Kari Leino

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.

Time course of changes in breathing pattern in morphine- and oxycodone-induced respiratory depression

The time course of changes in breathing pattern in opioid‐induced respiratory depression was characterised for two opioids. Intravenous morphine (0.039 mg.kg−1 bolus + 0.215 mg.kg−1.h−1 infusion) and oxycodone (0.05 mg.kg−1 bolus + 0.275 mg.kg−1.h−1 infusion) were administered to six healthy male volunteers for 2 h in a random, double‐blind and cross‐over fashion. Monitoring included pulse oximetry and noninvasive respiratory‐inductive plethysmography for the measurement of breathing pattern. The total amounts of drugs given were 35.1 (0.0) mg [mean (SD)] morphine and 41.3 (8.0) mg oxycodone. Four of the six oxycodone infusions had to be stopped at 99 (14) min because of respiratory depression as judged by pulse oximetry. No morphine infusions were stopped. The first changes in breathing pattern were a decrease in respiratory rate and an increase in the contribution of the rib cage to tidal volume, while the compensatory increase in tidal volume became evident later. A decrease in minute ventilation and inspiratory duty cycle were also found.

Validation of a new respiratory inductive plethysmograph

Background: The respiratory inductive plethysmograph (RIP) can be used to monitor changes in end‐expiratory lung volume (ΔEELV), and thus, used in intensive care when evaluating positive end‐expiratory pressure (PEEP)‐induced changes in lung volumes in order to optimise the ventilator settings. We validated the newest model of RIP (Respitrace PlusTM), both under laboratory and clinical conditions, and made a comparison with a previously validated RIP (RespigraphTM) in the measurement of tidal volume (VT), long‐term EELV and PEEP‐induced acute ΔEELV.

Renal effects of dexmedetomidine during coronary artery bypass surgery: a randomized placebo-controlled study

BackgroundDexmedetomidine, an alpha2-adrenoceptor agonist, has been evaluated as an adjunct to anesthesia and for the delivery of sedation and perioperative hemodynamic stability. It provokes dose-dependent and centrally-mediated sympatholysis. Coronary artery bypass grafting (CABG) with extracorporeal circulation is a stressful procedure increasing sympathetic nervous system activity which could attenuate renal function due the interrelation of sympathetic nervous system, hemodynamics and renal function. We tested the hypothesis that dexmetomidine would improve kidney function in patients undergoing elective CABG during the first two postoperative days.MethodsThis was a double-blind, randomized, parallel-group study. Patients with normal renal function and scheduled for elective CABG were randomized to placebo or to infusion of dexmedetomidine to achieve a pseudo steady-state plasma concentration of 0.60 ng/ml. The infusion was started after anesthesia induction and continued until 4 h after surgery. The primary endpoint was creatinine clearance. Other variables included urinary creatinine and output, fractional sodium and potassium excretion, urinary potassium, sodium and glucose, serum and urinary osmolality and plasma catecholamine concentrations. The data were analyzed with repeated-measures ANOVA or Cochran-Mantel-Haenszel test.ResultsSixty-six of 87 randomized patients were evaluable for analysis. No significant between-group differences were recorded for any indices of renal function except for a mean 74% increase in urinary output with dexmedetomidine in the first 4 h after insertion of a urinary catheter (p < 0.001). Confidence interval examination revealed that the sample size was large enough for the no-difference statement for creatinine clearance.ConclusionsUse of intravenous dexmedetomidine did not alter renal function in this cohort of relatively low-risk elective CABG patients but was associated with an increase in urinary output.This study was carried out in 1994-1997 and was thus not registered.

Effects of tramadol and meperidine on respiration, plasma catecholamine concentrations, and hemodynamics

STUDY OBJECTIVE To evaluate the effects of high analgesic doses of tramadol and meperidine on respiration, plasma catecholamine concentrations, and hemodynamic parameters. STUDY DESIGN Randomized, double-blind, cross-over, controlled volunteer study. SETTING Laboratory at a university hospital. SUBJECTS 8 healthy male volunteers. INTERVENTIONS Tramadol was given as a 150 mg bolus plus a succeeding 3-hour steady infusion of 250 mg (83.3 mg/hr). Meperidine was given in a similar manner as a bolus dose of 112.5 mg plus 187.5 mg in a 3-hour steady infusion (62.5 mg/hr). Experimental pain was induced using a tourniquet. MEASUREMENTS AND MAIN RESULTS Respiration was studied noninvasively with respiratory inductive plethysmography and pulse oximetry. Arterial line was used for measurement of hemodynamics and blood sampling. Tramadol did not have any clinically significant effects on respiration, breathing pattern, or hemodynamics, but an increase in plasma epinephrine levels was noted. Meperidine bolus decreased tidal volume (p < 0.05, difference from baseline) and pulse oxygen saturation (from 97% to 94%, p < 0.05), but during the succeeding infusion, the respiratory drive, measured as mean inspiratory flow, was enhanced (p < 0.05 difference from baseline), and the respiratory parameters returned to baseline level. No change in hemodynamics was noted, but a significant increase in plasma norepinephrine and epinephrine levels (from 0.9 to 1.6 nmol/L and from 0.3 to 0.8 nmol/L, respectively; p < 0.05) was observed after meperidine administration. Tramadol caused nausea more often than meperidine (p < 0.05, between treatments). CONCLUSIONS Tramadol exhibited a minimal effect on respiration and breathing pattern in healthy volunteers. The respiratory effects of meperidine bolus were predictable with decreasing tidal volume and pulse oxygen saturation. In contrast, during meperidine infusion, adequate respiration was preserved despite the large amount of meperidine infused.

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.

Local infiltration analgesia with levobupivacaine compared with intrathecal morphine in total hip arthroplasty patients

Recently, local infiltration analgesia (LIA) has been promoted for pain control after total hip arthroplasty (THA). We hypothesized that LIA would offer equal analgesic efficacy but less adverse effects, e.g., nausea and vomiting, when compared with an established regimen [intrathecal morphine (it‐M)] after THA.

Unrecognised obstructive sleep apnoea is common in severe peripheral arterial disease

Patients needing surgery for peripheral arterial disease (PAD) represent a severe form of atherosclerosis with an overall 5-yr mortality of 30% after revascularisation. The aetiology for poor post-operative clinical outcome in these high-risk patients is not fully established. Obstructive sleep apnoea (OSA) is associated with atherosclerosis and is an independent risk factor for fatal and nonfatal cardiac events. Here, we determine the prevalence of undiagnosed OSA in a homogenous group of PAD patients undergoing subinguinal surgical revascularisation. 82 consecutive patients (mean age 67±9 yrs, 52 males) with sinus rhythm and without congestive heart failure or previously diagnosed OSA were enrolled for pre-operative polysomnography and echocardiography. OSA was present in 70 (85%) patients (95% CI 75–93%), of whom 24 (34%) had severe OSA. OSA was mostly asymptomatic, and age- and sex-adjusted multivariate regression analysis showed no relation to obesity, metabolic syndrome or any manifestation of atherosclerosis, other than PAD. Left ventricular ejection fraction (p = 0.002) and high-density lipoprotein/total cholesterol ratio (p = 0.03) were the only independent predictors for the severity of OSA. Thus, prevalence of OSA is unexpectedly high in patients with PAD and is not related to classical risk factors of sleep apnoea.

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.