Tranexamic acid and aprotinin in low- and intermediate-risk cardiac surgery: a non-sponsored, double-blind, randomised, placebo-controlled trial.

OBJECTIVE: Tranexamic acid has been suggested to be as effective as aprotinin in reducing blood loss and transfusion requirements after cardiac surgery. Previous studies directly comparing both antifibrinolytics focus on high-risk cardiac surgery patients only or suffer from methodological problems. We wanted to compare the effectiveness of tranexamic acid versus aprotinin in reducing postoperative blood loss and transfusion requirements in the patient group representing the majority of cardiac surgery patients: low- and intermediate-risk patients. METHODS: We conducted a non-sponsored, double-blind, randomised, placebo-controlled trial in which 298 patients scheduled for low- or intermediate-risk (mean logistic EuroSCORE 4.1) first-time heart surgery with use of cardiopulmonary bypass were randomised to receive either tranexamic acid, high-dose aprotinin, or placebo. All patients had preoperative normal renal function. End points of the study were monitored from the time of surgery until patient discharge. This trial was executed between June 2004 and October 2006. RESULTS: Both antifibrinolytics significantly reduced blood loss and transfusion requirements when compared with placebo. Aprotinin was about twice as effective as tranexamic acid in reducing total postoperative blood loss (estimated median difference 155 ml, 95% confidence interval (CI) 60-260; p < 0.001). Accordingly, aprotinin reduced packed red blood cell transfusions more than tranexamic acid, although the difference did not reach statistical significance. Only aprotinin significantly reduced the proportion of transfused patients when compared with placebo (mean difference -20.9%, 95% CI 7.3-33.5; p = 0.013), and only aprotinin completely abolished bleeding-related re-explorations (mean difference 6.8%, 95% CI 1.6-13.4%; p = 0.004). Neither antifibrinolytic agent increased the incidence of mortality (mean difference tranexamic acid -0.4%, 95% CI -4.6 to 4.4; p = 0.79, mean difference aprotinin -1.3%, 95% CI -6.2 to 3.5; p = 0.62) or other serious adverse events when compared with placebo. CONCLUSION: Aprotinin has clinically significant advantages over tranexamic acid in patients with normal renal function scheduled for low- or intermediate-risk cardiac surgery.

Haemodynamics and left ventricular function in heart failure patients: comparison of awake versus intra-operative conditions.

BACKGROUND: Heart failure patients are increasingly subjected to surgery. Left ventricular (LV) function is generally assessed in awake patients, but intra-operative LV function is not well studied. AIM: To investigate the relation between LV function indices obtained in the catheterization laboratory and those obtained intra-operatively. METHODS: We enrolled 11 patients with heart failure (NYHA III-IV) scheduled for surgical interventions. LV function was assessed by pressure-volume loops (conductance catheter) during diagnostic catheterizations and intra-operatively under anaesthetized conditions. RESULTS: Compared to awake conditions, cardiac output was unchanged intra-operatively but ejection fraction was significantly reduced (-16%) due to increased end-diastolic volume (+13%). Systolic and diastolic LV pressure and afterload (E(A)) dropped significantly (-32%, -22%, -35%, respectively). LV systolic function assessed by dP/dt(MAX) and the end-systolic pressure-volume relation (E(ES)) was significantly reduced (-34%, -35%). LV diastolic stiffness was reduced (-44%). Ventricular-arterial coupling (E(A)/E(ES)) was maintained. CONCLUSION: Intra-operative cardiac output was unchanged compared to awake conditions due to a balance between reduced systolic and improved diastolic function. Ventricular-arterial coupling was maintained by a reduced afterload. Presumably, systolic function and afterload were reduced by anaesthesia, whereas diastolic function improved after pericardectomy. These findings provide insight into the combined effects of anaesthesia, thoracotomy and pericardectomy, and help to interpret LV function measurements in intra-operative conditions.

Alfentanil and placebo analgesia: no sex differences detected in models of experimental pain.

BACKGROUND: To assess whether patient sex contributes to the interindividual variability in alfentanil analgesic sensitivity, the authors compared male and female subjects for pain sensitivity after alfentanil using a pharmacokinetic-pharmacodynamic modeling approach. METHODS: Healthy volunteers received a 30-min alfentanil or placebo infusion on two occasions. Analgesia was measured during the subsequent 6 h by assaying tolerance to transcutaneous electrical stimulation (eight men and eight women) of increasing intensity or using visual analog scale scores during treatment with noxious thermal heat (five men and five women). Sedation was concomitantly measured. Population pharmacokinetic-pharmacodynamic models were applied to the analgesia and sedation data using NONMEM. For electrical pain, the placebo and alfentanil models were combined post hoc. RESULTS: Alfentanil and placebo analgesic responses did not differ between sexes. The placebo effect was successfully incorporated into the alfentanil pharmacokinetic-pharmacodynamic model and was responsible for 20% of the potency of alfentanil. However, the placebo effect did not contribute to the analgesic response variability. The pharmacokinetic-pharmacodynamic analysis of the electrical and heat pain data yielded similar values for the potency parameter, but the blood-effect site equilibration half-life was significantly longer for electrical pain (7-9 min) than for heat pain (0.2 min) or sedation (2 min). CONCLUSIONS: In contrast to the ample literature demonstrating sex differences in morphine analgesia, neither sex nor subject expectation (i.e., placebo) contributes to the large between-subject response variability with alfentanil analgesia. The difference in alfentanil analgesia onset and offset between pain tests is discussed.

Left ventricular function and chronotropic responses after normothermic cardiopulmonary bypass with intermittent antegrade warm blood cardioplegia in patients undergoing coronary artery bypass grafting.

OBJECTIVE: Recent studies indicate that normothermic cardiopulmonary bypass (CPB) with intermittent antegrade warm blood cardioplegia (IAWBC) may have metabolic and clinical advantages, but limited data exist on its effects on myocardial function. Therefore, we investigated the acute effects of this approach on systolic and diastolic left ventricular function and on chronotropic responses. METHODS: In 10 patients undergoing isolated CABG we obtained on-line left ventricular pressure-volume loops using the conductance catheter before and after normothermic CPB with IAWBC. Steady state and load-independent indices of left ventricular function derived from pressure-volume relations were obtained during right atrial pacing (80-100-120 beats/min) to determine baseline systolic and diastolic function and chronotropic responses. RESULTS: The mean time of CPB was 105+/-36 min (median 103, range 60-167 min) with a mean aortic cross-clamp time of 75+/-27 min (median 69, range 43-129 min). Baseline (80 beats/min) end-systolic elastance (E(ES)) did not change after CPB (1.22+/-0.53 to 1.12+/-0.28 mm Hg/ml, P>0.2), while the diastolic chamber stiffness constant (k(ED)) significantly increased (0.014+/-0.005 to 0.040+/-0.007 ml-1, P=0.018) and relaxation time constant (tau) significantly decreased (61+/-3 to 49+/-2 ms, P=0.004). Before CPB, incremental atrial pacing had no significant effects on E(ES) and tau but significant negative effects on kED (0.014+/-0.005 to 0.045+/-0.012 ml-1, P=0.013). After CPB, atrial pacing had significant positive effects on E(ES), tau and kED (E(ES): 1.12+/-0.28 to 2.60+/-1.54 mm Hg/ml, P=0.021; tau: 49+/-2 to 45+/-2 ms, P=0.009; kED: 0.040+/-0.007 to 0.026+/-0.005 mm Hg, P=0.010), indicating improved systolic and diastolic chronotropic responses. CONCLUSION: On-pump normothermic CABG with IAWBC preserved systolic function, increased diastolic stiffness, and improved systolic and diastolic chronotropic responses. Normalization of the chronotropic responses post-CPB is likely due to effects of successful revascularization and subsequent relief of ischemia.

Perioperative assessment of left ventricular function by pressure-volume loops using the conductance catheter method.

UNLABELLED: Interpretation of perioperative measurements of cardiac function during cardiac surgery is complicated by changes in loading conditions induced by anesthesia, cardiopulmonary bypass (CPB), and the surgical procedure itself. Quantification of left ventricular (LV) function by pressure-volume relations as obtained by the conductance catheter would be advantageous because load-independent indices can be determined. Accordingly, we evaluated methodological aspects of the conductance-catheter technique and documented LV function before and after CPB in eight patients undergoing coronary artery bypass grafting. LV pressure-volume loops by transesophageal echocardiography-guided transaortic application of the conductance catheter were obtained at steady-state and during preload reduction by temporary occlusion of the inferior cava. All patients remained hemodynamically stable, and no complications occurred. Complete data were acquired within 15 min before and after CPB. Cardiac output (5.2 +/- 1.3 L/min to 6.0 +/- 1.4 L/min) and LV ejection fraction (46% +/- 17% to 48% +/- 19%) did not change, but end-diastolic pressure increased significantly after CPB (8 +/- 2 mm Hg to 16 +/- 7 mm Hg; P < 0.05). Load-independent systolic indices remained constant (end-systolic elastance: 1.31 +/- 1.20 mm Hg/mL to 1.13 +/- 0.59 mm Hg/mL). Diastolic function changed significantly after CPB, as the relaxation time constant decreased from 64 +/- 6 ms to 52 +/- 5 ms (P < 0.05) and the chamber stiffness constant increased from 0.016 +/- 0.014/mL to 0.038 +/- 0.016/mL (P < 0.05). We conclude that the conductance catheter method provides detailed data on perioperative myocardial function and may be useful for evaluating the effects of new surgical and anesthetic procedures. IMPLICATIONS: Pressure-volume loops provide on-line quantification of intrinsic systolic and diastolic myocardial function in a load-independent fashion. This study shows the feasibility of perioperative pressure-volume analysis by use of the conductance-catheter method. This method provides detailed data about the immediate effects of surgery and may be used to evaluate complex cardiac procedures.

Propofol reduces perioperative remifentanil requirements in a synergistic manner: response surface modeling of perioperative remifentanil-propofol interactions.

BACKGROUND: Remifentanil is often combined with propofol for induction and maintenance of total intravenous anesthesia. The authors studied the effect of propofol on remifentanil requirements for suppression of responses to clinically relevant stimuli and evaluated this in relation to previously published data on propofol and alfentanil. METHODS: With ethics committee approval and informed consent, 30 unpremedicated female patients with American Society of Anesthesiologists physical status class I or II, aged 18-65 yr, scheduled to undergo lower abdominal surgery, were randomly assigned to receive a target-controlled infusion of propofol with constant target concentrations of 2, 4, or 6 microg/ml. The target concentration of remifentanil was changed in response to signs of inadequate anesthesia. Arterial blood samples for the determination of remifentanil and propofol concentrations were collected after blood-effect site equilibration. The presence or absence of responses to various perioperative stimuli were related to the propofol and remifentanil concentrations by response surface modeling or logistic regression, followed by regression analysis. Both additive and nonadditive interaction models were explored. RESULTS: With blood propofol concentrations increasing from 2 to 7.3 microg/ml, the C(50) of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy, from 4.4 ng/ml to 1.2 ng/ml for intubation, and from 6.3 ng/ml to 0.4 ng/ml for intraabdominal surgery. With blood remifentanil concentrations increasing from 0 to 7 ng/ml, the C(50) of propofol for the return to consciousness decreased from 3.5 microg/ml to 0.6 microg/ml. CONCLUSIONS: Propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal surgical stimulation in a synergistic manner. In addition, remifentanil decreases propofol concentrations associated with the return of consciousness in a synergistic manner.

Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index.

BACKGROUND: Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans. METHODS: The effect of steady-state concentrations of remifentanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentration range: propofol studies, 0-2.6 microg/ml; remifentanil studies, 0-2.0 ng/ml). Respiratory experiments consisted of ventilatory responses to three to eight increases in end-tidal Pco2 (Petco2). Invasive blood pressure, heart rate, and bispectral index were monitored concurrently. The nature of interaction was assessed by response surface modeling using a population approach with NONMEM. Values are population estimate plus or minus standard error. RESULTS: A total of 94 responses were obtained at various drug combinations. When given separately, remifentanil and propofol depressed cardiorespiratory variables in a dose-dependent fashion (resting V(i) : 12.6 +/- 3.3% and 27.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; V(i) at fixed Petco of 55 mmHg: 44.3 +/- 3.9% and 57.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; blood pressure: 9.9 +/- 1.8% and 3.7 +/- 1.1% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting V(i)). The effects of both drugs on heart rate and blood pressure were modest, with additive interactions when combined. Over the dose range studied, remifentanil had no effect on bispectral index even when combined with propofol (inert interaction). CONCLUSIONS: These data show dose-dependent effects on respiration at relatively low concentrations of propofol and remifentanil. When combined, their effect on respiration is strikingly synergistic, resulting in severe respiratory depression.