Alterations in heart rate variability in patients with peripheral arterial disease requiring surgical revascularization have limited association with postoperative major adverse cardiovascular and cerebrovascular events.

OBJECTIVE: Obstructive sleep apnea (OSA) is common in peripheral arterial disease (PAD) and associates with high mortality after surgery. Since abnormal heart rate variability (HRV) is predictive of postoperative complications, we investigated the relations of HRV with PAD, OSA and major adverse cardiovascular and cerebrovascular events (MACCE). MATERIALS AND METHODS: Seventy-five patients (67±9 years) scheduled for sub-inguinal revascularization and 15 controls (63±6 years) underwent polysomnography and HRV analyses. OSA with an apnea-hypopnea index (AHI) ≥20/hour was considered significant. HRV was measured during wakefulness, S2, S3-4 and rapid eye movement (REM) sleep with time and frequency domain methods including beat-to-beat variability, low frequency (LF) and high frequency (HF) power, and detrended fluctuation analysis (DFA). MACCE was defined as cardiac death, myocardial infarction, coronary revascularization, hospitalized angina pectoris and stroke. RESULTS: Thirty-six patients (48%) had AHI≥20/hour. During follow-up (median 52 months), 22 patients (29%) suffered a MACCE. Compared to controls, fractal correlation of HRV (scaling exponent alpha 1 measured with DFA) was weaker during S2 and evening wakefulness in all subgroups (+/-AHI≥20/hour, +/-MACCE) but only in patients with AHI≥20/hour during morning wakefulness. The LF/HF ratio was lower in all subgroups during S2 but only in patients with AHI ≥20/hour during evening or morning wake. In the covariance analysis adjusted for age, body mass index, coronary artery disease and PAD duration, the alpha 1 during morning wakefulness remained significantly lower in patients with AHI≥20/hour than in those without (1.12 vs. 1.45; p = 0.03). Decreased HF during REM (p = 0.04) and S3-4 sleep (p = 0.03) were predictive of MACCE. In analyses with all sleep stages combined, mean heart rate as well as very low frequency, LF, HF and total power were associated with OSA of mild-to-moderate severity (AHI 10-20/hour). CONCLUSIONS: HRV is altered in patients with PAD. These alterations have a limited association with OSA and MACCE.

Osteointegration of PLGA implants with nanostructured or microsized ß-TCP particles in a minipig model.

Bioresorbable suture anchors and interference screws have certain benefits over equivalent titanium-alloy implants. However, there is a need for compositional improvement of currently used bioresorbable implants. We hypothesized that implants made of poly(l-lactide-co-glycolide) (PLGA) compounded with nanostructured particles of beta-tricalcium phosphate (ß-TCP) would induce stronger osteointegration than implants made of PLGA compounded with microsized ß-TCP particles. The experimental nanostructured self-reinforced PLGA (85L:15G)/ß-TCP composite was made by high-energy ball-milling. Self-reinforced microsized PLGA (95L:5G)/ß-TCP composite was prepared by melt-compounding. The composites were characterized by gas chromatography, Ubbelohde viscometry, scanning electron microscopy, laser diffractometry, and standard mechanical tests. Four groups of implants were prepared for the controlled laboratory study employing a minipig animal model. Implants in the first two groups were prepared from nanostructured and microsized PLGA/ß-TCP composites respectively. Microroughened titanium-alloy (Ti6Al4V) implants served as positive intra-animal control, and pure PLGA implants as negative control. Cone-shaped implants were inserted in a random order unilaterally in the anterior cortex of the femoral shaft. Eight weeks after surgery, the mechanical strength of osteointegration of the implants was measured by a push-out test. The quality of new bone surrounding the implant was assessed by microcomputed tomography and histology. Implants made of nanostructured PLGA/ß-TCP composite did not show improved mechanical osteointegration compared with the implants made of microsized PLGA/ß-TCP composite. In the intra-animal comparison, the push-out force of two PLGA/ß-TCP composites was 35-60% of that obtained with Ti6Al4V implants. The implant materials did not result in distinct differences in quality of new bone surrounding the implant.

Sleep apnoea is associated with major cardiac events in peripheral arterial disease.

Obstructive sleep apnoea (OSA) is associated with atherosclerosis and cardiovascular events. Peripheral arterial disease (PAD) represents severe atherosclerosis with a high mortality after vascular surgery. The role of OSA in the prognosis of these patients is not yet established. 84 patients (aged 67 ± 9 years) scheduled for sub-inguinal surgical revascularisation were enrolled for preoperative polysomnography. The threshold for significant OSA was an apnoea/hypopnoea index ≥ 20 events·h(-1). Major adverse cardiovascular and cerebrovascular events (MACCE), including cardiac death, myocardial infarction, coronary revascularisation, angina pectoris requiring hospitalisation and stroke, were used as a combined end-point. During follow-up (median 52 months), 17 out of 39 patients with and six out of 45 patients without significant OSA suffered MACCE. In the multivariate Cox regression, the primary predictors of MACCE were significant OSA (hazard ratio (HR) 5.1 (95% CI 1.9-13.9); p=0.001) and pre-existing coronary artery disease (HR 4.4 (95% CI 1.8-10.6); p=0.001). Other significant predictors were a ≥ 4 year history of PAD (HR 3.8 (95% CI 1.3-11.5); p=0.02) and decreasing high-density lipoprotein/total cholesterol ratio (HR 0.95 per percentage (95% CI 0.90-1.00); p=0.048). OSA is associated with poor long-term outcome in patients with PAD following revascularisation. OSA might have an important role in the pathogenesis of cardiovascular morbidity and mortality in these patients.

Postoperative fentanyl patch versus subacromial bupivacaine infusion in arthroscopic shoulder surgery.

PURPOSE: The purpose of our study was to compare the effectiveness of subacromial bupivacaine infusion and a transdermal fentanyl patch in the treatment of postoperative pain after arthroscopic shoulder surgery. METHODS: Sixty patients with rotator cuff disease scheduled for elective arthroscopic shoulder surgery were enrolled in the study. For the treatment of postoperative pain, 30 patients constituted group F and received a 12.0-µg/h fentanyl patch for 72 hours and saline solution infusion in a subacromial manner at the rate of 4 mL/h. The remaining 30 patients constituted group B and received a placebo patch and an infusion of 2.5-mg/mL bupivacaine in a subacromial manner for 72 hours. The primary outcome measure was the postoperative numerical rating scale pain score. The consumption of opioids, ibuprofen, and acetaminophen was also recorded. The Constant scores and general recovery were followed up until the 90th postoperative day. RESULTS: There was no statistically significant difference in the numerical rating scale scores (P = .60) between the groups. No differences in the use of rescue analgesic were observed except that the patients receiving bupivacaine used more ibuprofen (median, 1,200 mg v 600 mg) during the day of surgery (P = .042). No difference was found in general recovery between the groups. CONCLUSIONS: A fentanyl patch delivering 12-µg/h fentanyl offers an easy and safe treatment option as a part of multimodal analgesia with few adverse effects in the treatment of postoperative pain in a carefully selected patient group after arthroscopic shoulder surgery. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

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.

Comparison of two spinal needle types to achieve a unilateral spinal block.

PURPOSE: Unilateral spinal anesthesia is beneficial in patients undergoing unilateral leg surgery. The direction and the shape of the spinal needle are thought to influence the unilateral distribution of the local anesthetic in the intrathecal space. Therefore, to study the effects of different spinal needles we compared the effects of the Whitacre and Quincke spinal needles. METHODS: This was a prospective, randomized, double-blind study of 60 consecutive outpatients scheduled for unilateral lower-limb surgery. The patients were randomized to receive spinal anesthesia with 1.2 ml of 0.5 % plain bupivacaine using either a 27-G Whitacre or a Quincke needle. One half of the local anesthetic was injected towards the nondependent side and the other half was directed cranially. The spread of spinal anesthesia, both sensory and motor blocks, was defined as the primary endpoint and was recorded at 10, 20, and 30 min after the spinal injection, at the end of the operation, 2 h after the spinal injection, and every 30 min thereafter until there was no motor block. Secondary endpoints included patient satisfaction and adverse effects. RESULTS: There was no difference in the spread of sensory or motor blocks between the Whitacre and the Quincke groups. However, the sensory and motor blocks on the operated and the nonoperated sides were significantly different at all testing times, as expected. There was no difference in the incidence of adverse effects or patient satisfaction scores between the Whitacre and the Quincke groups. CONCLUSION: Unilateral spinal block for outpatient surgery can be achieved with both pencil-point (Whitacre) and Quincke needles using 6.0 mg of plain bupivacaine. Neither the spread of sensory and motor blocks nor the corresponding recovery times appeared to be different between the groups. Nor was there any difference in patient satisfaction.

A national survey into perioperative anesthetic management of patients with a fractured neck of femur.

BACKGROUND: We made a survey among Finnish anesthesiologists concerning the current perioperative anesthetic practice of hip fracture patients for further development in patient care. METHODS: All members of the Finnish Society of Anesthesiologists with a known e-mail address (786) were invited to participate in an internet-based survey. RESULTS: The overall response rate was 55% (423 responses); 298 respondents participated in the care of hip fracture patients. Preoperative analgesia was mostly managed with oxycodone and paracetamol; every fifth respondent applied an epidural infusion. Most respondents (98%) employed a spinal block with or without an epidural catheter for intraoperative anesthesia. Midazolam, propofol and/or fentanyl were used for additional sedation. General anesthesia was used rarely. Postoperatively, paracetamol and non-steroidal anti-inflammatory drugs and occasionally peroral oxycodone, were prescribed in addition to epidural analgesia. CONCLUSIONS: The survey suggests that the impact of more individualised analgesia regimens, both preoperatively and postoperatively, should be investigated in further studies.

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-ß-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.

Intracoronary Levosimendan during Ischemia Prevents Myocardial Apoptosis.

BACKGROUND: Levosimendan is a calcium sensitizer that has been shown to prevent myocardial contractile depression in patients post cardiac surgery. This drug exhibits an anti-apoptotic property; however, the underlying mechanism remains elusive. In this report, we characterized the myocardial protective of levosimendan in preventing cardiomyocyte apoptosis and post-operative stunning in an experimental ischemia-reperfusion model. METHODS: Three groups of pigs (n = 8 per group) were subjected to 40 min of global, cardioplegic ischemia followed by 240 min of reperfusion. Levosimendan (65 µg/kg body weight) was given to pigs by intravenous infusion (L-IV) before ischemia or intracoronary administration during ischemia (L-IC). The Control group did not receive any levosimendan. Echocardiography was used to monitor cardiac function in all groups. Apoptosis levels were assessed from the left ventricle using the terminal transferase mediated dUTP nick end labeling (TUNEL) assay and immunocytochemical detection of Caspase-3. RESULTS: Pigs after ischemia-reperfusion had a much higher TUNEL%, suggesting that our treatment protocol was effective. Levels of apoptosis were significantly increased in Control pigs that did not receive any levosimendan (0.062 ± 0.044%) relative to those received levosimendan either before (0.02 ± 0.017%, p = 0.03) or during (0.02 ± 0.017%, p = 0.03) the ischemia phase. Longitudinal left ventricular contraction in pigs that received levosimendan before ischemia (0.75 ± 0.12 mm) was significantly higher than those received levosimendan during ischemia (0.53 ± 0.11 mm, p = 0.003) or Control pigs (0.54 ± 0.11 mm, p = 0.01). CONCLUSION: Our results suggested that pigs received levosimendan displayed a markedly improved cell survival post I-R. The effect on cardiac contractility was only significant in our perfusion heart model when levosimendan was delivered intravenously before ischemia.

In Vivo and In Vitro Study of a Polylactide-Fiber-Reinforced ß-Tricalcium Phosphate Composite Cage in an Ovine Anterior Cervical Intercorporal Fusion Model.

A poly-70L/30DL-lactide (PLA70)-ß-tricalcium phosphate (ß-TCP) composite implant reinforced by continuous PLA-96L/4D-lactide (PLA96) fibers was designed for in vivo spinal fusion. The pilot study was performed with four sheep, using titanium cage implants as controls. The composite implants failed to direct bone growth as desired, whereas the bone contact and the proper integration were evident with controls 6 months after implantation. Therefore, the PLA70/ß-TCP composite matrix material was further analyzed in the in vitro experiment by human and ovine adipose stem cells (hASCs and oASCs). The composites proved to be biocompatible as confirmed by live/dead assay. The proliferation rate of oASCs was higher than that of hASCs at all times during the 28 d culture period. Furthermore, the composites had only a minor osteogenic effect on oASCs, whereas the hASC osteogenesis on PLA70/ß-TCP composites was evident. In conclusion, the composite implant material can be applied with hASCs for tissue engineering but not be evaluated in vivo with sheep.

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.

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

BACKGROUND: Dexmedetomidine, 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. METHODS: This 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. RESULTS: Sixty-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. CONCLUSIONS: Use 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.

The effect of body mass index on the spread of spinal block in patients with rheumatoid arthritis.

PURPOSE: Body mass index (BMI) has a significant effect on the spread of sensory spinal block in rheumatoid patients. We tried to achieve the same spread of spinal block for patients in three different BMI groups and, on the basis of the results from a preliminary study, used a simple method feasible for clinical practice. We hypothesized that BMI-related inverse dosing of plain bupivacaine according to low, normal, and high BMI would result in no difference in block extent. METHODS: Together 75 patients with seropositive rheumatoid arthritis were included in three equal-sized groups according to BMI: low (<23 kg/m(2)), normal (23-28 kg/m(2)), and high (>28 kg/m(2)). Spinal anesthesia was induced with plain bupivacaine using doses 3.3, 3.0, and 2.7 ml, respectively. The spread of sensory block was recorded 30 min after injection of bupivacaine by use of a pin-prick test and a cold ice-filled container. RESULTS: Spreads of sensory block were different in low, normal, and high BMI groups (mean (SD); 14.0 (2.6), 14.5 (2.5), and 16.3 (2.5) dermatomes, respectively, P = 0.006) because of greater block extent in the high-BMI group. CONCLUSIONS: Despite three-step dosing of plain bupivacaine inversely related to BMI (low, normal, or high), comparable block extent was not achieved because of greater spread in the high-BMI group. Adjustment of plain bupivacaine dose according to BMI could be used to achieve a more predictable spread of spinal block, but further reduction of dose is needed in patients with high BMI.

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.

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.

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem in healthy subjects.

AIMS: To assess the effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem. METHODS: In a randomized cross-over study with two phases, 10 healthy subjects ingested 10 mg of zolpidem with or without oral voriconazole pretreatment. The concentrations of zolpidem were measured in plasma up to 24 h and pharmacodynamic variables were monitored for 12 h. RESULTS: Voriconazole increased the peak plasma concentration of zolpidem by 1.23-fold [P < 0.05; 90% confidence interval (CI) 1.05, 1.45] and the area under the plasma zolpidem concentration-time curve by 1.48-fold (P < 0.001; 90% CI 1.29, 1.74). The time to peak plasma zolpidem concentration was unchanged by voriconazole but the half-life was prolonged from 3.2 to 4.1 h (P < 0.01; 95% CI on the difference 0.27, 1.45). The pharmacodynamics of zolpidem were unaffected by voriconazole. CONCLUSION: Voriconazole caused a moderate increase in exposure to zolpidem in healthy young subjects but no clear pharmacodynamic changes were observed between the groups.

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

OBJECTIVE: 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. METHODS: A randomized crossover study design in 3 phases was used. Twelve healthy volunteers were given 20 microg/kg intravenous alfentanil without pretreatment (control), after oral voriconazole administration (400 mg twice on the first day and 200 mg twice on the second day), or after oral terbinafine administration (250 mg once daily for 3 days). Plasma concentrations of alfentanil were measured for 10 hours, and the pharmacokinetic parameters were calculated by use of noncompartmental methods. RESULTS: Voriconazole decreased the mean plasma clearance of intravenous alfentanil by 85%, from the control value of 4.4+/-2.4 mL.min-1.kg-1 to 0.67+/-0.27 mL.min-1.kg-1 (P<.001), and prolonged its elimination half-life from 1.5+/-0.49 hours to 6.6+/-1.8 hours (P<.001). The area under the alfentanil plasma concentration-time curve was increased by 6-fold by voriconazole (P<.001). Terbinafine had no statistically significant effect on the pharmacokinetics of alfentanil. Alfentanil administration caused nausea in 5 volunteers and vomiting in 2. These side effects all occurred in volunteers in the voriconazole phase. CONCLUSION: Oral voriconazole, but not terbinafine, markedly inhibited the metabolism of alfentanil. Caution should be exercised when alfentanil is given to patients receiving voriconazole. It is reasonable to assume that patients receiving voriconazole require 70% to 90% less alfentanil for the maintenance of analgesia than patients who are not receiving concomitant CYP3A inhibitors.

Effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of s-(+)- and R-(-)-Ibuprofen.

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 (C(max)) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t(1/2)) 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 C(max) was 116% of the control value (P < 0.05). The mean t(1/2) 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.

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

OBJECTIVE: Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. METHODS: We used a randomized, crossover study design. Ten healthy male volunteers were given either no pretreatment (control phase) or voriconazole (voriconazole phase) orally, 400 mg twice daily on the first day and 200 mg twice daily on the second day. Midazolam was given, either 0.05 mg/kg intravenously or 7.5 mg orally, 1 hour after the last dose of voriconazole and during the control phase. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and voriconazole were determined for 24 hours and pharmacodynamic variables measured for 12 hours. RESULTS: Voriconazole reduced the clearance of intravenous midazolam by 72% (P < .001) and increased its elimination half-life from 2.8 to 8.3 hours (P < .001). Voriconazole increased the peak concentration and the area under the plasma concentration-time curve of oral midazolam by 3.8- and 10.3-fold, respectively (P < .001). The bioavailability of oral midazolam was increased from 31% to 84% (P < .001). Voriconazole profoundly increased the psychomotor effects of oral midazolam (P < .001) but only weakly increased the effects of intravenous midazolam. CONCLUSION: When midazolam is given as small intravenous bolus doses, its effect is not increased to a clinically significant degree by voriconazole. The use of large midazolam doses increases the risk of clinically significant interactions also after its intravenous administration. The use of oral midazolam with voriconazole should be avoided, or substantially lower doses should be used.