Andrea Hastillo

Early and Late Forms of Cyclosporine Nephrotoxicity: Studies in Cardiac Transplant Recipients

To characterize the two forms of cyclosporine nephrotoxicity, we examined renal function in the immediate and late postoperative periods after cardiac transplantation. Moderate azotemia occurred during the first postoperative week in 58% of 43 cyclosporine-treated recipients, but in only 34% of 41 azathioprine-treated recipients, and 4% of 25 patients undergoing cardiopulmonary bypass for nontransplant surgery (both P less than .01 v cyclosporine). Acute renal failure developed in an additional 12% of the cyclosporine-treated group. Late postoperative renal dysfunction also occurred with a high prevalence. Life-table analysis indicated that at 6 months 55%, at 12 months 17%, at 24 months 4%, and at 36 months no cyclosporine-treated recipients retained normal renal function. Three renal biopsies performed in subjects with late nephrotoxicity demonstrated prominent interstitial fibrosis. Although one patient subsequently required chronic dialysis, reduction of cyclosporine dosage from a mean of 5.3 +/- 0.7 mg/kg/d to a mean of 2.3 +/- 0.3 mg/kg/d 9 to 21 months after transplantation with concurrent initiation of azathioprine therapy to prevent rejection led to an improvement of renal function in the five patients so treated. These data indicate that there are two distinct forms of cyclosporine nephrotoxicity. Although both occur with high prevalence, the early form does not appear to be a specific risk factor for the late form.

Spectrum of cardiovascular function during gram-negative sepsis

G RAM-NEGATIVE sepsis represents an increasingly important problem as a distinct disease entity in 1980. It presents a complex problem of altered cardiovascular physiology that results in a high mortality rate in spite of significant advances in antimicrobial therapeutics. This disease entity is relatively new, dating from 195 1, and the largest body of data on the subject exists in the surgical literature. From the cardiologist’s point of view, this problem has all but been neglected, and yet it represents the type of pathologically perturbated cardiovascular function that should be improved by further investigation. It is the purpose of this review to point out the significance of the problem, define the intolerable insult that leads to death, and then construct, utilizing data from both clinical studies and animal experimentation, the sequence of gram-negative sepsis into a systems model that organizes the existing voluminous and paradoxical data base. It is obvious that every paper on the subject could not be reviewed, but it is our opinion that a strong data base has been created that is amenable to critical systems analysis. This review does not purport to answer all questions but should stimulate new and innovative investigation in order to decrease the unacceptably high mortality rate of gramnegative sepsis.

Milrinone: Basic and Clinical Pharmacology and Acute and Chronic Management

Milrinone (Inocor-Sanofi-Winthrop) represents a second generation phosphodiesterase inhibitor currently approved for intravenous administration in the treatment of decompensated congestive heart failure. By inhibiting Type III phosphodiesterase, milrinone increases intracellular cyclic adenosine monophosphate. This results in a positive inotropic effect on the heart and vasodilatation in the periphery. The hemodynamic consequences of this action produce left ventricular afterload reduction, with an increase in cardiac output and a reduction in total peripheral resistance. Unlike the sympathomimetic amines, milrinone produces no tolerance and possesses the distinct advantage of directly decreasing pulmonary vascular resistance. Short-term intermittent infusion by peripheral administration, continuous infusion, long-term therapy, and intermittent outpatient therapy was demonstrated to be safe, efficacious, and cost effective. It is hypothesized that intravenous milrinone, by producing biventricular afterload reduction, offers an efficacious, cost-effective tool for the treatment of decompensated heart failure.

Effects of intracoronary streptokinase in acute myocardial infarction

Intracoronary streptokinase (SK) was administered to 11 patients with evolving acute transmural myocardial infarction 5.5 +/- 0.4 hours from the onset of symptoms. Ten patients (91%) had total coronary occlusion, and one had subocclusion of the vessel corresponding to the ECG site of infarction. Intracoronary nitroglycerin failed to restore patency of total occlusion in all patients. In 9 of 11 patients (82%), patency was restored or improved with intracoronary SK. Thrombolysis was successful in 8 of 11 patients (73%), and one patient with transient patency developed acute reocclusion. Average time from SK infusion to reperfusion was 24 +/- 7 minutes. Patients with successful thrombolysis had patency initially restored at a dosage of 61,000 +/- 15,000 IU of SK and received a total dosage of 136,000 +/- 17,000 IU. Patency persisted at late study in six of eight patients, and two patients developed late reocclusion. Successful thrombolysis was associated with significant improvement in left ventricular ejection fraction (LVEF) from early to late study, in contrast to deterioration of LVEF in patients with unsuccessful recanalization (p less than 0.001). Systemic fibrinolytic activity occurred in 8 of 11 patients at a mean dosage of 125,000 +/- 15,000 IU of SK and was unassociated with significant bleeding. Significant decrease in hemoglobin concentration in the early hospital phase occurred in patients receiving SK but did not differ from decreases occurring in a matched control population receiving conventional therapy for infarction. Thus intracoronary thrombolysis with SK was successful in the majority of patients during the early phase of evolving transmural infarction, and successful thrombolysis was associated with significant improvement in LVEF. Systemic fibrinolysis occurs in most patients despite small total doses of SK, and the significant decrease in hemoglobin in these patients may be unrelated to SK, since similar changes occurred in a control population receiving conventional therapy.

The contrasting effects of cyclosporin-A and azathioprine on arterial blood pressure and renal function following cardiac transplantation☆

The effects of cyclosporin-A and azathioprine on the postoperative development of systemic hypertension and renal dysfunction in patients undergoing cardiac transplantation were compared retrospectively in 18 patients receiving cyclosporin-A and in 12 patients receiving azathioprine. Twelve months postoperatively, the average mean blood pressure was 116 +/- 13 mm Hg and 98 +/- 7.5 mm Hg; the average preoperative serum creatinine was 1.2 +/- 0.3 mg% and 1.5 +/- 0.3 mg%; and the postoperative serum creatinine was 2.2 +/- 0.8 mg% and 1.1 +/- 0.2 mg% (P less than 0.0001) in the cyclosporin-A-and azathioprine-treated groups respectively. Hemodynamic studies were done to characterize the de novo postoperative hypertension developing in the cyclosporin-A group. The pre- and postoperative cardiac output was 3.7 and 4.91/min, respectively (P less than 0.01). The pre- and postoperative systemic vascular resistance was 1707 and 1941 dynes sec X cm-5, respectively (P greater than 0.2). Peripheral renin activity and 24-hour urinary catecholamine excretion were not elevated. The mechanism of the hypertension developing in cyclosporin-A-treated patients is unknown, but is associated with normalization of cardiac output, an abnormally elevated systemic vascular resistance, and modest impairment of renal function. These findings are in marked contrast to azathioprine-treated patients, in whom postoperative hypertension and renal dysfunction do not occur. These observations implicate cyclosporin-A as the major contributing factor in the development of hypertension and renal dysfunction.

Pretransplant transfusions in cardiac allograft recipients.

The role of pretransplant transfusion in cardiac allograft recipients was determined retrospectively in 68 patients. Three groups were studied: group 1 (n=29) received no pretransplant transfusion, group 2 (n=15) received transfusion over one year prior to transplantation, and Group 3 (n=24) received 5 or 10 50–100 ml units of random donor red blood cells or buffy coat 2–4 weeks prior to transplantation. Data were analyzed for survival, number of rejection episodes, and number of infections. Immunosuppression included azathioprine, prednisone, and antithymocyte globulin. Survival in transfused patients (groups 2 and 3) was 68% and 51% at 1 and 5 years, respectively, while in the nontrans-fused population (group 1) it was 35% and 16%. The incidence of rejection episodes per year of survival was similar in the three groups (group 1: 1.3, group 2: 1.1, group 3: 1.3; P<0.05). The number of infections per year of survival were greater in the transfused patients but this did not achieve statistical significance (group 1: 1.0, group 2: 1.2, group 3: 1.7; P<0.05). Thus, we conclude that cardiac transplant recipients who have received blood transfusions prior to transplantation may have enhanced survival over patients who have not received preoperative transfusions.

Cyclosporine-induced pericardial effusion after cardiac transplantation

Abstract In the last 5 years, there has been a significant proliferation in the number of centers in which orthotopic cardiac transplantation is performed. This has been attributed to better surgical management, patient selection criteria and the introduction of cyclosporine as the immunosuppressant of choice. 1 Initially, it was hoped that cyclosporine would prevent the problems of sudden, catastrophic rejection, development of a Cushingoid appearance and other complications of high-dose steroid therapy. It was also hoped that by monitoring drug levels and titrating the dose, the incidence and severity of rejection would decrease, the length of hospitalization in the immediate postoperative period would decrease and both short-term and long-term survival would increase. 2 It soon became apparent, however, that long-term cyclosporine immun osuppression is associated with severe systemic hypertension and progressive chronic renal insufficiency. 3 Both complications of cyclosporine therapy may lead to the necessity of decreasing the dose of cyclosporine, a readjustment of immunosuppressive protocols to low-dose triple drug therapy (azathioprine, prednisone and cyclosporine) and even the necessity of withdrawing cyclosporine. 4 Less frequently, we have observed significant pericardial effusions in patients who have received cardiac allografts. We will discuss our observations of pericardial disease in the orthotopic cardiac recipient maintained on cyclosporine.

Mechanical and subcellular function of rat myocardium during chronic ethanol consumption.

Abstract Hemodynamic, mechanical, and subcellular function in a rat model of chronic ethanol consumption (A) and pair-fed control rats (C) were evaluated over a 17-week course. Between 5 and 17 weeks, isovolumetric peak systolic pressure did not change (C = 260 ± 20 mmHg; A = 265 ± 35 mmHg;p > 0.1). At 17 weeks myocardial contractility as evaluated by (dP/dt-max)/32 x LVP began to decline in the A rats (Vmax = 1.46 ± 0.12, r = 0.89; C = 1.560 ± 0.09, r = 0.95) but this is not statistically significant. Neither the velocity of calcium uptake by the isolated sarcoplasmic reticulum (SR) nor the whole heart homogenate (H) was different between C and A rats during the 17-week period and the estimated quantitative content of SR/g Heart did not change (at 17 weeks: mg SR/g Heart = 0.15, C and A). Utilizing Triton X-100 purification of cardiac myofibrils, Mg2+-dependent, Ca2+-stimulated myofribrillar ATPase activity began to decline at 11 weeks (A = 80% of control) and continued to decline at 17 weeks (A = 72% of control). These data suggest that a depression of contractile protein function may be an early alcohol-induced derangement in myocardial contractility that precedes the onset of significant mechanical dysfunction.

Response to dynamic exercise of the orthotopically transplanted human heart in men immunosuppressed with cyclosporine

Abstract Experimental and human studies of the orthotopically transplanted human heart have shown that, at rest, the denervated heart is characterized by a high resting heart rate and a diminished chronotropic reserve. 1−5 Human studies have been carried out in relatively small numbers of patients before the more recent advances in immunosuppressive therapy and the increasingly sophisticated management of the patient who has had transplantation. We quantified the hemodynamic response to graded treadmill exercise in stable patients who continue their contemporary immunosuppressive therapy including cyclosporine, and undergo stress testing within 12 months of their successful orthotopic cardiac transplantation.