Population pharmacokinetic modelling of intravenous paracetamol in fit older people displays extensive unexplained variability.

AIMS: Paracetamol is the analgesic most used by older people. The physiological changes occurring with ageing influence the pharmacokinetics (PK) of paracetamol and its variability. We performed a population PK-analysis to describe the PK of intravenous (IV) paracetamol in fit older people. Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady-state concentration (Css-mean ) of 10 mg l-1 as target for effective analgesia. METHODS: A population PK-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age 77.3 years, range [61.8-88.5], body weight 79 kg [60-107]). All had received an IV paracetamol dose of 1000 mg (over 15 min) after elective knee surgery. RESULTS: A two-compartment PK-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css of 9.2 mg l-1 and 7.2 mg l-1 , for every 6 h and every 8 h respectively. Variability in paracetamol PK resulted in Css above 5.4 and 4.1 mg l-1 , respectively, in 90% of the population and above 15.5 and 11.7, respectively, in 10% at these dosing regimens. CONCLUSIONS: The target concentration was achieved in the average patient with 1000 mg every 6 h, while every 8 h resulted in underdosing for the majority of the population. Furthermore, due to a large (unexplained) interindividual variability in paracetamol PK a relevant proportion of the fit older people remained either under- or over exposed.

Good quality of life before cardiac arrest predicts good quality of life after resuscitation.

BACKGROUND: The survival rate of cardiac arrest patients is increasing. Our aim was to compare the quality of life before and after cardiac arrest and analyse the factors associated with outcome. METHODS: All adult cardiac arrest patients admitted to the Tampere University Hospital intensive care unit between 2009 and 2011 were included in a retrospective follow-up study if surviving to discharge and were asked to return a questionnaire after 6 months. Data on patient demographics and pre-arrest quality of life were retrieved from medical records. Data are given as means (SD) or medians [Q1 , Q3 ]. We used logistic regression to identify factors associated with better quality of life after cardiac arrest. RESULTS: Six months after cardiac arrest, 36% (79/222) were alive and 70% (55/79) of those patients completed the follow-up EuroQoL (EQ-5D) quality of life questionnaire. Median values for the EQ-5D before and after cardiac arrest were 0.89 [0.63, 1] and 0.89 [0.62, 1], respectively (P = 0.75). Only the EQ-5D prior to cardiac arrest was associated with better quality of life afterwards (OR 1.2; 95% CI 1.0-1.3; P = 0.02). CONCLUSIONS: Quality of life remained good after cardiac arrest especially in those patients who had good quality of life before cardiac arrest.

Cardiac arrest teams and medical emergency teams in Finland: a nationwide cross-sectional postal survey.

BACKGROUND: The implementation, characteristics and utilisation of cardiac arrest teams (CATs) and medical emergency teams (METs) in Finland are unknown. We aimed to evaluate how guidelines on advanced in-hospital resuscitation have been translated to practice. METHODS: A cross-sectional postal survey including all public hospitals providing anaesthetic services. RESULTS: Of the 55 hospitals, 51 (93%) participated in the study. All hospitals with intensive care units (university and central hospitals, n = 24) took part. In total, 88% of these hospitals (21/24) and 30% (8/27) of the small hospitals had CATs. Most hospitals with CATs (24/29) recorded team activations. A structured debriefing after a resuscitation attempt was organised in only one hospital. The median incidence of in-hospital cardiac arrest in Finland was 1.48 (Q1 = 0.93, Q3 = 1.93) per 1000 hospital admissions. METs had been implemented in 31% (16/51) of the hospitals. A physician participated in MET activation automatically in half (8/16) of the teams. Operating theatres (13/16), emergency departments (10/16) and paediatric wards (7/16) were the most common sites excluded from the METs' operational areas. The activation thresholds for vital signs varied between hospitals. The lower upper activation threshold for respiratory rate was associated with a higher MET activation rate. The national median MET activation rate was 2.3 (1.5, 4.8) per 1000 hospital admissions and 1.5 (0.96, 4.0) per every cardiac arrest. CONCLUSIONS: Current guidelines emphasise the preventative actions on in-hospital cardiac arrest. Practices are changing accordingly but are still suboptimal especially in central and district hospitals. Unified guidelines on rapid response systems are required.

Drowning in children: Utstein style reporting and outcome.

BACKGROUND: We report the incidence and mortality of paediatric drowning incidents according to 'Utstein Style for Drowning' guidelines. METHODS: Retrospective study including all the drowned children under 16 years of age who were hospitalised or died with or without attempted cardiopulmonary resuscitation (CPR) between 1997 and 2007 in the province of Uusimaa, Finland. Survival rates provided at hospital discharge and after 1-year follow-up period are reported. RESULTS: A total of 58 drowned children were either admitted to the paediatric intensive care unit or died during the study period. The median (interquartile range) age was 5.9 (3.1, 7.8) years. The annual incidence of drowning was 1.9/100,000 and was highest, 2.8/100,000, in children aged between 1 and 4 years. The annual mortality rate was 0.9/100,000. Of all the 58 patients, 14 (24%) died at the scene, 22 (38.1%) before the hospital discharge, and 26 (45%) within the 1 year. The number of non-fatal drownings was 1.2-fold that of fatal drownings. The survival rate of the 26 patients for whom CPR was initiated by emergency medical service (EMS) personnel was 42% at hospital discharge, with the 1-year survival rate being 27%. CONCLUSIONS: The incidence of drowning in children and the survival rate of those children in whom CPR was initiated by EMS personnel was in line with the previously reported. However, the overall mortality rate in drowned children was higher than estimated in previous studies.

The quality of manual chest compressions during transport--effect of the mattress assessed by dual accelerometers.

BACKGROUND: The quality of cardiopulmonary resuscitation (CPR) has an impact on survival. The quality may be impaired if the patient needs to be transported to the hospital with ongoing CPR. The aim of this study was to analyse whether the quality of CPR can be improved during transportation by using real-time audiovisual feedback. In addition, we sought to evaluate the real compression depths taking into account the mattress and stretcher effect. METHODS: Paramedics (n = 24) performed standard CPR on a Resusci Anne Mannequin in a moving ambulance. Participants were instructed to perform CPR according to European Resuscitation Council Resuscitation guidelines 2010. Each pair acted as their own controls performing CPR first without and then with the feedback device. Compression depth, rate and no-flow fraction and also the mattress effect were recorded by using dual accelerometers by two Philips, HeartStart MRx Q-CPR defibrillators. RESULTS: In the feedback phase, the mean compression depth increased from 51 (10) to 56 (5) mm (P < 0.001), and the percentage of compression fractions with adequate depth was 60% vs. 89% (P < 0.001). However, taking account of the mattress effect, the real depth was only 41 (8) vs. 44 (5) mm without and with feedback, respectively (P < 0.001). The values for compression rate did not differ. CONCLUSIONS: CPR quality was good during transportation in general. However, the results suggest that the feedback system improves CPR quality. Dual accelerometer measurements show, on the other hand, that the mattress effect may be a clinically relevant impediment to high quality CPR.

Vital dysfunctions after intensive care discharge: prevalence and impact on patient outcome.

BACKGROUND: Patients discharged from the intensive care unit (ICU) are at increased risk for serious adverse events (SAEs). Recording vital functions and comprehending the consequences of altered vitals on general wards may be suboptimal. This potentially endangers recovery after successful intensive care. We aimed to determine the prevalence of vital dysfunctions after ICU discharge and their effect on patient outcome. METHODS: A prospective observational study. Adult patients discharged from a tertiary referral hospital ICU to general wards without treatment limitations were visited 24 h afterwards; their vitals were measured and reported to ward staff. Attending ward nurse responsible for patient was interviewed. RESULTS: The cohort consisted of 184 patients who had survived the first 24 h on the ward without complications (age: 57 ± 16 years; male: 68%). The prevalence of objectively measured vital dysfunctions was 15%, and the attending nurse had been unusually concerned about the patient in 19% of cases. Of the 184 patients, 9.8% subsequently suffered an SAE. In a multivariate logistic regression model, only vital dysfunctions (odds ratio 3.79; 95% confidence interval 1.18-12.2) and nurse concern (3.63; 1.17-11.3) were independently associated with an increased incidence of SAE. Medical emergency team (MET) assistance was never considered necessary by ward staff. Sensitivity of observed altered vitals on SAEs was 50% and specificity 89%. Sensitivity of nurse concern was 26%, specificity 84%. CONCLUSIONS: Simple vital function measurement and attending ward nurse's subjective assessment facilitate early detection of post-ICU patients at risk. The threshold in seeking assistance through MET remains high.

Oxycodone clearance is markedly reduced with advancing age: a population pharmacokinetic study.

BACKGROUND: Oxycodone is a µ-opioid receptor agonist, the global use of which has increased vigorously during the past decade. The pharmacokinetic data of oxycodone available for elderly are limited, and there appear to be only little data on the population pharmacokinetics of oxycodone. METHODS: We analysed 1272 plasma oxycodone samples of 77 individuals (range of age 19-89 yr) with non-linear mixed effect modelling. Inter- and intra-individual variability of the model was estimated for clearances and distribution volumes. The effect of covariates was studied with simulations. RESULTS: Data were best described with a two-compartment linear model. Lean body mass and age were found to be significant covariates for elimination clearance and the volume of the central compartment. The population estimates of elimination clearance, volume of the central compartment, and the volume of distribution at steady state for a reference individual (male 35 yr, 70 kg, 170 cm) were 51.0 litre h(-1), 134, and 258 litres, respectively. The elimination half-life of oxycodone showed an age-dependent increase. The context-sensitive half-time at steady state increased from 3.8 to 4.6 h between the age of 25 and 85 yr, respectively. Simulations of repetitive bolus dosing showed a 20% increase in oxycodone concentration in the elderly. CONCLUSIONS: Age was found to be a significant covariate for oxycodone pharmacokinetics. In elderly patients, dosing should therefore be reduced and carefully titrated to avoid considerable accumulation of oxycodone and potentially hazardous side-effects.

Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients.

BACKGROUND: Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach. METHODS: Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models. RESULTS: The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration. CONCLUSIONS: The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.

The effect of tepid amino acid-enriched induction cardioplegia on the outcome of infants undergoing cardiac surgery.

BACKGROUND: Despite promising experimental results, no information has been published on the clinical effects of amino acid-enriched induction cardioplegic solution on outcome in children undergoing cardiac surgery. METHODS: This is a retrospective study of 185 consecutive patients younger than 12 months with one of the following defects undergoing open heart surgery: atrioventricular septal defect, transposition of the great arteries, tetralogy of Fallot or ventricular septal defect. Patients were divided into two groups according to the following myocardial protection approaches: tepid substrate-enriched induction cardioplegia followed by cold blood cardioplegia (n=113) or only cold blood induction cardioplegia (n=72). Patient allocation was determined by the anesthesiologist in charge of cardiopulmonary bypass (CPB). The primary outcome measure was postoperative myocardial injury assessed by troponin T level and inotrope score. RESULTS: Demographic data were similar for both groups. Cardioplegic induction had no overall effect for inotrope score (16.3 ± 9.2 vs.17.9 ± 10.0, p=0.276) or lactate release (1.8 ± 1.3 vs. 1.6 ± 0.8, p=0.110) on arrival to the paediatric intensive care unit. On the first postoperative day, there were no significant differences between the cardioplegia groups for inotrope score (13.7 ± 8.7 vs.14.3 ± 9.1, p=0.657), troponin T (2.4 ± 1.6 vs. 2.8 ± 2.7 µg/L, p=0.267), lactate (1.5 ± 2.0 vs. 1.5 ± 0.8, p=0.972), or any of the other clinical outcome measures. CONCLUSIONS: Compared to cold cardioplegia alone, the administration of tepid induction cardioplegia had no effect on the clinical outcome of infants who underwent cardiac surgery.

Dexmedetomidine inhibits gastric emptying and oro-caecal transit in healthy volunteers.

BACKGROUND: Dexmedetomidine is a potent and selective α2-adrenoceptor agonist used for perioperative and intensive care sedation with certain beneficial qualities. However, based on preclinical observations, it might inhibit gastric emptying and gastrointestinal transit, which could result in unwanted effects in intensive care patients. This study evaluated the effects of dexmedetomidine on gastric emptying and oro-caecal transit time in healthy volunteers. METHODS: Twelve healthy male subjects were given 1 µg kg(-1) of dexmedetomidine i.v. over 20 min followed by a continuous i.v. infusion of 0.7 µg kg(-1) h(-1) for 190 min. For comparison, subjects were also given 0.10 mg kg(-1) of morphine hydrochloride i.v. over 20 min and a placebo infusion in a randomized order. Gastric emptying was assessed with the paracetamol absorption test and oro-caecal transit time with the hydrogen breath test. RESULTS: The time to maximum paracetamol concentration in plasma was significantly longer, maximum paracetamol concentration was significantly lower, the area under the plasma paracetamol concentration-time curve was significantly smaller, and oro-caecal transit time was significantly longer during dexmedetomidine infusion compared with morphine or placebo infusion. CONCLUSIONS: Dexmedetomidine markedly inhibits gastric emptying and gastrointestinal transit in healthy volunteers.

Comparison of four pain scales in patients with hip fracture or other lower limb trauma.

BACKGROUND: The applicability of the Visual Analogue Scale (VAS) has been questioned in the assessment of pain in the elderly. We compared VAS with three other pain scales, Verbal Rating Scale (VRS), Red Wedge Scale (RWS) and Box Scale (BS), in hip fracture patients. METHODS: VAS, VRS, RWS and BS were compared in 140 analysable patients undergoing surgery, 70 with hip fracture and 70 with other lower limb trauma. Pain scores were recorded once a day, repeated after 10 min, for 4 subsequent days starting pre-operatively. The primary endpoint was the rate of successful pain measurements in hip fracture patients and 90% was chosen as a sufficient level for an applicable pain scale. RESULTS: Age was different between the groups (hip fracture 78 ± 11, other trauma 49 ± 11 years, P<0.0001). In hip fracture patients, 67-83% of pain measurements were successful with VAS, 82-100% with VRS, 83-96% with RWS and 79-91% with BS. The success rate with VAS was significantly <90% on 2 days (P<0.0001) and with BS on 1 day (P=0.04). All the other success rates with the four scales in both groups were above or not different from 90%. CONCLUSION: VRS and RWS were the most applicable scales, unlike VAS, which appeared to be an unreliable pain scale in perioperative hip fracture patients. In patients with other lower limb trauma, all four scales provided excellent applicability. Our results are in accordance with the accumulating evidence suggesting that VAS is not an ideal tool for pain measurement in the elderly.

Plasma levels of bupivacaine and its metabolites after subacromial infusions in concentrations 2.5 or 5.0 mg/ml.

BACKGROUND: We studied plasma bupivacaine concentrations in patients with a continuous subacromial bupivacaine infusion after an ambulatory arthroscopic shoulder surgery to evaluate whether it is feasible to discharge patients with an on-going infusion early on the operation day. METHODS: Sixteen ASA I-III patients undergoing elective arthroscopic shoulder surgery were randomized in 1:1 ratio to receive a continuous infusion of either 2.5 or 5.0 mg/ml bupivacaine subacromially for 48 h post-operatively. Before the commencement of the infusion, 20 ml of 5.0 mg/ml bupivacaine was injected subacromially in both groups. Plasma bupivacaine concentrations were defined as the primary endpoint and concentrations of its metabolites, side effects and pain scores as the secondary endpoints. RESULTS: The mean total plasma bupivacaine concentration increased up to 48 h, the highest mean being 0.87 (SD 0.30) µg/ml during the 5.0 mg/ml treatment and 0.24 (0.10) µg/ml during the 2.5 mg/ml bupivacaine treatment. After 48 h, there was a significant difference between the groups in the plasma levels. The highest mean 4-hydroxy-bupivacaine and desbutylbupivacaine concentrations were 0.11 and 0.22 µg/ml, respectively. In the pain scores, no significant difference was found. No clear signs of toxicity were observed. CONCLUSIONS: The concentrations of total bupivacaine and its metabolites remained below toxic levels. Excluding patients with renal or liver diseases, both 2.5 and 5.0 mg/ml bupivacaine as subacromial infusion 2 ml/h for 48 h following shoulder arthroscopy seem to be well tolerated, enabling patient discharge with an on-going infusion on the operation day. Because of similar side effects and pain scores in both groups, 2.5 mg/ml may be preferable.

Feasibility of a transmucosal sublingual fentanyl tablet as a procedural pain treatment in colonoscopy patients: a prospective placebo-controlled randomized study.

Since patients often experience pain and unpleasantness during a colonoscopy, the present study aimed to evaluate the efficacy and safety of sublingually administered fentanyl tablets for pain treatment. Furthermore, since the use of intravenous drugs significantly increases colonoscopy costs, sublingual tablets could be a cost-effective alternative to intravenous sedation. We conducted a prospective placebo-controlled randomized study of 158 patients to evaluate the analgesic effect of a 100 µg dose of sublingual fentanyl administered before a colonoscopy. Pain, sedation, nausea, and satisfaction were assessed during the colonoscopy by the patients as well as the endoscopists and nurses. Respiratory rate and peripheral arteriolar oxygen saturation were monitored throughout the procedure. There were no differences between the fentanyl and placebo groups in any of the measured variables. The median pain intensity values, as measured using a numerical rating scale, were 4.5 in the fentanyl group and 5 in the placebo group. The sedation and oxygen saturation levels and the respiratory rate did not differ between the groups. The majority of the colonoscopies were completed.Our results indicate that a 100 µg dose of sublingual fentanyl is not beneficial compared to the placebo in the treatment of procedural pain during a colonoscopy.

Voriconazole increases while itraconazole decreases plasma meloxicam concentrations.

This study investigated the effect of voriconazole, an inhibitor of cytochrome P450 2C9 (CYP2C9) and CYP3A4, and itraconazole, an inhibitor of CYP3A4, on the pharmacokinetics and pharmacodynamics of meloxicam. Twelve healthy volunteers in a crossover study ingested 15 mg of meloxicam without pretreatment (control), after voriconazole pretreatment, and after itraconazole pretreatment. The plasma concentrations of meloxicam, voriconazole, itraconazole, and thromboxane B(2) (TxB(2)) generation were monitored. Compared to the control phase, voriconazole increased the mean area under the plasma concentration-time curve from 0 to 72 h (AUC(0-72)) of meloxicam by 47% (P < 0.001) and prolonged its mean half-life (t(1/2)) by 51% (P < 0.01), without affecting its mean peak concentration (C(max)). In contrast, itraconazole decreased the mean AUC(0-72) and C(max) of meloxicam by 37% (P < 0.001) and by 64% (P < 0.001), respectively, and prolonged its t(1/2) and time to C(max). The plasma protein unbound fraction of meloxicam was unchanged by voriconazole and itraconazole. Lowered plasma meloxicam concentrations during the itraconazole phase were associated with decreased pharmacodymic effects of meloxicam, as observed by weaker inhibition of TxB(2) synthesis compared to the control and voriconazole phases. Voriconazole increases plasma concentrations of meloxicam, whereas itraconazole, unexpectedly, decreases plasma meloxicam concentrations, possibly by impairing its absorption.

Plasma concentrations of oral oxycodone are greatly increased in the elderly.

We compared the pharmacokinetics of 10 mg oral oxycodone in four groups of 10 patients each, aged 20-40, 60-70, 70-80, and 80-90 years. Patients aged 70-80 and 80-90 years had 50-80% higher mean exposure to oxycodone (P < 0.05) and a twofold higher plasma oxycodone concentration (P < 0.05) than the young adults 12 h after ingestion of the drug. Because oxycodone pharmacokinetics depend to a great extent on the age of the subject, it is important to titrate the analgesic dose individually, particularly in the elderly.

Pharmacokinetics of intravenous dexmedetomidine in children under 11 yr of age.

BACKGROUND: Information has been very limited on the pharmacokinetics of the selective alpha(2)-adrenoceptor agonist dexmedetomidine in children, particularly in children <2 yr of age. METHODS: Eight children aged between 28 days and 23 months and eight children aged between 2 and 11 yr undergoing either elective bronchoscopy or nuclear magnetic resonance imaging were included in the study. Dexmedetomidine 1 microg kg(-1) was infused i.v. over 5 min. Blood samples for the measurement of plasma concentrations of dexmedetomidine were collected for 5 h after starting the infusion. Pharmacokinetic calculations were based on non-compartmental methods. RESULTS: In the two groups of paediatric patients, the median (range) values for total plasma clearance of dexmedetomidine were 17.4 (14.1-27.6) and 17.3 (9.3-22.5) ml kg(-1) min(-1), for volume of distribution at steady state 3.8 (1.9-4.6) and 2.2 (1.3-2.8) litre kg(-1) (P<0.05), and for elimination half-life 139 (90-198) and 96 (69-140) min (P<0.05), respectively. The volume of distribution at steady state was negatively associated with subject age (r=-0.69, P<0.05). CONCLUSIONS: To reach a certain plasma concentration, children younger than 2 yr of age evidently need larger initial doses of dexmedetomidine than the older children, as young children have a larger volume of distribution of the drug than older children and adults. Since the total plasma clearance of dexmedetomidine is independent of age, similar rates of infusion can be used in younger and older children to maintain a steady-state concentration of dexmedetomidine in plasma.

Midazolam and other benzodiazepines.

The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. The main effects of benzodiazepines are sedation, hypnosis, decreased anxiety, anterograde amnesia, centrally mediated muscle relaxation and anti-convulsant activity. In addition to their action on the central nervous system, benzodiazepines have a dose-dependent ventilatory depressant effect and they also cause a modest reduction in arterial blood pressure and an increase in heart rate as a result of a decrease of systemic vascular resistance. The four benzodiazepines, widely used in clinical anaesthesia, are the agonists midazolam, diazepam and lorazepam and the antagonist flumazenil. Midazolam, diazepam and flumazenil are metabolized by cytochrome P450 (CYP) enzymes and by glucuronide conjugation whereas lorazepam directly undergoes glucuronide conjugation. CYP3A4 is important in the biotransformation of both midazolam and diazepam. CYP2C19 is important in the biotransformation of diazepam. Liver and renal dysfunction have only a minor effect on the pharmacokinetics of lorazepam but they slow down the elimination of the other benzodiazepines used in clinical anaesthesia. The duration of action of all benzodiazepines is strongly dependent on the duration of their administration. Based on clinical studies and computer simulations, midazolam has the shortest recovery profile followed by lorazepam and diazepam. Being metabolized by CYP enzymes, midazolam and diazepam have many clinically significant interactions with inhibitors and inducers of CYP3A4 and 2C19. In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.

Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole.

BACKGROUND: Triazolam is metabolized by CYP3A4 isozyme. Ketoconazole and itraconazole may seriously interact with some of the substrates of CYP3A4 (e.g., terfenadine); hence their possible interaction with triazolam in humans is important to uncover. METHODS: In this double-blind, randomized, three-phase crossover study, the interaction between ketoconazole, itraconazole, and triazolam was investigated. Nine healthy young volunteers received either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo (control phase) orally once a day for 4 days. On day 4, each ingested a single 0.25 mg dose of triazolam. Plasma concentrations of triazolam and antimycotics were determined, and pharmacodynamic effects were measured up to 17 hours. RESULTS: On average, ketoconazole and itraconazole increased the area under the triazolam concentration-time curve [AUC(0-infinity)] 22-fold and 27-fold (p < 0.001), the peak concentrations threefold (p < 0.001), and the elimination half-life sixfold and sevenfold (p < 0.001), respectively. In seven of the nine subjects, even the maximum concentration of triazolam in plasma was lower without the antimycotics than were the 17-hour concentrations during the ketoconazole and itraconazole phases. All pharmacodynamic effects (e.g., the Digit Symbol Substitution Test) revealed a significant difference between the antimycotic and placebo phases. CONCLUSIONS: Both ketoconazole and itraconazole seriously affect the pharmacokinetics of triazolam and increase the intensity and duration of its effects. Inhibition of CYP3A4 during the absorption and elimination phases of triazolam seems to explain the interaction observed. Because of the potentially hazardous consequences of this interaction, triazolam should be avoided if patients are using ketoconazole or itraconazole.

Measurement of pain in children with self-reporting and behavioral assessment.

There are several studies on the correlation of various pain-rating scales in adults but few such studies have been done on children. To gain information on the correlation of self-reporting pain scales (one verbal and two visual analog scales) with each other and with a scale based on behavioral assessment, we analyzed retrospectively the pain evaluations of 141 pediatric patients participating in our analgesic studies. Eighty-two patients were male and 59 were female. The ages ranged from 1.6 to 17.6 years. The patients were divided into three age groups. All pain-rating scales were correlated (P less than 0.001) with each other and they showed a good internal consistency. There were no differences in correlation coefficients between the age groups and the two sexes. Accordingly, any of the now-employed scales can be used in clinical analgesic studies in children on the condition that the child has comprehended the use of the scale during the preoperative visit.

The effect of ingestion time interval on the interaction between itraconazole and triazolam.

BACKGROUND: The plasma concentrations and effects of triazolam are markedly increased when it is ingested with itraconazole. The dependence of this interaction on the time interval of their ingestion and the possibility of avoiding the interaction by a correct daily dosing was studied. METHODS: Ten healthy volunteers took part in this randomized crossover study of five phases, each separated by 4 weeks. The subjects received a single 0.25 mg oral dose of triazolam either without itraconazole or with a single 200 mg dose of itraconazole that was ingested either simultaneously with triazolam or 3, 12, or 24 hours before triazolam. Plasma concentrations of triazolam and itraconazole were determined and pharmacodynamic effects were measured up to 17 hours. RESULTS: Itraconazole ingested simultaneously or 3, 12, or 24 hours before triazolam increased the mean area under the triazolam concentration-time curve 3.1-, 4.8-, 4.6-, and 3.8-fold (p < 0.001), respectively. The mean increase in the peak concentration of triazolam ranged from 1.4-fold (taken simultaneously, p < 0.05) to 1.8-fold (3 or 12 hours after itraconazole, p < 0.001). The elimination half-life of triazolam was increased about threefold (p < 0.001) during all itraconazole phases. Pharmacodynamic effects of triazolam were increased along with increased plasma concentrations of triazolam. CONCLUSIONS: Even a single 200 mg dose of itraconazole interacts considerably with triazolam when this hypnotic agent is ingested within 24 hours after itraconazole. Thus during the daily itraconazole use this interaction cannot be avoided by increasing the time interval between their intake. Furthermore, the risk of interaction is obvious for several days after the cessation of itraconazole therapy.