Adenosine-induced flow arrest to facilitate intracranial aneurysm clip ligation: dose-response data and safety profile.

BACKGROUND: Adenosine-induced transient flow arrest has been used to facilitate clip ligation of intracranial aneurysms. However, the starting dose that is most likely to produce an adequate duration of profound hypotension remains unclear. We reviewed our experience to determine the dose-response relationship and apparent perioperative safety profile of adenosine in intracranial aneurysm patients. METHODS: This case series describes 24 aneurysm clip ligation procedures performed under an anesthetic consisting of remifentanil, low-dose volatile anesthetic, and propofol in which adenosine was used. The report focuses on the doses administered; duration of systolic blood pressure <60 mm Hg (SBP(<60 mm Hg)); and any cardiovascular, neurologic, or pulmonary complications observed in the perioperative period. RESULTS: A median dose of 0.34 mg/kg ideal body weight (range: 0.29-0.44 mg/kg) resulted in a SBP(<60 mm Hg) for a median of 57 seconds (range: 26-105 seconds). There was a linear relationship between the log-transformed dose of adenosine and the duration of a SBP(<60 mm Hg) (R(2) = 0.38). Two patients developed transient, hemodynamically stable atrial fibrillation, 2 had postoperative troponin levels >0.03 ng/mL without any evidence of cardiac dysfunction, and 3 had postoperative neurologic changes. CONCLUSIONS: For intracranial aneurysms in which temporary occlusion is impractical or difficult, adenosine is capable of providing brief periods of profound systemic hypotension with low perioperative morbidity. On the basis of these data, a dose of 0.3 to 0.4 mg/kg ideal body weight may be the recommended starting dose to achieve approximately 45 seconds of profound systemic hypotension during a remifentanil/low-dose volatile anesthetic with propofol induced burst suppression.

An evaluation of remifentanil-sevoflurane response surface models in patients emerging from anesthesia: model improvement using effect-site sevoflurane concentrations.

INTRODUCTION: We previously reported models that characterized the synergistic interaction between remifentanil and sevoflurane in blunting responses to verbal and painful stimuli. This preliminary study evaluated the ability of these models to predict a return of responsiveness during emergence from anesthesia and a response to tibial pressure when patients required analgesics in the recovery room. We hypothesized that model predictions would be consistent with observed responses. We also hypothesized that under non-steady-state conditions, accounting for the lag time between sevoflurane effect-site concentration (Ce) and end-tidal (ET) concentration would improve predictions. METHODS: Twenty patients received a sevoflurane, remifentanil, and fentanyl anesthetic. Two model predictions of responsiveness were recorded at emergence: an ET-based and a Ce-based prediction. Similarly, 2 predictions of a response to noxious stimuli were recorded when patients first required analgesics in the recovery room. Model predictions were compared with observations with graphical and temporal analyses. RESULTS: While patients were anesthetized, model predictions indicated a high likelihood that patients would be unresponsive (> or = 99%). However, after termination of the anesthetic, models exhibited a wide range of predictions at emergence (1%-97%). Although wide, the Ce-based predictions of responsiveness were better distributed over a percentage ranking of observations than the ET-based predictions. For the ET-based model, 45% of the patients awoke within 2 min of the 50% model predicted probability of unresponsiveness and 65% awoke within 4 min. For the Ce-based model, 45% of the patients awoke within 1 min of the 50% model predicted probability of unresponsiveness and 85% awoke within 3.2 min. Predictions of a response to a painful stimulus in the recovery room were similar for the Ce- and ET-based models. DISCUSSION: Results confirmed, in part, our study hypothesis; accounting for the lag time between Ce and ET sevoflurane concentrations improved model predictions of responsiveness but had no effect on predicting a response to a noxious stimulus in the recovery room. These models may be useful in predicting events of clinical interest but large-scale evaluations with numerous patients are needed to better characterize model performance.

Comportamento da pressão intra-ocular segundo os efeitos cardiorrespiratórios e hemodinâmicos induzidos pela anestesia com desflurano, em cães submetidos à hipovolemia experimental

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effects of glucose infusion on the endocrine, metabolic and cardiorespiratory responses to halothane anaesthesia of ponies

Glucose was infused intravenously into six ponies during halothane anaesthesia, to evaluate its effect on their endocrine response to anaesthesia. The ponies were premedicated with acepromazine, and anaesthesia was induced with thiopentone and maintained with halothane in oxygen for two hours. Glucose was infused to maintain the plasma glucose concentration above 20 mmol/litre. Anaesthesia was associated with hypothermia, a decrease in haematocrit, hypotension, hyperoxaemia, respiratory acidosis and an increase in the plasma concentrations of lactate and arginine vasopressin. The concentration of β-endorphin in plasma increased transiently after 20 minutes but there were no changes in concentrations of adrenocorticotrophic hormone, dynorphin, cortisol or catecholamines. These data suggest that the glucose infusion attenuated the normal adrenal response of ponies to halothane anaesthesia.

The effect of changing the mode of ventilation on the arterial-to-end-tidal CO2 difference and physiological dead space in laterally and dorsally recumbent horses during halothane anesthesia

Objective - To evaluate the effect of changing the mode of ventilation from spontaneous to controlled on the arterial-to-end-tidal CO2 difference [P(a-ET)CO2] and physiological dead space (VD(phys)/VT) in laterally and dorsally recumbent halothane-anesthetized horses. Study Design - Prospective, experimental, nonrandomized trial. Animals - Seven mixed breed adult horses (1 male and 6 female) weighing 320 ± 11 kg. Methods - Horses were anesthetized in 2 positions - right lateral and dorsal recumbency - with a minimum interval of 1 month. Anesthesia was maintained with halothane in oxygen for 180 minutes. Spontaneous ventilation (SV) was used for 90 minutes followed by 90 minutes of controlled ventilation (CV). The same ventilator settings were used for both laterally and dorsally recumbent horses. Arterial blood gas analysis was performed every 30 minutes during anesthesia. End-tidal CO2 (PETCO2) was measured continuously. P(a-ET)CO2 and VD(phys)/VT were calculated. Statistical analysis included analysis of variance for repeated measures over time, followed by Student-Newman-Keuls test. Comparison between groups was performed using a paired t test; P < .05 was considered significant. Results - P(a-ET)CO2 and VD(phys)/VT increased during SV, whereas CV reduced these variables. The variables did not change significantly throughout mechanical ventilation in either group. Dorsally recumbent horses showed greater P(a-ET)CO2 and VD(phys)/VT values throughout. PaCO2 was greater during CV in dorsally positioned horses. Conclusions and Clinical Relevance - Changing the mode of ventilation from spontaneous to controlled was effective in reducing P(a-ET)CO2 and physiological dead space in both laterally and dorsally recumbent halothane-anesthetized horses. Dorsal recumbency resulted in greater impairment of effective ventilation. Capnometry has a limited value for accurate estimation of PaCO, in anesthetized horses, although it may be used to evaluate pulmonary function when paired with arterial blood gas analysis. © Copyright 2000 by The American College of Veterinary Surgeons.

Neonatal inhalatory anesthetic exposure: Reproductive changes in male rats

We investigated the effects of an inhalatory anesthetic (ethyl ether) during the neonatal period of brain sexual differentiation on the later fertility and sexual behavior of male rats. Animals were exposed to ethyl ether immediately after birth. At adulthood, body weight, testes wet weight, and plasma testosterone levels were not affected; however, neonatal exposure to ether showed alterations on male fertility: a decrease in the number of spermatids and spermatozoa, an increase in the transit time of cauda epididymal spermatozoa and a decrease in daily sperm production. An alteration of sexual behavior was also observed: decreased male sexual behavior and appearance of homosexual behavior when the male rats were castrated and pretreated with exogenous estrogen. Probably, the ether delayed or reduced the testosterone peak of the sexual differentiation period, altering the processes of masculinization and defeminization of the hypothalamus. Our results indicate that perinatal exposure to ethyl ether during the critical period of male brain sexual differentiation, acting as endocrine disruptors, has a long-term effect on the fertility and sexual behavior of male rats, suggesting endocrine disruption through incomplete masculinization and defeminization of the central nervous system. © 2002 Elsevier B.V. All rights reserved.

Pharmacokinetics of dexmedetomidine administered intravenously in isofluraneanesthetized cats

Objective-To determine the pharmacokinetics of dexmedetomidine administered as a short-duration IV infusion in isoflurane-anesthetized cats. Animals-6 healthy adult domestic female cats. Procedures-Dexmedetomidine hydrochloride was injected IV (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]) in isoflurane-anesthetized cats. Blood samples were obtained immediately prior to and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240, and 480 minutes following the start of the IV infusion. Collected blood samples were transferred to tubes containing EDTA, immediately placed on ice, and then centrifuged at 3,901 X g for 10 minutes at 4°C. The plasma was harvested and stored at -20°C until analyzed. Plasma dexmedetomidine concentrations were determined by means of liquid chromatography-mass spectrometry. Dexmedetomidine plasma concentration-time data were fitted to compartmental models. Results-A 2-compartment model with input in and elimination from the central compartment best described the disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats. Weighted mean ± SEM apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state were 402 ± 47 mL/kg and 1,701 ± 200 mL/kg, respectively; clearance and terminal half-life (harmonic mean ± jackknife pseudo-SD) were 6.3 ± 2.8 mL/min/kg and 198 ± 75 minutes, respectively. The area under the plasma concentration curve and maximal plasma concentration were 1,061 ± 292 min·ng/mL and 17.6 ± 1.8 ng/mL, respectively. Conclusions and Clinical Relevance-Disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats was characterized by a moderate clearance and a long terminal half-life.

Effect of dexmedetomidine on the minimum alveolar concentration of isoflurane in cats

This study reports the effects of dexmedetomidine on the minimum alveolar concentration of isoflurane (MAC iso) in cats. Six healthy adult female cats were used. MAC iso and dexmedetomidine pharmacokinetics had previously been determined in each individual. Cats were anesthetized with isoflurane in oxygen. Dexmedetomidine was administered intravenously using target-controlled infusions to maintain plasma concentrations of 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10, and 20ng/mL. MAC iso was determined in triplicate at each target plasma dexmedetomidine concentration. Blood samples were collected and analyzed for dexmedetomidine concentration. The following model was fitted to the concentration-effect data: where MAC iso.c is MAC iso at plasma dexmedetomidine concentration C, MAC iso.0 is MAC iso in the absence of dexmedetomidine, I max is the maximum possible reduction in MAC iso, and IC 50 is the plasma dexmedetomidine concentration producing 50% of I max. Mean±SE MAC iso.0, determined in a previous study conducted under conditions identical to those in this study, was 2.07±0.04. Weighted mean±SE I max, and IC 50 estimated by the model were 1.76±0.07%, and 1.05±0.08ng/mL, respectively. Dexmedetomidine decreased MAC iso in a concentration-dependent manner. The lowest MAC iso predicted by the model was 0.38±0.08%, illustrating that dexmedetomidine alone is not expected to result in immobility in response to noxious stimulation in cats at any plasma concentration. © 2011 Blackwell Publishing Ltd.

The Lanz® endotracheal tube decreases tracheal injury in dogs

Purpose: To determine, in dogs anesthetized with nitrous oxide (N2O), whether the endotracheal tube (ETT) cuffed with a Lanz® pressure regulating valve decreases the tracheal consequences of tracheal intubation. Methods: Sixteen mixed-breed dogs were allocated to two groups according to the ETT used: Control group (n = 8) - Rüsch ETT, and Lanz group (n = 8) - ETT with Lanz® pressure regulating valve. The ETT cuffs in both groups were inflated with air to an intracuff pressure of 30 cm H2O. Anesthesia was induced and maintained with pentobarbitone and N2O (1.5 L·min-1) and O2 (1 L·min-1). ETT cuff pressures were measured before (control) and 60, 120, and 180 min during N2O administration. The dogs were sacrificed, and biopsy specimens from four predetermined areas of the tracheal mucosa in contact with the ETT were collected for light and scanning electron microscopy (SM) examination. Results: Cuff pressures in the Control group were higher than in the Lanz group at all time points studied (P < 0.001), with an increase over time only in the Control group (P < 0.001). Median neutrophilic inflammatory infiltration values of the epithelial surface, and in the subepithelial layer in contact with the cuff, were higher in the Control group as compared to the Lanz group (3.0 vs 1.0 and 3.0 vs 1.5 respectively) (P < 0.05). On SM examination, median histological grades were higher in the Control group compared to Lanz group (2.9 vs 1.9 respectively), (P < 0.05). Conclusions: The Lanz® ETT decreases tracheal mucosal injury in dogs.

Noninvasive assessment of diffusion hypoxia following administration of nitrous oxide-oxygen.

The phenomenon of diffusion hypoxia is commonly believed to occur unless nitrous oxide-oxygen inhalation sedation is followed by "washout" with 100% oxygen for 5 minutes upon termination of the flow of nitrous oxide. When systematically studied, however, this phenomenon generally appears to be unfounded. The present study evaluated the effect of breathing room air instead of 100% oxygen in healthy (ASA 1) human volunteers following administration of sedative concentrations of nitrous oxide. The occurrence of hypoxia was determined objectively, using pulse oximetry and a standardized psychomotor skills test (Trieger test). Diffusion hypoxia was not observed using these criteria.

DNA damage in patients who underwent minimally invasive surgery under inhalation or intravenous anesthesia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Cardiorespiratory, endocrine and metabolic changes in ponies undergoing intravenous or inhalation anaesthesia

Six Welsh gelding ponies (weight 246 ± 6 kg) were premedicated with 0.03 mg/kg of acepromazine intravenously (i.v.) followed by 0.02 mg/kg of detomidine i.v. Anaesthesia was induced with 2 mg/kg of ketamine i.v. Ponies were intubated and lay in left lateral recumbency. On one occasion anaesthesia was maintained for 2 h using 1.2% halothane in oxygen. The same group of ponies were anaesthetized 1 month later using the same induction regime and anaesthesia was maintained with a combination of detomidine, ketamine and guaiphenesin, while the ponies breathed oxygen-enriched air. Electrocardiogram, heart rate, mean arterial blood pressure, cardiac output, respiratory rate, blood gases, temperature, haematocrit, glucose, lactate and cortisol were measured and cardiac index and systemic vascular resistance were calculated in both groups. Beta-endorphin, met-enkephalin, dynorphin, arginine vasopressin (AVP), adrenocorticotrophic hormone (ACTH) and catecholamines were measured in the halothane anaesthesia group only and 11-deoxycortisol during total intravenous anaesthesia (TIVA) only. Cardiorespiratory depression was more marked during halothane anaesthesia. Hyperglycaemia developed in both groups. Lactate and AVP increased during halothane anaesthesia. Cortisol increased during halothane and decreased during TIVA. There were no changes in the other hormones during anaesthesia. Recovery was smooth in both groups. TIVA produced better cardiorespiratory performance and suppressed the endocrine stress response observed during halothane anaesthesia.

Adhesion and dispersion of salmeterol xinofoate from lactose interactive mixtures for inhalation - can surface roughness of carriers determine performance

The objective was to understand the influence of the surface roughness of lactose carriers on the adhesion and dispersion of salmeterol xinafoate (SX) from interactive mixtures. The surface roughness of lactose carriers was determined by confocal microscopy. Particle images and adhesion forces between SX and lactose particles were determined by Atomic Force Microscopy. The dispersion of SX (2.5%) from interactive mixtures with lactose was determined using a twin-stage impinger (TSI) with a Rotahaler® at an airflow rate of 60L/min. SX was analysed using a validated HPLC assay. The RMS Rq of lactose carriers ranged from 0.93-2.84μm, the Fine Particle Fraction (FPF) of SX ranged between 4 and 24 percent and average adhesion force between a SX and lactose particles ranged between 49 and 134 nN. No direct correlation was observed between the RMS Rq of lactose carriers and either the FPF of SX for the interactive mixtures or the adhesion force of a SX on the lactose particles; however, the presence of fine lactose associated with the carrier surface increased the FPF of SX. Dispersion through direct SX detachment from the carrier surface was not consistent with the poor correlations described and was more likely to occur through complex particulate interactions involving fine lactose.

Effect of water vapour stabilization of raw materials on the quality of the inhalation product

Generation of raw materials for dry powder inhalers by different size reduction methods can be expected to influence physical and chemical properties of the powders. This can cause differences in particle size, size distribution, shape, crystalline properties, surface texture and energy. These physical properties of powders influence the behaviour of particles before and after inhalation. Materials with an amorphous surface have different surface energy compared to materials with crystalline surface. This can affect the adhesion and cohesion of particles. Changes in the surface nature of the drug particles results in a change in product performance. By stabilization of the raw materials the amorphous surfaces are converted into crystalline surfaces. The primary aim of the study was to investigate the influence of the surface properties of the inhalation particles on the quality of the product. The quality of the inhalation product is evaluated by measuring the fine particle dose (FPD). FDP is the total dose of particles with aerodynamic diameters smaller than 5,0 μm. The secondary aim of this study was to achieve the target level of the FPD and the stability of the FPD. This study was also used to evaluate the importance of the stabilization of the inhalation powders. The study included manufacturing and analysing drug substance 200 μg/dose inhalation powder batches using non-stabilized or stabilized raw materials. The inhaler formulation consisted of micronized drug substance, lactose <100μm and micronized lactose <10μm. The inhaler device was Easyhaler®. Stabilization of the raw materials was done in different relative humidity, temperature and time. Surface properties of the raw materials were studied by dynamic vapour sorption, scanning electron microscopy and three-point nitrogen adsorption technique. Particle size was studied by laser diffraction particle size analyzer. Aerodynamic particle size distribution from inhalers was measured by new generation impactor. Stabilization of all three raw materials was successful. A clear difference between nonstabilized and stabilized raw materials was achieved for drug substance and lactose <10μm. However for lactose <100μm the difference wasn’t as clear as wanted. The surface of the non-stabilized drug substance was more irregular and the particles had more roughness on the surface compared to the stabilized drug substances particles surface. The surface of the stabilized drug particles was more regular and smoother than non-stabilized. Even though a good difference between stabilized and non-stabilized raw materials was achieved, a clear evidence of the effect of the surface properties of the inhalation particles on the quality of the product was not observed. Stabilization of the raw materials didn’t lead to a higher FPD. Possible explanations for the unexpected result might be too rough conditions in the stabilization of the drug substance or smaller than wanted difference in the degree of stabilization of the main component of the product <100μm. Despite positive effects on the quality of the product were not seen there appears to be some evidence that stabilized drug substance results in smaller particle size of dry powder inhalers.

Combined inhalation and oral supplementation of Vitamin A and Vitamin D: A possible prevention and therapy for tuberculosis

Tuberculosis is continuing as a problem of mankind. With evolution, MDR and XDR forms of tuberculosis have emerged from drug sensitive strain. MDR and XDR strains are resistant to most of the antibiotics, making the management more difficult. BCG vaccine is not providing complete protection against tuberculosis. Therefore new infections are spreading at a tremendous rate. At the present moment there is experimental evidence to believe that Vitamin A and Vitamin D has anti-mycobacterial property. It is in this context, we have hypothesized a host based approach using the above vitamins that can cause possible prevention and cure of tuberculosis with minimal chance of resistance or toxicity. (C) 2015 Elsevier Ltd. All rights reserved.