Aprotinin and tranexamic acid for high transfusion risk cardiac surgery.

BACKGROUND: Studies have shown that aprotinin and tranexamic acid can reduce postoperative blood loss after cardiac operation. However, which drug is more efficacious in a higher risk surgical group of patients, has yet to be defined in a randomized study. METHODS: With informed consent, 80 patients undergoing elective high transfusion risk cardiac procedures (repeat sternotomy, multiple valve, combined procedures, or aortic arch operation) were randomized in a double-blind fashion, to receive either high dose aprotinin or tranexamic acid. Patient and operative characteristics, chest tube drainage and transfusion requirements were recorded. RESULTS: There was no significant difference between the 2 treatment groups with respect to age, cardiopulmonary bypass time, complications (myocardial infarction, stroke, death), chest tube drainage (6, 12, or 24 hours), blood transfusions up to 24 hours postoperatively, total allogeneic blood transfusions for entire hospital stay, or induction/postoperative hemoglobin levels. However, multiple regression analysis revealed a positive relationship between cardiopulmonary bypass time and 24 hour blood loss in the tranexamic acid group (p = 0.001), unlike the aprotinin group where 24 hour blood loss is independent of cardiopulmonary bypass time (p = 0.423). CONCLUSIONS: Overall, there was no significant difference in blood loss, or transfusion requirements, when patients received either aprotinin or tranexamic acid for high transfusion risk cardiac operation. Aprotinin, when given as an infusion in a high-dose regimen, was able to negate the usual positive effect of cardiopulmonary bypass time on chest tube blood loss.

Metaanalysis of prophylactic drug treatment in the prevention of postoperative bleeding.

Prophylactic drug treatment is one of several strategies to reduce postoperative blood loss and potentially limit homologous blood use in open heart surgery. A computerized MEDLINE search supplemented with manual bibliography reviews was performed for randomized clinical trials published in peer-reviewed English-language journals from January 1980 to June 1993. A metaanalysis was conducted of trials evaluating desmopressin (group DD, n = 13), epsilon-aminocaproic acid or tranexamic acid (group EA, n = 4), and aprotinin (group AP, n = 16). Eligible studies used placebo controls and administered the drug in a prophylactic manner. The primary study end point was postoperative chest tube loss (mL, mean +/- standard deviation). There was a significant reduction in postoperative chest tube loss detected for each of the active treatments versus the placebo (DD versus controls: percent reduction 0.11, p = 0.0021; EA versus controls: percent reduction 0.30, p < 0.0001; and AP versus controls: percent reduction 0.36, p < 0.0001). Therapy with EA or AP was associated with a greater reduction in chest tube loss than DD (EA versus DD, p = 0.0033, and AP versus DD, p < 0.0001). Secondary study end points were transfusion requirements, chest reexploration, and perioperative mortality. The volume of postoperative red cell transfusion (mean +/- standard deviation) was reduced with EA (p < 0.0001) or AP treatment (p < 0.0001) compared with a placebo or DD, whereas the proportion of patients given transfusions was limited only in the AP-treated patients (odds ratio 0.23; 95% confidence interval, 0.16 to 0.33; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiopulmonary bypass, rewarming, and central nervous system dysfunction.

BACKGROUND: During cardiopulmonary bypass a nasopharyngeal temperature greater than 38 degrees C at the end of rewarming may indicate cerebral hyperthermia. This could exacerbate an ischemic brain injury incurred during cardiopulmonary bypass. METHODS: In a cohort of 150 aortocoronary bypass patients neuropsychologic test scores of 66 patients whose rewarming temperature exceeded 38 degrees C were compared with those who did not. There were no differences between groups with respect to demographic and intraoperative variables. RESULTS: A trend was seen for hyperthermic patients to do worse on all neuropsychologic tests in the early postoperative period but not at 3-month follow-up. By analysis of covariance hyperthermic patients did worse on the visual reproduction subtest of the Weschler memory scale at 3 months (p = 0.02), but this difference was not found by linear regression (p = 0.10). CONCLUSIONS: We were unable to demonstrate any significant deterioration in patients rewarmed to greater than 38 degrees C in the early postoperative period. The poorer performance in the visual reproduction subtest of the Wechsler memory scale at 3 months in the group rewarmed to more than 38 degrees C is interesting but far from conclusive. Caution with rewarming is still advised pending more in-depth study of this issue.

Normothermic versus hypothermic cardiopulmonary bypass: central nervous system outcomes.

The recent advent of "warm heart" surgery has resulted in reexamination of the neuroprotective effects of hypothermia in the setting of cardiopulmonary bypass (CPB). Hypothermia has been shown to confer significant protection in the setting of transient, but not permanent, ischemia. The mechanism of this neuroprotection is unclear at this time. Reduction in cerebral metabolic rate is believed to be less important compared with the effect of hypothermia on the release of excitatory neurotransmitters, catecholamines, or other mediators of cellular injury. It is for this reason that mild hypothermia (33-35 degrees C) is believed to confer significant neuroprotection. Two large randomized trials of warm versus cold heart surgery have been reported. Neither study found a difference in terms of neuropsychologic dysfunction. However, one study identified a threefold increase in strokes in the "warm" patients. The reasons for this difference are not clear; however, there were various differences in technique and patient population that may have been important. There are other reports of large series of patients undergoing normothermic bypass, with no increase in stroke rate over what is reported elsewhere in the literature. To date, the evidence would suggest that neuropsychologic function is not affected by CPB temperature, suggesting that the transient ischemia is not an important mechanism in this injury. Stroke after CPB is usually the result of permanent ischemia, and hypothermia's effect in this setting is minimal. It would seem unlikely that hypothermia offers anything more than modest benefits in the clinical situation where there is no circulatory arrest.

Ketamine concentrations during cardiopulmonary bypass.

PURPOSE: To describe the serum concentrations of ketamine following a clinically relevant dosing schedule during cardiopulmonary bypass (CPB). DESIGN: Prospective case series. SETTING: Tertiary care teaching hospital. PATIENTS: Six patients undergoing coronary artery bypass grafting and over age 60 yr. INTERVENTION: Following induction of anaesthesia each patient received a bolus of ketamine 2 mg.kg-1 followed by an infusion of 50 micrograms.kg-1.min-1 which ran continuously until two hours after bypass. MAIN OUTCOME MEASURES: Ketamine serum concentrations were measured at five minutes after bolus, immediately following aortic cannulation, 10 and 20 min on CPB, termination of CPB, termination of the drug infusion and three and six hours after infusion termination. RESULTS: At the time of aortic cannulation, ketamine concentrations were 3.11 +/- 0.81 micrograms.ml-1, these levels decreased by one third with the initiation of CPB. By the end of CPB the concentrations had returned to levels roughly equivalent to those observed at the time of aortic cannulation. Following cessation of the infusion, ketamine concentration declined in a log-linear fashion with a half-life averaging 2.12 hr. (range 1.38-3.09 hr). CONCLUSION: This dosage regimen maintained general anaesthetic concentrations of ketamine throughout the operative period. These levels should result in brain tissue concentrations in excess of those previously shown to be neuroprotective in animals. Thus we conclude that this infusion regimen would be reasonable to be use in order to assess the potential neuroprotective effects of ketamine in humans undergoing CPB.

Central-nervous-system dysfunction after warm or hypothermic cardiopulmonary bypass.

The increasing popularity of warm heart surgery led us to assess the effect of temperature during cardiopulmonary bypass (CPB) on neuropsychological function after coronary surgery. 34 patients enrolled in a randomised trial of normothermic versus hypothermic CPB were subjected to a battery of psychomotor and memory tests before and after their operations. The mean nasopharyngeal temperature for warm CPB was 34.7 (SD 0.5) degrees C and that for hypothermic CPB was 27.8 (2.0) degrees C. In all seven neuropsychological tests the postoperative scores were better in the warm CPB than in the hypothermic group, although only one difference achieved significance (trial-making test A; p less than 0.023). Thus, neurological function after normothermic CPB seems to be no worse than that after hypothermic procedures.

Cardiopulmonary bypass, temperature, and central nervous system dysfunction.

BACKGROUND: Neurological injury is an important cause of morbidity and mortality after cardiac surgery. With the advent of warm heart surgery, the neuroprotective role of hypothermic cardiopulmonary bypass (CPB) has come under increasing scrutiny. Preliminary work by us in the area found no increased risk of neurological morbidity with normothermic CPB in a small group of patients and suggested a possible benefit. The purpose of the present study is to compare the incidence of neurological and neuropsychological dysfunction in a larger number of patients randomized to warm or cold aortocoronary bypass surgery. METHODS AND RESULTS: With the approval of the institutional research ethics committee, 201 aortocoronary bypass patients were randomized to normothermic or moderate hypothermic CPB and subjected to neurological and neuropsychological evaluation. These subjects were a subset of patients enrolled in a large multicenter trial comparing warm versus cold heart surgery. The examinations took place preoperatively, 5 days after operation, and a 3-month follow-up. The examination consisted of a clinical neurological examination and a brief neuropsychological test battery. The neuropsychological tests included the Buschke selective reminding procedure, the Wechsler memory scale-revised visual reproduction subtest, the trial making test (parts A and B), the Wechsler adult intelligence scale-revised digit symbol subtest, and the grooved pegboard test. The examiner and subjects were unaware of the CPB temperature allocation (warm, > 34 degrees C; cold, < or = 28 degrees C). Statistical analysis was performed using the SAS statistical software package. Two hundred one patients were enrolled in the study. Of these, 155 patients completed the entire protocol and were included in the final analysis (warm group, n = 78; cold group, n = 77). One patient in the warm group died perioperatively from a massive hemispheric stroke. Another warm group patient was unable to complete neuropsychological evaluation because of a perioperative stroke. Thus, 153 patients completed the entire series of neuropsychological tests. A total of 6 patients (warm group, n = 2; cold group, n = 4; P = NS) suffered from perioperative focal neurological deficits. There was a consistent deterioration in scores from tests of psychomotor speed/coordination (trial making, digit symbol, pegboard) in the early postoperative period, which resolved by the 3-month follow-up. Tests of memory (Buschke, Wechsler memory scale) showed no evidence of patient deterioration in the postoperative period. No difference was seen between the warm and cold groups. CONCLUSIONS: In this randomized trial of normothermic versus hypothermic CPB, we found deterioration in scores of tests of psychomotor speed but not of memory in the early postoperative period. We were unable to demonstrate any neuroprotective effect from moderate hypothermia in this patient population.

Phase 1 human trial of adenosine-potassium cardioplegia.

BACKGROUND: The cardioprotective role of adenosine in various models of ischemia-reperfusion, including adenosine supplementation to cardioplegic formulations, has been studied extensively. The appropriate dose of adenosine in humans is uncertain and could be limited by systemic hypotension or AV block. METHODS AND RESULTS: An open-label, nonrandomized phase 1 adenosine dose-ranging study was performed. Patients scheduled for primary isolated coronary bypass surgery were eligible for the study. Antegrade warm blood potassium cardioplegia (ratio, 4:1, blood to crystalloid) was administered in the routine fashion, with adenosine added to the initial 1000-mL dose and final 500-mL dose. Patients were studied in blocks of 4 per concentration. An escalating adenosine dosage schedule was planned to produce blood cardioplegia concentrations from 0 to 250 mumol/L, and the blocks were tested sequentially. Stopping rules were defined for systemic hypotension (phenylephrine dose during cardiopulmonary bypass > or = 5.0 mg; phenylephrine dose during cardioplegic induction > or = 800 micrograms) and AV block (permanent pacemaker insertion; temporary pacing dependency for > 90 minutes after cardiopulmonary bypass). Doses of 1, 2.5, 5, 10, and 25 mumol/L were well tolerated. With 50 mumol/L, systemic hypotension occurred during cardioplegic induction in 3 of 4 patients versus 1 of 24 (P < .005) at all lower concentrations (880 +/- 217 versus 297 +/- 286 micrograms phenylephrine per patient). The studies were repeated with an 8:1 blood-to-crystalloid cardioplegia delivery system. Adenosine concentrations of 0 (n = 4), 15 (n = 12), 20 (n = 8), and 25 mumol/L (n = 4) were tested. Hypotension during cardioplegic induction was more prevalent (P = .05) with the higher doses (15 mumol/L, 394 +/- 189 micrograms, 1 of 12 patients; 20 mumol/L, 360 +/- 355 micrograms, 2 of 8 patients; 25 mumol/L, 600 +/- 478 micrograms, 2 of 4 patients). There were no differences with respect to systemic hypotension during cardiopulmonary bypass or for pacing > 90 minutes after discontinuation of cardiopulmonary bypass, and no patient required permanent pacing. There have been no deaths, Q-wave myocardial infarctions, intra-aortic balloon pump insertions, or cerebral infarctions in the total sample of 56 patients. CONCLUSIONS: Our initial investigations have shown that adenosine can be safely administered during cardiopulmonary bypass. The authors recommend that further studies are warranted using adenosine 15 to 25 mumol/L, depending on the delivery system.

Phase 2 studies of adenosine cardioplegia.

BACKGROUND: Laboratory evidence supports the use of adenosine-supplemented cardioplegia. An initial phase 1 dose-ranging clinical evaluation demonstrated that an adenosine concentration of 15 mumol/L could be safely administered with warm blood cardioplegia and suggested that phase 2 studies were warranted. METHODS AND RESULTS: Two separate double-blind, randomized, placebo-controlled trials were performed in patients undergoing primary, isolated, nonemergent coronary artery bypass graft surgery. Patients were randomized to receive adenosine 15 mumol/L versus placebo in the first study (n = 200) and adenosine 50 or 100 mumol/L versus placebo in the second study (n = 128). Adenosine was infused with both initial and final doses of warm antegrade blood cardioplegia. The data from the 2 trials were combined using the methods of Mantel and Haenszel, and the results of the meta-analysis are presented as the relative risk with their associated 95% confidence intervals (CI). The different study groups were comparable with respect to all preoperative clinical characteristics, angiographic findings, and intraoperative variables. In both trials 1 and 2, no differences were found between groups in the incidence of the individual primary or secondary outcomes. Similarly, when both studies were combined, there was no significant evidence of any consistent treatment benefit (primary: death: relative risk [RR] = 1.02, 95% CI = 0.06, 16.6; myocardial infarction by CK-MB: RR = 0.84, CI = 0.54, 1.31; low output syndrome: RR = 1.38, CI = 0.29, 6.42; any of the above: RR = 0.98, CI = 0.78, 1.25; secondary: Q-wave myocardial infarction: RR = 1.30, CI = 0.41, 4.13; myocardial infarction by troponin T: RR = 0.7, CI = 0.40, 1.21; inotrope requirement: RR = 0.9, CI = 0.46, 1.79; intra-aortic balloon pump requirement: RR = 0.6, CI = 0.07, 4.81; P > 0.20). CONCLUSIONS: Despite promising experimental data, adenosine supplementation of warm blood cardioplegia did not demonstrate any statistically significant benefit in patients undergoing elective coronary artery bypass graft surgery. Although sample sizes were relatively small, based on our interim analyses, it is unlikely that increased patient enrollment would reveal any substantive clinical differences between groups.