Roque Pifarre

Increased Incidence of Lymphoproliferative Disorder after Immunosuppression with the Monoclonal Antibody OKT3 in Cardiac-Transplant Recipients

BACKGROUND A sudden increase in the incidence of post-transplantation lymphoproliferative disorder among the patients in our cardiac-transplantation program was temporally related to introduction of the immunosuppressive drug OKT3. This monoclonal antibody has come to be widely used in recent years both to prevent and to treat rejection after cardiac transplantation. METHODS In order to identify variables that predict the development of post-transplantation lymphoproliferative disorder, we analyzed retrospectively a series of 154 consecutive cardiac-transplant recipients at a single institution. Univariate analyses and multivariate analysis by logistic regression were performed. RESULTS Among 75 patients who did not receive OKT3, post-transplantation lymphoproliferative disorder developed in 1 (1.3 percent), as compared with 9 of 79 patients who received the drug (11.4 percent); the incidence among the OKT3-treated patients was ninefold higher (odds ratio, 9.5; 95 percent confidence interval, 1.6 to 54.7). According to multivariate analysis, the only factor significantly associated with the development of post-transplantation lymphoproliferative disorder was the use of OKT3 (P = 0.001). A significant increase in risk with increasing doses was also apparent: 4 of 65 patients who received a cumulative dose of 75 mg of OKT3 or less (6.2 percent) had post-transplantation lymphoproliferative disorder, whereas 5 of 14 patients who received more than 75 mg had the disorder (35.7 percent; P less than 0.001). CONCLUSION The addition of OKT3 to the immunosuppressive regimen increases the incidence of post-transplantation lymphoproliferative disorder after cardiac transplantation, and the risk increases sharply after cumulative doses greater than 75 mg. We suggest that the risks and benefits of prophylactic OKT3 administration be reassessed in the light of these findings, particularly since the value of prophylactic immunotherapy in cardiac-transplant recipients remains to be clearly established.

A Multicenter, Double-Blind, Placebo-Controlled Trial of Aprotinin for Reducing Blood Loss and the Requirement for Donor-Blood Transfusion in Patients Undergoing Repeat Coronary Artery Bypass Grafting

BACKGROUND Aprotinin is a serine protease inhibitor that reduces blood loss and transfusion requirements when administered prophylactically to cardiac surgical patients. To examine the safety and dose-related efficacy of aprotinin, a prospective, multicenter, placebo-controlled trial was conducted in patients undergoing repeat coronary artery bypass graft (CABG) surgery. METHODS AND RESULTS Two hundred eighty-seven patients were randomly assigned to receive either high-dose aprotinin, low-dose aprotinin, pump-prime-only aprotinin, or placebo. Drug efficacy was determined by the reduction in donor-blood transfusion up to postoperative day 12 and in postoperative thoracic-drainage volume. The percentage of patients requiring donor-red-blood-cell (RBC) transfusions in the high- and low-dose aprotinin groups was reduced compared with the pump-prime-only and placebo groups (high-dose aprotinin, 54%; low-dose aprotinin, 46%; pump-prime only, 72%; and placebo, 75%; overall P = .001). The number of units of donor RBCs transfused was significantly lower in the aprotinin-treated patients compared with placebo (high-dose aprotinin, 1.6 +/- 0.2 U; low-dose aprotinin, 1.6 +/- 0.3 U; pump-prime-only, 2.5 +/- 0.3 U; and placebo, 3.4 +/- 0.5 U; P = .0001). There was also a significant difference in total blood-product exposures among treatment groups (high-dose aprotinin, 2.2 +/- 0.4 U; low-dose aprotinin, 3.4 +/- 0.9 U; pump-prime-only, 5.1 +/- 0.9 U; placebo, 10.3 +/- 1.4 U). There were no differences among treatment groups for the incidence of perioperative myocardial infarction (MI). CONCLUSIONS This study demonstrates that high- and low-dose aprotinin significantly reduces the requirement for donor-blood transfusion in repeat CABG patients without increasing the risk for perioperative MI.

Accelerated Angina Pectoris Clinical, Hemodynamic, Arteriographic, and Therapeutic Experience in 85 Patients

Eighty-five patients with accelerated (preinfarction) angina are reported. Six suffered acute myocardial infarction awaiting catheterization and coronary angiography, so were not studied. Seventy-nine had coronary arteriography and other angiographic and hemodynamic studies. Fifteen of these 79 patients had normal coronary arteriograms; 64 had significant coronary artery obstruction. The clinical manifestations in 64 abnormal patients did not differ from those with normal arteriograms. Hemodynamic abnormalities correlated with the severity of arteriographic abnormalities. Of 70 patients with coronary artery disease, including the six not studied because of infarction, 48 were treated surgically with a mortality of 12.5%. Mortality for those 22 patients treated without surgery was 27%. Mortality could be correlated with certain risk factors: (1) congestive heart failure; (2) more than three-vessel coronary disease; (3) left ventricular end-diastolic pressure > 12 mm Hg; (4) cardiac index <2.7 liters/min/m2; (5) stroke index <35 ml/beat/m2; (6) estimated cardiac work (mean aortic pressure × cardiac index) <240 units; and (7) ejection fraction <0.50. Cardiac catheterization and angiography were performed without major complications in 97% of patients.

Successful treatment of heart transplant rejection with photopheresis.

Photopheresis is a potential therapy for rejection in which reinfusion of mononuclear cells exposed to ultraviolet-A light ex vivo, after treatment with 8-methoxypsoralen in vivo, initiates host immune responses that specifically inhibit the cytotoxicity of the photomodulated mononuclear cells. Between May 1990 and January 1991, 7 heart transplant (HT) patients (age 42.2 +/- 16.7 [mean +/- SD] years) on triple immunosuppression (cyclosporine, corticosteroids, and azathioprine) had 9 episodes of non-hemodynamically compromising moderate rejection that were treated with photopheresis. These episodes of rejection occurred at an average of 114.4 +/- 180.5 (range 8-575) days after HT. After oral administration the mean serum level of 8-methoxypsoralen achieved was 129.0 +/- 72.4 ng/ml. An average of 10.4 +/- 9.6 x 10(9) mononuclear cells were treated with each photopheresis procedure. Photopheresis was performed twice when less than 5 x 10(9) mononuclear cells had been treated with the first procedure. Of 9 rejection episodes treated with photopheresis, 5 required 1 procedure and 4 required 2 procedures. Photopheresis was used to treat a single episode of rejection in 5 pts. and 2 separate rejection episodes in 2 additional pts. Eight of 9 episodes of rejection were successfully reversed by photopheresis as assessed by endomyocardial biopsy (EMB) performed 7 days after treatment. Immunohistochemical analysis of EMB samples revealed that postphotopheresis cell counts for T cells, B cells, and macrophages were reduced compared to pretreatment values and correlated with the histopathologic resolution of rejection. Hemodynamics were normal prephotopheresis and remained unchanged at the time when the postphotopheresis EMB showed no evidence rejection No adverse effects have been observed with photopheresis. Over a follow-up period of 5.3 +/- 4.0 months, rejection and infection rates/pt./follow-up months were 0.3 +/- 0.4 and 0.04 +/- 0.07, respectively. The preliminary, short term results of this pilot study indicate that photopheresis may be efficacious in the treatment of moderate rejection in hemodynamically stable HT patients and thus may be an alternative to corticosteroid pulses.

Hemodynamic response to changes in ventilatory patterns in patients with normal and poor left ventricular reserve.

Hemodynamic effects of controlled mechanical ventilation (CMV), intermittent mandatory ventilation (IMV), and intermittent mandatory ventilation with 5 cm H2O PEEP (IMV5PEEP) were studied in 20 patients after aortocoronary bypass surgery. Significant increases in cardiac index (CI) and stroke volume index (SI) (p < 0.01) resulted in patients with normal left ventricular end-diastolic pressure (LVEDP) and ejection fraction (EF) changing from CMV to IMV. With a change from IMV to IMVSPEEP, the CI and SI returned to CMV values. However, in patients with increased LVEDP with an EF of less than 0.6, suggesting poor ventricular function and reserve, when the mode of ventilation was changed from CMV to IMV, right atrial pressure (RAP) and pulmonary artery occlusion pressure (PAOP) significantly increased (p < 0.01) with an associated significant decrease in mean arterial pressure (MAP), CI, SI (p < 0.01). When these patients were placed on IMV5PEEP, the hemodynamic variables returned to the values obtained during CMV. We conclude that changing from CMV to IMV has salutory effects on the patients hemodynamic values with normal left ventricular function. But in patients with failing left ventricle, volume overload of right ventricle which occurs with the institution of spontaneous respiration during IMV has deleterious effects on the hemodynamic variables. These deleterious effects can be effectively negated by the application of IMV5 PEEP.

Treatment of cardiogenic shock in myocardial infarction by intraaortic balloon counterpulsation and surgery

Thirty-seven patients in cardiogenic shock due to acute myocardial infarction were treated with intraaortic balloon counterpulsation and/or surgery. Eighteen of these patients were treated with counterpulsation alone; eight survived and five were in functional class I or II at the time of follow-up; two were in functional class III, and one was in functional class IV. Nineteen patients were treated surgically, eight survived and seven were in functional class I or II at the time of follow-up; one was in functional class III. Good functional recovery with counterpulsation alone is most common with inferior infarction. With surgery, functional recovery depends not only on the extent of the infarction and the coronary anatomy, but also on the ability to perform surgery within 12 hours of infarction or to support the patient with mechanical means for 10 to 14 days after the infarction and then perform surgery.

Transient bundle branch block following use of hypothermic cardioplegia in coronary artery bypass surgery: High incidence without perioperative myocardial infarction

Hypothermic cardioplegia (HCP) is a method commonly used for myocardial preservation at the time of aortic cross-clamping during coronary artery bypass grafting (CABG). This study assessed the frequency and significance of transient bundle branch block (BBB) in 50 patients undergoing CABG using HCP compared to 61 controls. All patients had normal QRS complexes on preoperative ECG. CLinical, hemodynamic, and operative data were similar in both groups. Seventeen (34%) of the HCP group and four (6%) of the controls developed postoperative BBB (p less than 0.001). These changes were transient in all but three patients in the HCP group. None of the HCP patients with transient BBB had evidence of perioperative myocardial infarction. Clinical and operative parameters did not provide prediction of development of transient BBB. This study demonstrates that transient BBB in the immediate post-CABG period occurs commonly with the use of HCP and does not indicate myocardial necrosis.

Qualitative evaluation of coronary flow during anesthetic induction using thallium-201 perfusion scans.

Qualitative distribution of coronary flow using thallium-201 perfusion scans immediately postintubation was studied in 22 patients scheduled for elective coronary artery bypass surgery. Ten patients received a thiopental (4 mg/kg) and halothane induction. Twelve patients received a fentanyl (100 μg/kg) induction. Baseline thallium-201 perfusion scans were performed 24 h prior to surgery. These scans were compared with the scans performed postintubation. A thallium-positive scan was accepted as evidence of relative hypo-perfusion. Baseline hemodynamic and ECG data were obtained prior to induction of anesthesia. These data were compared with the data obtained postintubation. Ten patients developed postintubation thallium-perfusion scan defects (thallium-positive scan), even though there was no statistical difference between their baseline hemodynamics and hemodynamics at the time of intubation. There was no difference in the incidence of thallium-positive scans between those patients anesthetized by fentanyl and those patients anesthetized with thiopental-halothane. The authors conclude that relative hypoperfusion, and possibly ischemia, occurred in 45% of patients studied, despite stable hemodynamics, and that the incidence of these events was the same with two different anesthetic techniques.

Increase in Severity of Proximal Coronary Disease after Successful Distal Aortocoronary Grafts Its Nature and Effects

Aortocoronary vein grafts were placed in seven patients to bypass severe proximal stenosis in nine coronary arteries. Routine postoperative angiography showed patent grafts in all patients and substantial increase of proximal occlusive disease, diffusely or at the points of narrowing, in six of nine arteries (four patients), with complete obstruction of four of the six vessels. Two of the four patients experienced improvement in angina which was sustained despite the advanced proximal disease. The third patient suffered a late postoperative myocardial infarction and the fourth had recurrence of angina, both probably as a result of the increased proximal disease. The possibility is considered that a successful vein graft, by diverting flow from the poststenotic segment, may accelerate its occlusion and that consequences of advancing occlusive disease may not be prevented by vein-grafting surgery.

Experimental Evidence of Cerebral Injury from Profound Hypothermia During Cardiopulmonary Bypass

Abstract. Choreoathetosis, seizures, and impaired mental development continue to occur in children undergoing cardiopulmonary bypass (CPB) and profound hypothermia with or without circulatory arrest. Although there is some evidence that the hypothermia itself may be causing these neurologic problems, skepticism remains because of lack of evidence from experimental studies simulating the clinical setting. In this experimental study, we examined the effect of profound and moderate hypothermia on the brain while maintaining normal flow rates during CPB. Ten adult mongrel dogs equally divided into two groups were anesthetized and subjected to CPB and varying levels of hypothermia (group 1, ≤15°C; group 2, ≤32°C). Both groups were kept at the desired temperature for 1 hour prior to rewarming and discontinuation of CPB. The dogs were euthanized 4–6 weeks later and neuropathologic studies were performed. The mean CPB flow rates during cooling and at the desired rectal temperature were comparable in both groups: group 1, 108 ± 10 ml/kg/min versus 106 ± 7 ml/kg/min in group 2 (p= NS) and 95 ± 12 ml/kg/min in group 1 versus 101 ± 5 ml/kg/min in group 2 (p= NS). Because of the difference in temperature between the two groups, the mean cooling time (onset of CPB to desired rectal temperature) was longer in group 1 (70 ± 14 minutes) than in group 2 (28 ± 11 minutes, p= 0.007). Hence, the total mean CPB time was also longer in group 1 (198 ± 25 minutes) than in group 2 (143 ± 13 minutes, p= 0.002). The lowest mean blood and rectal temperature achieved in group 1 were 11 ± .9°C and 12 ± 1°C versus 29 ± .4°C (p < 0.001) and 30 ± .6°C (p= 0.001), respectively, in group 2 (p= 0.001). Neuronal loss and degeneration was noted in all dogs in group 1 ranging from 2 to 8 cells per 1000 cells counted compared to none in group 2 (p= 0.05). These lesions occurred in both the basal ganglia and the cortex, although they were more marked in the caudate when compared to the cortex and cerebellum. Both in the cortex and in the caudate, neuronal loss was more marked around the capillaries. We conclude that the use of profound hypothermia of ≤15°C and maintenance of normal flow rates during cooling at this temperature for 1 hour produces neuronal loss and degeneration in the brain. These lesions being more marked around capillaries points to the vulnerability of the neurons, probably because of their high lipid content to injury from the cold perfusate.