Midazolam and hydroxymidazolam plasma concentrations can be monitored with selected biochemical and physiological parameters of palliative care patients.

RATIONALE & OBJECTIVE: Midazolam is one of top three drugs used in palliative care. Its use increases in the last days of hospice patients' lives while safe dosage can be challenging. Equations currently used to estimate glomerular filtration rate, e.g: the Cockroft-Gault (eGFRCR) and the Modification of Diet in Renal Disease (eGFRMDRD) ones, do not generate precise calculations, especially in palliative patients exhibiting variations in body parameters. Our aim was to seek new relationships between mean midazolam (Mavg) and alfahydroxymidazolam (OH-Mavg) concentrations in plasma, and selected biochemical and physiological parameters of palliative patients, to enable optimal midazolam pharmacotherapy. STUDY DESIGN, PARTICIPANTS AND INTERVENTIONS: The pilot study included 11 Caucasians, aged 42-95, with advanced cancer disease, receiving midazolam in a hospice in-patient unit. We tested correlations among Mavg, BMI, eGFRMDRD, midazolam clearance (CL), OH-Mavg, bilirubin (Bil) and blood creatinine concentration (Cr). F test and leave-one out (LOO) validation was applied to verify the correlations' significance and predictive ability. RESULTS: We found ten statistically significant (p < 0.05) correlations related to midazolam pharmacokinetics and physiological factors. We formulated two equations with high degree of predictive ability, based on the eGFRMDRD→CL and the (Bil + BMI × Ln(Cr))→Mavg-(OH-Mavg) correlations. The limitations of the study mainly revolve around its pilot nature and the need to continue testing the results on a bigger population. No funding to disclose. CONCLUSIONS: The significance of correlations corresponding to the arithmetic expressions confirms that Bil, BMI, Ln(Cr) analyzed simultaneously report a series of processes on which midazolam metabolism depends. Two of ten correlations proposed came close to meet all LOO validation criteria. Current findings can help optimize midazolam treatment in palliative therapy.

Pharmacokinetics and Pharmacodynamics of 3 Doses of Oral-Mucosal Dexmedetomidine Gel for Sedative Premedication in Women Undergoing Modified Radical Mastectomy for Breast Cancer.

BACKGROUND: Buccal dexmedetomidine (DEX) produces adequate preoperative sedation and anxiolysis when used as a premedication. Formulating the drug as a gel decreases oral losses and improves the absorption of buccal DEX. We compared pharmacokinetic and pharmacodynamic properties of 3 doses of buccal DEX gel formulated in our pharmaceutical laboratory for sedative premedication in women undergoing modified radical mastectomy for breast cancer. METHODS: Thirty-six patients enrolled in 3 groups (n = 12) to receive buccal DEX gel 30 minutes before surgery at 0.5 µg/kg (DEX 0.5 group), 0.75 µg/kg (DEX 0.75 group), or 1 µg/kg (DEX 1 group). Assessments included plasma concentrations of DEX, and pharmacokinetic variables calculated with noncompartmental methods, sedative, hemodynamic and analgesic effects, and adverse effects. RESULTS: The median time to reach peak serum concentration of DEX (Tmax) was significantly shorter in patients who received 1 µg/kg (60 minutes) compared with those who received 0.5 µg/kg (120 minutes; P = .003) and 0.75 µg/kg (120 minutes; P = .004). The median (first quartile-third quartile) peak concentration of DEX (maximum plasma concentration [Cmax]) in plasma was 0.35 ng/mL (0.31-0.49), 0.37 ng/mL (0.34-0.40), and 0.54 ng/mL (0.45-0.61) in DEX 0.5, DEX 0.75, and DEX 1 groups (P = .082). The 3 doses did not produce preoperative sedation. The 1 µg/kg buccal DEX gel produced early postoperative sedation and lower intraoperative and postoperative heart rate values. Postoperative analgesia was evident in the 3 doses in a dose-dependent manner with no adverse effects. CONCLUSIONS: Provided that it is administered 60-120 minutes before surgery, sublingual administration of DEX formulated as an oral-mucosal gel may provide a safe and practical means of sedative premedication in adults.

Development and Validation of an LC-MS-MS Method for the Detection of 40 Benzodiazepines and Three Z-Drugs in Blood and Urine by Solid-Phase Extraction.

An analytical method for the detection of 40 benzodiazepines, (±)-zopiclone, zaleplon and zolpidem in blood and urine by solid-phase extraction liquid chromatography-tandem mass spectrometry was developed and validated. Twenty-nine of 43 analytes were quantified in 0.5 mL whole blood for investigating postmortem, drug-facilitated sexual assault (DFSA) and driving under the influence of drugs cases (DUID). The four different dynamic ranges of the seven-point, linear, 1/x weighted calibration curves with lower limits of quantification of 2, 5, 10 and 20 µg/L across the analytes encompassed the majority of our casework encountered in postmortem, DFSA and DUID samples. Reference materials were available for all analytes except α-hydroxyflualprazolam, a hydroxylated metabolite of flualprazolam. The fragmentation of α-hydroxyflualprazolam was predicted from the fragmentation pattern of α-hydroxyalprazolam, and the appropriate transitions were added to the method to enable monitoring for this analyte. Urine samples were hydrolyzed at 55°C for 30 min with a genetically modified ß-glucuronidase enzyme, which resulted in >95% efficiency measured by oxazepam glucuronide. Extensive sample preparation included combining osmotic lysing and protein precipitation with methanol/acetonitrile mixture followed by freezing and centrifugation resulted in exceptionally high signal-to-noise ratios. Bias and between-and within-day imprecision for quality controls (QCs) were all within ±15%, except for clonazolam and etizolam that were within ±20%. All 29 of the 43 analytes tested for QC performance met quantitative reporting criteria within the dynamic ranges of the calibration curves, and 14 analytes, present only in the calibrator solution, were qualitatively reported. Twenty-five analytes met all quantitative reporting criteria including dilution integrity. The ability to analyze quantitative blood and qualitative urine samples in the same batch is one of the most useful elements of this procedure. This sensitive, specific and robust analytical method was routinely employed in the analysis of >300 samples in our laboratory over the last 6 months.

Influence of midazolam-related genetic polymorphism on conscious sedation during upper gastrointestinal endoscopy in a Korean population.

Genetic polymorphism can result in abnormal pharmacodynamics that subsequently leads to the individual variance in sedative effects and adverse reactions. The aim of this study was to elucidate the association between midazolam-related genetic polymorphism and sedative effects, including adverse reactions, under conscious sedation during upper gastrointestinal endoscopy. We prospectively enrolled 100 eligible patients undergoing upper gastrointestinal endoscopy. The efficacy of the sedation, adverse reactions, plasma concentration of midazolam and 1-hydroxymidazolam were investigated as well as the genetic polymorphism of MDR1 and CYP3A5. The correlation between genetic polymorphism and sedative effects was assessed. Regarding MDR1 gene, the plasma concentration of midazolam was greater in patients with CGC haplotype (P = 0.012), while it was lower in patients with CAC haplotype (P = 0.005) than in those with other haplotypes. However, genetic polymorphism of neither MDR1 nor CYP3A5 correlated with the plasma concentration of 1-hydroxymidazolam. CGT haplotype of MDR1 was significantly correlated with sedation grade after midazolam administration (P = 0.042). In contrast, genetic polymorphism of CYP3A5 was not correlated with sedation grade. There was no association between genetic polymorphism of MDR1 or CYP3A5 and selected adverse reactions related to midazolam. Genetic polymorphism of MDR1 influences the concentration of midazolam and the sedation grade. However, it is not associated with adverse reactions such as paradoxical response and retrograde amnesia.

Pharmacodynamic Interaction of Remifentanil and Dexmedetomidine on Depth of Sedation and Tolerance of Laryngoscopy.

BACKGROUND: Dexmedetomidine is a sedative with modest analgesic efficacy, whereas remifentanil is an opioid analgesic with modest sedative potency. Synergy is often observed when sedative-hypnotics are combined with opioid analgesics in anesthetic practice. A three-phase crossover trial was conducted to study the pharmacodynamic interaction between remifentanil and dexmedetomidine. METHODS: After institutional review board approval, 30 age- and sex- stratified healthy volunteers were studied. The subjects received consecutive stepwise increasing target-controlled infusions of dexmedetomidine, remifentanil, and remifentanil with a fixed dexmedetomidine background concentration. Drug effects were measured using binary (yes or no) endpoints: no response to calling the subject by name, tolerance of shaking the patient while shouting the name ("shake and shout"), tolerance of deep trapezius squeeze, and tolerance of laryngoscopy. The drug effect was measured using the electroencephalogram-derived "Patient State Index." Pharmacokinetic-pharmacodynamic modeling related the administered dexmedetomidine and remifentanil concentration to these observed effects. RESULTS: The binary endpoints were correlated with dexmedetomidine concentrations, with increasing concentrations required for increasing stimulus intensity. Estimated model parameters for the dexmedetomidine EC50 were 2.1 [90% CI, 1.6 to 2.8], 9.2 [6.8 to 13], 24 [16 to 35], and 35 [23 to 56] ng/ml, respectively. Age was inversely correlated with dexmedetomidine EC50 for all four stimuli. Adding remifentanil did not increase the probability of tolerance of any of the stimuli. The cerebral drug effect as measured by the Patient State Index was best described by the Hierarchical interaction model with an estimated dexmedetomidine EC50 of 0.49 [0.20 to 0.99] ng/ml and remifentanil EC50 of 1.6 [0.87 to 2.7] ng/ml. CONCLUSIONS: Low dexmedetomidine concentrations (EC50 of 0.49 ng/ml) are required to induce sedation as measured by the Patient State Index. Sensitivity to dexmedetomidine increases with age. Despite falling asleep, the majority of subjects remained arousable by calling the subject's name, "shake and shout," or a trapezius squeeze, even when reaching supraclinical concentrations. Adding remifentanil does not alter the likelihood of response to graded stimuli.

Simple method to detect triclofos and its metabolites in plasma of children by combined use of liquid chromatography tandem-mass spectrometry and gas chromatography-mass spectrometry.

Triclofos sodium (TCS) and chloral hydrate (CH) are widely used as sedatives for children, but no analytical method to simultaneously monitor concentrations of blood TCS, CH and their metabolites, trichloroacetic acid (TCA) and trichloroethanol (TCEOH), has been reported. The present study aimed to develop a simple analytical method for TCS and its metabolites (TCA, TCEOH and CH) in small-volume plasma from children. After acidification of specimens, TCS formic acid adduct or the metabolites derivatized using water/sulfuric acid/methanol (6:5:1, v/v) were measured by combined use of liquid chromatography tandem-mass spectrometry and gas chromatography mass-spectrometry. The limits of detection and quantification levels (µg/ml) were 0.10 and 0.29 for TCS, 0.24 and 0.72 for TCA, 0.10 and 0.31 for TCEOH, and 0.25 and 0.76 for CH, respectively. The mean recoveries were 82.8-107% for TCS, 85.4-101% for TCA, 91.6-107% for TCEOH, and 88.9-109% for CH. Within-run and between-run precision (percent of relative standard deviation, %RSD) using this method ranged from 1.1 to 15.7% and 3.6 to 13.5%, respectively, for TCS and all of its metabolites. The calibration curves were obtained with standard spiked plasma, and all of the coefficients of determination were more than 0.975. Subsequently, we applied the present method to plasma taken from five children after sedation induced by CH and TCS. In addition to TCS and CH, elevated TCA and TCEOH concentrations were detected. This new method can be applied for the pharmacokinetic analysis of TCS and its metabolites and the determination of the optimal TCS dosage in children.

Impact of dexmedetomidine on hemodynamics in rabbits

Abstract Purpose: To evaluate the effects of single intravenous administration of Dexmedetomidine (DEX) on hemodynamics in rabbits. Methods: A total of 32 New Zealand white rabbits were randomly divided into the control group (Group C), Group D1 (2.75 μg/kg), Group D2 (5.5 μg/kg), and Group D3 (8.25 μg/kg) to compare systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), central venous pressure (CVP), left ventricular systolic pressure (LVSP), left ventricular end-stage diastolic pressure (LVEDP), left ventricular developmental pressure (LVDP), +dp/dtmax, -dp/dtmax, and t-dp/dtmax at different time points. Results: The levels of SBP, DBP, HR, LVSP, and LVEDP in Group D1, D2, and D3 were lower than that of Group C from T1 to T5 (P<0.05), but there was no significant difference at T6 and T7 (P>0.05). Compared with T0, the levels of SBP, DBP, HR, LVSP, LVEDP, and left arterial pressure (LAP) from T1 to T7 were decreased (P<0.05), but there was no significant difference in the other indexes (P>0.05). Conclusion: Dexmedetomidine can decrease blood pressure and heart rate in rabbits in a dose-dependent manner, but there is no effect on the myocardial systolic and diastolic function.

Comparison of the effects of sodium phenobarbital in wild type and humanized constitutive androstane receptor (CAR)/pregnane X receptor (PXR) mice and in cultured mouse, rat and human hepatocytes.

Phenobarbital (PB), a constitutive androstane receptor (CAR) activator, produces liver tumours in rodents by a mitogenic mode of action involving CAR activation. In this study, the hepatic effects of sodium phenobarbital (NaPB) were compared in male C57BL/6J wild type (WT) mice and in humanized mice, where both the mouse CAR and pregnane X receptor (PXR) have been replaced by their human counterparts (hCAR/hPXR mice). Investigations were also performed in cultured male C57BL/6J and CD-1 mouse, male Sprague-Dawley rat and male and female human hepatocytes. The treatment of WT and hCAR/hPXR mice with 186-984 ppm NaPB in the diet for 7 days resulted in increased relative liver weight, hypertrophy and induction of cytochrome P450 (CYP) enzyme activities. Treatment with NaPB also produced dose-dependent increases in hepatocyte replicative DNA synthesis (RDS), with the effect being more marked in WT than in hCAR/hPXR mice. While the treatment of cultured C57BL/6J and CD-1 mouse, Sprague-Dawley rat and human hepatocytes with 100 and/or 1000 µM NaPB for 4 days induced CYP enzyme activities, increased RDS was only observed in mouse and rat hepatocytes. However, as a positive control, epidermal growth factor increased RDS in hepatocytes from all three species. In summary, although human hepatocytes are refractory to the mitogenic effects of NaPB, treatment with NaPB induced RDS in vivo in hCAR/hPXR mice, which is presumably due to the human CAR and PXR receptors operating in a mouse hepatocyte regulatory environment. As the response of the hCAR/hPXR mouse to the CAR activator NaPB differs markedly from that of human hepatocytes, the hCAR/hPXR mouse is thus not a suitable animal model for studies on the hepatic effects of nongenotoxic rodent CAR activators.

Impact of clinical factors and UGT1A9 and CYP2B6 genotype on inter-individual differences in propofol pharmacokinetics.

PURPOSE: Propofol is one of the most widely used fast-acting intravenously administered anesthetics. However, although large inter-individual differences in dose requirements and recovery time have been observed, there are few previous studies in which the association between several potential covariates, including genetic factors such as the UGT1A9 and CYP2B6 genotypes, and propofol pharmacokinetics was simultaneously examined. This study aimed to identify factors determining propofol pharmacokinetics. METHODS: Eighty-three patients were enrolled, and their blood samples were collected 1, 5, 10, and 15 min after administering a single intravenous bolus of propofol at a dose of 2.0 ml/kg to measure propofol plasma concentration. Area under the time-plasma concentration curve from zero up to the last measurable time point (AUC15min) was determined from the concentration data. The inter-individual variability of the propofol pharmacokinetics was evaluated by investigating relationships between AUC15min and genotype of UGT1A9 and CYP2B6; clinical factors, such as age, sex, body mass index (BMI), and preoperative hematological examination; and hemodynamic variables measured by a pulse dye densitogram analyzer. The Spearman rank correlation coefficient and the Mann-Whitney U test were used for the statistical analysis of continuous and categorical values, respectively. Subsequently, clinical factors that had p values of < 0.05 in the univariate analysis were examined in a multivariate analysis using multiple linear regression analysis. RESULTS: Age, BMI, indocyanine green disappearance ratio (K-ICG), hepatic blood flow (HBF), preoperative hemoglobin level, and sex were correlated with AUC15min (p < 0.05) in univariate analysis. Multivariate analysis performed to adjust for age, BMI, K-ICG, HBF, preoperative hemoglobin level, and sex revealed only BMI as an independent factor associated with AUC15min. CONCLUSIONS: This study demonstrated that BMI influences propofol pharmacokinetics after its administration as a single intravenous injection, while UGT1A9 and CYP2B6 SNPs, other clinical factors, and hemodynamic variables do not. These results suggest that BMI is an independent factor associated with propofol pharmacokinetics in several potential covariates. CLINICAL TRIALS REGISTRATION NUMBER: University Hospital Medical Information Network (UMIN000022948).

Population Pharmacokinetics of Dexmedetomidine in Infants.

Despite limited pharmacokinetic (PK) data, dexmedetomidine is increasingly being used off-label for sedation in infants. We aimed to characterize the developmental PK changes of dexmedetomidine during infancy. In this open-label, single-center PK study of dexmedetomidine in infants receiving dexmedetomidine per clinical care, ≤10 blood samples per infant were collected. A set of structural PK models and residual error models were explored using nonlinear mixed-effects modeling in NONMEM. Covariates including postmenstrual age (PMA), serum creatinine, and recent history of cardiac surgery requiring cardiopulmonary bypass were investigated for their influence on PK parameters. Univariable generalized estimating equation models were used to evaluate the association of hypotension with dexmedetomidine concentrations. A total of 89 PK samples were collected from 20 infants with a median PMA of 44 weeks (range, 33-61). The median maximum dexmedetomidine infusion dose during the study period was 1.8 µg/(kg·h) (0.5-2.5), and 16/20 infants had a maximum dose >1 µg/(kg·h). A 1-compartment model best described the data. Younger PMA was a significant predictor of lower clearance. Infants with a history of cardiac surgery had ∼40% lower clearance compared to those without a history of cardiac surgery. For infants with PMA of 33 to 61 weeks and body weight of 2 to 6 kg, the estimated clearance and volume of distribution were 0.87 to 2.65 L/(kg·h) and 1.5 L/kg, respectively. No significant associations were found between dexmedetomidine concentrations and hypotension. Infants with younger PMA and recent cardiac surgery may require relatively lower doses of dexmedetomidine to achieve exposure similar to older patients and those without cardiac surgery.

Mechanistic investigation of the negative food effect of modified release zolpidem.

AIMS: When administered orally as either an immediate or modified release dosage form, zolpidem demonstrates a negative food effect, i.e. decrease in Cmax and AUC. The aim of the study was to arrive at a better understanding of the absorption of this BCS class I compound in vivo and to simulate the observed plasma profiles using in vitro and in silico methods. METHODS: Pharmacokinetic profiles of zolpidem are presented from a bioavailability (8mg intravenous; 10mg immediate release Stilnox®; 10mg and 12.5mg modified release Ambien® CR) and from a food effect study (12.5mg modified release Ambien® CR). The dissolution behavior of the 12.5mg strength was investigated using compendial methods in the USP apparatus II and using biorelevant methods in the USP apparatus III and IV. The mean plasma profiles as well as selected individual plasma profiles were simulated with Simcyp® and GastroPlus™. The absorption behavior was additionally investigated using the Qgut model, which entails algebraic deconvolution of all individual profiles, incorporating both first pass gut and liver extraction. RESULTS: It was possible to simulate the mean plasma profiles using a "middle-out" approach, based on in vitro data combined with pharmacokinetic parameters obtained after intravenous administration, using PBPK software (Simcyp® and GastroPlus™), resulting in average fold error (AFE) values <1.5. Deconvolution verified that the in vivo absorption rate from the modified release formulation is controlled by the formulation in the fasted state, whereas in the fed state, the absorption rate is mainly controlled by gastric emptying. One-stage in vitro tests suggested that interactions with meal components, resulting in incomplete release, may be the source of the negative food effect for both the immediate and modified release formulations. CONCLUSIONS: The present study demonstrated that a combination of biorelevant dissolution testing with modeling approaches enables a mechanistic understanding of the absorption of zolpidem from various formulations and can serve as a useful biopharmaceutical approach for the development of modified release solid oral dosage forms.

Remifentanil prevents increases of blood glucose and lactate levels during cardiopulmonary bypass in pediatric cardiac surgery.

INTRODUCTION: Cardiopulmonary bypass (CPB) can cause stress response that increases levels of cytokine and catecholamine in plasma, resulting in hyperglycemia. In adults, it has been demonstrated that remifentanil infusion during CPB could prevent increases of cytokine, catecholamine, and blood glucose levels, but such effects of remifentanil in children have not been elucidated. AIM: In this study, we investigated the preventive effects of remifentanil on blood glucose and lactate levels during CPB in children. MATERIALS AND METHODS: This retrospective study included children who underwent ventricular septal defect or atrial septal defect closure. Data for patients who did not receive, during CPB period, remifentanil infusion (non-Remi group) and patients who received remifentanil infusion at 0.5 µg/kg/min (Remi group) during CPB were used for analysis. Primary outcomes were lactate and blood glucose levels just before and after CPB. Data are presented as medians and interquartile ranges. Data were analyzed by the Mann-Whitney U-test and Chi-square test. A P < 0.05 was considered statistically significant. RESULTS: During CPB, 13 and 11 patients were allocated into Remi and non-Remi groups, respectively. Pre-CPB lactate and blood glucose levels were not significantly different between the two groups, but post-CPB lactate and blood glucose levels in the Remi group were significantly lower than that in the non-Remi group. CONCLUSION: 0.5 µg/kg/min remifentanil infusion during CPB suppresses the increases of blood glucose and lactate levels in children.

Sedation in colonoscopy by using three different propofol infusion methods and analysis of plasma concentration levels: a prospective comparative study / Sedação em colonoscopia: utilização do propofol em estudo comparativo entre três diferentes modos de administração

ABSTRACT Background: The propofolemia becomes directly linked to the clinical effects of this anesthetic and is the focus for studies comparing propofol clinical use, in different administration methods routinely used in endoscopy units where sedation is widely administered to patients. Aim: To evaluate the effects of three different regimens of intravenous propofol infusion in colonoscopies. Methods: A total of 50 patients that underwent colonoscopies were consecutively assigned to three groups: 1) intermittent bolus infusion; 2) continuous manually controlled infusion; 3) continuous automatic infusion. Patients were monitored with Bispectral IndexTM (BIS) and propofol serum levels were collected at three different timepoints. The development of an original dilution of propofol and an inventive capnography catheter were necessary. Results: Regarding clinical outcomes, statistical differences in agitation (higher in group 1, p=0.001) and initial blood pressure (p=0.008) were found. As for propofol serum levels, findings were similar in consumption per minute (p=0.748) and over time (p=0.830). In terms of cost analysis, group 1 cost was R$7.00 (approximately US$2,25); group2, R$17.50 (approximately US$5,64); and group 3, R$112.70 (approximately US$36,35, p<0.001). Capnography was able to predict 100% of the oxygen saturation drop (below 90%). Conclusion: The use of propofol bolus administration for colonoscopies, through continuous manually controlled infusion or automatic infusion are similar regarding propofolemia and the clinical outcomes evaluated. The use of an innovative capnography catheter is liable and low-cost solution for the early detection of airway obstruction.

RESUMO Racional: A propofolemia está diretamente relacionada com os efeitos clínicos desse anestésico e é foco de diversos estudos comparando os usos clínicos do propofol e os diferentes métodos de administração, como realizado amplamente nos centros de endoscopia. Objetivo: Avaliar os efeitos de três diferentes regimes de infusão de propofol intravenoso em colonoscopias. Métodos: Ao todo 50 pacientes que foram submetidos à colonoscopia foram consecutivamente divididos em três grupos: 1) infusão em bolus intermitente; 2) perfusão contínua controlada manualmente; 3) infusão automática contínua. Os pacientes foram monitorados com Bispectral IndexTM (BIS) e os níveis séricos de propofol foram coletados em três momentos diferentes. Foi necessário a preparação de uma diluição específica de propofol e o desenvolvimento de um cateter de capnografia original manufaturado para a realização do estudo. Resultados: Em relação aos desfechos clínicos, houve diferença estatística na agitação (maior no grupo 1, p=0,001) e pressão arterial inicial (p=0,008). Com relação aos níveis séricos de propofol, os resultados foram semelhantes no consumo por minuto (p=0,748) e ao longo do tempo (p=0,830). Em termos de análise de custo, no grupo 1 o custo foi de R$ 7,00 (aproximadamente US$ 2,25); grupo 2, R$ 17,50 (aproximadamente US$ 5,64); e grupo 3, R$ 112,70 (cerca de US$ 36,35, p<0,001). A capnografia foi capaz de diagnosticar 100% das dessaturações de oxigênio (abaixo de 90%). Conclusão: O uso de propofol em bolus para colonoscopias, por meio de infusão contínua controlada manualmente ou infusão automática são semelhantes quanto à propofolemia e os resultados clínicos avaliados. Além disso, o uso de um cateter de capnografia inovador é solução de baixo custo para a detecção precoce da obstrução da via aérea.

Driving impairment due to propofol at effect-site concentrations relevant after short propofol-only sedation.

Australian guidelines state "Following brief surgery or procedures with short acting anaesthetic drugs, the patient may be fit to drive after a normal night's sleep. After long surgery or procedures requiring longer lasting anaesthesia, it may not be safe to drive for 24 hours or more". The increasing use of the short-acting anaesthetic drug propofol as a solitary sedative medication for simple endoscopy procedures suggests a need to review this blanket policy. Thirty patients presenting for elective day surgery were recruited as volunteers for a pre-procedure driving simulation study and randomised to propofol or placebo arms. Driving ability was assessed at baseline and then, in the propofol group, at three effect-site concentrations. Driving impairment at these concentrations of propofol was compared to that of a third group of volunteers with a blood alcohol concentration of 0.05% (g/100 ml). Driving impairment at 0.2 µg/ml propofol effect-site concentration was not statistically different to placebo. Impairment increased with propofol effect-site concentration (P=0.002) and at 0.4 µg/ml it was similar to that found with a blood alcohol concentration of 50 mg/100 ml (0.05%). Plasma propofol concentrations of 0.2 µg/ml, as might be found approximately an hour after short (<1 hour duration) propofol-only sedation for endoscopy, were not associated with driving impairment in our young cohort of volunteers.

The myocardial protective effect of dexmedetomidine in high-risk patients undergoing aortic vascular surgery.

OBJECTIVE: The aim of the study was to assess the effect of dexmedetomidine in high-risk patients undergoing aortic vascular surgery. DESIGN: A randomized prospective study. SETTING: Cairo University, Egypt. MATERIALS AND METHODS: The study included 150 patients undergoing aortic vascular surgery. INTERVENTION: The patients were classified into two groups (n = 75). Group D: The patients received a loading dose of 1 µg/kg dexmedetomidine over 15 min before induction and maintained as an infusion of 0.3 µg/kg/h to the end of the procedure. Group C: The patients received an equal volume of normal saline. The medication was prepared by the nursing staff and given to anesthetist blindly. MEASUREMENTS: The monitors included the heart rate, mean arterial blood pressure, central venous pressure, electrocardiogram (ECG), serum troponin I level, end-tidal sevoflurane, and total dose of morphine in addition transthoracic echocardiography to the postoperative in cases with elevated serum troponin I level. MAIN RESULTS: The dexmedetomidine decreased heart rate and minimized the changes in blood pressure compared to control group (P < 0.05). Furthermore, it decreased the incidence of myocardial ischemia reflected by troponin I level, ECG changes, and the development of new regional wall motion abnormalities (P < 0.05). Dexmedetomidine decreased the requirement for nitroglycerin and norepinephrine compared to control group (P < 0.05). The incidence of hypotension and bradycardia was significantly higher with dexmedetomidine (P < 0.05). CONCLUSION: The dexmedetomidine is safe and effective in patients undergoing aortic vascular surgery. It decreases the changes in heart rate and blood pressure during the procedures. It provides cardiac protection in high-risk patients reflected by decreasing the incidence of myocardial ischemia and serum level of troponin. The main side effects of dexmedetomidine were hypotension and bradycardia.

Unrepaired Tetralogy of Fallot-related Pathophysiologic Changes Reduce Systemic Clearance of Etomidate in Children.

BACKGROUND: Pathophysiologic changes in children with congenital heart disease may alter the effect of drugs by influencing the pharmacokinetics (PK). Considering the limited literature that describes the PK of etomidate in pediatric patients, especially in those with tetralogy of Fallot (TOF), our aim was to characterize the PK of etomidate and explore the effects of TOF. METHODS: Twenty-nine pediatric patients (15 with TOF and 14 with normal cardiac anatomy) scheduled to undergo elective surgery under general anesthesia were recruited in the study. All children received etomidate 60 µg/kg/min intravenously until a bispectral index of ≤50 was reached for 5 seconds during anesthesia induction. Arterial blood samples were drawn and analyzed. Population analysis was performed by using NONMEM to define PK characteristics. The estimates were standardized to a 70-kg adult using a per-kilogram model. RESULTS: Data consisting of 244 samples from 29 children with a mean age of 236 days (range, 86-360 days) were used, including a TOF group with a mean age of 250 days (range, 165-360 days) and a normal cardiac anatomy group with a mean age of 221 days (range, 86-360 days). A 3-compartment disposition model was best fitted to describe the PK of etomidate. The introduction of TOF as a covariate for systemic clearance (Cl1) improved the model and resulted in a significant reduction of objective function (Δobjective function = -7.33; P = .0068), which means that TOF was a significant covariate of Cl1, and the etomidate Cl1 in children with TOF (1.67 × (weight [WT]/70 kg) L/min) was lower than those with normal cardiac anatomy (2.28 × (WT/70 kg) L/min). Other PK parameter values were as follows: V1 = 8.05 × (WT/70 kg) L; V2 = 13.7 × (WT/70 kg) L; V3 = 41.3 × (WT/70 kg) L; Cl2 = 3.35 × (WT/70 kg) L/min; Cl3 = 0.563 × (WT/70 kg) L/min. CONCLUSIONS: A decreased systemic clearance for etomidate in children with TOF resulted in a lower required infusion rate and variation with time to achieve the same plasma concentration and maintain an equivalent target concentration or have longer sedation and recovery times after bolus or continuous infusion than normal children.

SEDATION IN COLONOSCOPY BY USING THREE DIFFERENT PROPOFOL INFUSION METHODS AND ANALYSIS OF PLASMA CONCENTRATION LEVELS: A PROSPECTIVE COMPARATIVE STUDY.

Background: The propofolemia becomes directly linked to the clinical effects of this anesthetic and is the focus for studies comparing propofol clinical use, in different administration methods routinely used in endoscopy units where sedation is widely administered to patients. Aim: To evaluate the effects of three different regimens of intravenous propofol infusion in colonoscopies. Methods: A total of 50 patients that underwent colonoscopies were consecutively assigned to three groups: 1) intermittent bolus infusion; 2) continuous manually controlled infusion; 3) continuous automatic infusion. Patients were monitored with Bispectral IndexTM (BIS) and propofol serum levels were collected at three different timepoints. The development of an original dilution of propofol and an inventive capnography catheter were necessary. Results: Regarding clinical outcomes, statistical differences in agitation (higher in group 1, p=0.001) and initial blood pressure (p=0.008) were found. As for propofol serum levels, findings were similar in consumption per minute (p=0.748) and over time (p=0.830). In terms of cost analysis, group 1 cost was R$7.00 (approximately US$2,25); group2, R$17.50 (approximately US$5,64); and group 3, R$112.70 (approximately US$36,35, p<0.001). Capnography was able to predict 100% of the oxygen saturation drop (below 90%). Conclusion: The use of propofol bolus administration for colonoscopies, through continuous manually controlled infusion or automatic infusion are similar regarding propofolemia and the clinical outcomes evaluated. The use of an innovative capnography catheter is liable and low-cost solution for the early detection of airway obstruction.

Racional: A propofolemia está diretamente relacionada com os efeitos clínicos desse anestésico e é foco de diversos estudos comparando os usos clínicos do propofol e os diferentes métodos de administração, como realizado amplamente nos centros de endoscopia. Objetivo: Avaliar os efeitos de três diferentes regimes de infusão de propofol intravenoso em colonoscopias. Métodos: Ao todo 50 pacientes que foram submetidos à colonoscopia foram consecutivamente divididos em três grupos: 1) infusão em bolus intermitente; 2) perfusão contínua controlada manualmente; 3) infusão automática contínua. Os pacientes foram monitorados com Bispectral IndexTM (BIS) e os níveis séricos de propofol foram coletados em três momentos diferentes. Foi necessário a preparação de uma diluição específica de propofol e o desenvolvimento de um cateter de capnografia original manufaturado para a realização do estudo. Resultados: Em relação aos desfechos clínicos, houve diferença estatística na agitação (maior no grupo 1, p=0,001) e pressão arterial inicial (p=0,008). Com relação aos níveis séricos de propofol, os resultados foram semelhantes no consumo por minuto (p=0,748) e ao longo do tempo (p=0,830). Em termos de análise de custo, no grupo 1 o custo foi de R$ 7,00 (aproximadamente US$ 2,25); grupo 2, R$ 17,50 (aproximadamente US$ 5,64); e grupo 3, R$ 112,70 (cerca de US$ 36,35, p<0,001). A capnografia foi capaz de diagnosticar 100% das dessaturações de oxigênio (abaixo de 90%). Conclusão: O uso de propofol em bolus para colonoscopias, por meio de infusão contínua controlada manualmente ou infusão automática são semelhantes quanto à propofolemia e os resultados clínicos avaliados. Além disso, o uso de um cateter de capnografia inovador é solução de baixo custo para a detecção precoce da obstrução da via aérea.

[Case Report : Monitored Anesthesia Care (MAC) with Dexmedetomidine.]

Dexmedetomidine (DEX) is a sedative used for monitored anesthesia care (MAC). DEX has been used frequently for MAC because of its less respiratory depressant effect We used DEX in four patients with severe complications who needed surgery under MAC. We started MAC with continuous infusion of 0.5-0.9 µtg - kg(-1) . hr(-1) of DEX, without initial loading dose, combined with regional anesthesia, and gradually either increased or decreased continuous infusion according to Ramsay sedation scale (RSS). The simulated plasma concentrations of DEX were calculated by AnestAs- sistTM PK . PD(-1). All patients were well sedated and operations were completed safely, although simulated plasma concentrations of DEX were low. Remarkable cardiovascular responses and respiratory depression were not observed. Our study indicated that the usage of DEX without initial loading dose combined with regional anesthesia could be an option for patients with severe complications undergoing MAC.

Propofol sedation with a target-controlled infusion pump and bispectral index monitoring system in elderly patients during a complex upper endoscopy procedure.

BACKGROUND AND AIMS: Although the usefulness of propofol sedation during endoscopic submucosal dissection (ESD) for gastric neoplasms was reported previously, information is limited on its use in elderly patients. We investigated the safety and efficacy of propofol sedation with a target-controlled infusion (TCI) pump and bispectral index (BIS) monitoring system (TCI/BIS system) in elderly patients during gastric ESD. METHODS: Included were 413 consecutive gastric ESD procedures involving 455 lesions (379 patients) performed in patients under propofol sedation with a TCI/BIS system between October 2009 and September 2013. Patients were divided into 3 groups: group A, age <70 years (n = 162); group B, age ≥70 and <80 years (n = 171); and group C, age ≥80 years (n = 80). We compared the propofol dose and adverse events (eg, hypotension and hypoxemia) during ESD. RESULTS: Older groups required a lower target concentration of propofol (group A: median 2.1 µg/mL [interquartile range (IQR), 1.9-2.3]; group B: median 1.6 µg/mL [IQR, 1.3-1.8]; and group C: median 1.4 µg/mL [IQR, 1.2-1.6]; P < .0001). Hypotension tended to occur in the younger group, and hypoxemia occurred at a significantly higher rate in the older groups, although the number of cases was small. Low preoperative systolic blood pressure (≤125 mm Hg) was associated with hypotension (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.12-2.70; P = .013) and abnormal pulmonary function was associated with hypoxemia in groups B and C (OR, 4.54; 95% CI, 1.01-31.5; P = .048). CONCLUSIONS: Elderly patients required lower doses of propofol with the TCI/BIS system than younger patients. Attention to hypoxemia is necessary in elderly patients, particularly patients with abnormal pulmonary function.

Bromoderma mimicking pyoderma gangrenosum caused by commercial sedatives.

Bromoderma is a rare skin disorder caused by bromide intake. It presents as single or multiple papillomatous nodules or plaques, and ulcers studded with small pustules on the face or limbs. The clinical features of bromoderma are similar to those of pyoderma gangrenosum. A 41-year-old Japanese woman was diagnosed with pyoderma gangrenosum 11 years prior to presentation. Pyoderma had repeatedly appeared over her entire body despite treatment. She also frequently complained of syncopal episodes. She was admitted to our hospital after loss of consciousness and an episode of generalized convulsion. Laboratory tests revealed a negative serum anion gap and hyperchloremia. Her serum bromide level was significantly elevated, suggesting bromide intoxication. The patient had a 10-year history of high serum bromide levels. After the intake of bromide-containing sedatives was stopped, there was no recurrence of pyoderma in the absence of treatment. In conclusion, this case was diagnosed as bromoderma with commercial sedative-induced bromide intoxication. Although the US Food and Drug Administration have banned the use of bromides, over-the-counter (OTC) treatments containing bromides are still used in Japan and other countries. Long-term use of OTC medicines containing bromvalerylurea may result in the development of bromoderma. If unclarified neurological or psychiatric symptoms are associated with pyoderma, we propose measurement of the patient's serum chloride concentration. Determination of hyperchloremia is helpful for the diagnosis of chronic intoxication with bromides.