The mismatching of alveolar ventilation and perfusion (VA/Q) is the major determinant of impaired gas exchange. The gold standard for analyzing VA/Q distribution is the multiple inert gas elimination technique (MIGET), conventionally based on gas chromatography (GC), and, although simple in principle, a technically demanding procedure limiting its use. A new technique based on micropore membrane inlet mass spectrometry (MMIMS) combined MIGET with mass spectrometry, simplifying the sample handling process, and potentially providing VA/Q distributions for a general clinical approach. The kinetics of volatile anesthetics are well known in patients with healthy lungs. The uptake and distribution of inhaled anesthetics have usually been modeled by physiologic models. However, these models have limitations, and they do not consider ventilation/perfusion matching. Respiratory diseases account for a large part of morbidity and mortality and are associated with pulmonary VA/Q mismatch that may affect uptake and elimination of volatile anesthetics. The objectives of the studies were firstly to investigate assessment of VA/Q mismatch by MMIMS and secondly to investigate the effects of asthma-like VA/Q mismatch on the kinetics of volatile anesthetics in an experimental porcine model. Anesthetized and mechanically ventilated piglets were studied. In study I, a direct comparison of MIGET by MMIMS with the conventional MIGET by GC in three animal models that covered a wide range of VA/Q distributions was preformed. The two methods agreed well, and parameters derived from both methods showed good agreement with externally measured references. In studies II–IV, a stable method of inducing and maintaining asthma-like VA/Q mismatch with methacholine (MCh) administration was established, and the effect of VA/Q mismatch on the pharmacokinetics of desflurane and isoflurane was investigated. The present model of bronchoconstriction demonstrates a delay in volatile anesthetic uptake and elimination, related to the heterogeneity of MCh-inhalation induced ventilation. The difference in solubility of volatile anesthetics has a significant influence on their uptake and elimination under VA/Q mismatch. The higher blood soluble isoflurane is affected to a lesser degree than the fairly insoluble desflurane.

O presente estudo teve como objetivo avaliar os efeitos do halotano, isofluorano e sevofluorano sobre o índice biespectral, parâmetros cardiorrespiratórios e hemogasométricos em cadelas submetidas a ovariosalpingohisterectomia. Foram utilizadas 48 cadelas, sem raça definida, com peso médio de 15,09±4,29 kg, com idade média de 3,9±1,23 anos, encaminhadas para realização do procedimento de orivariosalpingohisterectomia. Os animais foram distribuídos aleatoriamente em seis grupos de oito animais, sendo designados como AH, AMH, AI, AMI, AS e AMS. Os animais dos grupos AH, AI e AS receberam acepromazina na medicação pré-anestésica na dose de 0,1 mg.kg-1 por via intramuscular. Já os animais dos grupos AMH, AMI e AMS receberam na medicação pré-anestésica acepromazina, na dose de 0,05 mg.kg-1, associada a meperidina, na dose de 3 mg.kg-1, administrados por via intramuscular. A indução da anestesia foi realizada com o auxílio de propofol, na dose de 5 mg.kg-1, lentamente por meio da via intravenosa. Uma vez que os animais apresentaram relaxamento mandibular foi realizada a entubação orotraqueal, sendo em seguida conectada ao circuito valvular circular do aparelho de anestesia, e mantidas em respiração espontânea com halotano (grupos AH e AMH), isofluorano (grupos AI e AMI) ou sevofluorano (grupos AS e AMS), diluídos em oxigênio a 100%. Foram mensurados o índice biespectral (BIS), eletromiografia (EMG), freqüência cardíaca (FC), pressão arterial sistólica (PAS), pressão arterial diastólica (PAD), pressão arterial média (PAM), temperatura retal, freqüência respiratória (FR), tensão de dióxido de carbono no final da expiração (ETCO2), saturação periférica de oxigênio na oxi-hemoglobina (SpO2), relação entra a pressão parcial de oxigênio no sangue arterial e a fração inspirada de oxigênio hemogasometria arterial (pH, PaCO<2, PaO2, HCO3- e DB). Os parâmetros verificados e registrados em todos os grupos desde M0 até M5, sendo estes: M0; 15 minutos após a administração da medicação pré-anestésica, M1; 10 minutos de manutenção anestésica, M2; ligadura do pedículo ovariano direito, M3; sutura da musculatura, M4; sutura de pele, M5; 10 minutos após o fim da administração do anestésico. Em todos os grupos houve forte correlação do índice biespectral e a fração expirada de anestésico. Quanto ao índice biespectral, o grupo AMH apresentou índices inferiores em M2 quando comparado com AI, AMI e AS; neste mesmo momento AI apresentou índices superiores em relação a AMS. Não houve diferença entre os grupos estudados em relação aos parâmetros cardiovasculares. Todos os agentes causaram depressão respiratória, evidenciado pelo incremento na PaCO2, e a ocorrência de acidemia. Conclui-se que os três agentes avaliados possuíram correlação inversa com o índice biespectral, o grupo AMS apresentou valores inferiores de BIS, todos os agentes promoveram estabilidade cardiovascular e de maneira semelhante, desencadearam depressão respiratória e acidemia. / The objective of this study was evaluation effects of the halothane, isoflurane and sevoflurane on bispectral index, cardiopulmonary and hemogasometrics parameters in bitches undergoing ovariohysterectomy. Fourth-eight mongrel bitches (weight: 15,09±4,29 kg) with 3,9±1,23 years old, send to HOVET-USP for surgical procedure of ovariohysterectomy. The animals were randomly allocated in six grupos of eight animals, designed with AH, AMH, AI, AMI, AS e AMS. The animals of the AH, AI and AS group were premedicated with acepromazine (0,1 mg.kg-1, i.m.) and the animals of the AMH, AMI and AMS groups receive acepromazine (0,05 mg.kg-1, i.m.) and meperidine (3 mg.kg-1, i.m.). Fifteen minutes later, propofol was titrated to allow endotracheal intubation and connected in valvular circuit of anesthesia machine and was maintained in spontaneously breathing with halotane (groups AH and AMH), isoflurane (AI and AMI) and sevoflurane (AS and AMS) in 100% oxygen delivery. Bispectral index (BIS), heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), rectal temperature (RT), respiratory rate (RR), end-tidal of carbon dioxide (ETCO2), peripheral oxihemoglobin saturation, relationship of the arterial oxygen pressure and inspiration fraction of oxygen, inspiration fraction of anesthetics, end-tidal anesthetics, and gasometrical parameters (pH, PaCO2, PaO2, HCO3- and BD) was evaluated. The parameters was evaluated in all groups in moments M0 to M5, M0 fifteen minutes after de pre-medication administration; M1, ten minutes of anesthetic maintains; M2, transfixation of left ovarian; M3 muscle suture; M4, skin suture, M5, ten minutes of the end of anesthetic. All groups were having strong correlation of the bispectral index and end-tidal anesthetic. The AMH group has minor values of bispectral index in M2 when compare with AI, AMI and AS groups; in this moment AI group present to values when compare with AMS. The cardiovascular parameters havent difference between groups. All agents caused reduction of respiratory function, evidenced for increase in PaCO2 and acidemia. The tree agents has inverse correlation with bispectral index, the AMS group, present minor values of BIS, all agents promoted cardiovascular stability and decrease of respiratory function.

Dor neuropática (DN) é definida como “dor iniciada ou causada por lesão primária ou disfunção em sistema nervoso”, porém sua prevalência depende do tipo de trauma e da disfunção relacionada. Apesar desta condição dolorosa ser considerada altamente prevalente e debilitante, os tratamentos disponíveis são relacionados a efeitos adversos dificultando a adesão. Devido a isso, buscam-se alternativas não farmacológicas para o tratamento deste tipo de dor, entre elas, as técnicas de neuromodulação periférica, como acupuntura (AC) e eletroacupuntura (EA). Estas técnicas podem ser combinadas com intervenções farmacológicas e não farmacológicas e têm apresentado resultados promissores no tratamento da dor neuropática. No entanto, seus mecanismos de ação não estão totalmente elucidados, desta forma a utilização de modelos animais é de grande valia para o estudo destes mecanismos no tratamento da dor neuropática e da patofisiologia deste tipo de dor crônica. É importante salientar que a aplicação de AC e EA em animais acordados é complexa, visto que gera desconforto e pode alterar a analgesia induzida pelo tratamento. Em muitos estudos a anestesia com isoflurano é utilizada durante a aplicação dos tratamentos, porém sua utilização pode gerar um viés no estudo, considerando a possível interferência do fármaco nos resultados comportamentais e neuroquímicos. Outro importante foco de estudo consiste em comparar as duas técnicas, AC e EA, buscando determinar qual destas é a mais eficaz no tratamento da dor neuropática. Considerando o exposto acima, os objetivos desta tese foram: 1) avaliar os parâmetros comportamentais e neuroquímicos dos efeitos da utilização de anestesia na aplicação de AC e EA em ratos submetidos ao modelo de DN; 2) comparar os efeitos da AC e EA em modelo animal de DN por meio de parâmentros comportamentais, neuroquímicos e histológicos. Considerando os resultados obtidos nesta tese, concluímos que o isoflurano aumenta a analgesia promovida por AC e EA, provavelmente diminuindo o efeito do estresse gerado pela aplicação dos tratamentos em animais acordados, resultado que é corroborado pela diminuição do nível de S100β periférico (marcador de morte neuronal central); Por outro lado, o isoflurano diminuiu os níveis de fator de crescimento neuronal (NGF) no nervo periférico lesado, indicando diminuição do processo de regeneração neural, enquanto a EA aumentou. Ao mesmo tempo, o isoflurano alterou os efeitos dos tratamentos nos comportamentos exploratórios e nos níveis de N-metil D-aspartato em tronco encefáfio e medula espinhal. A AC apresentou-se mais eficaz no tratamento da DN em comparação à EA, porém nenhum dos tratamentos foi capaz de alterar os danos causados pela indução da DN no músculo gastrocnemio esquerdo dos animais demonstrado na histologia. Todavia, este resultado não alterou a analgesia gerada pelos tratamentos. / Neuropathic pain (NP) is defined as "pain initiated or caused by primary injury or dysfunction in the nervous system," but its prevalence depends on the type of trauma and related dysfunction. Although this painful condition is considered to be highly prevalent and debilitating, the available treatments are related to adverse effects, making adherence difficult. Because of this, non-pharmacological alternatives for the treatment of this type of pain are sought, among them, the techniques of peripheral neuromodulation, such as acupuncture (AC) and electroacupuncture (EA). These techniques can be combined with pharmacological and non-pharmacological interventions and have shown promising results in the treatment of neuropathic pain. However, its mechanisms of action are not fully elucidated, so the use of animal models is of great value for the study of these mechanisms in the treatment of neuropathic pain and the pathophysiology of this type of chronic pain. It is important to emphasize that the application of AC and EA in awake animals is complex, since it generates discomfort and can alter the analgesia induced by the treatment. In many studies, anesthesia with isoflurane is used during the application of the treatments, but its use may generate a bias in the study, considering the possible interference of the drug in the behavioral and neurochemical results. Another important focus of the study is to compare the two techniques, AC and EA, seeking to determine which is the most effective in the treatment of neuropathic pain. Considering the above, the objectives of this thesis were: 1) to evaluate the behavioral and neurochemical parameters of the effects of the use of anesthesia in the application of AC and EA in rats submitted to the DN model; 2) to compare the effects of AC and EA on animal model of DN by means of behavioral, neurochemical and morphological parameters. Considering the results obtained in this thesis, we conclude that isoflurane increases the analgesia promoted by AC and EA, probably decreasing the effect of the stress generated by the application of the treatments in agreed animals, a result that is corroborated by the decrease in the level of peripheral S100β (biomarker of central neuronal injury); On the other hand, isoflurane decreased the levels of neural grown factor (NGF) in the injured peripheral nerve, indicating a decrease in the neural regeneration process, while the EA increased. At the same time, isoflurane altered the effects of treatments on exploratory behaviors and N-metil-D-aspartato (NMDA) levels in the brainstem and spinal cord. AC was more effective in the treatment of DN compared to EA, but none of the treatments was able to alter the damage caused by DN induction in the left gastrocnemius muscle of the animals showed in histology. However, this result did not alter the analgesia generated by the treatments.

Orientador: Carlos Alan Candido Dias Junior / Resumo: O presente estudo teve por objetivo investigar e comparar as alterações relacionadas à reatividade vascular e aos biomarcadores de estresse oxidativo e da inflamação em ratos anestesiados com isoflurano ou sevoflurano. Para alcançar nossos objetivos, ratos Wistar machos adultos foram distribuídos aleatoriamente em três grupos experimentais: não anestesiado (grupo controle) e anestesiados com isoflurano (grupo Iso) ou sevoflurano (grupo Sevo). A responsividade vascular à fenilefrina (PHE) e acetilcolina (ACh) na presença ou ausência de éster N-nitro-L-arginina-metílico (L-NAME) foram avaliadas em anéis de aorta torácica com endotélio intacto (E +) e endotélio desnudo (E-). Os metabólitos do óxido nítrico (NO) (NOx), a peroxidação lipídica, a função antioxidante, os níveis de citocinas e a atividade das metaloproteinases de matriz extracelular (MMPs) também foram avaliados. Nenhuma diferença significativa foi observada com relação aos dados hemodinâmicos e temperatura entre os grupos anestesiados. Nos anéis com endotélio intacto, a anestesia com o sevoflurano reduziu a vasoconstrição induzida pela PHE e pelo KCL quando comparado ao grupo controle e Iso, respectivamente (P ˂ 0.05). O isoflurano aumentou significativamente a vasoconstrição induzida pela PHE e pelo KCl, nos anéis com endotélio desnudo (P ˂ 0.05). Níveis de NO reduzidos foram observados após a anestesia com sevoflurano (P = 0.01), mas não com isoflurano. O estresse oxidativo foi significativamente aumentado em ambo... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The current study aimed to investigate and compare the changes on vascular reactivity, biomarkers of oxidative stress and inflammation of rats anesthetized with isoflurane or sevoflurane. Adult Wistar rats were assigned to three experimental groups (n = 6 per group): Non-anesthetized (Control group) and anesthetized with isoflurane (Iso group) or sevoflurane (Sevo group). Vascular responsiveness to phenylephrine (PHE) and acetylcholine (ACh) in the presence or absence of Nω-nitro-L-arginine-methyl ester (L-NAME) was evaluated in thoracic aortic rings with intact endothelium (E+) and denuded endothelium (E-). Nitric oxide (NO) metabolites (NOx), lipid peroxidation, antioxidant function, cytokines levels and matrix metalloproteinases (MMPs) activity were also assessed. In intact endothelium-aortic rings sevoflurane impairs PHE-induced vasoconstriction versus control group and reduces KCl-induced vasoconstriction versus Iso group (P ˂ 0.05). In denuded endothelium-aortic rings isoflurane increases vasoconstriction induced by both PHE and KCl (P ˂ 0.05). Sevoflurane, but not isoflurane, reduces NO (P = 0.01). Oxidative stress was increased in Sevo and Iso groups (P ˂ 0.05). While sevoflurane reduced IL-10 and IL-1β, isoflurane increased IL-1β. MMP-2 activity in aorta was increased in Sevo (P ˂ 0.05), but not in Iso group. We concluded that 150 minutes of anesthesia with sevoflurane, but not with isoflurane, impairs vascular responsiveness to vasoconstrictors agents. Also, while b... (Complete abstract click electronic access below) / Doutor

Veterinarians routinely conduct surgical operations on animals while veterinary technicians administer anesthetic gas to sedate the animal prior to an operation. One commonly used anesthetic agent in veterinary clinics is isoflurane. Veterinary workers have the potential to be exposed to this gas during surgical operations. The Occupational Safety and Health Administration (OSHA) does not have a specific Permissible Exposure Limit (PEL) for isoflurane, however The National Institutes for Health (NIH) does advise that workers should not be exposed to isoflurane in concentrations exceeding 2 parts per million (ppm) for an 8 hour Time Weighted Average (TWA). Animal clinics vary in the amount of surgeries they perform. Some clinics specialize in surgical services and therefore conduct a high volume of surgeries, while others that perform general practice work may conduct a far lower volume of surgeries. The research objectives for this study were to determine if veterinary workers are exposed to isoflurane levels above the concentration recommended by NIH and to quantify any disparity that exists between worker exposures at two veterinary facilities. A portable infrared ambient air analyzer (Miran SapphIRe, XL, ThermoScientific) was used to measure area concentrations of isoflurane and sorbent tube sampling via OSHA Method 103 was used to determine personal exposures to isoflurane. For the three days that sampling took place at the low volume clinic, personal sampling (samples taken in the breathing zone of a worker) during surgery showed that isoflurane concentrations exceeded the NIOSH recommended limit for 3 of the 5 samples when assuming a 6-hour gas exposure. When assuming exposure only lasted for the 2 hours that sampling occurred, 1 of the 5 samples exceeded the NIOSH recommended limit. For the three days that sampling was conducted at the high volume clinic, none of the 6 samples taken exceeded the NIOSH recommended exposure limit. The average isoflurane exposure to workers at the high volume clinic was 1.72 ppm while the average for the low volume clinic was 3.77 ppm. The average isoflurane exposure for veterinarians was 2.05 ppm and the average for veterinary technicians was 3.16 ppm. These data provide evidence that veterinary technicians may face higher exposures to isoflurane gas than veterinarians. There is also evidence that workers at the low volume clinic may be exposed to greater concentrations of isoflurane than workers at the high volume clinic. The average isoflurane concentrations were lower for the high volume clinic likely due to the fact that they relied only on an injectable sedative and no delivery of anesthetic gas for most operations. The high volume clinic also used more sophisticated equipment than the low volume clinic for the capture of waste gases.

Worldwide, millions of young and elderly patients receive procedures that could not be performed without the use of anesthetics. Unfortunately, emerging animal and human data suggest an association between exposure to general anesthesia and impairment of cognitive function in pediatric and geriatric patients. Recent laboratory data have shown that general anesthetics are potentially damaging to the developing and aging brain. However, the mechanism by which this happens is still unknown. General anesthetics affect learning and memory, a brain function involving neural plasticity. An important form of neural plasticity receiving attention is postnatal neurogenesis. This process is highly regulated and involved in hippocampal functions under physiological conditions. This dissertation hypothesizes that anesthetic induced alteration of postnatal neurogenesis may explain the cognitive impairment observed in some pediatric and geriatric patients after anesthesia. In order to accurately address this hypothesis, in the first portion of this dissertation, an animal model is used to examine the effects of two different anesthetics on cognition and new cell proliferation in young and aged rats. Furthermore, the second and third portion of this dissertation emphasizes on the effects of these two widely used anesthetics on each of the various stage of postnatal neurogenesis in young and aged rats.

It has been estimated that over 200,000 healthcare professionals may be exposed to waste anesthetic gases and are at risk of occupational injury. In 1977, the National Institute for Occupational Safety and Health (NIOSH) issued the publication: Criteria for a Recommended Standard....Occupational Exposure to Waste Anesthetic Gases and Vapors. This publication was based primarily on scientific evidence from human and animal studies suggesting that chronic exposures to anesthetic gases increases the risk of both spontaneous abortion and congenital abnormalities in offspring among female workers and wives of male workers exposed to waste anesthetic gases. In this recommended standard, NIOSH defines the recommended exposure limits (REL) for nitrous oxide and halogenated anesthetics. NIOSH recommended a time-weighted average (TWA) REL of 25 parts per million (ppm) for nitrous oxide over the period of administration. The REL for halogenated anesthetic gases is a ceiling limit of two ppm.In this study, waste anesthetic gas exposures to seven Post Anesthesia Care Unit (PACU) nurses were quantified during one day of air sampling within their breathing zones. Nitrous Oxide was sampled using a ChemExpressTM Personal Monitor (Assay Technology, Inc. Pleasanton, CA) attached to the nurse's lapel for approximately three hours. A total of 15 samples were collected. Isoflurane, desflurane, and sevoflurane were sampled using a ChemExpressTM Personal Monitor (Assay Technology, Inc. Pleasanton, CA) attached to the nurse's lapel for approximately three hours. A total of 15 samples were collected. In addition, Isoflurane, desflurane, and sevoflurane were also sampled using Anasorb© 747 sorbent tubes (SKC, Inc. Eighty Four, PA) to compare the passive and active sampling methods. The tubes were attached to the nurses lapel for one hour. A total of 15 samples were collected. The exposures to nitrous oxide and halogenated anesthetics were below the NIOSH RELs. An Analysis of Variance (ANOVA) showed a statistically significant difference (p < 0.05) in the active and passive sampling methodologies.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 5 uppsatser.

Honors Project--Smith College, Northampton, Mass., 2009. / Includes bibliographical references (p. 54-57).