Heparin-coated circuits reduce myocardial injury in heart or heart-lung transplantation: a prospective, randomized study.

BACKGROUND: The effects of heparin-coated (HC) circuits have been primarily investigated in routine cardiac operations with limited duration of cardiopulmonary bypass (CPB) and ischemia. Their benefits have not been conclusively proven but could be more significant when CPB and ischemic times are longer, such as during heart transplantation (HTx) or heart-lung transplantation (HLTx). METHODS: In a 22-month period, 29 patients undergoing HTx and HLTx were randomly divided into two groups using HC (Duraflo II, n = 14, 10 HTx and 4 HLTx) or uncoated but identical circuits (NHC group, n = 15, 10 HTx and 5 HLTx). All patients received full systemic heparinization (3 mg/kg) during CPB. Plasma endotoxin, interleukin (IL)-6, IL-8, IL-10, IL-12, and cardiac troponin-I were measured before heparin administration, immediately after aortic cross-clamping, 5, 30, 60, 90, 120 minutes, and 12 and 24 hours after aortic declamping. The intensive care unit (ICU) staff and the laboratory technologists were blinded as to the use of HC circuits. RESULTS: No statistically significant differences between groups were found with respect to all baseline values, duration of CPB and aortic cross-clamping, graft ischemic time, doses of heparin, postoperative blood loss and transfusion, peak lactate and creatine kinase-MB isoenzyme values, duration of mechanical ventilation, or length of ICU stay. One patient in each group died during the hospital stay. Patients in the HC group needed more protamine sulfate after CPB. Although endotoxin levels were similar in the two groups, significantly lower IL-6, IL-8, and IL-10 levels were observed 1 hour after aortic declamping in the HC group. The release of cardiac troponin-I was also significantly reduced in the HC group 12 and 24 hours after reperfusion. CONCLUSIONS: The use of HC circuit limits both pro- and anti-inflammatory responses to CPB. It may also reduce myocardial injury after prolonged duration of CPB and ischemia.

Can cardioplegia management influence cytokine responses during clinical cardiopulmonary bypass?

BACKGROUND: Cytokines play an important role in the inflammatory response associated with cardiopulmonary bypass (CPB) and may contribute to postoperative complications. Although it has been shown that the production of tumor necrosis factor a (TNF-a) and interleukin (IL)-6 were higher following normothermic CPB than hypothermic CPB, whether different cardioplegic management could influence the release of cytokines remains unknown. METHODS: We compared the blood concentrations of four cytokines (TNF-a, IL-6, IL-8, and IL-10) in two groups of patients undergoing complete revascularization with CPB in the same study period. Seventeen patients received cold crystalloid cardioplegia at a Belgian center (group-CC), while 21 patients received warm blood cardioplegia at a center in Hong Kong (group-WB). Blood samples were collected before and after surgery in each patient. RESULTS: There were no differences between the 2 groups in terms of age, sex ratio, number of grafts, duration of CPB and aortic crossclamping. All patients survived their hospital stay. The levels of TNF-a, IL-6 and IL-8 after surgery were higher in group-CC than in group-WB. However, IL-10 levels were significantly lower at the end of surgery in group-CC than in group-WB. CONCLUSIONS: Our data suggest that the use of warm blood cardioplegia, rather than cold crystalloid cardioplegia, may reduce the inflammatory response to CPB. This observation warrants future randomized investigation to determine its clinical relevance.

Does steroid pretreatment increase endotoxin release during clinical cardiopulmonary bypass?

OBJECTIVE: The mechanism involved in the endotoxemia frequently recognized during cardiopulmonary bypass remains unclear. It has also been suggested that endotoxin levels were higher in steroid-pretreated patients undergoing cardiopulmonary bypass. METHODS: Twenty patients undergoing cardiopulmonary bypass were randomly pretreated with steroids (methylprednisolone, 30 mg/kg) or placebo. Blood samples for endotoxin measurement were drawn simultaneously from the superior and inferior venae cavae before heparin administration, 5 and 50 minutes after the onset of bypass, 5 minutes after aortic declamping, at the end of bypass, and 1, 2, and 20 hours after the end of cardiopulmonary bypass. RESULTS: The perioperative variables in the two groups were similar. Blood endotoxin levels were higher in the inferior vena cava than in the superior vena cava immediately after the onset of bypass. Endotoxin levels in inferior vena cava blood were significantly lower in steroid-pretreated patients than those in patients not receiving steroids. CONCLUSIONS: Endotoxin is released during cardiopulmonary bypass from the region drained by the inferior vena cava. Steroid pretreatment may actually reduce endotoxin release during bypass.

Thrombus formation on a calcific and severely stenotic bicuspid aortic valve.

We report on a case of thrombus formation on a native bicuspid aortic valve, which was found during an elective operation for aortic valve replacement. Although no apparent predisposing cause of thrombosis could be ascertained, severe calcific stenosis of the bicuspid valve and cardiac catheterization may have played a role. The patient is in excellent condition 9 months after the operation.

Hepatic release of interleukin-10 during cardiopulmonary bypass in steroid-pretreated patients.

With its antiinflammatory properties, interleukin (IL)-10 may play an important role in limiting complications associated with cardiopulmonary bypass (CPB). We previously demonstrated that pretreatment with steroids can significantly increase IL-10 production during CPB, but neither the heart nor the lung was found to be its main source. To define whether the liver is the source of IL-10, hepatic venous cannulation was performed in 12 patients undergoing CPB. Each patient received 30 mg/kg of methylprednisolone before operation. Plasma levels of IL-10 were simultaneously measured in peripheral arterial blood and hepatic venous blood before heparin administration, before aortic cross-clamping, and 5, 30, 60, 90, and 120 minutes after aortic declamping. The duration of CPB and aortic cross-clamping was 113 +/- 7 minutes and 75 +/- 6 minutes (mean +/- SEM), respectively. IL-10 levels 30 minutes after declamping were significantly higher in hepatic venous blood than in arterial blood (1187 +/- 573 pg/ml vs 911 +/- 405 pg/ml, p < 0.01 by Wilcoxon's signed-rank test). To determine whether steroids can also induce the release of another antiinflammatory cytokine, IL-4, plasma IL-4 levels were measured simultaneously. IL-4 was detected in the arterial blood of only 4 of the 12 patients, transiently after aortic declamping. IL-4 was not detected in hepatic venous blood. In conclusion, the liver is a major source of IL-10 during CPB. However, steroid-treated patients do not show an increase in IL-4, and the liver is not the source of IL-4 during and after CPB.

Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass.

Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-6, and interleukin-8, and anti unflammatory cytokines, such as interleukin-10, may play an important role in patient responses to cardiopulmonary bypass. We sought to define whether the myocardium and the lungs serve as important sources of these cytokines under conditions of cardiopulmonary bypass. Ten patients (age 64 +/- 3 years, mean +/- standard error of the mean) undergoing elective coronary artery bypass grafting were monitored with an arterial catheter, a coronary sinus catheter, and pulmonary artery catheter. Plasma levels of tumor necrosis factor-alpha, interleukin-6, interleukin-8, and interleukin-10 were measured simultaneously in peripheral arterial blood, coronary sinus blood, and mixed venous blood before heparin administration, 1 minute before aortic crossclamping, 5 minutes after aortic declamping, and at 0.5, 1, 1.5 and 2 hours after aortic declamping. The durations of cardiopulmonary bypass and aortic crossclamping were 114 +/- 9 and 64 +/- 5 minutes, respectively. Levels of tumor necrosis factor-alpha and interleukin-6 were significantly higher in coronary sinus blood than in arterial blood after aortic declamping. Tumor necrosis factor-alpha and interleukin-6 levels were also higher in mixed venous blood than in arterial blood within 1 hour after declamping. There were no significant differences among the three sampling sites with respect to interleukin-8 and interleukin-10 levels. In one patient who had postoperative myocardial infarction, however, interleukin-8 levels were three times as high as in coronary sinus blood than in arterial blood. These data indicate that the myocardium is a major source of tumor necrosis factor-alpha and interleukin-6 in patients undergoing cardiopulmonary bypass. The lungs may consume rather than release proinflammatory cytokines in the early phase of reperfusion. The source under these conditions of the antünflammatory cytokine interleukin-10 remains to be determined.

Steroid administration in heart and heart-lung transplantation: is the timing adequate?

BACKGROUND: The release of cytokines after cardiopulmonary bypass may play an important role in postoperative morbidity. The release of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin (IL)-6 and IL-8, is even greater in patients undergoing heart transplantation (HTx) than coronary artery grafting. We tested the hypothesis that in HTx patients the earlier administration of steroids, before rather than after cardiopulmonary bypass as usual, can reduce the inflammatory response. METHODS: In 20 consecutive patients who underwent HTx or heart-lung transplantation (HLTx), plasma levels of tumor necrosis factor alpha, IL-6, IL-8, and anti-inflammatory cytokine IL-10 were measured before heparin administration, at aortic cross-clamping and declamping, and 0.5, 1, 1.5, 2, 4, 12, and 24 hours after aortic declamping. In 10 patients (group I, 6 HTx and 4 HLTx), 500 mg of methylprednisolone was first given as usual at 1.5 hours after aortic declamping (at the end of cardiopulmonary bypass). In the next 10 patients (group II, 6 HTx and 4 HLTx), the first doses of methylprednisolone were given 1 hour before operation. In both groups, 125 mg of methylprednisolone were given every 8 hours thereafter during the first postoperative day. RESULTS: The ischemic time and cardiopulmonary bypass time were similar in the two groups (166 +/- 16 minutes versus 157 +/- 13 minutes, and 192 +/- 21 minutes versus 186 +/- 20 minutes, respectively, mean +/- standard error of the mean). At 30 minutes after aortic declamping and throughout the next 4 hours, tumor necrosis factor alpha levels were significantly lower in group II than in group I (all p < 0.03). Interleukin-8 values 1 hour after declamping were also lower in group II than in group I (49 +/- 15 pg/mL versus 130 +/- 38 pg/mL, p < 0.02). Interleukin-10 levels were significantly higher in group II than in group I from 30 minutes after declamping through 2 hours after (all p < 0.03). Interleukin-6 levels were similar in the two groups. CONCLUSIONS: Earlier steroid administration in the immunosuppressive protocol for HTx or HLTx may be preferable to reduce the inflammatory response to cardiopulmonary bypass, as reflected by a lower production of tumor necrosis factor alpha and IL-8, and a greater release of IL-10.

Human cytokine responses to cardiac transplantation and coronary artery bypass grafting.

Cardiac surgery with cardiopulmonary bypass triggers an inflammatory response involving proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6, and interleukin-8. To elucidate the pathophysiology of this cytokine response, we explored the possible differences in cytokine responses between patients undergoing heart transplantation and those undergoing coronary artery bypass grafting. Plasma levels of tumor necrosis factor-alpha, interleukin-6, interleukin-8, and interleukin-10 were measured in eight patients undergoing heart transplantation (mean age 44 years) and eight patients undergoing coronary artery bypass grafting (mean age 61 years). Duration of cardiopulmonary bypass and ischemic time were both longer in the heart transplantation group than in the coronary artery bypass grafting group (133 +/- 26 min vs 100 +/- 31 min, p < 0.05, and 130 +/- 47 min vs 58 +/- 21 min, p < 0.005, respectively). Samples were collected before heparin administration, at aortic crossclamping and declamping, and at 0.5, 1, 1.5, 2, 4, 12, and 24 hours after declamping. Tumor necrosis factor-alpha levels were significantly higher 30 minutes after aortic declamping in the heart transplantation group than in the coronary artery bypass grafting group (68 +/- 30 vs 18 +/- 5 pg/ml, p < 0.05). Interleukin-6 and interleukin-8 levels were also significantly higher 90 minutes after declamping in patients undergoing heart transplantation than in those undergoing coronary artery bypass grafting (310 +/- 63 vs 169 +/- 24 pg/ml, p < 0.05, and 73 +/- 17 vs 24 +/- 5 pg/ml, p < 0.01, respectively). Furthermore, interleukin-6 and interleukin-8 values 90 minutes after declamping were significantly correlated with the ischemic time (r = 0.72 and r = 0.82, respectively, both p < 0.05). Interleukin-10 levels in both groups rose to reach a peak value of around 115 pg/ml 1 hour after declamping. Patients undergoing heart transplantation exhibited a second peak of tumor necrosis factor-alpha, interleukin-8, and interleukin-10 levels 12 hours after declamping, probably related to the administration of rabbit antihuman thymocyte immunoglobulin (Thymoglobuline) 3 hours after declamping. Interleukin-6 levels decreased more significantly 12 and 24 hours after declamping in patients undergoing heart transplantation, probably related to methylprednisolone therapy. In conclusion, cardiopulmonary bypass is associated with the production of both proinflammatory and antiinflammatory cytokines. The production of proinflammatory cytokines in patients undergoing heart transplantation is higher than that in patients undergoing coronary artery bypass grafting, and this increase could be related to the longer duration of ischemia in the former group. The later course of cytokine levels after heart transplantation may be further influenced by immunosuppressive therapy.

Late results of valve replacement with the Björk-Shiley valve (1973 to 1982)

Cardiac valve replacement with use of only the Björk-Shiley prosthesis was performed in 1253 patients between January 1973 and December 1982. There were 828 patients having aortic valve replacement, 280 patients having mitral valve replacement, and 145 patients having double valve replacement with aortic and mitral valve prostheses. Patient outcome was stratified according to multiple variables, including valve position and valve model (spherical versus convexo-concave discs). No valve failure due to strut fracture was identified in 26 high-risk patients (mitral valve replacement with greater than or equal to 29 mm implanted in patients less than or equal to 50 years of age) followed up for a mean of 10 years postoperatively. Fifteen patients had late thrombosis of their Björk-Shiley prosthesis (0.28 per 100 patient-years), but there was no significant difference in risk of valve thrombosis comparing the spherical and convexo-concave discs (0.27 per 100 patient-years versus 0.27 per 100 patient-years). One hundred two patients had 128 thromboembolic episodes; rates of thromboembolism after aortic valve replacement, mitral valve replacement, and double valve replacement were 2.1, 4.3, and 4.6 per 100 patient-years, respectively. Percentages of patients free from thromboemboli after aortic valve replacement, mitral valve replacement, and double valve replacement were 93% +/- 1%, 86% +/- 2%, and 89% +/- 3% at 5 years postoperatively and 87% +/- 2%, 79% +/- 5%, and 77% +/- 8% 10 years postoperatively. There was no significant difference in the rates of thromboemboli for spherical and convexo-concave discs for all patients and for each of the subgroups. Ten-year actuarial survival estimates for patients dismissed alive from the hospital after aortic valve replacement, mitral valve replacement, and double valve replacement with the Björk-Shiley valve were 65% +/- 4%, 63% +/- 5%, and 55% +/- 8%, respectively. Overall event-free survival (freedom from death, thromboembolism, anticoagulant-related bleeding, endocarditis, and reoperation) was similar for the three patient groups. Performance of the Björk-Shiley valve as judged by late patient follow-up is similar to other mechanical valves, and modifications in disc design do not appear to have reduced the threat of late valve thrombosis and thromboemboli. Evidence does not support elective explantation of this prosthesis.

Effect of positive end-expiratory pressure on right ventricular function in humans.

The effect of positive end-expiratory pressure (PEEP) on right ventricular (RV) function in humans is complex. Previous studies have been limited in their interpretation by not defining either pericardial pressure (Ppc) or RV volumes. Accordingly, we measured RV volumes and pressures and Ppc as PEEP was increased from zero to 15 cm H2O in 12 patients after thoracotomy, using a pulmonary arterial catheter equipped with a rapid responding thermistor that allowed measurement of RV ejection fraction (ef), while Ppc was measured via a pericardial balloon catheter. RV end-diastolic volume (EDV) was estimated as the ratio of stroke volume (SV) to RVef, whereas RV end-systolic volume (ESV) was estimated as RV EDV-SV. Right atrial pressure (Pra) was defined as end-diastolic pressure, and pulmonary arterial pressures (Ppa), both peak and mean, were used as end-systolic pressures. PEEP increased Ppc, Pra, and lung compliance (Cl). Cardiac output also decreased but not significantly. Neither mean nor peak systolic Ppa, nor RVef was significantly altered by PEEP. There was no relation between either RV filling pressure (Pra-Ppc) and EDV or the change in RV filling pressure and EDV, although EDV varied significantly as PEEP varied for individuals (p less than 0.05). Similarly, there was no relation between Ppa and ESV when either mean or peak Ppa values relative to Ppc were used. The relations between EDV and both SV and RVef were weak (r = 0.54 and 0.55, respectively). RVef varied inversely with ESV (r = -0.77), although it showed no relation to transmural peak Ppa (r = 0.28).(ABSTRACT TRUNCATED AT 250 WORDS)

Mass concentration of creatine kinase MB isoenzyme and lactate dehydrogenase isoenzyme 1 in diagnosis of perioperative myocardial infarction after coronary bypass surgery.

Recent advances in methodology allow the mass concentration of creatine kinase MB isoenzyme (CK-MB), and of lactate dehydrogenase isoenzyme 1 (LD1) to be determined quickly and easily as routine, emergency tests. We evaluated these tests as diagnostic criteria of perioperative myocardial infarction (PMI) after coronary bypass surgery. These tests were compared with the usual measurements of CK-MB activity by immunoinhibition and LD1 by electrophoresis and with other biological markers of myocardial infarction such as total CK, total LD, and aspartate aminotransferase. Sixty-one patients who underwent coronary bypass grafting were followed pre- and postoperatively by enzyme determinations and electrocardiography; a subgroup was monitored by myocardial scintigraphy. CK-MB mass appeared to be the best marker of PMI during the first 48 h, although LD1 was the marker of choice from days 2 to 4.

Liver-function studies in heart-transplant recipients treated with cyclosporin A.

Cyclosporine (CsA) hepatotoxicity has been reported but has not been studied systematically. This study includes 17 patients undergoing heart transplantation (HTx) and being treated with CsA, azathioprine, and corticosteroids. We assessed liver function in these patients before HTx and during the following month by five biological tests: total bile acids (BA), alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), and total bilirubin in serum, and the aminopyrine breath test (ABT). With these tests we could classify the patients into three groups before HTx: normal (group I), mildly altered (group II), and severely altered (group III) liver function. During CsA therapy we did not observe any changes in any test results except for BA and GGT, and these only in group III. The ABT improved significantly in this group. During kinetic studies in patients without liver dysfunction, we confirmed a direct interference of CsA on BA secretion mechanism, but not the GGT increase, which remains to be explained.

Comparison of the effect of beta adrenergic antagonists with different ancillary properties on isolated canine and human coronary arteries.

Experiments were performed on canine and human isolated coronary arteries to characterise human coronary beta adrenoceptors and to determine whether or not beta blocking agents with different ancillary properties unmask the alpha adrenergic effect of noradrenaline in a similar way. The inhibitory effects of atenolol (a beta1 selective antagonist), epanolol (a beta1 selective antagonist with modest intrinsic sympathetic activity), and propranolol (a non-selective antagonist) were assessed on isoproterenol concentration-response curves. Regression analysis provided slopes not significantly different from unity and similar pA2 values for each agent in both preparations. In a second group of experiments, the effects of noradrenaline (10 mumol.litre-1) were assessed in the absence and presence of beta blockade. At equipotent doses (1 log or 2 log units from the pA2 values) each beta blocking agent unmasked the alpha effect of noradrenaline in the same way. This alpha effect of noradrenaline (10 mumol.litre-1) was completely abolished by prazosin 1 mumol.litre-1 in canine coronary arteries but only partially antagonised in human coronary arteries. Thus the property of a beta blocking agent to unmask the alpha adrenergic effect of adrenaline is mainly related to its affinity for the coronary smooth muscle beta adrenoceptors. These beta adrenoceptors were very similar in both preparations and appear to be mainly beta1. The alpha adrenoceptors seem, nevertheless, to be different and resistant to prazosin in human preparations.

[Effects of physical training on the denervated human heart after orthotopic cardiac transplantation]. / Effets de l'entraînement physique sur le coeur humain dénervé après transplantation cardiaque orthotopique.

Three patients who had undergone an orthotopic cardiac transplantation followed a course of supervised intermittent physical training (60 to 80 per cent of the maximum load) involving three weekly sessions of thirty minutes, for a period of 150 +/- 80 days. During maximal effort, we observed increases of 50 per cent in the load in watts (0.05 less than p less than 0.1), 40 per cent in oxygen consumption (0.1 less than p less than 0.2), 10 per cent in heart rate (p = 0.5) and 21 per cent in systolic blood pressure (0.7 less than p less than 0.8). The respiratory equivalent for oxygen decreased by 21 per cent (0.025 less than p less than 0.05) and the respiratory quotient by 5 per cent (0.4 less than p less than 0.05). For a given submaximal effort (30 watts) the following decreases were observed: 9 per cent in oxygen consumption (V'O2) (0.1 less than p less than 0.2), 32 per cent in the minute ventilation (V'E) (0.05 less than p less than 0.1), 22 per cent in the respiratory equivalent for oxygen (REO2) (0.025 less than p less than 0.05), 8 per cent in the respiratory quotient (RQ) (0.2 less than p less than 0.3) and 11 per cent in the heart rate (HR) (0.1 less than p less than 0.2). The systolic blood pressure (SBP) increased by 6 per cent (0.2 less than p less than 0.3). No changes were observed in these parameters in the postoperative follow-ups (10 to 24 months) of two patients who did not undergo physical training. Physical training is, therefore, necessary in the process of physical readaptation of patients after orthotopic cardiac grafts.

[Early exercise test after revascularization and rehabilitation]. / Epreuve d'effort précoce après revascularisation coronaire et revalidation.

Ergospirometry was performed on 51 patients before their discharge from hospital, that is between the seventh and tenth days after myocardial revascularization by cardiac bypass surgery. The aim of our study is to show that this type of measurement can be performed with reasonable safety and that it gives an accurate assessment of the patient's ability to withstand exercise. It employs a metabolic approach: study of oxygen consumption (V'O2), carbon dioxide release (V'CO2), the respiratory quotient (RQ), the minute ventilation (V'E) and the respiratory equivalent for oxygen (REO2). The patients withstood a mean load of 82 +/- 17.7 watts for a mean V'O2 of 1.186 +/- 0.258 l/min STPD and a mean V'E of 46.5 +/- 10 l/min BTPS. Changes in respiratory and metabolic parameters as a function of load are discussed, as is the advice that can be given to the patient regarding physical rehabilitation.

Metabolic implications during a 20-km run after heart transplantation.

The aim of the present study was to evaluate a heart transplanted patient who ran a 20-km race 9 months after surgery. Thirty-six healthy male subjects were studied during the same run and served as control group. Biochemical variables were determined in blood and urine samples collected before and after the race. Post-exercise blood urea increased by 23% (P less than 0.05) in the control group but remained unchanged in the patient. Blood lactate increased far more in the transplanted patient (7.07 mmol/L) than in the control subjects (2.53 mmol/L). The exercise induced a 5.46- and 0.67-fold increase in creatine phosphokinase activity in the transplanted patient and control group, respectively. The creatinine and urea urinary excretion and clearance decreased by 40%-60% after exercise for all subjects. It may be concluded that the heart transplanted patient responded for most registered variables in the same way as normal subjects, but some differences occurred on the renal side due to the use of an immunosuppressive drug.

[Giant condyloma of the anus: tumor of Buschke-Loewenstein (author's transl)]. / Condylome acuminé géant de l'anus: tumeur de Buschke-Loewenstein.

The authors report a case of a Buschke-Loewenstein tumor located at the anus. Initial treatment with Bleomycin was remarkably effective. A recurrence 3 months later did not respond any more to Bleomycin. Multiple surgical resections were performed in association with this form of chemotherapy.