Dynamics of soluble interleukin-2 receptor levels immediately after heart transplantation. Attenuation of increase by OKT3 therapy.

Quantification of T cell activation after cardiac transplant by measuring serum soluble interleukin 2 receptor levels daily may give insight into immunologic dynamics after cardiac allograft implantation. It was our hypothesis that this protein would demonstrate a characteristic rise after heart transplant not related to severe rejection that was distinct from a control group, and that this increase could be attenuated with OKT3 therapy. We measured soluble interleukin 2 receptor levels daily for two weeks in 26 patients undergoing orthotopic cardiac transplantation (19 receiving triple therapy immunosuppression with cyclosporine, azathioprine, and prednisone, and 7 with OKT3 added days 1 through 5). Interleukin-2 receptor levels for transplant patients were compared with 15 control subjects (14 undergoing bypass surgery and one valve replacement). Mean soluble interleukin-2 receptor level for the entire two-week period was higher for transplants versus controls; 839 +/- 31 U/ml vs. 504 +/- 20 U/ml (mean +/- SEM; P less than .05). Patients receiving OKT3 had a lower level (670 +/- 39 U/ml) than those not (902 +/- 36 U/ml, P less than .05) despite the fact that mean biopsy scores for the observation period were not significantly different. No significant rejection or infection episodes occurred in any patient. These results describe, for the first time, sequential changes in soluble interleukin 2 receptor levels early after heart transplant and demonstrate that the characteristic early rise can be attenuated with short-term OKT3 administration.

Blood-pool radionuclide angiography in patients with a Novacor left ventricular assist device.

Blood-pool radionuclide angiography was used to investigate the left ventricular function in eight patients who received a Novacor assist device as a bridge-to-cardiac transplantation. Studies were performed during maximal and minimal tolerated assist device flows. The left ventricular ejection fraction, volumes, cardiac output, and the pump ejection fraction were computer-assessed. All patients had severe left ventricular dilation and hypokinesis before insertion of the assist device, with a mean ejection fraction of 18% +/- 4% which improved to 44% +/- 18% (p less than 0.01) during maximal assist device flows, but fell to 25% +/- 15% (p less than 0.01) during minimal flows. The ventricular volumes became normal at maximal assist device flow but increased significantly (p less than 0.05) during minimal flow. The pump was well visualized and had an ejection fraction of 82% +/- 7%. These data indicate that this assist device effectively unloads the left ventricle. The deterioration in ejection fraction following decrease in assist device flow is in keeping with the dependency of these patients on the device to sustain adequate hemodynamics.

Insensitivity of noninvasive tests to detect coronary artery vasculopathy after heart transplant.

Obstructive coronary artery vasculopathy can be a major problem after cardiac transplant. The use of noninvasive tests to detect coronary artery vasculopathy was studied in 73 consecutive patients after heart transplant. Angiographically or autopsy-proved coronary artery disease was noted in 19 consecutive patients (26%) followed prospectively for 2.5 +/- 1.3 years (mean +/- standard deviation). Patients underwent yearly surveillance echocardiographic, rest/exercise-gated wall motion, oral dipyridamole thallium, ambulatory electrocardiographic monitor and angiographic studies. Positive test results were defined by decrease in ejection fraction, wall motion abnormality, failure to increase ejection fraction, lack of systolic blood pressure increase, and ischemic ST changes at maximal exercise (or on ambulatory monitor). Wall motion abnormalities and depressed ejection fraction on echocardiography were also abnormal studies as were fixed or reversible perfusion defects on thallium scan. Angiograms were considered positive when 50% luminal narrowing was observed and autopsy coronary artery vasculopathy was defined as cross-sectional coronary obstruction greater than or equal to 70%. No procedure that was examined proved to be a sensitive noninvasive detector of heart transplant coronary artery vasculopathy. All except ambulatory electrocardiographic monitoring had positive predictive values less than 50%. Interestingly, of the techniques evaluated, echocardiography was most sensitive (53%). The poor predictive ability of noninvasive testing in this population may be due to the fact that these tests are designed to detect effects of ischemia rather than coronary obstruction alone. Use of these particular noninvasive modalities routinely after heart transplant to detect coronary artery vasculopathy should be reconsidered because of their low sensitivity and predictive value when used as a surveillance screen.

Maximal expiratory flow patterns after single-lung transplantation in patients with and without chronic airways obstruction.

BACKGROUND: A biphasic-plateau pattern in the maximal expiratory flow-volume (MEFV) curve has been described after single-lung transplantation (SLT) in patients with chronic airways obstruction (CAO). It has been theorized that this pattern is either related to stenosis at the anastomotic or subanastomotic site, or the sum of the airflow contribution from the native lung with airways obstruction and transplanted lung. SUBJECTS AND METHODS: We analyzed data in 16 patients with CAO who had undergone transplantations (5 men, 11 women; mean age [+/- SD], 53.8 +/- 4.9 years), and 9 patients with pulmonary vascular disease (PVD) without airways obstruction who had undergone transplantations (2 men, 7 women; mean age, 35.4 +/- 11.4 years). RESULTS: In the patients with PVD, there were no significant changes in static or dynamic lung volumes or in the MEFV curve after SLT. In the patients with CAO, indexes of airways obstruction improved significantly after SLT, and the typical biphasic-plateau pattern developed in the MEFV curve. In one patient with CAO who required pneumonectomy of the native lung after SLT, the biphasic pattern was absent. CONCLUSIONS: These results support the view that this MEFV pattern is a result of airflow from the native and transplanted lungs in patients with CAO. In addition, the results show that in patients with no prior airways obstruction, SLT does not alter static or dynamic lung volumes or maximal expiratory flow rate.

Differential perfusion: potential complication of femoral-femoral bypass during single lung transplantation.

Single lung transplantation may be performed without pump oxygenation in the majority of patients. From April 1987 to August 1989, 3 of 12 patients undergoing single lung transplantation required pump oxygenation. One patient required pump oxygenation because of a marked drop in oxygen saturation during test clamping of the pulmonary artery; one patient was brought to the operating room while receiving extracorporeal membrane oxygenation; and one patient had such markedly elevated pulmonary artery pressures that pump oxygenation was used to lower pressure in the pulmonary circuit, allowing safe pulmonary artery clamping. These three patients had cannulas placed in the femoral vein and femoral artery. The latter two patients manifested marked upper body oxygen desaturation while maintaining excellent lower body oxygen saturation during their transplant procedures. Ventricular fibrillation, induced by alternating current, was used as a means to correct this differential perfusion. Should pump oxygenation be necessary during single lung transplantation, the region of the body adjacent to the arterial cannula may be perfused with oxygenated blood, and the remainder of the patient may be perfused with deoxygenated blood. Induced ventricular fibrillation is one method to correct this potentially fatal problem.

Induction immunotherapy in heart transplantation with T10B9.1A-31: a phase I study.

Cytolytic induction therapy of heart transplantation with OKT3 (immunoglobulin G2a isotype, anti CD3 idiotype) or T10B9.1A-31 (immunoglobulin MK isotype, anti-T-cell receptor alpha beta idiotype) was done in an open-label trial to determine the safety and efficacy of the latter monoclonal antibody. A total of nine patients undergoing orthotopic heart transplantation received a 10-day course of either T10B9.1A-31 (T10B9) (n = 4) 18 mg on bypass and 6 mg intravenously every 12 hours or OKT3 (n = 5) 10 mg on cardiopulmonary bypass and 5 mg intravenously daily. Endomyocardial biopsy surveillance revealed no rejection during induction therapy with T10B9, and one OKT3 induction failure was successfully treated with T10B9, all without significant side effects. T10B9 effectively prevented the onset of early acute rejection in heart transplantation with minimal side effects. T10B9 reversed rejection in one patient whose OKT3 induction failed. Results are encouraging and warrant further investigation.

Sudden death caused by bradycardia and asystole in a heart transplant patient with coronary arteriopathy.

The mechanism of death as a result of allograft ischemic heart disease is not well characterized. Ventricular tachycardia and fibrillation may not be the terminal events they often are in the general population. We report observations in a 41-year-old man with cardiac allograft arteriopathy who died suddenly while wearing an ambulatory monitor. The lethal rhythm was a progressive bradycardia terminating in asystole. Autopsy revealed epicardial and small vessel intramyocardial, coronary arteriopathy, and only mild allograft rejection. It is our belief that ischemia caused the bradycardic sudden death. We would like to hypothesize that prophylactic permanent pacemaker implantation may prevent bradycardic sudden death and improve survival in heart transplant patients with coronary disease.

Biliary surgery after cardiac transplantation.

Many patients have undergone successful cardiac transplantation. These patients are at risk of developing the same surgical diseases as the general population. The side effects of immunotherapy may mandate intervention at a different point in the natural history of these processes. From February 1984 through December 1989, 24 patients underwent an operative biliary tract procedure following cardiac transplantation. Seventeen patients underwent elective cholecystectomy with intraoperative cholangiography. The mean hospital stay was 5.4 days, and there was no morbidity or mortality. Seven patients underwent urgent procedures; four of them developed severe complications and three died as a result of their biliary tract disease. Two patients in the urgent group had previously exhibited symptoms of biliary tract disease, and five were previously asymptomatic. There was no significant difference in time from transplantation to biliary procedure between the elective group (mean, 17 months; range, 3 weeks to 47 months) and the urgent group (mean, 18 months; range, 3 weeks to 44 months). Patients who undergo cardiac transplantation should be screened for cholelithiasis. The presence of symptoms should not be required before recommending operative intervention.

Comparison of hemodynamics and ejection fraction during left heart bypass.

Temporary mechanical circulatory support during the postcardiotomy period has seen widespread application over the past 5 years. Recovery of sufficient cardiac function to allow removal of such support has usually been assessed by bedside hemodynamic variables during stepwise decrement of assist flows. To assess the efficacy of this approach and obtain prognostic information, 12 patients who required left heart bypass after coronary operations and who showed an indication of ventricular recovery, as evidenced by return of a pulsatile wave on arterial pressure tracing, were studied using blood pool radionuclide angiography during stepwise decrement of assisted flows. Hemodynamic variables (mean arterial pressure, heart rate, central venous pressure, pulmonary artery pressure, cardiac index, and systemic vascular resistance) did not correlate with survival during reduction of assist flows. Pulmonary artery pressure at maximum assisted flows and measured ejection fraction at flows of 60% or less of maximum flows correlated with survival; furthermore, if ejection fraction increased as assist flows were decreased, prognosis appeared excellent. Measurement of left ventricular ejection fraction during stepwise decrement of assisted flows in the postcardiotomy setting may provide valuable prognostic information and more clearly identify those patients who may be successfully separated from mechanical circulatory support.

Attenuation of waiting time mortality with heterotopic heart transplantation.

As the number of heart transplants and the number of transplant programs has increased, so has the waiting time for a suitable organ. To more accurately assess the magnitude of this increase and the influence of recipient size, we reviewed waiting times for large (body surface area greater than or equal to 1.95 m2) and small (body surface area less than 1.95 m2) patients with respect to era of transplantation. Patients who underwent transplantation early (1984 to December 31, 1986) waited 35 +/- 47 days (mean +/- standard deviation), whereas patients who underwent transplantation in the late era (1987 to September 30, 1989) waited 83 +/- 102 days (p = 0.001). Large patients waited longer (130 +/- 142 days) in the late era than did small patients (60 +/- 67 days; p = 0.008). During the heterotopic era (October 1, 1989 to June 30, 1990), waiting times for large patients who received a heterotopic transplant (67 +/- 46 days) were significantly shorter than those for patients who received an orthotopic transplant (166 +/- 157 days; p = 0.05). Waiting times for small patients remained unchanged. In addition, waiting time mortality decreased from 24% to 9% (p less than 0.05). Comparison of orthotopic and heterotopic procedures performed during the same era revealed no significant differences in recipient age, preoperative status, graft ischemic time, donor age, early and midterm survival, or early postoperative functional status. Heterotopic heart transplantation may effectively increase the size of the donor pool, decrease the waiting time, and decrease waiting time mortality without increasing the morbidity of the procedure.

Heterotopic heart transplantation and native heart ventricular arrhythmias.

Heterotopic heart transplantation has been said to be contraindicated in patients with serious native heart arrhythmias that produce hemodynamic instability. Placement of heterotopic allografts, however, can theoretically act as a biological biventricular assist device to provide hemodynamic support during these unstable rhythms. Further, this operation might beneficially alter the hemodynamic milieu of heart failure such that the arrhythmias are ameliorated. Described is our experience with 4 patients with heart failure receiving heterotopic cardiac allografts, documenting changes in native heart arrhythmia that occurred. These cases demonstrate that heterotopic grafts can adequately sustain hemodynamics during malignant native heart dysrhythmia. We believe native heart ventricular arrhythmias are not a contraindication to heterotopic heart transplantation.

Cardiac surgical procedures following myocardial infarction.

Advances in myocardial preservation have made possible operative intervention early post-myocardial infarction or in the face of an evolving myocardial infarction. Results are dictated by preoperative factors primarily related to the ravages of low flow state. Resuscitation of the myocardium is possible under the vast majority of circumstances.

Comparison of Delphin and BioMedicus pumps.

There is an increasing use of centrifugal pump systems for cardiopulmonary bypass (CPB) and circulatory assistance. The BioMedicus and Delphin centrifugal pump systems were tested in two side-by-side, identical in vitro flow loops for blood trauma and flow probe accuracy. Blood parameters tested were hemoglobin, hematocrit, lactate dehydrogenase, free plasma hemoglobin, and platelet counts. The Delphin pump demonstrated significant increases in plasma hemoglobin levels at the three flow rates tested: 2 L/min (p less than 0.05), 4 L/min (p less than 0.005), and 6 L/min (p less than 0.05). After 4 hr of pumping, the drop in platelet counts was significantly greater in the BioMedicus loop as compared with the Delphin loop (p less than 0.05) at the 2 L/min and 4 L/min flow rates; however, platelet levels remained within normal ranges in both systems. At 6 L/min, no statistical difference in platelet counts was noted. The flow probe readings were found to deviate by as much as 58% of stopwatch timed flow rate comparisons at low flow rates, but improved to within 10% or better at 6 L/min.

Effects of donor position on harvested lung quality.

Potential lung donors are frequently maintained in one position for prolonged periods of time prior to harvest. This study was designed to determine if the effects of gravity induced by maintaining an animal model in the supine position for 24 hr would have adverse effects on the harvested lung. Group 1 pigs were anesthetized, instrumented, mechanically ventilated, and the lungs harvested within 90 min. Group 2 pigs were anesthetized, instrumented, and mechanically ventilated in an identical manner then maintained in the same dorsal-spinal recumbency position for 24 hrs. Hemodynamic and respiratory parameters were stable and not statistically different between the two groups for the baseline and 1 hr time period measurements. There were no significant differences between the two groups for shunt fractions, wet/dry ratios, blood flow distribution, or flush solution distribution. We conclude that in anesthetized pigs there is no evidence that routine repositioning protocols improve blood flow distribution, shunting, or dependent edema.

Multi-organ procurement utilizing cardiopulmonary bypass and profound hypothermic circulatory arrest.

Despite advances in preservation solutions, hypothermia remains a critical component of organ preservation for transplantation. Many surgeons involved in multi-organ procurement procedures have expressed concern about the possible detrimental effects of cardiopulmonary bypass and profound hypothermic circulatory arrest on non-thoracic transplant organ function. In order to assess the validity of these concerns, a review of 20 multi-organ harvest procedures performed utilizing cardiopulmonary bypass and profound hypothermic circulatory arrest was undertaken. In all instances this technique was combined with organ flushing utilizing cold preservation solution. Adequate data was available to assess post-transplant organ function of all organs recovered in 16 procedures. Indication for the use of this technique was procurement of a heart-lung bloc in 16 instances and donor instability (hypotension) refractory to volume loading and inotropic agents in 4 instances. Organs obtained, including all organs from unstable donors which would otherwise have been lost, functioned, acceptably. Additionally, blood drained into the pump was used for recipient transfusion in 8 instances. This report documents that cardiopulmonary bypass and profound hypothermic circulatory arrest may be easily combined with traditional procurement flushing techniques and it provides excellent organ preservation for subsequent transplantation. This approach can optimize organ recovery from hemodynamically unstable donors, increasing the number available for transplantation.

Left ventricular function in patients with centrifugal left ventricular assist device.

We used blood pool radionuclide angiography to study the left ventricular (LV) ejection fraction (EF) in 17 patients with a centrifugal assist device (AD) placed because of severe postoperative LV dysfunction. During maximal LVAD flow, the 12 patients who could be weaned had a higher LV-EF than the 5 who could not be weaned (18 +/- 12% vs. 9 +/- 2%, p = 0.04). Sequential studies during variable AD flows in 12 patients revealed an increase in LV-EF from 15 +/- 7% at maximal flows to 33 +/- 8% during minimal flows (p less than 0.005) in the 10 patients who could be weaned and no change in LV-EF in 2 patients who could not be weaned. The LV-EF during maximal LVAD flow rates was similar in the 10 patients with long-term survival (192 +/- 129 days) and in the 7 patients with only short-term (9 +/- 6 days) survival (LV-EF 17 +/- 12% vs. 12 +/- 6%, p = ns). The long-term survivors, however, had a substantial increase in LV-EF from 20 +/- 13% to 34 +/- 9% (p less than 0.01), as the LVAD flow was decreased from maximal to minimal, whereas the short-term survivors had an insignificant increase in LV-EF from 12 +/- 7% to 21 +/- 12% (p = ns). The long-term survivors increased the LV-EF from maximal to minimal LVAD flows by 182%, in contrast with the short-term survivors, who increased the LV-EF by only 44%.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of an atraumatic small centrifugal pump for second-generation cardiopulmonary bypass.

A small and light direct-drive centrifugal pump has been developed for cardiopulmonary bypass. In the development process, blood compatibility studies including a hemolysis study, an in vitro fluid dynamic performance study, and in vivo durability and feasibility studies were performed. The centrifugal pump with a 50 mm diameter impeller resulted in almost the same index of hemolysis value as did a Bio-Medicus centrifugal pump. Heat dissipation from the motor was prevented by using a flexible drive cable. Forty-eight-hour sealing durability around the driving axis was accomplished by using a fluoro-rubber V-ring that connected to the hard chrome-plated stainless steel. In vitro and in vivo performances of the pump were satisfactory. Thrombus formation behind the impeller was prevented by using a holed impeller that generated blood flow from the back to the surface of the impeller. Elimination of air during priming procedures was also easier with this modification. This centrifugal pump has one-quarter of the priming volume, size, and weight of magnetically coupled centrifugal pump systems.

Implantable sensor for intraoperative and postoperative monitoring of blood flow: a preliminary report.

We have developed an implantable 20 MHz Doppler flow sensor, to monitor blood flow in patients after operation. During surgery the sensor is wrapped around a blood vessel and secured in place with a releasable tie. No tissue puncturing techniques are required. The lead wires, together with a release cable, are exteriorized through the chest wall. Several days after operation, the tie is externally released, and the sensor is pulled out. Twenty-seven sensors were implanted in 24 dogs for up to 16 days. All were extracted successfully with minimal visible behavioral reaction in the awake dogs and caused no thrombosis or vascular damage. The Doppler velocity signals had excellent linear correlations (r = 0.99) with data from electromagnetic flow sensors and timed blood collections. In addition, the sensors were applied to coronary artery bypass grafts in 31 patients for up to 2 days after operation. High-quality signals were obtained, and intraoperatively recorded signals agreed well with simultaneous electromagnetic flow tracings. All sensors were extracted with minimal discomfort to the awake patients and with no complications. Thus, the implantable flow sensor is a safe, reliable, accurate, and simple method for intraoperative and postoperative monitoring of blood flow in vessels 2.5 to 5 mm in diameter.

Intraoperative determination of mediastinal constraints for a total artificial heart.

The anatomic constraints to mediastinal fit of a total artificial heart (TAH) were largely neglected during the early developmental stages, precipitating failure due to compression or torsion of intrathoracic conduits and vascular structures. Cadaveric studies quantifying anatomic constraints are limited by postmortem factors causing distortion of critical structures. This study defines the anatomic constraints and parameters necessary for designing an implantable TAH. Importantly, these parameters were measured in 12 consecutive patients undergoing orthotopic cardiac transplant (mean body surface area, 2.0 +/- 0.1 m2) after native heart amputation. A full sized contour model of the cylindrical TAH (diameter, 97 mm; width, 78 mm) was inserted into the pericardial cavity to verify fit, which was found adequate in each case, with no identifiable compression of adjacent vascular structures. Intraoperative measurements obtained define intrathoracic and pericardial constraints for a cardiac prosthesis (mean pericardial dimensions: length, 133.0 mm; width, 154.0 mm; depth, 129.0 mm). The parameters measured will provide useful reference for other prosthetic devices, since they were obtained intraoperatively rather than postmortem. The current dimensions of our TAH were found to be acceptable for orthotopic implantation.