Orientador: Newton Nunes / Banca: Carlos Augusto Araujo Valadão / Banca: Luiz Gonzaga Pompermayer / Banca: Silvia Renata Gaido Cortopassi / Banca: José Antonio Marques / Resumo: Avaliaram-se os efeitos hemodinâmicos, eletrocardiográficos e hemogasométricos decorrentes da aplicação do butorfanol em cães anestesiados pelo desfluorano. Utilizaram-se vinte cães adultos, machos e fêmeas, clinicamente saudáveis separados igualmente em dois grupos GP e GB e induzidos à anestesia com propofol, por via intravenosa, na dose de 8,4 l 0,8 mg/kg. Após a intubação com sonda orotraqueal de Magill, manteve-se a anestesia inalatória com desfluorano (10V%), diluído em O2 puro (30 mL/kg/min), através de circuito anestésico tipo "semi fechado". Decorridos 40 minutos do início da anestesia inalatória foram administrados 0,05 mL/kg de solução de cloreto de sódio a 0,9% (placebo) ou 0,4 mg/kg de butorfanol, ambos por via intramuscular, respectivamente, aos animais do GP e GB. Considerou-se o período imediatamente anterior a estas aplicações como o momento zero (M0) para o registro dos parâmetros. Novas mensurações foram realizadas 15 minutos após (M15) e subseqüentemente a intervalos de 15 minutos, por um período de 60 minutos (M30, M45, M60 e M75). Os dados numéricos obtidos foram submetidos à Análise de Perfil, sendo considerado o nível de significância de p£0,05. A administração do butorfanol reduziu a freqüência cardíaca (FC), pressões arteriais sistólica (PAS), diastólica (PAD) e média (PAM), pressão média da artéria pulmonar (PAPm), resistência periférica total (RPT) e pressão de perfusão coronariana (PPC) ao longo de todo o período experimental. A pressão média do átrio direito (PADm) diminuiu em M30, M45 e M75 no GB quando comparado ao GP. O trabalho ventricular esquerdo (TVE) e índice do trabalho ventricular esquerdo (ITVE) diminuíram somente aos 15 minutos após a administração do opióide. Os intervalos RR e QT apresentaram valores de M0 menor que os demais no GB... (Resumo completo, clicar acesso eletrônico abaixo). / Abstract: The aim of this work was to evaluate alterations due to butorphanol administration in desflurane anesthetized dogs over hemodynamic, electrocardiography and blood gas analysis. Twenty adult dogs, males and females, clinically healthy, weighing 12l3 kg were used for this purpose. The dogs were separated in two groups (GP and GB) and general anesthesia was induced by intravenous administration of propofol (8.4l 0.8 mg/kg). All dogs were submitted to inhalatory anesthesia with desflurane (10V%), diluted in O2 (30 mL/kg/min), through a semi-closed anesthetic circuit. After 40 minutes of induction, animals from GP received saline solution at 0.9% (0.05 mL/kg) and from GB received butorphanol (0.4 mg/kg), both applied intramuscularly. Observations of the variables started immediately before the application of the agents (M0). Serial measurements were carried out in 15-minute intervals after the administration of butorphanol or saline up to 75 minutes, respectively M15, M30, M45, M60 and M75. Numeric data were submitted to profile analysis (p£0.05). Mean values for heart rate (HR), systolic (SAP), diastolic (DAP) and mean arterial pressure (MAP), mean pulmonary artery pressure (PAPm), total vascular resistance (TVR) and coronary perfusion pressure (CPP) were decreased after butorphanol administration. Mean right atrial pressure (RAPm) decreased at M30, M45 e M75 for GB when compared with GP and the left ventricular work (LVW) and left ventricular work index (LVWI) were significantly decreased 15 minutes after butorphanol administration. RR and QT intervals increased while the breathing rate (BR) decreased at M30. Mean values for PaCO2 and base deficit (BD) increased after butorphanol administration. Mean values for arterial pH were lower at M30, M45, M60 and M75 in GB when compared with GP and body temperature (T°C) gradually decreased for both groups... (Complete abstract, access undermentioned eletronic address) / Doutor

Orientador: Paulo do Nascimento Junior / Resumo: Introdução: Reduzir o fluxo de gases frescos (FGF) para menos de 1 L.min-1 durante a anestesia resulta no aquecimento e umidificação dos gases inalados, redução de custos e menor exposição ocupacional. O Composto A é formado pelo sevoflurano quando reage com absorvedores de dióxido de carbono contendo bases fortes em FGF mínimo, sendo nefrotóxico em animais. Até o momento, nenhum dado conclusivo mostrou aumento do risco em seres humanos para anestesia com sevoflurano em FGF mínimo. Objetivos: avaliar a função renal pós-operatória de pacientes submetidos a cirurgia cardíaca com circulação extracorpórea (CEC), quando anestesiados com sevoflurano FGF de 0,5 mL.min-1, em comparação ao FGF de 2 L.min-1. Método: duzentos e quatro pacientes adultos de ambos os sexos agendados para cirurgia cardíaca com CEC anestesiados com sevoflurano foram randomizados em dois grupos diferenciados pelo FGF: FGF mínimo (0,5 L.min-1) ou FGF alto (2,0 L.min-1). A medida da creatinina basal pré-operatória foi comparada diariamente aos valores obtidos nos primeiros cinco dias de pós-operatório, e o débito urinário de 24 horas foi monitorado, de acordo com os guidelines KDIGO para definir lesão renal aguda (LRA). As medidas da creatinina sérica também foram obtidas 20 e 120 dias após a alta hospitalar. Resultados: A análise por protocolo envolveu 88 e 92 pacientes no grupo FGF mínimo e FGF alto, respectivamente. A LRA pós-operatória ocorreu em 55 pacientes, 26 pacientes (29,5%) no grupo FGF mínimo e 29 p... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Reducing fresh gas flow (FGF) to less than 1 L.min-1 during anesthesia results in warming and humidification of inhaled gases, cost reduction and less occupational exposure. Compound A is generated by sevoflurane when it reacts with carbon dioxide absorbers with strong bases at minimal FGF and is nephrotoxic in animals. To date, no conclusive data has shown increased risk for minimal FGF sevoflurane anesthesia in humans. Objectives: To evaluate the postoperative renal function of patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) when anesthetized with sevoflurane at 0.5 mL.min-1 FGF compared to 2 L.min-1 FGF. Method: Two hundred and four adult patients of both sexes scheduled for on-pump cardiac surgery under sevoflurane anesthesia were randomly allocated to two groups differentiated by FGF: minimal FGF anesthesia (0.5 L.min-1) or high FGF anesthesia (2.0 L.min-1). Baseline creatinine measured before surgery was compared daily to values assayed on the first five postoperative days, and 24-hour urinary output was monitored, according to the KDIGO guideline to define acute kidney injury (AKI). Creatinine measurements were also obtained 20 and 120 days after hospital discharge. Results: Per protocol analyses involved 88 and 92 patients in the minimal and high FGF groups, respectively. Postoperative AKI occurred in 55 patients, 26 patients (29.5%) in the minimal FGF group and 29 patients (31.5%) in the high FGF group (P = 0.774). Patients with AK... (Complete abstract click electronic access below) / Doutor

一氧化二氮，俗稱笑氣，是現代臨床麻醉最為常用的一種麻醉劑。然而，關於一氧化二氮效能及安全性的研究至今仍存在爭議。近來，一個稱為ENIGMA的臨床研究項目對2,050個施行大手術的病人接受麻醉情況及術後併發癥進行了研究。研究發現手術中施行一氧化二氮麻醉的病人術後傷口感染率較之對照組上升了35%。另一方面，對423個ENIGMA病人的長期隨訪研究發現，在術中接受一氧化二氮麻醉的病人中慢性術後痛的發病率相對對照組降低了56%。 對於這些臨床發現的分子機制，目前知之甚少。 因此我們進行了一系列實驗來研究一氧化二氮導致術後感染以及預防慢性痛的分子機制。 / 一氧化二氮對基因穩定性的影響 / 在對93個接受直腸結腸大型外科手術的病人進行的隨機對照試驗中，我們比較了接受一氧化二氮麻醉及其對照組病人的外周白細胞脫氧核糖核酸（DNA）損傷情況和術後傷口感染率。通過單細胞凝膠電泳（彗星實驗），我們發現術中一氧化二氮麻醉顯著增加了手術24小時后病人的DNA損傷情況 （p < 0.001）。且這種變化是劑量依賴的，r = 0.33; p = 0.03。並且，在DNA損傷程度及術後傷口感染率間存在顯著相關。術後DNA損傷程度每增加十個單位，傷口感染率則隨之增加17%。 / 一氧化二氮對DNA損傷應答及修復的影響 / 利用大鼠模型，我們對一氧化二氮導致基因不穩定的機制進行了研究。Sprague Dawley大鼠暴露於一氧化二氮中2小時後，我們對其DNA損傷應答及修復基因的轉錄情況進行了檢測。脂多糖（LPS）注射大鼠模擬了圍手術期的炎癥反應。我們發現LPS刺激的白細胞經一氧化二氮處理后，其編碼DNA連接酶IV的LIG4基因的轉錄量顯著降低（p < 0.05）。LIG4基因的下調導致了一氧化二氮麻醉後圍手術期的免疫抑制效應。 / NMDA受體抑制在一氧化二氮預防性鎮痛中的作用 / 在大鼠慢性神經痛模型中，我們檢測了一氧化二氮鎮痛作用的機制。我們發現一氧化二氮處理組的機械痛覺過敏相較對照組顯著降低（p = 0.001）。一氧化二氮處理后，神經痛大鼠脊髓背角中的c-Fos表達量也顯著降低，這表明了一氧化二氮對神經元活性的影響。該影響可能是NMDA受體抑制的結果。另外，我們還觀察到一氧化二氮的鎮痛特徵與NMDA受體非競爭性拮抗劑MK-801的鎮痛效果相似。 / 基因表達改變在一氧化二氮預防性鎮痛中的作用 / 一氧化二氮鎮痛效果的遲發性和延續性提示了除受體拮抗之外的其他作用機制的存在。我們發現在大鼠坐骨神經壓迫損傷模型中，一氧化二氮處理顯著降低了同側脊髓背角組織中LIG4基因的轉錄及表達（p = 0.006）。同時一氧化二氮處理降低了星形膠質細胞在同側脊髓背角中的活化。我們的研究表示一氧化二氮影響DNA修復， 抑制脊髓背角基因的表達，從而起到預防性鎮痛的作用。 / 總而言之，一氧化二氮通過抑制鉀硫氨酸合成酶，削弱DNA修復和基因組穩定性，從而成為導致術后傷口感染的危險因素。另一方面，這一機制也阻止了脊髓背角中異常突觸的建立，從而預防了神經損傷導致的慢性神經痛的建立。另外，一氧化二氮的鎮痛機制也和NMDA受體抑制作用有關。 / Nitrous oxide is a commonly administered anesthetic and analgesic agent in contemporary clinical anesthesia. However, the efficacy and safety of nitrous oxide delivery remains a subject of debate. The recent Evaluation of Nitrous oxide In a Gas Mixture for Anaesthesia (ENIGMA) Trial found that nitrous oxide administration, in 2,050 patients undergoing major surgery, increased the incidence of wound infection by 35%. On the other hand, in a long term follow-up study of 423 ENIGMA patients in Hong Kong, the risk of chronic postsurgical pain was reduced by 56% in patients who received nitrous oxide in the index surgery. Little is known about the mechanisms associated with these clinical observations; we therefore conducted a series of experiments to determine the molecular changes after nitrous oxide administration leading to postoperative wound infection and preventive analgesia. / Genomic Instability after Nitrous Oxide Administration / In a randomized controlled trial of 93 patients undergoing major colorectal surgery, we compared the changes of deoxyribonucleic acid (DNA) damage in circulating leukocytes and rates of wound infection in patients who were exposed to nitrous oxide or not. Using single cell gel electrophoresis (CometAssay), we found that intraoperative nitrous oxide administration produced significant DNA damage, 24 hours after surgery, compared with controls, p < 0.001. The changes were dose-dependent, r = 0.33; p = 0.03. In addition, there was a significant correlation between DNA damage and postoperative wound infection. For every 10 units increase in the percentage of DNA in tail after surgery compared with baseline, there was 17% increase in the risk of wound infection. / DNA Damage Response and Repair / In a rat model, we explored the mechanism of genomic instability after nitrous oxide administration. In Sprague Dawley rats exposed to nitrous oxide anesthesia for 2 hours, we tested the transcription of an array of DNA damage response and repair genes. Lipopolysaccharide (LPS) was added to mimic postoperative inflammation. In the mRNA that were extracted and analyzed by real-time polymerase chain reaction (RT-PCR), we found the transcription of gene encoding for DNA Ligase IV (LIG4 gene) was significantly reduced after nitrous oxide administration in LPS-stimulated leukocytes (p < 0.05). The down regulation of LIG4 gene contributed to perioperative immunosuppression following nitrous oxide exposure. / Role of N-methyl-D-aspartate receptor (NMDAR) Blockade for Preventive Analgesia with Nitrous Oxide / Using a rat model of chronic neuropathic pain, we tested the mechanisms underlying nitrous oxide analgesia. In Sprague Dawley rats undergoing unilateral constrictive injury to the sciatic nerve, we found that mechanical hyperalgesia was significantly reduced with nitrous oxide compared with controls (p = 0.01). In addition, c-Fos expression was decreased in spinal dorsal horn suggesting that neuron excitability was reduced after nitrous oxide administration which could be caused by blockade of the NMDA receptor. Interestingly, the characteristics of analgesia were similar to that provided by MK-801, a noncompetitive antagonist of NMDA receptors. / Transcriptional Changes for Nitrous Oxide Analgesia / The onset of nitrous oxide analgesia was delayed and outlasted actual receptor antagonism. We therefore explored mechanisms, other than NMDA receptor blockade, for nitrous oxide analgesia. Specifically, in rats undergoing sciatic nerve constrictive injury, we found that transcription of LIG4 gene was down-regulated in the ipsilateral spinal dorsal horn after nitrous oxide administration (p = 0.006). There was a decrease in DNA ligase IV expression and a reduction in the activation of astrocytes. Our data suggested that regulation of DNA repair and suppression spinal dorsal horn gene transcription is one of the alternative mechanisms for nitrous oxide analgesia. / In summary, nitrous oxide administration is a risk factor for postoperative wound infection. This is related to irreversible inhibition of the enzyme methionine synthase, impaired DNA repair and genomic instability. The same mechanism however prevented aberrations of synaptic regeneration in the spinal dorsal horn and could therefore prevent the development of chronic neuropathic pain after direct nerve injury. Nitrous oxide analgesia was also related to NMDA receptor blockade. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chen, Yan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 126-157). / Abstract also in Chinese. / Declaration of origination --- p.I / Abstract: --- p.II / Acknowledgements --- p.VIII / Table of Contents --- p.X / List of Tables --- p.XV / List of Figures --- p.XVI / List of Abbreviations --- p.XVIII / Chapter Part I: --- Literature Review --- p.1 / Chapter Chapter 1 --- A review of nitrous oxide: Historical, clinical and mechanistic Perspectives --- p.2 / Chapter 1.1 --- History of Nitrous Oxide --- p.2 / Chapter 1.2 --- Clinical Pharmacology of Nitrous Oxide --- p.4 / Chapter 1.3 --- Evaluation of Nitrous oxide In the Gas Mixture for Anesthesia (ENIGMA) Trial --- p.9 / Chapter 1.4 --- Efficacy and Toxicity of Nitrous Oxide: Biochemical and Molecular Mechanisms --- p.14 / Chapter 1.4.1 --- Immunosuppression Following Nitrous Oxide Administration --- p.14 / Chapter 1.4.2 --- Analgesia with Nitrous Oxide - Molecular Mechanisms --- p.17 / Chapter 1.4.2.1 --- Direct molecular target --- p.17 / Chapter 1.4.2.2 --- Interaction with γ aminobutyric acid type A (GABAA) receptors --- p.19 / Chapter 1.4.2.3 --- Regulation of opioid system --- p.20 / Chapter 1.4.2.4 --- Regulation of noradrenergic neurons --- p.21 / Chapter 1.4.2.5 --- N-methyl-d-aspartate (NMDA) receptor inhibition --- p.22 / Chapter 1.4.2.6 --- Long-term Preventive Analgesia with Nitrous Oxide --- p.23 / Chapter 1.4.3 --- Summary --- p.24 / Chapter Part II: --- Experiments --- p.26 / Chapter Chapter 2 --- Study Hypothesis and Objectives --- p.27 / Chapter 2.1 --- Genomic Instability after Nitrous Oxide Administration --- p.27 / Chapter 2.2 --- DNA Damage Response and Repair --- p.28 / Chapter 2.3 --- NMDA Receptor Blockade for Preventive Analgesia with Nitrous Oxide --- p.28 / Chapter 2.4 --- Transcriptional Changes for Nitrous Oxide Analgesia --- p.28 / Chapter Chapter 3 --- Genomic Instability After Nitrous Oxide Administration: A Randomized Controlled Trial --- p.32 / Chapter 3.1 --- Introduction --- p.32 / Chapter 3.2 --- Methods and Materials --- p.36 / Chapter 3.2.1 --- Study Participants --- p.36 / Chapter 3.2.2 --- Study Procedures --- p.36 / Chapter 3.2.3 --- Randomization --- p.37 / Chapter 3.2.4 --- Anesthetic Care --- p.37 / Chapter 3.2.5 --- Postoperative Care --- p.38 / Chapter 3.2.6 --- Measurement of Genomic Instability --- p.44 / Chapter 3.2.7 --- Statistical Analysis --- p.47 / Chapter 3.2.8 --- Sample Size Calculation --- p.47 / Chapter 3.3 --- Results --- p.48 / Chapter 3.4 --- Discussion --- p.61 / Chapter 3.4.1 --- Principal Findings --- p.61 / Chapter 3.4.2 --- Comparison to Other Studies --- p.61 / Chapter 3.4.3 --- Strengths and Limitations --- p.63 / Chapter 3.4.4 --- Implications --- p.64 / Chapter 3.4.5 --- Conclusions --- p.64 / Chapter Chapter 4 --- DNA Damage Response and Repair After Nitrous Oxide Administration / Chapter 4.1 --- Introduction --- p.65 / Chapter 4.1.1 --- DNA Damage Response and Repair Pathways --- p.65 / Chapter 4.1.2 --- Nitrous oxide and DNA Damage Response and Repair --- p.69 / Chapter 4.2 --- Materials and Methods --- p.70 / Chapter 4.2.1 --- Animals --- p.70 / Chapter 4.2.2 --- Nitrous Oxide Administration --- p.70 / Chapter 4.2.3 --- Lipopolysaccharide-Induced Infection Model --- p.72 / Chapter 4.2.4 --- Sample Collection and Preparation --- p.72 / Chapter 4.2.5 --- Single Cell Gel Electrophoresis (CometAssay) --- p.72 / Chapter 4.2.6 --- RNA Extraction for Gene Transcription Study --- p.72 / Chapter 4.2.7 --- Reverse Transcription Polymerase Chain Reaction (RT PCR) --- p.73 / Chapter 4.2.8 --- Quantitative RT PCR --- p.74 / Chapter 4.2.9 --- Statistical Analysis --- p.76 / Chapter 4.3 --- Results --- p.76 / Chapter 4.3.1. --- Genome Instability in Rat Leukocytes after Nitrous Oxide Administration --- p.76 / Chapter 4.3.2. --- Effect of Nitrous Oxide on the Transcription of DNA Damage Response Genes --- p.78 / Chapter 4.3.3. --- Effects of Nitrous Oxide on DNA Damage Response Genes in Animals Treated with Lipopolysaccharide --- p.80 / Chapter 4.4 --- Discussion --- p.84 / Chapter 4.4.1 --- Principal Findings --- p.84 / Chapter 4.4.2 --- Implications --- p.84 / Chapter 4.4.3 --- Limitation of our Study --- p.85 / Chapter 4.4.4 --- Conclusions --- p.87 / Chapter Chapter 5 --- Preventive Analgesia with Nitrous Oxide: Role of NMDA Receptor Blockade / Chapter 5.1. --- Introduction --- p.88 / Chapter 5.1.1. --- The ENIGMA Trial: Long Term Follow-up --- p.89 / Chapter 5.1.2. --- Nitrous oxide prevents chronic postsurgical pain: putative mechanisms --- p.89 / Chapter 5.1.3. --- Hypothesis --- p.90 / Chapter 5.2. --- Materials and methods --- p.91 / Chapter 5.2.1. --- Animals --- p.91 / Chapter 5.2.2. --- Chronic constriction injury (CCI) to induce neuropathic pain --- p.91 / Chapter 5.2.3. --- Behavioral test --- p.93 / Chapter 5.2.4. --- Nitrous oxide administration --- p.93 / Chapter 5.2.5. --- Dizocilpine (MK-801) pretreatment --- p.94 / Chapter 5.2.6. --- Tissue Collection, Preparation and Western Blot --- p.94 / Chapter 5.2.7. --- Statistical Analysis --- p.96 / Chapter 5.3. --- Results --- p.96 / Chapter 5.3.1. --- Preventive Analgesia with Nitrous oxide --- p.96 / Chapter 5.3.2. --- Nitrous oxide analgesia via NMDA receptors block --- p.99 / Chapter 5.3.3. --- Preventive analgesia with NMDA receptors Blockade --- p.101 / Chapter 5.4. --- Discussion --- p.103 / Chapter 5.4.1 --- Principal Findings --- p.103 / Chapter 5.4.2 --- Our Findings compared with Other Studies --- p.103 / Chapter 5.4.3 --- Limitations of the Study --- p.104 / Chapter 5.4.4 --- Conclusions --- p.105 / Chapter Chapter 6 --- Transcriptional Changes for Nitrous Oxide Analgesia --- p.106 / Chapter 6.1 --- Introduction --- p.106 / Chapter 6.1.1 --- Neuro-immune Interactions in the Development of Chronic Neuropathic Pain --- p.106 / Chapter 6.1.2 --- Nitrous Oxide Interferes Astrocytes and Glial Responses --- p.107 / Chapter 6.2 --- Materials and methods --- p.109 / Chapter 6.2.1 --- Chronic Constriction Injury Pain Model and Nitrous Oxide Administration --- p.109 / Chapter 6.2.2 --- Lumbar Dorsal Horn Tissue Collection, Preparation and Immunoflurescence --- p.109 / Chapter 6.2.3 --- RNA Extraction and Quantitative RT PCR for Gene Transcription Study --- p.110 / Chapter 6.2.4 --- Protein Extraction and Western Blot for protein Expression Study --- p.110 / Chapter 6.2.5 --- Statistical Analysis --- p.111 / Chapter 6.3 --- Results --- p.112 / Chapter 6.3.1 --- Time Course of LIG4 Gene Transcription after Constrictive Nerve Injury --- p.112 / Chapter 6.3.2 --- Nitrous oxide reduced DNA ligase IV expression in spinal dorsal horn --- p.114 / Chapter 6.3.3 --- Nitrous oxide Reduced Astrocytes Activation in Spinal Dorsal Horn --- p.116 / Chapter 6.4 --- Discussions --- p.119 / Chapter 6.4.1 --- Principal Findings --- p.119 / Chapter 6.4.2 --- Our Findings in Relation to Other Studies --- p.119 / Chapter 6.4.3 --- Limitations of Our Study --- p.120 / Chapter 6.4.4 --- Conclusions --- p.120 / Chapter Part III: --- Conclusions --- p.122 / Chapter Chapter 7 --- Conclusions and Future Perspectives --- p.123 / Chapter 7.1 --- Conclusions --- p.123 / Chapter 7.2 --- Future Perspectives --- p.124 / Chapter Part IV --- References --- p.126

Orientador: Carlos Augusto Araujo Valadão / Banca: Newton Nunes / Banca: Paulo Sérgio Patto dos Santos / Banca: Aury Nunes de Moraes / Banca: Nilson Oleskovicz / Resumo: A administração intravenosa de anestésicos voláteis halogenados pode ser considerada uma alternativa à aplicação pela via inalatória, e neste contexto, as formulações emulsificadas têm mostrado segurança, eficiência e bons planos anestésicos. Neste estudo, objetivou-se comparar os efeitos hemodinâmicos e respiratórios das administrações intravenosa e inalatória de isofluorano em cães, após a determinação da taxa de infusão intravenosa de 6,99 mL/kg/h deste halogenado em emulsão lipídica. Para tanto, foram utilizados oito cães, os quais formaram três grupos distintos: grupo IV - anestesia intravenosa por infusão de emulsão lipídica com isofluorano; grupo E - anestesia inalatória com isofluorano, associada à infusão intravenosa de emulsão lipídica sem o halogenado; e grupo IN - anestesia inalatória com isofluorano, associada à infusão intravenosa de solução de NaCl 0,9%. Foram evidenciadas diminuições da contratilidade cardíaca, índice cardíaco e pressão arterial sistêmica a partir de 10 e 40 minutos de anestesia, respectivamente, nos grupos IV e E. A hipotensão no grupo IV resultou em acidose metabólica, porém, hipoxemia não foi observada. O grupo IN apresentou manutenção do índice cardíaco, apesar de reduções do índice de resistência vascular sistêmica e pressão arterial. A taxa de infusão intravenosa determinada foi efetiva na manutenção de plano de anestesia cirúrgica em cães. As infusões intravenosas de isofluorano e emulsão lipídica causaram depressão cardíaca e hipotensão. Em relação à função respiratória, nenhum dos grupos mostrou efeitos deletérios. / Abstract: The intravenous administration of halogenated anesthetics can be considered an alternative to the application by the inhalation route, moreover, emulsified formulations have been showing safety, efficiency and appropriated anesthetic depth. The aim of this study was to compare the effects of isoflurane anesthesia by intravenous or inhalational route on hemodynamic and respiratory variables, after the determination of the intravenous infusion rate of 6.99 mL/kg/h of this anesthetic in lipid emulsion, in dogs. Therefore, eight dogs were distributed in three different protocols: IV group - intravenous anesthesia with emulsified isoflurane; E group - inhalational anesthesia with isoflurane associated to intravenous infusion of lipid emulsion; and IN group - inhalational anesthesia with isoflurane associated to intravenous infusion of 0.9% NaCl solution. The results regarding IV and EM groups revealed decreases of heart contractility, cardiac index and systemic blood pressure starting from 10 and 40 minutes of anesthesia, respectively. The hypotension in the IV group resulted in metabolic acidosis, however, hypoxemia was not observed. The IN group demonstrated maintenance of cardiac index, despite of reduction of the blood pressure and systemic vascular resistance index. The intravenous infusion rate determined was effective in the maintenance of an anesthetic depth of general anesthesia in dogs. The intravenous infusions of isoflurane and lipid emulsion caused cardiac depression and hypotension. In relation to respiratory function, the inhalational route and the intravenous infusions of isoflurane and lipid emulsion did not result in harmful effects. / Doutor

Made available in DSpace on 2014-06-11T19:31:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-11-28Bitstream added on 2014-06-13T20:41:23Z : No. of bitstreams: 1 almeida_rm_dr_jabo.pdf: 437070 bytes, checksum: e5cd6f576c7b9ff4974078130d3e9da5 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A administração intravenosa de anestésicos voláteis halogenados pode ser considerada uma alternativa à aplicação pela via inalatória, e neste contexto, as formulações emulsificadas têm mostrado segurança, eficiência e bons planos anestésicos. Neste estudo, objetivou-se comparar os efeitos hemodinâmicos e respiratórios das administrações intravenosa e inalatória de isofluorano em cães, após a determinação da taxa de infusão intravenosa de 6,99 mL/kg/h deste halogenado em emulsão lipídica. Para tanto, foram utilizados oito cães, os quais formaram três grupos distintos: grupo IV – anestesia intravenosa por infusão de emulsão lipídica com isofluorano; grupo E - anestesia inalatória com isofluorano, associada à infusão intravenosa de emulsão lipídica sem o halogenado; e grupo IN - anestesia inalatória com isofluorano, associada à infusão intravenosa de solução de NaCl 0,9%. Foram evidenciadas diminuições da contratilidade cardíaca, índice cardíaco e pressão arterial sistêmica a partir de 10 e 40 minutos de anestesia, respectivamente, nos grupos IV e E. A hipotensão no grupo IV resultou em acidose metabólica, porém, hipoxemia não foi observada. O grupo IN apresentou manutenção do índice cardíaco, apesar de reduções do índice de resistência vascular sistêmica e pressão arterial. A taxa de infusão intravenosa determinada foi efetiva na manutenção de plano de anestesia cirúrgica em cães. As infusões intravenosas de isofluorano e emulsão lipídica causaram depressão cardíaca e hipotensão. Em relação à função respiratória, nenhum dos grupos mostrou efeitos deletérios. / The intravenous administration of halogenated anesthetics can be considered an alternative to the application by the inhalation route, moreover, emulsified formulations have been showing safety, efficiency and appropriated anesthetic depth. The aim of this study was to compare the effects of isoflurane anesthesia by intravenous or inhalational route on hemodynamic and respiratory variables, after the determination of the intravenous infusion rate of 6.99 mL/kg/h of this anesthetic in lipid emulsion, in dogs. Therefore, eight dogs were distributed in three different protocols: IV group – intravenous anesthesia with emulsified isoflurane; E group – inhalational anesthesia with isoflurane associated to intravenous infusion of lipid emulsion; and IN group - inhalational anesthesia with isoflurane associated to intravenous infusion of 0.9% NaCl solution. The results regarding IV and EM groups revealed decreases of heart contractility, cardiac index and systemic blood pressure starting from 10 and 40 minutes of anesthesia, respectively. The hypotension in the IV group resulted in metabolic acidosis, however, hypoxemia was not observed. The IN group demonstrated maintenance of cardiac index, despite of reduction of the blood pressure and systemic vascular resistance index. The intravenous infusion rate determined was effective in the maintenance of an anesthetic depth of general anesthesia in dogs. The intravenous infusions of isoflurane and lipid emulsion caused cardiac depression and hypotension. In relation to respiratory function, the inhalational route and the intravenous infusions of isoflurane and lipid emulsion did not result in harmful effects.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The aim of this study was to evaluate acute and subacute renal and hepatic toxicity of the oral administration of tepoxalin in cats submitted to hypotension with isoflurane. Eighteen adult male mongrel cats were used in this study, weighing between 3 and 5 kg and clinically healthy. The animals were divided into three groups, which were anesthetized and submitted to hypotension with isoflurane (CON), or which, in addition, tepoxalin was administered two hours prior to the hypotension procedure (PRE) or after the hypotension procedure (POS). The animals from groups PRE and POS also received the same doses of tepoxalin every 24 hours, during the five days following the procedure. In order to achieve a condition of moderate hypotension, animals were induced and maintained with isoflurane in variable concentration, for maintenance of mean arterial pressure (MAP) between 45 and 60 mmHg, during 60 minutes. Complete blood count and serum concentrations of alanine aminotransferase (ALT), alkaline phosphatase (FA) and urea (U) were evaluated at baseline and 24 hours, 48 hours and 7 days after hypotension. Serum concentration of creatinine (Cr), fractional excretion of sodium (FENa) and urinary concentrations of Cr, gamma-glutamyl transferase (GGT), proteinuria and albuminuria were evaluated at baseline and 24 hours, 48 hours and 7 days after hypotension. The model chosen was efficient in maintaining the proposed condition of hypotension. No physiological changes were observed in complete blood count, serum biochemistry profile (ALT, FA, U and Cr), FENa and urinary GGT. An increase in urine protein-creatinine ratio was observed in CON and PRE at 24 and 48 hours after hypotension. Urine albumin-creatinine ratio showed increase in CON at 24 hours and maintained elevated values with regard to the other groups until 7 days after hypotension. The authors conclude that administration of tepoxalin does not cause changes in hepatic parameters, urea, creatinine, fractional excretion of sodium and urinary GGT in cats submitted to anesthetic hypotension. However, there is a risk of mild renal injury by administering the drug prior to the hypotensive procedure. / Este estudo objetivou avaliar a toxicidade renal e hepática, aguda e subaguda, da administração oral da tepoxalina em gatos submetidos à hipotensão com isofluorano. Foram utilizados 18 gatos, machos, adultos, sem raça definida, com peso entre 3 e 5 kg e comprovadamente hígidos. Os animais foram alocados em três grupos, os quais foram anestesiados e submetidos à hipotensão com isofluorano (CON), ou que ainda receberam tepoxalina duas horas antes do procedimento de hipotensão (PRÉ) ou após a recuperação anestésica do procedimento de hipotensão (PÓS). Os animais dos grupos PRÉ e PÓS também receberam as mesmas doses de tepoxalina a cada 24 horas, durante cinco dias pós procedimento. Para a caracterização de um quadro de hipotensão moderada, os animais foram induzidos e mantidos anestesiados com isofluorano em vaporização variável, para a manutenção da pressão arterial média (PAM) entre 45 e 60 mmHg durante 60 minutos. Foram avaliados hemograma e concentrações séricas de alanina amino-transferase (ALT), fosfatase alcalina (FA) e ureia (U) no período basal e 24 horas, 48 horas e 7 dias após a hipotensão. A concentração sérica de creatinina (Cr), a fração de excreção de sódio (FENa) e as concentrações urinárias de Cr, gama-glutamiltransferase (GGT), proteínas totais e albumina foram avaliadas no momento basal e 24 horas, 48 horas e 7 dias após a hipotensão. O modelo escolhido foi eficiente na manutenção do quadro de hipotensão proposto. Não foram observadas alterações fisiológicas no hemograma, bioquímica sérica (ALT, FA, U e Cr), FENa e na GGT urinária. Observou-se elevação estatística na razão proteína-creatinina na urina no CON e no PRÉ em relação ao PÓS às 24 e às 48 horas de avaliação. A razão albumina-creatinina na urina apresentou elevação estatística no CON em relação aos demais à partir das 24 horas de avaliação, mantendo essa elevação até os 7 dias de avaliação. Concluiuse que a administração de tepoxalina não causou alterações de parâmetros hepáticos, ureia, creatinina, FENa e GGT urinária em gatos submetidos à hipotensão anestésica, entretanto há o risco de ocorrência de injúria renal discreta devido à proteinúria observada no grupo em que a tepoxalina foi administrada antes do procedimento hipotensor.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / This study aimed to evaluate the possible renal and hepatic toxicities, acute and subacute, of the administration of tepoxalin in dogs submitted to hypotension with isoflurane. A total of 12 dogs were used, which received 10 mg kg-1 of tepoxalin PO two hours before induction of hypotension (T) or were only submitted to hypotension with isoflurane (C). For the subacute study, animals in T were treated with tepoxalin during 5 days, following the hypotensive procedure. The dogs were submitted to hypotension (MAP= 50-60mmHg) for isoflurane in a circular circuit valve, with adjusted FR for the ETCO2 remained between 35-45mmHg. ToC was maintained between 37 and 38oC. HR, SAP, MAP, DAP, CVP, ETCO2 and ETIso were evaluated at 0, 10 and every 10 min up to 60min of hipotension. pH, PaO2, PaCO2, SaO2, HCO3-, BD, Na+, K+, Ca2+ and bleeding time evaluations were carried out before hypotension and at 30 and 60min of hipotension. For renal and hepatic evaluation, serum levels of U, Cr, ALT, alkaline phosphatase, GGT and urinary levels of GGT, Cr and GGT:Cr ratio were determined at 12h, 24h and seven days after the procedure. During the anesthetic procedure, only CVP presented elevation in relation to 0min in both groups at 50 and 60min of evaluation. In blood gas and electrolyte measurement, only Na+ presented levels below to basal at 60min in T, and this same group showed increased values at all intervals, in comparison between groups. Moreover, bleeding time was shown to be more elevated at 30min of evaluation in animals in T, when compared to the ones in C. The variables corresponding to creatinine depuration, GGT:Cr ratio and UV remained stable during the evaluations; however, urinary GGT levels presented increased values in animals in C when compared to T, at 60min of evaluation. At this same interval, urinary Cr values were elevated in T. Serum levels of ALT, alkaline phosphatase, U and Cr presented minor alterations, remaining within reference values; however, GGT presented increased values at 60min of evaluation, when compared to 0min. On the seventh day of evaluation, a reduction in leukocyte number was observed in animals in T, when compared to C. Side effects were not observed in both groups. The prior administration of tepoxalin in healthy dogs submitted to hypotension did not cause significant effects upon renal and hepatic functions. Moreover, daily administrations during five days, following the anesthetic procedure, did not alter the functions of the organs mentioned. Therefore, tepoxalin showed to be a safe NSAID to be used in healthy dogs, submitted to hypotension during anesthesia with isoflurane. / Objetivou-se avaliar as possíveis toxicidades renal e hepática, aguda e subaguda, da administração de tepoxalina em cães submetidos à hipotensão com isofluorano. Foram utilizados 12 cães, os quais receberam 10mg kg-1 de tepoxalina VO duas horas antes da indução da hipotensão (T) ou somente foram submetidos à hipotensão com isofluorano (C). Para o estudo subagudo, os animais do T foram tratados com tepoxalina, durante cinco dias, seguidos ao procedimento hipotensor. Os cães foram submetidos à hipotensão (PAM = 50-60mmHg) por isofluorano em circuito circular valvular, com FR ajustada para que o ETCO2 permanecesse entre 35-45mmHg. A TºC foi mantida entre 37 e 38ºC. Avaliaram-se FC, PAS, PAM, PAD, PVC, ETCO2, e ETIso em 0, 10 e a cada 10min até 60min da hipotensão. As avaliações de pH, PaO2, PaCO2, SaO2, HCO3-, DB, Na+, K+ e Ca2+ e tempo de sangramento foram realizadas antes da hipotensão e aos 30 e 60min da hipotensão. Para a avaliação renal e hepática foram determinados os níveis séricos de U, Cr, ALT, FA, GGT e os níveis urinários de GGT, Cr e a proporção GGT:Cr em 12h, 24h e sete dias após o procedimento. Durante o procedimento anestésico somente a PVC apresentou elevação em relação aos 0min, em ambos os grupos aos 50 e 60min de avaliação. Na mensuração dos gases sanguíneos e eletrólitos, apenas o Na+ demonstrou níveis menores que o basal aos 60min no T, e este mesmo grupo apresentou valores aumentados em todos os momentos, na comparação entre os grupos. Ainda, o tempo de sangramento foi maior aos 30min de avaliação, nos animais do T, quando comparado aos do C. As variáveis correspondentes à depuração da creatinina, razão GGT:Cr e DU permaneceram estáveis durante as avaliações, porém, os níveis de GGT urinária apresentaram valores aumentados nos animais do C, quando comparados ao T, aos 60min de avaliação. Nesse mesmo momento, os valores de Cr urinária estavam aumentados dentro do T. Os níveis séricos de ALT, FA, U e Cr apresentaram poucas alterações, permanecendo dentro dos limites de referência, porém, a GGT apresentou valores aumentados aos 60min de avaliação, comparando-se com 0min. No sétimo dia de avaliação, observou-se redução do número de leucócitos nos animais do T, quando comparados aos do C. Não foram observados efeitos colaterais em ambos os grupos. A administração prévia de tepoxalina em cães hígidos submetidos à hipotensão, não ocasionou efeitos significativos sobre as funções renal e hepática dos mesmos. Da mesma forma, administrações diárias durante cinco dias, seguidas ao procedimento anestésico, não alteraram as funções dos referidos órgãos. Portanto, a tepoxalina demonstrou ser um AINE seguro para utilização em cães hígidos, submetidos à hipotensão durante anestesia com isofluorano.