Pungent general anesthetics activate transient receptor potential-A1 to produce hyperalgesia and neurogenic bronchoconstriction

BACKGROUND: Volatile anesthetics such as isoflurane and halothane have been in clinical use for many years and represent the group of drugs most commonly used to maintain general anesthesia. However, despite their widespread use, the molecular mechanisms by which these drugs exert their effects are not completely understood. Recently, a seemingly paradoxical effect of general anesthetics has been identified: the activation of peripheral nociceptors by irritant anesthetics. This mechanism may explain the hyperalgesic actions of inhaled anesthetics and their adverse effects in the airways. METHODS: To test the hypothesis that irritant inhaled anesthetics activate the excitatory ion-channel transient receptor potential (TRP)-A1 and thereby contribute to hyperalgesia and irritant airway effects, we used the measurement of intracellular calcium concentration in isolated cells in culture. For our functional experiments, we used models of isolated guinea pig bronchi to measure bronchoconstriction and withdrawal threshold to mechanical stimulation with von Frey filaments in mice. RESULTS: Irritant inhaled anesthetics activate TRPA1 expressed in human embryonic kidney cells and in nociceptive neurons. Isoflurane induces mechanical hyperalgesia in mice by a TRPA1-dependent mechanism. Isoflurane also induces TRPA1-dependent constriction of isolated bronchi. Nonirritant anesthetics do not activate TRPA1 and fail to produce hyperalgesia and bronchial constriction. CONCLUSIONS: General anesthetics induce a reversible loss of consciousness and render the patient unresponsive to painful stimuli. However, they also produce excitatory effects such as airway irritation and they contribute to postoperative pain. Activation of TRPA1 may contribute to these adverse effects, a hypothesis that remains to be tested in the clinical setting.

Genotoxicity of anesthetics evaluated in vivo (animals)

The anesthesia has been improved all over the years. However, it can have impact on health, in both patients and animals anesthetized, as well as professionals exposed to inhaled anesthetics. There is continuing effort to understand the possible effects of anesthetics at molecular levels. Knowing the effects of anesthetic agents on genetic material could be a valuable basic support to better understand the possible mechanisms of these agents. Thus, the purpose of this review is to provide an overview on the genotoxic potential, evaluated in animal models, of many anesthetics that have already been used and those currently used in anesthesia.

Incidencia de fibrilación auricular en las primeras 72 horas del post operatorio de revascularización miocárdica

Determinar la incidencia de fibrilación auricular en las primeras 72 horas del post operatorio en pacientes llevados a revascularización miocárdica utilizando dos técnicas de anestésia una convencional (AC) con anestésicos inhalados y opioides y otra con dexmedetomidina (AD.). cohorte retrospectivo, en donde se seleccionarán dos grupos de estudio, un grupo de expuestos, pacientes llevados a revascularización miocárdica con utilización técnica anestésica convencional y un grupo de no expuestos pacientes llevados a revascularización miocárdica con uso de dexmedetomidina como técnica de anestesia; A estos grupos se les hizo seguimiento por 72 horas para determinar la presencia de fibrilación auricular y la terapéutica instaurada.

Anesthetic Activation of Central Respiratory Chemoreceptor Neurons Involves Inhibition of a THIK-1-Like Background K(+) Current

At surgical depths of anesthesia, inhalational anesthetics cause a loss of motor response to painful stimuli (i.e., immobilization) that is characterized by profound inhibition of spinal motor circuits. Yet, although clearly depressed, the respiratory motor system continues to provide adequate ventilation under these same conditions. Here, we show that isoflurane causes robust activation of CO(2)/pH-sensitive, Phox2b-expressing neurons located in the retrotrapezoid nucleus (RTN) of the rodent brainstem, in vitro and in vivo. In brainstem slices from Phox2b-eGFP mice, the firing of pH-sensitive RTN neurons was strongly increased by isoflurane, independent of prevailing pH conditions. At least two ionic mechanisms contributed to anesthetic activation of RTN neurons: activation of an Na(+)-dependent cationic current and inhibition of a background K(+) current. Single-cell reverse transcription-PCR analysis of dissociated green fluorescent protein-labeled RTN neurons revealed expression of THIK-1 (TWIK-related halothane-inhibited K(+) channel, K(2P)13.1), a channel that shares key properties with the native RTN current (i.e., suppression by inhalational anesthetics, weak rectification, inhibition by extracellular Na(+), and pH-insensitivity). Isoflurane also increased firing rate of RTN chemosensitive neurons in urethane-anesthetized rats, again independent of CO(2) levels. In these animals, isoflurane transiently enhanced activity of the respiratory system, an effect that was most prominent at low levels of respiratory drive and mediated primarily by an increase in respiratory frequency. These data indicate that inhalational anesthetics cause activation of RTN neurons, which serve an important integrative role in respiratory control; the increased drive provided by enhanced RTN neuronal activity may contribute, in part, to maintaining respiratory motor activity under immobilizing anesthetic conditions.

A study of the effect of hemorrhage on the cardiorespiratory actions of halothane, isoflurane and sevoflurane in the dog

Objective To compare the cardiorespiratory changes induced by equipotent concentrations of halothane (HAL), isoflurane (ISO) and sevollurane (SEVO) before and after hemorrhage.Study design. Prospective, randomized clinical trial.Animals. Twenty-four healthy adult dogs weighing 15.4 +/- 3.4 kg (mean +/- SD).Methods. Animals were randomly allocated to one of three groups (n = 8 per group). In each group, anesthesia was maintained with 1.5 minimum alveolar concentration of HAL (1.3%), ISO (1.9%,) and SEVO (3.5%) in oxygen. Controlled ventilation was performed to maintain eucapnia. Cardiorespiratory variables were evaluated at baseline (between 60 and 90 minutes after induction), immediately after and 30 minutes after the withdrawal of 32 mL kg(-1) of blood (400% of the estimated blood volume) over a 30-minute period.Results. During baseline conditions, ISO and SEVO resulted in higher cardiac index (CI) than HAL. Heart rates were higher with SEVO at baseline. while mean arterial pressure (MAP) and mean pulmonary arterial pressure did not differ between groups. Although heart rate values were higher for ISO and SEVO after hemorrhage, only ISO resulted in a higher CI when compared with HAL. In ISO-anesthetized dogs, MAP was higher immediately after hemorrhage, and this was related to better maintenance of CI and to an increase in systemic vascular resistance index from baseline.Conclusions. Although the hemodynamic responses of ISO and SEVO are similar in normovolaemic dogs, ISO results in better maintenance of circulatory function during the early period following a massive blood loss. Clinical relevance Inhaled anesthetics should be used judiciously in animals presented with blood loss. However, if an inhalational agent is to be used under these circumstances, ISO may provide better hemodynamic stability than SEVO or HAL.

Efeitos do halotano, isoflurano e sevoflurano sobre a função renal em cães sob pinçamento aórtico infra-renal

JUSTIFICATIVA E OBJETIVOS: O pinçamento infra-renal da aorta abdominal pode produzir alterações renais. O objetivo do estudo foi avaliar os efeitos do halotano, isoflurano e sevoflurano sobre a função renal, em cães submetidos a pinçamento aórtico infra-renal. MÉTODO: O estudo aleatório foi realizado em 30 cães, distribuídos em três grupos, de acordo com o anestésico halogenado utilizado durante a anestesia, em concentrações equipotentes de 0,75 CAM: GH (n = 10) - halotano a 0,67%; GI (n = 10) - isoflurano a 0,96%; e GS (n = 10) - sevoflurano a 1,8%. em todos os animais foi realizada ligadura infra-renal da aorta, por período de 30 minutos. Os atributos renais foram estudados nos momentos: C (controle), após 15 (Ao15) e 30 (Ao30) minutos de pinçamento aórtico, e após 15 (DAo15) e 30 (DAo30) minutos do despinçamento aórtico. RESULTADOS: A depuração de água livre foi menor nos grupos GI e GS, em relação ao GH, após o despinçamento aórtico (p < 0,05). Durante o pinçamento aórtico, nos três grupos, houve aumento do débito urinário, da excreção urinária de sódio e da depuração de sódio, e diminuição da osmolaridade urinária (p < 0,05). A resistência vascular renal e a fração de filtração aumentaram somente em GS (p < 0,05), enquanto a excreção fracionária de sódio aumentou em GH e GI (p < 0,05). Após o despinçamento aórtico, houve normalização dos atributos que haviam se alterado, com exceção da osmolaridade urinária, que continuou em níveis menores do que os do controle em todos os grupos (p < 0,05). A resistência vascular renal e a fração de filtração continuaram mais elevadas em GS, acompanhadas por diminuição do fluxo sangüíneo renal e da depuração de para-aminohipurato de sódio (p < 0,05). CONCLUSÕES: No cão nas condições experimentais empregadas, a inalação de halotano e isoflurano a 0,75 CAM, mas não de sevoflurano, atenuou a principal alteração após o pinçamento infra-renal da aorta, que é o aumento da resistência vascular renal.

Effects of constant rate infusion of anesthetic or analgesic drugs on general anesthesia with isoflurane: A retrospective study in 200 dogs

Constant rate infusion (CRI) shows several advantages in balanced anesthesia, such as reduction of requirement for inhaled anesthetics and control of pain. The most commonly used drugs in these protocols are local anesthetics, dissociative, and opioids, which may be administered alone or in combinations. We evaluated the records of 200 dogs that underwent various surgical procedures with anesthetic or analgesic CRI in the perioperative period during 2011 and 2012 at the Veterinary Hospital of Franca University (Unifran), and identified possible complications during the transoperative period. Records evaluated included clinical state, laboratory tests, drugs used in premedication and induction, and CRI protocol. Acepromazine and morphine were the main drugs used in premedication. Propofol was used to induce anesthesia alone or in combination with other agents. We evaluated records of the 25 different CRI protocols. Fentanyl was the main drug employed in CRI, either alone or in combination. There were 128 episodes of anesthetic complications during CRI;the most common were hypotension, hypertension, and tachycardia, which occurred in 43 (32%), 35 (26.3%), and 19 (14.2%) dogs, respectively. Cardiac arrhythmia was reported in only 4 dogs. Signs of respiratory depression were present in dogs treated with 6 different CRI protocols. The consumption of isoflurane (vol %) reduced between 15.7% and 21.05% after 30minutes of the CRI in the fentanyl and fentanyl-lidocaine-ketamine CRI groups (p<0.05). In conclusion, CRI is a valid component of balanced anesthesia in dogs, safe, and has a low incidence of adverse effects. However, future studies are warranted to describe the results of the clinical use of CRI to better characterize and refine this technique.

Efeitos do cloridrato de remifentanil, administrado em infusão contínua, na concentração alveolar mínima(CAM) de isofluorano em felinos

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

Avaliação de danos no material genético em anestesiologistas

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Evaluation of administration of isoflurane at approximately the minimum alveolar concentration on depression of a nociceptive withdrawal reflex evoked by transcutaneous electrical stimulation in ponies

OBJECTIVE: To investigate effects of isoflurane at approximately the minimum alveolar concentration (MAC) on the nociceptive withdrawal reflex (NWR) of the forelimb of ponies as a method for quantifying anesthetic potency. ANIMALS: 7 healthy adult Shetland ponies. PROCEDURE: Individual MAC (iMAC) for isoflurane was determined for each pony. Then, effects of isoflurane administered at 0.85, 0.95, and 1.05 iMAC on the NWR were assessed. At each concentration, the NWR threshold was defined electromyographically for the common digital extensor and deltoid muscles by stimulating the digital nerve; additional electrical stimulations (3, 5, 10, 20, 30, and 40 mA) were delivered, and the evoked activity was recorded and analyzed. After the end of anesthesia, the NWR threshold was assessed in standing ponies. RESULTS: Mean +/- SD MAC of isoflurane was 1.0 +/- 0.2%. The NWR thresholds for both muscles increased significantly in a concentration-dependent manner during anesthesia, whereas they decreased in awake ponies. Significantly higher thresholds were found for the deltoid muscle, compared with thresholds for the common digital extensor muscle, in anesthetized ponies. At each iMAC tested, amplitudes of the reflex responses from both muscles increased as stimulus intensities increased from 3 to 40 mA. A concentration-dependent depression of evoked reflexes with reduction in slopes of the stimulus-response functions was detected. CONCLUSIONS AND CLINICAL RELEVANCE: Anesthetic-induced changes in sensory-motor processing in ponies anesthetized with isoflurane at concentrations of approximately 1.0 MAC can be detected by assessment of NWR. This method will permit comparison of effects of inhaled anesthetics or anesthetic combinations on spinal processing in equids.

Conscious Sedation with Inhaled 50% Nitrous Oxide/Oxygen Premix in Photodynamic Therapy Sessions for Vulvar Lichen Sclerosus Treatment

Photodynamic therapy has been described as an effective therapeutic option in selected cases of anogenital lichen sclerosus that are refractory to first-line treatments. However, procedure-related pain is a limiting factor in patient adherence to treatment. The authors report the case of a 75-year-old woman with highly symptomatic vulvar lichen sclerosus, successfully treated with photodynamic therapy. An inhaled 50% nitrous oxide/oxygen premix was administered during sessions, producing a pain-relieving, anxiolytic, and sedative effect without loss of consciousness. This ready-to-use gas mixture may be a well-tolerated and accepted alternative to classical anesthetics in Photodynamic therapy, facilitating patients' adherence to illumination of pain-prone areas.

Cardiovascular response during trigeminal ganglion compression for trigeminal neuralgia according to the use of local anesthetics

There are controversies about the use of local anesthetics during balloon compression for trigeminal neuralgia (TN) as a protective factor for cardiovascular events. The objective of this study was to investigate cardiovascular parameters (blood pressure and heart rate [HR]) of patients that underwent trigeminal balloon compression with local anesthetics compared to a control group (placebo). This is a randomized controlled study; 55 patients were randomized into two groups: study (deep sedation and trigeminal block with 0.8-mL lidocaine 2%) and control group (deep sedation and trigeminal injection of 0.8-mL saline). Blood pressure and HR were measured in five distinct moments: preoperative, during puncture for local anesthesia/placebo, during puncture with the catheter, during balloon compression, and final evaluation. Statistical analysis was performed with Pearson`s chi (2) and McNemar tests and the analysis of variance for repetitive measures. The means of systolic and diastolic blood pressures (SBP and DBP, respectively) were higher in the control group when compared to the study group at the evaluation during puncture with the catheter (p < 0.001) and balloon compression (p < 0.001 and p = 0.018 for DBP and SBP, respectively). There was an increase in the HR in the control group during the procedure (p = 0.017). The use of local anesthetics during the trigeminal balloon compression for TN can have a preventive role for the risk of cardiovascular events.

Reversible cardiomyopathy associated with acute inhaled marijuana use in a young adult

Marijuana is a frequently used recreational drug. We describe the first published case of marijuana related cardiomyopathy.

Epidermal iontophoresis: II. Application of the ionic mobility-pore model to the transport of local anesthetics

Purpose, An in vitro study was carried out to determine the iontophoretic permeability of local anesthetics through human epidermis. The relationship between physicochemical structure and the permeability of these solutes was then examined using an ionic mobility-pore model developed to define quantitative relationships. Methods. The iontophoretic permeability of both ester-type anesthetics (procaine, butacaine, tetracaine) and amide-type anesthetics (prilocaine, mepivacaine, lidocaine, bupivacaine, etidocaine, cinchocaine) were determined through excised human epidermis over 2 hrs using a constant d.c. current and Ag/AgCl electrodes. Individual ion mobilities were determined from conductivity measurements in aqueous solutions. Multiple stepwise regression was applied to interrelate the iontophoretic permeability of the solutes with their physical properties to examine the appropriateness of the ionic mobility-pore model and to determine the best predictor of iontophoretic permeability of the local anesthetics. Results. The logarithm of the iontophoretic permeability coefficient (log PCj,iont) for local anesthetics was directly related to the log ionic mobility and MW for the free volume form of the model when other conditions are held constant. Multiple linear regressions confirmed that log PCj,iont was best defined by ionic mobility (and its determinants: conductivity, pK(a) and MW) and MW. Conclusions. Our results suggest that of the properties studied, the best predictors of iontophoretic transport of local anesthetics are ionic mobility (or pK(a)) and molecular size. These predictions are consistent with the ionic mobility pore model determined by the mobility of ions in the aqueous solution, the total current, epidermal permselectivity and other factors as defined by the model.

Comparison of Inhaled Nitric Oxide Versus Oxygen on Hemodynamics in Patients With Mitral Stenosis and Severe Pulmonary Hypertension After Mitral Valve Surgery

Pulmonary hypertension represents an important cause of morbidity and mortality in patients with mitral stenosis who undergo cardiac surgery, especially in the postoperative period. The aim of this study was to test the hypothesis that inhaled nitric oxide (iNO) would improve the hemodynamic effects and short-term clinical outcomes of patients with mitral stenosis and severe pulmonary hypertension who undergo cardiac surgery in a randomized, controlled study. Twenty-nine patients (4 men, 25 women; mean age 46 2 years) were randomly allocated to receive iNO (n = 14) or oxygen (n = 15) for 48 hours immediately after surgery. Hemodynamic data, the use of vasoactive drugs, duration of stay, and short-term complications were assessed. No differences in baseline characteristics were observed between the groups. After 24 and 48 hours, patients receiving iNO had a significantly greater increase in cardiac index compared to patients receiving oxygen (p < 0.0001). Pulmonary vascular resistance was also more significantly reduced in patients receiving iNO versus oxygen (-117 dyne/s/cm(5), 95% confidence interval 34 to 200, vs 40 dyne/s/cm5, 95% confidence interval 34 to 100, p = 0.005) at 48 hours. Patients in the iNO group used fewer systemic vasoactive drugs.(mean 2.1 +/- 0.14 vs 2.6 +/- 0.16, p = 0.046) and had a shorter intensive care unit stay (median 2 days, interquartile range 0.25, vs median 3 days, interquartile range 7, p = 0.02). In conclusion, iNO immediately after surgery in patients with mitral stenosis and severe pulmonary hypertension improves hemodynamics and may have short-term clinical benefits. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:1040-1045)