Akihiko Kawai

Clinical trial of tacrolimus versus cyclosporine in lung transplantation

BACKGROUND A prospective clinical trial was undertaken to compare the efficacy of tacrolimus (FK 506) versus cyclosporine as the primary immunosuppressive agent after lung transplantation. METHODS Between October 1991 and May 1994, 133 single-lung and bilateral-lung recipients were randomized to receive either cyclosporine (n = 67) or tacrolimus (n = 66). The two groups were similar in age, sex, and underlying disease. RESULTS One-year and 2-year survival rates were similar in the two groups, although the trend was toward increased survival with tacrolimus. Acute rejection episodes per 100 patient-days were fewer (p = 0.07) in the tacrolimus group (0.85) than in the cyclosporine group (1.09). Obliterative bronchiolitis developed in significantly fewer patients in the tacrolimus group (21.7%) compared with the cyclosporine group (38%) (p = 0.025), and there was greater freedom from obliterative bronchiolitis over time for patients receiving tacrolimus (p < 0.03). Significantly more cyclosporine-treated patients (n = 13) required crossover to tacrolimus than tacrolimus-treated patients to cyclosporine (n = 2) (p = 0.02). The switch to tacrolimus controlled persistent acute rejection in 6 of 9 patients. The overall incidence of infections was similar in the two groups, although bacterial infections were more common with cyclosporine (p = 0.0375), whereas the risk of fungal infection was higher with tacrolimus (p < 0.05). CONCLUSIONS This trial demonstrates the advantage of tacrolimus in reducing the risk of obliterative bronchiolitis, the most important cause of long-term morbidity and mortality after lung transplantation.

Transplant candidate's clinical status rather than right ventricular function defines need for univentricular versus biventricular support☆☆☆★★★♢♢♢

We have studied our experience since 1988 with 31 patients who required a mechanical circulatory bridge to transplantation and also had biventricular failure (mean right ventricular ejection fraction 11.8%) to better define the need for biventricular or total artificial heart support versus univentricular support. Clinical factors including preoperative inotropic need, fever without detectable infection, diffuse radiographic pulmonary edema, postoperative blood transfusion, and right ventricular wall thickness were compared with hemodynamic parameters including cardiac index, right ventricular ejection fraction, central venous pressure, mean pulmonary arterial pressure, and total pulmonary resistance for ability to predict need for mechanical or high-dose inotropic support for the right ventricle. Patients were grouped according to need for right ventricular support after left ventricular-assist device implantation: none (group A, 14) inotropic drugs (group B1, 7), and right ventricle mechanical support (group B2, 10). There were no differences in preimplantation hemodynamic variables. Groups B1 and B2 had significantly lower mixed venous oxygen saturation (39.2% vs 52.5% in group A; p < 0.001), greater level of inotropic need (p < 0.02), greater impairment of mental status, and lower ratio of right ventricular ejection fraction to inotropic need (0.37 vs 0.56 for group A; p < 0.02) before left ventricular-assist device implantation. A significant discriminator between groups B1 and B2 was the presence of a fever without infection within 10 days of left ventricular-assist device implantation (43% in group B1 vs 70% in group B2). Group B2 had more patients with preimplantation pulmonary edema seen on chest radiography and a greater requirement for postoperative blood transfusion (5 units of cells in group B1 vs 14.8 units in group B2. Right ventricular wall thickness at left ventricular-assist device explantation was 0.83 cm in group B2 vs 0.44 cm in group B1 (p < 0.05). Transplantation rates after bridging were 100% in group A, 71% in group B1, and 40% in group B2. Clinical factors that reflect preimplantation degree of illness and perioperative factors that result in impairment of pulmonary blood flow or reduced perfusion of the right ventricle after left ventricular-assist device implantation are now considered to be more predictive of the need for additional right ventricular support than preimplantation measures of right ventricular function or hemodynamic variables.

A prospective trial of tacrolimus (FK 506) in clinical heart transplantation: Intermediate-term results

Between January 1, 1989, and December 31, 1994, we have treated 122 primary heart recipients with FK 506 (group I) and 121 with cyclosporine (group II). Fifty patients in the cyclosporine (CyA) group received no lympholytic induction (CyA alone) and 71 others received lympholytic induction with either rabbit antithymocyte globulin or OKT3 (CyA+LI). The mean follow-up was longer in the FK 506 group than in the CyA groups (3.2 +/- 1.3 vs 2.3 +/- 1.8 years; p< 0.01). Patient survival did not differ on the basis of the type of immunosuppression used. At 3 months after transplantation, the freedom from rejection in the FK 506 group was higher than that of the CyA-alone group (47% vs 22%, p < 0.01) but similar to that of the CyA+LI group (47% vs 53%). The linearized rejection rate (episodes/100 patient-days) of the FK 506 group (0.09 episodes) was lower (p < 0.05) than that of the CyA-alone group (0.26) and the CyA+LI group (0.13). The requirement for pulsed steroids to treat rejection was less in common in the FK 506 group than in either CyA group. Eighteen patients in the CyA group had refractory rejections; all resolved with FK 506 rescue. Two patients in the FK 506 group had refractory rejection that resolved with total lymphoid irradiation (n=1) and methotrexate therapy (n=1). Patients receiving FK 506 had a lower risk of hypertension and required a lower dose of steroids. Although the mean serum creatinine concentration at 1 year was higher in the FK 506 group, this difference disappeared after 2 years. No patients required discontinuation of FK 506 because of its side effects. Our intermediate-term results indicate that FK 506 compares favorably with CyA as a primary immunosuppressant in heart transplantation.

Solid tumors after heart transplantation: Lethality of lung cancer

BACKGROUND Prolonged nonspecific immunosuppression after solid-organ transplantation is associated with an increased risk of certain cancers. This study examined the development of solid-organ tumors after cardiac transplantation. METHODS Thirty-eight solid tumors were identified in 36 (5.9%) of 608 cardiac transplant recipients who survived more than 30 days. Two patients had two types of skin tumors (basal cell and squamous cell). The tumors included the following types: skin (15), lung (10), breast (1), bladder (2), larynx (2), liver (1), parotid (1), testicle (1), uterus (2), melanoma (2), and Merkels cell (1). Four immunosuppression regimens based on cyclosporin A or FK 506 were used during this period. RESULTS There was no association between the incidence of solid tumors and the use of lympholytic therapy. After the diagnosis of tumor was made, the actuarial 2-year survival rates of recipients with skin, lung, and other solid tumors were 71%, 22%, and 23%, respectively. Eight of 10 patients with lung cancer were in stage IIIA or higher at the time of diagnosis. CONCLUSION Skin and lung tumors are the most frequent solid tumors in heart transplant recipients. Skin tumors (except Merkels cell carcinoma and melanoma) usually have a benign course, whereas lung and other tumors developing in cardiac transplant recipients carry a poor prognosis. Advanced disease stage at the time of diagnosis is responsible for the dismal outcome of recipients in whom solid tumors develop. Close postoperative tumor surveillance after cardiac transplantation is warranted.

Two-dimensional Echocardiographic Automated Border Detection Accurately Reflects Changes in Left Ventricular Volume

The objective of this study was to determine the relationship of on-line measurements of left ventricular cavity area generated by echocardiographic automated border detection to true volume measured by an intraventricular balloon in an isovolumically contracting isolated canine heart preparation. Seven excised dog hearts had placement of an intraventricular balloon and were perfused in an ex vivo apparatus. Left ventricular area data from the midventricular short-axis plane and pressure data were recorded on a computer through a customized hardware and software interface with the ultrasound system. Left ventricular volumes were varied from 5 ml to maximal values (30 to 40 ml) at 1-milliliter increments. Three increasing and decreasing volume ramps were analyzed on each of seven hearts for a total of 1260 simultaneous measurements. Linear regression analysis correlated mean automated border detection area with absolute volume from each preparation. A predominantly linear relationship was observed with an average correlation of r = 0.97 (y = 0.16x-0.69, SEE = 0.31 cm2, p < 0.01). Left ventricular area measures for six of seven dogs varied little during isovolumic contraction (< 0.4 cm2) but did show a systematic cardiac cycle-related variability in one dog (28% change in area, maximum to minimum, over all volumes). In conclusion, the relationship between cross-sectional area and left ventricular volume was predominantly linear and varied little during isovolumic contractions in the normal canine left ventricle. Echocardiographic automated border detection appears to be a promising method to reflect changes in left ventricular volume.

Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients

Lung transplant recipients who have persistent acute cellular rejection are at increased risk for the development of chronic rejection, the leading cause of reduced long-term survival. This study evaluated the use of aerosolized cyclosporine as rescue therapy for unremitting acute rejection. Between June 1993 and March 1996, 18 patients with rejection that failed to resolve after therapy with pulse steroids and antilymphocyte globulin were enrolled in the study. Aerosolized cyclosporine A (300 mg) treatment was initiated for 10 consecutive days followed by a maintenance regimen of 3 days per week. Efficacy was assessed by graft histologic and pulmonary function testing. With the use of linear regression, results in these patients were compared with those in 23 control patients, matched for histologic acute rejection, who had continued to receive conventional rescue therapy. Two patients were unable to tolerate the treatments and were withdrawn from the study. Significant improvement in histologic rejection occurred in 14 of the remaining 16 patients after a mean of 37 days of aerosolized cyclosporine therapy. Measures of forced vital capacity and forced expiratory volume in 1 second (change in percent predicted/100 days plus or minus the standard error) increased over time in the treated patients whereas the condition of control patients declined despite repeated attempts at conventional rescue (forced vital capacity, aerosolized cyclosporine group, 4.6 +/- 2.9 vs control group -8.1 +/- 1.9, p = 0.001; forced expiratory volume in 1 second, aerosolized cyclosporine group, 2.1 +/- 4.4 vs control group -9.8 +/- 2.6, p = 0.043). Renal and hepatic toxicity during cyclosporine therapy was not observed. The incidence of acute histologic rejection (> or = A2) decreased from 2.49 +/- 0.68 episodes/100 days before aerosolized cyclosporine therapy to 0.72 +/- 0.3 episodes/100 days (p < 0.05). In summary, aerosolized cyclosporine is a safe and effective therapy for acute rejection that has failed to improve with conventional treatment.

Automated Echocardiographic Measures of Right Ventricular Area as an Index of Volume and End-Systolic Pressure-Area Relations to Assess Right Ventricular Function

BACKGROUND On-line determination of right ventricular (RV) volume to assess its function is clinically difficult. Echocardiographic automated border detection measures of left ventricular (LV) cavity area have been shown to reflect changes in volume, and pressure-area relations have been used to estimate LV contractility. The potential for RV cavity area to estimate changes in volume and to assess RV function, however, has not been evaluated. Accordingly, the objective of this study was to determine the relation between echocardiographic automated border-detected RV cross-sectional area and true volume and to assess the potential for end-systolic pressure-area relations to estimate RV function in an isovolumically contracting isolated canine heart preparation. METHODS AND RESULTS Eight excised dog hearts with both right and left intraventricular balloons were perfused in an ex vivo apparatus in which both ventricular volumes were controlled independently. RV area data from the level of the left midventricular short-axis plane and pressure data were recorded on a computer through a customized hardware and software interface with the ultrasound system. RV volumes were varied from 9.4 +/- 3.9 to 43.8 +/- 6.9 mL at each of three different LV volume ranges (low range, 12.5 +/- 3.8 mL; medium range, 23.9 +/- 5.6 mL; and high range, 37.5 +/- 5.4 mL). The variation of RV area during isovolumic contraction, which we called deformational area change, was considerable (1.49 +/- 0.68 cm2 mean +/- SD) but did not change significantly with changing RV and LV volumes. Linear regression analysis correlated the maximum, minimum, and mean automated border-detected RV area during isovolumic contraction with absolute volume. A predominantly linear relation was observed, with the group mean r = .98 (y = 0.16x + 0.97; SEE = 0.21 cm2). The effect of LV volume on RV area-volume relation was a significant parallel downward shift (P < .05) by increases in LV volume. End-systolic pressure-area and pressure-volume relations using simultaneously RV pressure were both highly linear and covaried with changing LV volume. CONCLUSIONS Echocardiographic automated border-detected RV area reflects changes in RV volume under a constant LV volume, and the derived end-systolic pressure-area relation has potential for on-line assessment of RV function.

Effects of milrinone for right ventricular failure after left ventricular assist device implantation

Abstract Right ventricular failure after left ventricular assist device implantation sometimes requires additional mechanical right ventricular support. The effectiveness of nitrates, prostaglandin, or nitric oxide inhalation in such cases has already been reported. However, there are few reports on the administration of phosphodiesterase inhibitor for right ventricular failure after left ventricular assist device implantation. We report two patients with right ventricular failure after left ventricular assist device implantation successfully treated with milrinone. Both had residual pulmonary hypertension due to high pulmonary vascular resistance after left ventricular assist device implantation. However, intravenous milrinone caused a significant reduction in pulmonary vascular resistance and an increase in left ventricular assist device flow. Milrinone acts as both an inotropic agent and a direct vasodilator, and thus may avoid the need for mechanical support for right ventricular failure due to residual pulmonary hypertension after left ventricular assist device implantation.

Differential regional function of the right ventricle during the use of a left ventricular assist device

The use of a left ventricular assist device (LVAD) as a bridge to transplant is associated with a 52% incidence of RV failure requiring additional inotropic or mechanical support (RVAD). This study evaluated the differential performance of the RV free wall and septum to identify the need for additional RV support. Cross-sectional views of the RV were obtained immediately before, and 1 hr after, Novacor LVAS implantation in 12 consecutive patients using transesophageal echocardiography. Each image was divided into a free wall portion (FW) and a septal portion (SP) by grids drawn from the center of gravity of the end-diastolic endocardial outline to the junction between the FW and the SP. Percentage change between preimplant and postimplant for RV ejection fraction (RVEF), fractional area change for the FW (FAC-FW) and the SP (FAC-SP), and fractional shortening of the FW to SP distance (F-S) is reported for patients based upon the need for RV support: minimal (Group 1), maximal (Group 2). After LVAS implantation, patients showed a reduction in SP fractional area change. However, this reduction was most pronounced in Group 2. The degree of SP impairment may explain the mechanism of RV failure in patients on an LVAD.

Perioperative donor bone marrow infusion augments chimerism in heart and lung transplant recipients

BACKGROUND We and others have demonstrated that a low level of donor cell chimerism was present for years after transplantation in tissues and peripheral blood of heart and lung recipients; it was associated, in the latter, with a lower incidence of chronic rejection. To augment this phenomenon, we initiated a trial combining simultaneous infusion of donor bone marrow with heart or lung allotransplantation. METHODS Between September 1993 and January 1995, 15 nonconditioned patients received either heart (n = 10) or lung (n = 5) allografts concurrently with an infusion of unmodified donor bone marrow (3.0 x 10(8) cells/kg), and were maintained on immunosuppressive regimen consisting of tacrolimus and steroids. RESULTS There was no complication associated with the infusion of donor bone marrow. Chimerism was detectable in 73% of bone marrow-augmented patients up to the last sample tested. Of the 5 control recipients who did not receive bone marrow infusion, only 1 had detectable chimerism by flow on postoperative day 15, which dwindled to an undetectable level by postoperative day 36. None of the patients had evidence of donor-specific immune modulation by mixed lymphocyte reaction. CONCLUSIONS The combined infusion of donor bone marrow and heart or lung transplantation, without preconditioning of the recipient, is safe and is associated with an augmentation of donor cell chimerism.