% lower (33.1 v 44.3 fmol.mg-1 protein, p less than 0.02), and beta 2 adrenoceptors were 36% lower (8.9 v 14.0 fmol.mg-1 protein, p less than 0.02). The cAMP production following non-selective beta adrenoceptor stimulation (isoprenaline 5 mumol.litre-1) was reduced by 38% in the amiodarone treated group (14.2 to 8.7 pmol.min-1.mg-1 protein, p = 0.05). Terbutaline stimulated cAMP production was reduced by 49% (8.3 to 4.3 pmol.min-1.mg-1 protein, p = 0.03). Fluoride stimulated cAMP production was not significantly different (9.4 v 8.4 pmol.min-1.mg-1 protein, p = 0.15). CONCLUSIONS: Chronic treatment with amiodarone is associated with a non-selective downregulation of beta adrenoceptors. beta Adrenoceptor stimulated cAMP production was also reduced. The "beta blocking effect" of amiodarone is probably related to downregulation of beta adrenoceptors.

Complement activation during extracorporeal circulation. In vitro comparison of Duraflo II heparin-coated and uncoated oxygenator circuits.

The degree of complement activation during cardiopulmonary bypass is considered a valuable parameter of biocompatibility of the extracorporeal circuit. In an in vitro setting with a heart-lung machine primed with fresh whole blood and saline solution, the C3 activation products C3b, iC3b, and C3c and the terminal complement complex were measured in double-antibody enzyme immunosorbent assays. No differences were found between seven sets treated with Duraflo II heparin coating and seven uncoated sets after 2 hours of circulation. C3 activation products (expressed as median and 95% confidence intervals) increased from 4.5 AU (2.8 to 12.3 AU) to 16.5 AU (10.0 to 19.4 AU) in the uncoated sets (p = 0.02) and from 4.6 AU (2.2 to 5.8 AU) to 19.3 AU (3.5 to 27.1 AU) in the coated sets (p = 0.02). Terminal complement complex increased from 5.7 AU (2.7 to 11.3 AU) to 13.6 AU (8.2 to 17.8 AU) in the uncoated sets (p = 0.02) and from 7.9 AU (4.6 to 11.4 AU) to 17.3 AU (9.4 to 35.1 AU) in the coated sets (p = 0.02). A significant drop in thrombocyte levels was observed in both coated and uncoated sets. In a supplementary series, the sterilization process did not influence the results. Although Duraflo II heparin coating is considered highly effective in preventing coagulation, it did not prevent complement activation in the present in vitro study. We hypothesize that the mode by which the heparin molecule is bound to the surface may be essential to obtain effects on both coagulation and complement system.

Heart transplantation in Norway. Morphological monitoring of cardiac allograft rejection. A 3-year follow-up.

A brief description is given of the most important morphological changes in endomyocardial biopsy specimens taken from cyclosporin A (CyA)-treated cardiac allograft recipients. The National Hospital of Norway was, in 1983, the first Scandinavian hospital to perform a heart transplantation, an event facilitated by the new immunosuppressive drug CyA. Up to now (February 1987), 38 allogeneic orthotopic transplants have been carried out on a total of 37 patients, of whom 32 are alive and clinically well. There was no operative mortality, but 5 patients died of other causes: Two early rejections, one arrhythmia due to moderate rejection, one Toxoplasma myocarditis and one early graft failure due to donor heart coronary artery disease. The observation time ranges from six weeks to 39 months. The first 9 patients received CyA and prednisolone; all subsequent recipients were treated with Azathioprine additionally. Thirty six grafts were controlled by 557 sequential biopsy procedures which yielded 2783 endomyocardial specimens for histopathological examination. A histological diagnosis of rejection was made 99 times in 32 grafts (mean 2,6). Twenty four biopsies were obtained on clinical indication in 15 patients, and rejection was diagnosed in 11 biopsies. Evaluation of endomyocardial biopsies is important in monitoring cardiac recipients and provides a morphological index of acute rejection. Serial biopsies with adequate endomyocardial sampling from different areas of the right ventricle make it possible to diagnose acute cellular rejection at an early stage and are essential to control immunosuppressive treatment. Endomyocardial biopsy is a safe and reliable procedure and plays an important role in the management of cardiac allograft rejection.

Single lung transplantation. Morphological surveillance by transbronchial biopsy.

Seven cases of single lung transplantation are reported. The recipients were all below 60 years of age and severely disabled with end-stage lung disease. Transplantation was performed according to ABO blood group compatibility and negative lymphocytotoxic cross-match between donor and recipient irrespective of HLA mismatch. Recipients' diagnoses were sarcoidosis (3), alfa-1 antitrypsin deficiency (3), and idiopathic emphysema (1). Mean recipient age was 48 +/- 2.4 years (range 45-52). Donor age was 29.7 +/- 5.6 years (range 16-49). The immunosuppressive regimen included cyclosporin A, azathioprine, steroids and rabbit antithymocyte globulin. Excellent graft function was achieved. Six patients survived the postoperative period and are alive 4-18 months posttransplant. One patient died after the operation due to pneumonia with respiratory distress syndrome. Graft function was also monitored by transbronchial biopsy, and 57 biopsy procedures were performed without fatal complications. Acute cellular rejection was seen in 16 biopsy specimens from 5 recipients (grade 1 and 2 rejection in 14, grade 3 rejection in 2). Neither severe rejection with septal necrosis (grade 4) nor obliterative bronchiolitis was seen. The rejection rate was 0.03 episodes per patient/month. In contrast to other reports, episodes of cellular rejection occurred throughout the observation period, and were not mainly limited to the first 4 months posttransplant. Graft vascular occlusive disease or chronic vascular rejection was found in 6 biopsy specimens from one recipient. Five patients experienced 7 episodes of cytomegalovirus infection. The cytomegalovirus infection rate was 0.01 episodes per patient/month. The incidence of infection was significantly lower compared to previous studies of rejection in other lung graft combinations. Both infections and rejection episodes may contribute to the development of obliterative bronchiolitis. Almost one third of the specimens (30%) showed lymphocytic bronchitis without perivascular inflammation. The absence of perivascular infiltrates and exclusion of infectious agents leaves in question the aetiology of this inflammation. The lymphocytic bronchitis could be ischaemic, related to aspiration, or represent recurrent sarcoidosis, or, in fact, express bronchial rejection. All biopsy specimens regarded as rejection with cellular infiltrates in the lung parenchyma also showed a lymphocytic bronchitis. The impact of HLA mismatch on cellular and vascular rejection is unclear. Transbronchial biopsy is a reasonably safe and reliable method in the diagnosis of rejection and infection in single lung transplantation.

Some observations on cerebral perfusion during cardiopulmonary bypass.

Blood flow was recorded with an electromagnetic flow probe on one internal carotid artery (ICA) during cardiopulmonary bypass (CPB) in 5 patients. The ICA flow was monitored continuously along with arterial blood pressure, epidural intracranial pressure, and cerebral electrical activity using a cerebral function monitor (3 patients). The ICA flow increased by 50 to 100% at the inception of extracorporeal circulation. This rapid enhancement of flow occurred within a thirty-second period and was due to rapid arterial hemodilution caused by introduction of the priming solution. A transitory fall in ICA flow was observed during subsequent minutes when the well-recognized drop in blood pressure took place and the cerebral perfusion pressure (CPP = blood pressure - epidural intracranial pressure) was reduced to less than 30 mm Hg. In only one instance, however, when CPP fell to 15 mm Hg, was the fall in flow lower than the prebypass level. Throughout the rest of CPB, with steady-state hemodilution and CPP levels in the range of 30 to 50 mm Hg, ICA flow was markedly enhanced (50 to 100% above the prebypass level). The flow pattern, however, disclosed a pressure-passive system, indicating that cerebral autoregulation was impaired or that the CPP levels were lower than the individual lower limit of cerebral autoregulation during the period of steady-state hemodilution on CPB. A transient depression of cerebral electrical activity was seen in 2 patients shortly after the introduction of CPB. This phenomenon is suggestive of qualitatively insufficient perfusion and was observed even when ICA bulk flow was increased (hematocrit values, 13 to 17%).

Cerebral carbon dioxide reactivity during nonpulsatile cardiopulmonary bypass.

Five patients undergoing extensive cerebral monitoring during cardiopulmonary bypass (CPB) procedures were subjected to studies on cerebral CO2 reactivity during nonpulsatile CPB. The cerebral monitoring included recording of arterial blood pressure (BP), central venous pressure (CVP), epidural intracranial pressure (EDP), cerebral electrical activity by a cerebral function monitor (CFM), and middle cerebral artery (MCA) flow velocity by transcranial Doppler technique. The cerebral perfusion pressure (CPP) was thus continuously recorded (CPP = BP - EDP). During steady-state CPB with constant hematocrit, temperature, and arterial carbon dioxide tension (PaCO2), MCA flow velocity varied with changing CPP in a pressure-passive manner, indicating that the cerebral autoregulation was not operative. During moderately hypothermic (28 to 32 degrees C), nonpulsatile CPB, with steady-state hematocrit, temperature, and pump flow, we deliberately and rapidly changed PaCO2 for periods of 1 or 2 minutes by increasing gas flow to the membrane oxygenator, thereby testing the cerebral CO2 reactivity. Nineteen CO2 reactivity tests, performed at CPP levels ranging from 17 to 75 mm Hg, disclosed that the cerebral CO2 reactivity decreased with CPP, especially with CPP levels below 35 mm Hg. In these patients, concomitant changes in CPP during the CO2 reactivity test could be compensated for by adjusting the observed change in MCA flow velocity. The corrected CO2 reactivity values obtained in this way ranged from below 1.0 (observed at CPP levels below 20 mm Hg) to a 3.0 to 4.5% X mm Hg-1 change in PaCO2 (observed at CPP levels above 35 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Dissociation between cerebral autoregulation and carbon dioxide reactivity during nonpulsatile cardiopulmonary bypass.

Five patients undergoing cardiopulmonary bypass (CPB) procedures were extensively monitored because of anticipated high risk for neurological complications. Arterial blood pressure (BP), central venous pressure, and epidural intracranial pressure (EDP) were continuously recorded throughout CPB; thus, information on the cerebral perfusion pressure (CPP) was also continuously available (CPP = BP - EDP). Cerebral electrical activity was recorded by a cerebral function monitor. The flow velocity in the middle cerebral artery (MCA) was recorded using a transcranial Doppler technique. During steady-state CPB (constant hematocrit, constant temperature, and constant flow from the heart-lung machine) partial pressure of arterial carbon dioxide (PaCO2) was repeatedly changed to study the effect of changes in this variable on MCA flow velocity during nonpulsatile bypass. During CPB with constant temperature, hematocrit, and PaCO2, the effect of changes in CPP on MCA flow velocity was recorded and analyzed. During nonpulsatile, moderately hypothermic (28 degrees to 32 degrees C), low-flow (1.5 L/min/m2) CPB, there was no evidence of cerebral autoregulation, with CPP levels ranging from 20 to 60 mm Hg. The CO2 reactivity, however, was clearly present and in the range of 1.9 to 4.1%/mm Hg, indicating that there was a dissociation between cerebral autoregulation and CO2 reactivity under these circumstances.

The CarboMedics valve: midterm follow-up with analysis of risk factors.

BACKGROUND: This study examined the midterm results with the CarboMedics prosthetic valve. METHODS: From 1987 through 1991 a total of 569 patients received the CarboMedics prosthesis. RESULTS: Early mortality was 4.9% and related to emergency operation, presence of diabetes mellitus, coronary artery disease, preoperative New York Heart Association class, duration of cardiopulmonary bypass, and aortic cross-clamp time. Midterm follow-up with respect to mortality was 100% complete. All patients were followed up in the hospital after 1 year. In addition 86% of the patients responded to a questionnaire. Mean follow-up was 3 years (range, 0 to 5.6 years). Cumulative survival at 1 and 4 years was 91.2% +/- 1.2% and 83.7% +/- 1.8%, respectively. Five patients experienced obstructive valve thrombosis (0.3%/patient-year), 16 patients had major thromboembolic events (0.9%/patient-year), and 10 patients had major warfarin-related bleeding (0.6%/patient-year) requiring hospitalization or blood transfusions. Eight patients were reoperated on for paraprosthetic leak (0.4%/patient-year). Prosthetic valve endocarditis developed in 4 patients (0.2%/patient-year). No structural valve failure was observed. CONCLUSIONS: Midterm follow-up demonstrates that the CarboMedics mechanical prosthesis is reliable and has an acceptable rate of valve-related complications.

Cerebral perfusion during nonpulsatile cardiopulmonary bypass.

The recording of middle cerebral artery (MCA) flow velocity by the transcranial Doppler method offers a new, noninvasive, continuous technique for studies of cerebral circulation. Comparative studies of electromagnetic internal carotid artery (ICA) flowmetry and MCA flow velocity by the transcranial Doppler technique have demonstrated that observed changes in MCA flow velocities reflect concomitant changes in cerebral circulation. Eleven high-risk patients undergoing cardiopulmonary bypass (CPB) procedures were included in a pilot study. Arterial blood pressure (BP), central venous pressure, and epidural intracranial pressure (EDP) were recorded during CPB. Cerebral electrical activity was recorded by a cerebral function monitor. Flow velocity in the MCA was increased during nonpulsatile CPB in 10 of the 11 patients. This increase was related to the degree of hemodilution, and the flow velocity during steady-state CPB was 80 to 300% of the prebypass value. The MCA flow velocity changed, however, in a pressure-passive manner with the cerebral perfusion pressure (CPP = BP - EDP) in the individual patient, which indicates that cerebral autoregulation was not operative. During the first 15 minutes after termination of bypass, the MCA flow velocity was reduced, but remained higher than the prebypass level, 110 to 210% of the level during the last 5 minutes preceding CPB.

Experiences with closed chest, temporary atrio-arterial, ventricular bypass with a centrifugal pump after open heart surgery.

Twelve patients with refractory myocardial failure following open heart surgery were treated with a temporary left (10), right (1) or biventricular (1) assist circuits driven by extracorporeal pumps. Ten of 11 patients were weaned from the pump oxygenator. During left ventricular assist, maximal pump flow was 2.2 +/- 0.6 l/min per m2 at a cardiac index of 2.5 +/- 0.9 l/min per m2. Diuresis was above 1 ml/kg body weight per h in 7 of 9 patients perfused for 13-36 h. Seven patients were weaned from the assist pump after 13-33 h of ventricular bypass with 4 hospital survivors. Two patients died after circulatory assistance of multiple organ failure, 1 from cerebral damage. In the other patients, the main problems were cardiac. Three patients are currently long term survivors 12-17 months after surgery.

Risk factors for total and cause-specific mortality in human cardiac transplantation. Prolonged extracorporeal bypass time: a high risk factor for rejection and infection.

Data from the first 103 human heart transplantations in 100 recipients performed at a single centre from November 1983 to January 1990 were analysed to detect risk factors for overall and cause-specific mortality. Twenty-two patients died. Cumulative 1 year graft survival was 82% and 5 year, 68%. Acute and chronic rejection was the cause of death in 9 patients, disseminated infection in 8 and cancer in 3. One patient died from cerebral haemorrhage and 1 from acute cardiac failure. The mean observation time was 803 days (range: 1-2 308 days). Total follow-up was 226.6 graft years. Risk factors were analysed by univariate and multivariate methods. The type of immunosuppression regimen and recipient age above 50 years were independent risk factors for mortality. Histocompatibility mismatching (HLA-DR) and type of immunosuppression were independent risk factors for lethal rejection and a female recipient was an independent risk factor for lethal infection. Prolonged time on extracorporeal bypass was an independent risk factor for both lethal rejection and infection, and also for overall mortality. The impact of extracorporeal bypass time on rejection and infection is discussed, and the importance of prospective HLA matching in heart transplantation is stressed. The association between recipient female sex and infection remains uncertain.

Complete replacement of the ascending aorta and the aortic valve with coronary reimplantation.

In 6 patients with cystic medial necrosis of the ascending aorta and the aortic root complete elective replacement of these structures with coronary reimplantation was performed. Two patients died from postoperative left ventricular failure, 4 patients survived and were hemodynamically unaffected at follow-up. Also the heart size in these patients decreased postoperatively. Survival seemed mainly related to the degree of preoperative cardiac failure and cardiomegaly.