Biomedical subjects
Publications and source records attributed to C D Fraser.
We describe our results with cervical esophagoesophageal anastomosis. This approach has been used with success in 4 patients. It has the advantage of avoiding esophagectomy in patients with benign disease and allows restoration of esophageal continuity in patients having limited options for esophageal replacement.
Neurological side effects associated with cyclosporine immunosuppressive therapy are generally believed to occur with CsA blood concentrations above the therapeutic range. The effects of high blood CsA levels on cerebral hemodynamics, metabolism, and electrophysiologic activity were studied in acute (no CsA prior treatment) and chronic (with CsA prior treatment) dogs. In acute animals, when parenteral CsA (10 mg/kg or 25 mg/kg) was administered intravenously (CsA blood level 2000-22,000 ng/ml), slight but significant time-dependent decreases in cerebral blood flow (CBF), prolongation of absolute latencies of somatosensory-evoked potential (SSEP), and brainstem auditory-evoked responses (BAER) were noted. In the CsA chronically administered animals (oral CsA 25 mg/kg/24 hr for 14 days, CsA blood level 1077 ng/ml), baseline cerebral physiologic parameters were normal, and the cerebral responses to further administration of CsA (25 mg/kg, CSA blood level 56,000 ng/ml) intravenously were similar to those of the acute animals. Animals given Cremophor EL, the solvent for parenteral CsA preparation, showed similar cerebral responses to those observed in animals given CsA. Thus this study showed that CsA, regardless of the dose given, whether chronically or acutely administered, or the solvent for CsA all induced similar cerebral physiologic responses. We suggest that the cerebral physiologic and functional changes associated with parenteral CsA administration were small and were likely caused by its solvent, Cremophor EL, rather than CsA itself. Furthermore on the basis of our results, it is unlikely that high blood CsA per se can account for neurological side effects that occur in immunosuppressed patients.
We investigated the acute and chronic effects of left lung autotransplantation (LLA) on the left pulmonary vascular pressure-flow (LP/Q) relationship in conscious dogs. Continuous LP/Q plots were generated in chronically instrumented conscious dogs 2 days, 2 wk, 1 mo, and 2 mo after LLA. Identically instrumented normal conscious dogs were studied at equal time points post-surgery. LLA had little or no effect on baseline systemic hemodynamics or blood gases. In contrast, compared with normal conscious dogs, striking active flow-independent pulmonary vasoconstriction was observed 2 days post-LLA. The slope of the LP/Q relationship was increased from a normal value of 0.275 +/- 0.021 to 0.699 +/- 0.137 mmHg.ml-1.min-1.kg-1 2 days post-LLA. Pulmonary vasoconstriction of similar magnitude was also observed on a chronic basis at 2 wk, 1 mo, and even 2 mo post-LLA. Pulmonary vasoconstriction post-LLA was not due to fixed resistance at the left pulmonary arterial or venous anastomotic sites. Finally, systemic arterial blood gases were unchanged when total pulmonary blood flow was directed to exclusively perfuse the transplanted left lung. Thus, LLA results in both acute and chronic pulmonary vasoconstriction in conscious dogs. LLA should serve as a useful stable experimental model to assess the specific effects of surgical transplantation on pulmonary vascular regulation.
Numerous techniques have been devised for the harvesting of individual organs during a multiorgan procurement operation. Cardiopulmonary bypass with profound hypothermia (PH) has been employed in successful harvesting of heart-lung, kidney, pancreas, and liver grafts. This report summarizes our experience using CPB-PH for the harvesting of multiple organs from 10 brain-dead donors during the period from July 1983 to January 1988. Organs harvested included 10 heart-lungs, 17 kidneys (3 kidneys were not harvested due to anatomy and elevated creatinine), 1 liver, and 1 pancreas. Mean ischemic time for the distantly procured heart-lung grafts was 281 +/- 10 min. Adequate pulmonary function, as assessed by arterial blood gases, was observed in each heart-lung recipient (mean PO2 was 119 +/- 46 mmHg, 164 +/- 47 mmHg, 130 +/- 30 mmHg, 114 +/- 26 mmHg at immediate post-CPB, 6 hr postop, 24 hr postop, and postextubation, respectively). Mean length of intubation was 34 +/- 8 hr. Mean creatinines of kidney recipients at days 2, 7, and current creatinine were 7.4 +/- 3.6 mg%, 3.6 +/- 2.4 mg%, and 1.6 +/- 0.66 mg%, respectively. Eight kidney recipients (47%) required dialysis, (2 patients required only a single dialysis). Ninety-four percent of the kidney transplant patients are alive, and 88% (15/17) have functioning kidneys. One liver and 1 pancreas were harvested during this time period. Preservation was satisfactory in both the pancreas (Johns Hopkins Hospital) and liver (Dr. Thomas Starzl, personal communication). The technique of CPB-PH has resulted in excellent function of heart-lung grafts. Follow-up of the transplanted kidneys, liver, and pancreas utilizing this technique shows equal or better function compared with standard techniques. This technique offers other advantages in addition to satisfactory multiorgan preservation. Placement of an unstable patient on CPB ensures adequate organ perfusion and allows for a gradual yet uniform cooling of all organ systems. Cooling to a core temperature of 10-15 degrees C requires 30 min, during which time preliminary intraabdominal and mediastinal dissection can be carried out. Following cessation of CPB and subsequent exsanguination, organs can be more easily dissected in a near-bloodless field. This technique does not preclude additional crystalloid organ flushing. Since multiorgan procurement occurs with virtually every donor, this technique may be the optimal method providing excellent preservation, ease of dissection, and better control of hemodynamics during the operation.
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Twenty-three dairy calves underwent heart-lung allotransplantation after donor organs were procured using either donor core-cooling through cardiopulmonary bypass (CPB) or pulmonary artery flush (PAF) to assess which method provides optimal graft preservation. In Groups 1 (control) and 2, donors were cooled to 15 degrees C on CPB and organs were either immediately transplanted (Group 1) or stored in saline solution (4 degrees C) for 4 hours (Group 2) prior to transplantation. In Group 3, donors were pretreated with prostaglandin E1 prior to PAF with modified Euro-Collins solution. Organs were stored in saline solution (4 degrees C) for 4 hours and were then transplanted. Acute cardiopulmonary function following transplantation was assessed by the ratio of end-systolic pressure to end-systolic dimension, extravascular lung water (EVLW), lung compliance, arterial oxygenation, and lung biopsy. Cardiac function after the transplantation procedure was similar in all groups, but EVLW values and lung biopsy scores were worse after PAF. Arterial O2 tension appeared lower after PAF, but not significantly so. Core-cooling provides superior static preservation and thus improved graft function in the acute bovine model.
Eight beagles receiving heterotopic (cervical) cardiac allografts from outbred donors were evaluated by serial 31P NMR, septal endocardial biopsy, and left ventricular pressure measurements for signs of rejection. Early postoperative myocardial energy levels, as assessed by ratios of phosphocreatine to inorganic phosphate (PCr/Pi) and phosphocreatine to beta-ATP (PCr/B-ATP), were acceptable in all recipients. In these nonimmunosuppressed animals, the mean ratios of PCr/Pi and PCr/B-ATP progressively decreased, with a greater than 25% reduction noted by postoperative day two and greater than 50% reduction by day three. In sharp contrast, left ventricular end-diastolic pressures remained stable and at baseline levels for the first three postoperative days, and only then markedly increased. Likewise, histologic evidence of rejection did not become prominent until postoperative day four. These results suggest that metabolic abnormalities significantly precede either functional or histologic changes in rejecting allografts. The early detection of these metabolic changes by 31P NMR appears to have important potential for the noninvasive diagnosis of cardiac allograft rejection.
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To evaluate changes in coronary blood flow during allograft rejection, 16 beagles with cervical cardiac allografts from mongrel donors were immunosuppressed postoperatively for 7 days with cyclosporine (20 mg/kg orally) and prednisone (0.5 mg/kg orally). They were weaned from immunosuppression over 3 days and then treated with methylprednisolone (30 mg/kg/day IV), cyclosporine (20 mg/kg orally), and prednisone (0.5 mg/kg orally) for 4 days. Previous experiments with this model have suggested the utility of phosphorus 31 nuclear magnetic resonance spectroscopy (31P NMR) in the diagnosis of rejection. Therefore in 10 dogs (NMR group) bioenergetic changes during rejection were assessed using the 31P NMR index of the ratio of phosphocreatine to inorganic phosphate (PCr/Pi). To correlate coronary blood flow and graft ischemia with allograft rejection, six dogs (FLOW group) underwent placement of a magnetic flow probe on the left anterior descending coronary artery to determine mean and peak coronary flow. In both NMR and FLOW groups, grafts were evaluated by endomyocardial biopsy (grading 0 to 8 for increasing rejection), and measurement of lactate production and left ventricular end-diastolic pressure. During the initial 7 days of immunotherapy, cellular rejection was effectively suppressed, and the bioenergetic status of the grafts remained stable (day 7: PCr/Pi = 70% of baseline, biopsy score = 2.0). During weaning of immunotherapy, however, the metabolic profile of the grafts decayed (day 10: PCr/Pi = 45% of baseline, biopsy score = 5.8; p less than 0.05 vs day 0). After 4 days of augmented immunosuppression, PCr/Pi recovered to 83% of baseline; this metabolic recovery corresponded with an improvement in mean biopsy score to 3.2.(ABSTRACT TRUNCATED AT 250 WORDS)
The development of a noninvasive screening test for the detection of cardiac allograft rejection would improve the potential for management of heart transplant recipients. To assess the possibility that changes in myocardial high-energy phosphate metabolism precede frank rejection, 17 beagles received cervical cardiac allografts. Recipients underwent serial phosphorus 31 nuclear magnetic resonance spectroscopy, endocardial biopsy (blindly graded, 0 to 8), and left ventricular pressure measurements starting on the day of surgery. The first (less than 24 hours) spectrum was considered the baseline for all additional studies. The phosphocreatine to inorganic phosphate ratio (PCr/Pi), an index of myocardial bioenergetic supply/demand balance, was determined and expressed as a percentage of baseline of initial and all subsequent spectra. To evaluate the predictive utility of the PCr/Pi ratio, a 50% decrease from baseline was designated as a positive test and was correlated with biopsy-proved rejection (score greater than 3). When PCr/Pi values were compared with the subsequent day's biopsy score, we observed a 91% sensitivity, 90% specificity, and a predictive value of 92%. We conclude that the PCr/Pi ratio is sensitive in predicting heterotopic allograft rejection in its earliest stages. Thus phosphorus 31 nuclear magnetic resonance holds promise for clinical use in the noninvasive diagnosis and monitoring of cardiac rejection.
The effects of preserving the heart and lungs with an autoperfused working heart-lung preparation or simple hypothermia via cardiopulmonary bypass were studied in 18 dairy calves that had combined heart-lung transplantation. Group 1 (n = 6) served as the control group in which animals were cooled with cardiopulmonary bypass and immediately had allotransplantations. In group 2 (n = 6), cardiopulmonary function was maintained in the autoperfusion circuit for 4 hours, followed by transplantation. In group 3 (n = 6), the organs were harvested after cooling by cardiopulmonary bypass, stored in cold (4 degrees C) saline solution for 4 hours, and then transplanted. Cardiopulmonary function was compared between the three groups for 6 hours after implantation. Cardiac function was determined by the ratio of the end-systolic pressure to end-systolic dimension. Pulmonary function was evaluated by the measurement of extravascular lung water, arterial oxygenation on 100% inspired oxygen static lung compliance, and histologic lung injury score. All measurements in groups 2 and 3 were similar to those of the control group at 6 hours after implantation. One may use either the hypothermic cardiopulmonary preservation method after cardiopulmonary bypass or the autoperfused working heart-lung preparation for distant organ procurement and expect adequate cardiopulmonary function after transplantation.