Mika Valtonen

Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting

Background Alpha2 ‐Adrenergic agonists decrease sympathetic tone with ensuing attenuation of neuroendocrine and hemodynamic responses to anesthesia and surgery. The effects of dexmedetomidine, a highly specific alpha2 ‐adrenergic agonist, on these responses have not been reported in patients undergoing coronary artery bypass grafting. Methods Eighty patients scheduled for elective coronary artery bypass grafting received, in a double‐blind manner, either a saline placebo or a dexmedetomidine infusion, initially 50 ng [center dot] kg‐1 [center dot] min‐1 for 30 min before induction of anesthesia with fentanyl, and then 7 ng [center dot] kg‐1 [center dot] min‐1 until the end of surgery. Filling pressures, blood pressure, and heart rate were controlled by intravenous fluid and by supplemental anesthetics and vasoactive drugs. Results Compared with placebo, dexmedetomidine decreased plasma norepinephrine concentrations by 90%, attenuated the increase of blood pressure during anesthesia (3 vs. 24 mmHg) and surgery (2 vs. 14 mmHg), but increased slightly the need for intravenous fluid challenge (29 vs. 20 patients) and induced more hypotension during cardiopulmonary bypass (9 vs. 0 patients). Dexmedetomidine decreased the incidence of intraoperative (2 vs. 13 patients) and postoperative (5 vs. 16 patients) tachycardia. Dexmedetomidine also decreased the need for additional doses of fentanyl (3.1 vs. 5.4), the increments of enflurane (4.4 vs. 5.6), the need for beta blockers (3 vs. 11 patients), and the incidence of fentanyl‐induced muscle rigidity (15 vs. 33 patients) and postoperative shivering (13 vs. 23 patients). Conclusions Intraoperative intravenous infusion of dexmedetomidine to patients undergoing coronary artery revascularization decreased intraoperative sympathetic tone and attenuated hyperdynamic responses to anesthesia and surgery but increased the propensity toward hypotension.

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam.

Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam.

Levosimendan Facilitates Weaning From Cardiopulmonary Bypass in Patients Undergoing Coronary Artery Bypass Grafting With Impaired Left Ventricular Function

BACKGROUND Levosimendan is a compound with vasodilatory and inotropic properties. Experimental data suggest effective reversal of stunning and cardioprotective properties. METHODS This prospective, randomized, placebo-controlled, double-blind study included 60 patients with 3-vessel coronary disease and left ventricular ejection fraction (LVEF) of less than 0.50. Levosimendan administration (12 microg/kg bolus, followed by an infusion of 0.2 microg/kg/min) was started immediately after induction anesthesia. Predefined strict hemodynamic criteria were used to assess the success of weaning. If weaning was not successful, CPB was reinstituted and an epinephrine infusion was started. If the second weaning attempt failed, intraaortic balloon pumping (IABP) was instituted. RESULTS The groups had comparable demographics. The mean (standard deviation) preoperative LVEF was 0.36 (0.8) in both groups. The baseline cardiac index was 1.8 (0.3) L/min/m(2) in the levosimendan group and 1.9 (0.4) L/min/m(2) in the placebo group. The mean duration of CPB to primary weaning attempt was 104 (25) minutes in the levosimendan and 109 (22) minutes in the placebo group. Primary weaning was successful in 22 patients (73%) in the levosimendan group and in 10 (33%) in the placebo group (p = 0.002). The odds ratio for failure in primary weaning was 0.182 (95% confidence interval, 0.060 to 0.552). Four patients in the placebo group failed the second weaning and underwent IABP compared with none in the levosimendan group (p = 0.112). CONCLUSIONS Levosimendan significantly enhanced primary weaning from CPB compared with placebo in patients undergoing 3-vessel on-pump coronary artery bypass grafting. The need for additional inotropic or mechanical therapy was decreased.

Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S-(+)- and R-(−)-Ibuprofen

ABSTRACT Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(−)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(+)- and R-(−)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(+)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (Cmax) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t1/2) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(+)-ibuprofen was 183% of the control value (P < 0.001) and its mean Cmax was 116% of the control value (P < 0.05). The mean t1/2 of S-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P < 0.05) by fluconazole. The geometric mean S-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(−)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure to S-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism of S-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.

Voriconazole, but not terbinafine, markedly reduces alfentanil clearance and prolongs its half-life.

Alfentanil is a short‐acting synthetic opioid analgesic, which is extensively metabolized, mainly by hepatic cytochrome P450 (CYP) 3A enzymes. Concomitant administration of alfentanil and CYP3A inhibitors may lead to clinically important drug interactions. We investigated the possible interactions between alfentanil and orally administered voriconazole and terbinafine.

Effects of levosimendan on renal function in patients undergoing coronary artery surgery.

OBJECTIVES To evaluate the effect of levosimendan on postoperative renal function in patients with compromised heart function undergoing on-pump coronary artery bypass graft surgery. DESIGN A prospective, randomized, placebo-controlled, double-blind substudy. SETTING Cardiothoracic surgery, anesthesiology, and intensive care units at 2 university hospitals. PARTICIPANTS Sixty patients with left ventricular ejection fraction ≤50% were randomized into 2 parallel treatment groups. INTERVENTIONS Levosimendan or placebo was started after the induction of anesthesia with a 12-μg/kg bolus in 10 minutes followed by the infusion of 0.2 μg/kg/min for the next 23 hours and 50 minutes. MEASUREMENTS AND RESULTS Serum cystatin C and plasma creatinine were measured at baseline; at 6 and 24 hours after declamping the aorta; and on the 1st, 2nd, and 5th postoperative days. Urine N-acetyl-β-glucosaminidase (U-NAG) was measured at baseline and at 6 and 24 hours after declamping of the aorta. Renal function was estimated with calculated glomerular filtration rate (eGFR). The changes in plasma creatinine, serum cystatin C, and urine NAG were not significant among the placebo and the levosimendan groups at any of the measuring points. CONCLUSIONS After coronary artery surgery, levosimendan did not have a significant influence on the kidney function measured with these specific kidney markers.

New mini-extracorporeal circulation system (ECC.O) is a safe technique in coronary surgery

Objectives. Cardiopulmonary bypass (CPB) is known to cause the systemic inflammatory reaction after cardiac surgery. New coated and closed loop circuit systems may reduce this inflammation response and improve the surgical outcome. This study was designed to evaluate the safety and efficacy of the mini-extracorporeal circulation system (ECC.O) in CABG patients. Design. Forty patients undergoing elective coronary surgery were randomized into two groups, the ECC.O group and the standard CPB group. Routine hemodynamic monitoring and biochemical measurements were registered according to the hospital practice. Results. The clinical outcome of the patients was similar in both groups. There were no significant differences between the groups in the duration of intubation following surgery, the length of intensive care unit-stay or the total hospital stay. The haemoglobin level was significantly higher (p=0.0069) during and after the perfusion in the ECC.O group. Conclusions. The ECC.O system can be safely used in CABG patients and it maintains haemoglobin level better than conventional CPB.

Effect of voriconazole on the pharmacokinetics of diclofenac

The nonsteroidal anti‐inflammatory drug diclofenac is extensively metabolized by cytochrome P450 (CYP) enzymes, mainly by CYP2C9. Our objective was to study the effect of voriconazole, a potent inhibitor of several CYP enzymes, on the pharmacokinetics of diclofenac. This study had a two‐way, open, crossover design and included 10 healthy Caucasian male subjects. In the control phase, the subjects ingested a single 50‐mg oral dose of diclofenac. In the voriconazole phase, the subjects ingested voriconazole 400 mg twice daily on the first day and 200 mg twice daily on the second day, and 50 mg diclofenac was given 1 h after the last dose of voriconazole. Plasma diclofenac concentrations were determined for up to 24 h post‐dose. In the voriconazole phase, the area under the plasma concentration–time curve of diclofenac was 178% (95% CI 143–212%; P < 0.001) and the peak plasma concentration was 214% (95% CI 128–300%; P < 0.05) of the respective control value. Voriconazole did not affect significantly the elimination half‐life or time to maximum concentration of diclofenac. The renal clearance of diclofenac was decreased by 47% (95% CI −76% to −16%; P < 0.01) by voriconazole. In conclusion, voriconazole increased exposure to diclofenac, probably mainly by inhibition of its cytochrome P450 (CYP)‐mediated metabolism. The inhibition of CYP2C9, and to some extent that of CYP3A4 and CYP2C19 enzymes during the first‐pass metabolism of diclofenac seems to be involved in the interaction. The clinical importance of the interaction between voriconazole and diclofenac remains to be studied, but lower doses of diclofenac may be adequate for patients receiving voriconazole.

Adenosine in myocardial protection given through three windows of opportunity. An experimental study with pigs

Objective –Adenosine (ADO) has been shown to have beneficial effects against tissue injury after myocardial ischemia. However, the timing and dose of ADO administration have not been defined. This study was designed to determine the cardioprotective effect of exogenous ADO in an experimental open heart surgery model in pigs. Design –The animals were openly divided into two groups both undergoing 30 min of total cardiac arrest. In the control group animals received cold crystalloid cardioplegic solution. In the ADO group ADO was added to cardioplegic solution and in addition ADO was infused to the superior vena cava for 2 h starting 30 min before cardiac arrest. The pumping function of the heart was measured with echocardiography and myocardial blood flow was measured with microspheres and positron emission tomography (PET). Cardiomyocyte apoptosis was detected and tumor necrosis factor (TNF) levels were measured. Results –Better post-ischemic pumping function was found in the ADO group (relative decrease 43.7% vs 55.4%, p = 0.20 between the groups). The cardiac output decreased significantly from the baseline values ( p < 0.05 in both groups). There was a temporary decrease in myocardial blood flow post-ischemically, followed by a compensatory increase during the later reperfusion period. The cardiomyocyte apoptosis was induced significantly in both groups. Conclusions –In this experiment two important details were noticed. Firstly, cardiomyocyte apoptosis is involved in ischemia-reperfusion injury associated with open heart surgery. Secondly, PET is a comparable method with the microsphere technique when coronary flow is studied. No significant effects of ADO against ischemia-reperfusion injury could be shown. However, there were some signs of positive outcome, even though statistical significance could not be reached.

Cardiomyocyte Apoptosis After Antegrade and Retrograde Cardioplegia During Aortic Valve Surgery

BACKGROUND Retrograde delivery is associated with inadequate perfusion of cardioplegia to all regions of the heart, but the effects on cardiomyocyte death and functional outcome remain unknown. We compared antegrade and retrograde cardioplegia in a randomized clinical trial to see whether it has effect on cardiomyocyte apoptosis and left ventricular function. METHODS Patients underwent elective aortic valve replacement surgery due to aortic valve stenosis. They were randomly allocated to receive antegrade (n = 10) or retrograde (n = 10) cardioplegia. Apoptotic cardiomyocytes (terminal transferase-mediated dUTP nick end labeling, caspase activation) and RNA levels of apoptosis-regulating proteins were studied in transmyocardial biopsies obtained before and after the operation. Magnetic resonance imaging and transesophageal echocardiography were performed, and cardiac enzymes were measured. RESULTS Clinical outcome and cardiac enzyme release were comparable between the groups. Cardiomyocyte apoptosis was significantly increased (terminal transferase-mediated dUTP nick end labeling) in the left ventricle after the operation in the retrograde, but not in the antegrade group (respectively, 0.00% [0.039%] versus 0.092% [0.205%], p = 0.01; and 0.00% [0.00%] versus 0.023% [0.054%], p = 0.14). Expression of apoptosis-regulating proteins BAX, BAD, and BCL-2 were comparable between groups. By transesophageal echocardiography, the systolic mitral annulus movement was decreased immediately after the operation in the retrograde group. By magnetic resonance imaging, the left ventricle mass index was reduced preoperatively to 9 months postoperatively in the antegrade group. CONCLUSIONS In contrast to antegrade cardioplegia, retrograde cardioplegia is associated with increased cardiomyocyte apoptosis, impaired immediate postoperative systolic function, and lack of long-term favorable left ventricle remodeling after aortic valve replacement, suggesting inadequate myocardial protection.