Mechanisms of bone loss after cardiac transplantation.

To determine the mechanism of bone loss after cardiac transplantation (CTX), we studied 50 men 0.5-47 months after CTX (ages 18-64 years) who received prednisolone and cyclosporin to prevent rejection, and 40 healthy men as controls (ages 20-70 years). We measured bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA), bone resorption using urinary cross-linked N-terminal telopepides of type I collagen (NTx), and bone formation using osteocalcin (BGP) and bone alkaline phosphatase (BAP). The results from the controls were used to calculate z scores. BMD was significantly decreased at the lumbar spine, femoral neck, and total body, and bone turnover was significantly increased as assessed by NTx/creatinine, BGP, and BAP as compared with controls (p < 0.01 for all measurements). To evaluate the cause of the increased bone turnover we measured serum parathyroid hormone (PTH) by IRMA, and this was also elevated (p < 0.001). There was a significant correlation between serum PTH and BGP (r = 0.58, p < 0.01). To evaluate the cause of the increase in PTH, we measured serum calcium and it was decreased (p < 0.001), serum phosphorus was increased (p < 0.001), serum creatinine was increased (p < 0.001), and serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D, RIA] was decreased (p = 0.03). Serum PTH correlated weakly with serum calcium (r = -0.41, p < 0.003) and with serum creatinine (r = 0.35, p = 0.01). There was a weak, but significant, correlation between serum creatinine and 1,25(OH)2D3 (r = 0.33, p = 0.03). Serum levels of testosterone and dehydroapiandrosterone sulfate were decreased after CTX but did not correlate with any other parameters. There was a weak negative correlation between prednisolone daily dose and serum BGP level (r = 0.29, p = 0.06) in those patients whose prednisolone current dose was >7.5 mg/day. We conclude that: (1) the low BMD found after CTX is associated with increased bone turnover which results, in turn, from renal impairment; (2) prednisolone is involved in rapid bone loss, whereas mild secondary hyperparathyroidism may be a major contributor to disorder of bone remodeling after this rapid loss; and (3) decreased androgen levels may not be a major factor resulting in bone loss in men after CTX.

Pathology of surgically excised primary cardiac tumors.

Between 1957 and March 1991, 106 patients with 110 neoplasms that originated in the heart were treated surgically at the Mayo Clinic and had pathologic material available for review. The study group consisted of 39 male and 67 female patients, who ranged in age from 2 to 80 years. Benign atrial myxomas (64 in the left atrium and 16 in the right atrium) were the most commonly encountered neoplasm. The other benign tumors were nine fibromas, five lipomatous tumors, seven valvular fibroelastic papillomas, and one cardiac hamartoma (so-called oncocytic cardiomyopathy). In addition, eight patients had a primary cardiac malignant lesion: angiosarcoma, leiomyosarcoma, and malignant fibrous histiocytoma in two patients each and sarcoma (not otherwise specified) and osteogenic sarcoma in one patient each. The angiosarcomas originated in the right atrium, and the other malignant tumors originated in the left atrium. The histologic feature that most frequently predicted an adverse clinical outcome was the presence of mitotic figures, although highly cellular tumors and those with necrosis also tended to have a malignant course.

Preservation of the lung. Comparison of topical cooling and cold crystalloid pulmonary perfusion.

Topical cooling of the lung was compared with cold crystalloid pulmonary artery perfusion with modified Euro-Collins solution in a canine model of unilateral left lung allotransplantation with ligation of the recipient's contralateral pulmonary artery and main bronchus. Lung preservation for 6 hours was achieved by topical cooling and storage at 4 degrees C after absorption atelectasis in five dogs and in a further five dogs by pulmonary arterial perfusion of Euro-Collins solution; 60 ml/kg at 4 degrees C, modified with MgSO4 6 mmol/L followed by storage at 4 degrees C. Dogs in the perfusion group were pretreated with an infusion of the synthetic analog of prostaglandin I2, iloprost (20 ng/kg/min). The ischemic times were 5.97 hours +/- 0.09 for the topical cooling group and 5.96 hours +/- 0.04 for the perfusion group. After transplantation, artificial ventilation at a fixed oxygen concentration was continued until the recipient's death or elective termination of the experiment at 24 hours. Assessment of pulmonary preservation was by animal survival, blood gas analyses, and measurement of lung weight and water in the transplanted lung. No animal in the topical cooling group survived more than 5.5 hours after transplantation; all perfusion recipients survived 24 hours. Oxygenation in the topical cooling group was significantly reduced 1 hour after contralateral ligation: Oxygen tension was 224.2 mm Hg +/- 5.8 before ligation and 92.6 mm Hg +/- 22.3 after ligation (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Preservation of the lung: comparison of flush perfusion with cold modified blood and core cooling by cardiopulmonary bypass.

Clinically applied techniques for lung preservation of flush perfusion with cold modified blood and core cooling by means of cardiopulmonary bypass were compared in a canine model of single left lung transplantation with immediate ligation of the contralateral bronchus and pulmonary artery. In the cold modified blood group (n = 5), after pretreatment with the synthetic prostacyclin analogue iloprost (20 ng/kg/min), lung preservation was achieved by pulmonary artery perfusion with a solution of autologous donor blood, albumin, and mannitol. In the cardiopulmonary bypass group (n = 7), donors were cooled to an esophageal temperature of 10 degrees C before harvest of the heart-lung bloc. Donor organs were stored at 4 degrees C for 6 hours. After transplantation, artificial ventilation at a fixed oxygen concentration was continued until death or until animals were killed at 24 hours. Assessment of lung preservation was by recipient survival, blood gas analyses, and measurement of total lung water content. All cold modified blood recipients survived for 24 hours; four of seven bypass recipients died within 7 hours of operation. There was no change in oxygenation in the cold modified blood group at 1 hour after contralateral ligation: paO2, 212.2 mm Hg +/- 8.5 preligation; 227.2 mm Hg +/- 11.5 postligation. Oxygenation in the bypass group was reduced at 1 hour (paO2, 182.6 +/- 7.6 mm Hg preligation; 139.8 +/- 32.1 mm Hg postligation), but the difference did not reach statistical significance. The difference between groups at 1 hour was significant (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Revision of the 1990 working formulation for cardiac allograft rejection: the Sheffield experience.

OBJECTIVE: To audit the 1990 International Society for Heart and Lung Transplantation cardiac rejection criteria and to evaluate the impact on classification and clinical outcomes of a modification in which grade 2 is abolished and grades 1A and 1B are amalgamated into a single "grade 1." METHODS: 1652 heart biopsies were reviewed over a four year period. The initial 1348 biopsies (group 1), using the original 1990 criteria, were analysed in terms of diagnostic grade and compared with the 304 biopsies analysed with the modified scheme (group 2). Differences in grading with the 1990 scheme were compared between two groups (1.1 and 1.2) reflecting early and late experience with grading. Subsequently all the grade 2 and grade 1B biopsies were rescored in terms of the modified scheme. Clinical results in terms of actuarial patient survival at one year and freedom from 3A rejection were similarly audited. RESULTS: The relative ratios of potentially significant rejection (grade 3A, 3B, 4) remained constant over the entire study in groups 1.1, 1.2, and 2. A 50% reduction in grade 2 biopsy reporting was noted comparing early and late parts of group 1. At subsequent review of the group 1 grade 2 biopsies, 97% could be reassigned to grades 0 or 1 in the modified scheme, with the majority of these diagnoses reflecting Quility effect/biopsy site reactions. Two cases (3%) of the 77 grade 2 biopsies were regraded as grade 3A rejection, with both occurring within three months of transplantation. None of the grade 1B biopsies had high grade cardiac rejection on review, most of these biopsies similarly showing pronounced Quility effect and biopsy site reactions. Actuarial survival at one year rose from 86% to 90% during the study, with freedom from 3A rejection remaining unchanged at 80%. CONCLUSIONS: The original working formulation produces consistent grading except at grade 2, which is judged to be a misnomer resulting from Quility effect and other non-rejection phenomena. While acceptable standardisation can be achieved with the 1990 scheme, the modified scheme has advantages in that it appears to encourage clear discrimination between significant and non-significant cardiac rejection. Overall, elimination of grade 2 did not produce an increase in higher grades of cardiac rejection, and thus the value of this diagnostic grade is questioned.

Distension reduces the vasoreactivity of the internal mammary artery.

Although the vasoreactivity of internal mammary artery grafts is beneficial in the long term, after mobilisation, vasospasm reduces flow through the vessel. This may be overcome and flow improved by distension. To assess the effects of distension on the vasoreactivity of the artery we have measured changes in isometric tension in rings of distended and undistended human internal mammary artery. For an equivalent wall tension, the diameter of the distended artery was 1922 microns (CL 1858 to 1986) and undistended 1684 microns (CL 1628 to 1739), (P < 0.001). In response to 25 mM potassium the increase in isometric tension, as a percent of resting tension, was 35% (CL 31 to 39) in undistended and 5% (CL 3 to 6) in distended segments (P < 0.001), with 10 microM noradrenaline increases were 57% (CL 47 to 66) and 3% (CL 2 to 5), respectively (P < 0.001). The reduction in developed tension in segments contracted with potassium and relaxed with 1 microM acetylcholine was 65% (CL 47 to 83) in undistended, and 15% (CL -1 to 32) in distended (P < 0.01). With 10 microM glyceryl trinitrate relaxation was 96% (CL 87 to 105) and 17% (CL -9 to 43), respectively (P < 0.01). Similarly, after contraction by noradrenaline, with acetylcholine, undistended segments relaxed by 50% (CL 44 to 55) and distended by 14% (CL 8 to 21) (P < 0.01), with glyceryl trinitrate relaxation was 90% (CL 80 to 99) and 7% (CL -4 to 19), respectively (P < 0.001). Distension produces a profound reduction in vasoreactivity of the internal mammary artery which is not due to endothelial damage alone.

Long-term anaesthesia with alfentanil and midazolam for lung transplantation in the dog.

An anaesthetic regime was developed for lung transplantation in the dog using a continuous infusion of alfentanil and midazolam. This combination of agents provided excellent analgesia and also produced loss of consciousness. Cardiovascular stability was well maintained over a 24-h period of anaesthesia following lung transplantation. Although no animals were allowed to recover from anaesthesia in the present series, the regime described is likely to be suitable for recovery anaesthesia, particularly since both of the agents used can be reversed with specific antagonists.

Use of milrinone in cardiac surgical patients.

Milrinone is shown in 10 patients to be a valuable pharmacological bridge to heart transplantation; it can stabilize and improve decompensated chronic heart failure (CHF) in cases where the response to beta-agonists is inadequate. One patient who had suffered an acute myocardial infarction with heart failure resistant to vasodilators, beta-agonists, and balloon counterpulsation was stabilized with milrinone for 21 days. He was then maintained on ACE inhibitors until heart transplantation 3 months later. The other nine patients with severe decompensated CHF were stabilized on milrinone for between 11 and 51 days. Seven of them received a donor heart. Two patients died of bacteremic shock and terminal heart failure before a suitable organ could be found (31 and 51 days). All patients were clinically improved within 48 hours of the addition of IV milrinone to their therapy. In 55 patients following cardiac surgery, the efficacy and safety of milrinone in the treatment of low cardiac output states is demonstrated. Milrinone has a useful role in the management of patients with circulatory failure both before and after cardiac surgery, and this paper reviews the relevant current literature.

Coronary artery-right ventricular fistula after endomyocardial biopsy.

A coronary artery-right ventricular fistula developed after endomyocardial biopsy in a recipient of an orthotopic cardiac transplant.

Pulmonary "cyclosporinoma" mimicking infection after heart transplantation.

Tissue from a transthoracic needle biopsy, which was performed as part of the investigation of an undiagnosed left upper lobe opacity in a patient after orthotopic heart transplantation, revealed numerous macrophages loaded with oil globules. No causative organisms were present. High-pressure liquid chromatography showed a similar profile to the oil in which cyclosporine is suspended. The lesion appears to have been caused by aspiration of cyclosporine.

Successful treatment with trisodium phosphonoformate for primary cytomegalovirus infection after heart transplantation.

Primary cytomegalovirus infection in the patient who is receiving immunosuppression therapy is associated with a high morbidity and mortality. We report a patient who developed primary cytomegalovirus infection 37 days after heart transplantation with a rapidly deteriorating course. Treatment with the new antiviral drug trisodium phosphonoformate (Foscarnet-Astra) was initiated as a lifesaving measure with rapid, dramatic improvement in the patient's condition and subsequent recovery.

Myocardial ischaemia during tracheal extubation in patients after cardiac surgery: an observational study.

This study examines whether there is a temporal relationship between tracheal extubation and myocardial ischaemia in haemodynamically stable patients extubated within 6 h of cardiac surgery. Fifty-two patients were studied during three time periods: 1, from 2 h until 30 min before extubation (90 min); 2, from 30 min before until 30 min after extubation (60 min); 3, from 30 min until 2 h after extubation (90 min). Significant ST segment changes were defined as a reversible ST segment depression of 2 mm or greater or an elevation of 3 mm or greater from baseline, lasting for 1 min or more. Fourteen patients (26.9%) had ST segment changes. The ischaemic burden in periods 2 and 3 was increased compared with that in period 1; the mean (SD) was: period 1, 19.2 (18.8) min; period 2, 35.4 (24.9) min; period 3, 39.6 (24.5) min; however, the mean ST deviation (mm) did not change. ST segment changes were associated with an increased heart rate; they were not related to arterial pressure. We conclude that there is a temporal relationship between ST segment changes and tracheal extubation after cardiac surgery.

Comparison of cold flush perfusion with modified blood versus modified Euro-Collins solution for lung preservation.

Single flush perfusion of the lung represents one concept of pulmonary preservation that has provided satisfactory results in both experimental and clinical situations. The technique has allowed successful distant organ procurement, with consequent enlargement of the available donor pool. Both cold modified blood (CMB) and modified Euro-Collins solution (ECS) are currently used as perfusates, although the volumes of each used clinically are different. CMB is administered at 20 ml/kg and ECS at 60 ml/kg. Both techniques combine the use of a prostaglandin to enhance preservation. In this study these two perfusion techniques were compared in a canine model of unilateral left lung allotransplantation after 6 hours of storage, with subsequent ligation of the recipient's contralateral pulmonary artery and bronchus. Equal volumes of both solutions were used (20 ml/kg) to determine whether the blood vehicle was necessary to provide good preservation at this volume. Assessment of pulmonary preservation was determined by animal survival, blood gas analyses, hemodynamic values, and measurement of lung water content. All animals survived the 24-hour experimental period in stable condition. Postoperative oxygenation was well maintained at control values throughout this period with no significant difference between groups. The pulmonary vascular resistance index was significantly higher in the CMB group at 1 hour (p less than 0.05). Lung compliance, assessed by peak-inspiratory pressure, was impaired to a greater extent in the CMB group than in the ECS animals (p less than 0.01 at 12 and 24 hours).(ABSTRACT TRUNCATED AT 250 WORDS)

Rib cage mechanics after median sternotomy.

A substantial reduction in lung volumes occurs after sternotomy, but the mechanism or mechanisms are unclear. Measurements were made of lung volumes and of chest wall motion with four pairs of magnetometers (two pairs for anteroposterior rib cage, one for lateral rib cage, and one for anteroposterior abdominal dimensions) in 16 men before and one week and three months after coronary artery grafting. Reductions in all lung volumes occurred after sternotomy and were greater in the supine than in the sitting position. Supine vital capacity was reduced one week after surgery, with almost complete recovery at three months. One week after sternotomy there was a significant reduction in tidal volume from a mean (95% confidence limits) value of 0.88 (0.76-1.00) litre to 0.61 (0.52-0.70) l, and in supine rib cage displacement from 3.87 (1.96-5.78) mm to 0.44 (-0.61-1.49) mm in the lateral plane. Respiratory frequency increased from 16 (13-19) to 21 (19-24)/min. Coordination of the rib cage was assessed by measuring the difference in timing of onset of chest wall motion and airflow in four planes. At one week nine of 14 patients showed uncoordination between airflow and rib cage motion in one or more dimensions, and this was still present in three patients at three months. No loss of the temporal relation between airflow and abdominal wall motion was detected. The results suggest that reduced and uncoordinated rib cage expansion contributes to the restrictive ventilatory defect that follows median sternotomy.

The value of the electrocardiogram in the diagnosis of acute rejection after orthotopic heart transplantation.

The value of a change in summated electrocardiographic voltage as a predictor of cardiac rejection is uncertain in patients treated with low-dose triple immunotherapy (cyclosporin, azathioprine, and corticosteroids) following orthotopic cardiac transplantation. Ten recipients were studied daily and the summated QRS voltages from 600 electrocardiograms were calculated. A single observer graded 147 endomyocardial biopsies. During the study period there were 18 episodes of acute rejection with myocyte necrosis. Only three episodes of rejection were heralded by a significant change in QRS voltage, yielding a positive predictive value of 13% for the technique. Three episodes of severe bacterial infection were preceded by significant decreases in QRS voltage. In one patient with a global pericardial effusion, QRS voltage was related to the depth of effusion measured by echocardiography. These data show that QRS voltage is of extremely limited value in the prediction of cardiac rejection in patients treated with low-dose triple immunotherapy.