Volatile anesthetics influence blood-brain barrier integrity by modulation of tight junction protein expression in traumatic brain injury

Disruption of the blood-brain barrier (BBB) results in cerebral edema formation, which is a major cause for high mortalityrnafter traumatic brain injury (TBI). As anesthetic care is mandatory in patients suffering from severe TBI it may be importantrnto elucidate the effect of different anesthetics on cerebral edema formation. Tight junction proteins (TJ) such as zonularnoccludens-1 (ZO-1) and claudin-5 (cl5) play a central role for BBB stability. First, the influence of the volatile anestheticsrnsevoflurane and isoflurane on in-vitro BBB integrity was investigated by quantification of the electrical resistance (TEER) inrnmurine brain endothelial monolayers and neurovascular co-cultures of the BBB. Secondly brain edema and TJ expression ofrnZO-1 and cl5 were measured in-vivo after exposure towards volatile anesthetics in native mice and after controlled corticalrnimpact (CCI). In in-vitro endothelial monocultures, both anesthetics significantly reduced TEER within 24 hours afterrnexposure. In BBB co-cultures mimicking the neurovascular unit (NVU) volatile anesthetics had no impact on TEER. In healthyrnmice, anesthesia did not influence brain water content and TJ expression, while 24 hours after CCI brain water contentrnincreased significantly stronger with isoflurane compared to sevoflurane. In line with the brain edema data, ZO-1 expressionrnwas significantly higher in sevoflurane compared to isoflurane exposed CCI animals. Immunohistochemical analysesrnrevealed disruption of ZO-1 at the cerebrovascular level, while cl5 was less affected in the pericontusional area. The studyrndemonstrates that anesthetics influence brain edema formation after experimental TBI. This effect may be attributed tornmodulation of BBB permeability by differential TJ protein expression. Therefore, selection of anesthetics may influence thernbarrier function and introduce a strong bias in experimental research on pathophysiology of BBB dysfunction. Futurernresearch is required to investigate adverse or beneficial effects of volatile anesthetics on patients at risk for cerebral edema.

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.

Cardiopulmonary and acid-base effects of desflurane and sevoflurane in spontaneously breathing cats

The cardiopulmonary effects of desflurane and sevoflurane anesthesia were compared in cats breathing spontaneously. Heart (HR) and respiratory (RR) rates; systolic (SAP), diastolic (DAP) and mean arterial (MAP) pressures; partial pressure of end tidal carbon dioxide (PETCO(2)), arterial blood pH (pH), arterial partial pressure of oxygen (PaO(2)) and carbon dioxide (PaCO(2)); base deficit (BD), arterial oxygen saturation (SaO(2)) and bicarbonate ion concentration (HCO(3)) were measured. Anesthesia was induced with propofol (8 +/- 2.3 mg/kg IV) and maintained with desflurane (GD) or sevoflurane (GS), both at 1.3 MAC. Data were analyzed by analysis of variance (ANOVA), followed by the Tukey test (P < 0.05). Both anesthetics showed similar effects. HR and RR decreased when compared to the basal values, but remained constant during inhalant anesthesia and PETCO(2) increased with time. Both anesthetics caused acidemia and hypercapnia, but BD stayed within normal limits. Therefore, despite reducing HR and SAP (GD) when compared to the basal values, desflurane and sevoflurane provide good stability of the cardiovascular parameters during a short period of inhalant anesthesia (T20-T60). However, both volatile anesthetics cause acute respiratory acidosis in cats breathing spontaneously. (c) 2004 ESFM and AAFP. Published by Elsevier Ltd. All rights reserved.

Effects of isoflurane on echocardiographic parameters in healthy dogs

Obejective To study the echocardiographic effects of isoflurane at an end-tidal concentration approximating 1.0 times the minimum alveolar concentration (MAC) in healthy unpremedicated dogs.Study design Prospective experimental trial.Animals Sixteen mature mongrel dogs of either sex weighing 11.06 +/- 2.72 kg.Methods After performing a baseline echocardiogram in the awake animal, anesthesia was induced with increasing inspired concentrations of isoflurane via a face mask until tracheal intubation was possible. Following intubation, the end-tidal concentration was decreased to 1.4% for the rest of the anesthetic period. Serial echocardiograms were recorded at 25, 40, and 55 minutes after the end-tidal concentration was reached.Results No changes were observed in heart rate. However, significant decreases were seen in left ventricular end-diastolic diameter (Mean maximal change: 13.8%), interventricular septal thickness during systole (15.2%), interventricular septal thickening fraction (72.2%), left ventricular free wall thickening fraction (63.5%), ejection fraction (39.9%), and fractional shortening (46.7%). In addition, peak flow velocities across mitral, pulmonic, and aortic valves were significantly lower than baseline values. Decreases were also observed in end-diastolic left ventricular volume index (approximately 32.1% from the awake value), stroke index (58.2%), and cardiac index (55.3%) when compared with awake measurements.Conclusions Our results indicate that 1 x MAC isoflurane caused significant myocardial depression in healthy dogs. These changes in myocardial function need to be considered carefully when isoflurane is to be used in dogs with poor cardiovascular reserve.

Efeitos do desfluorano, sevofluorano e isofluorano sobre variáveis respiratórias e hemogasométricas em cães

Com este estudo objetivou-se avaliar, comparativamente, os efeitos de três anestésicos inalatórios sobre variáveis respiratórias e hemogasométricas em cães. Para tal, utilizaram-se 30 cães sadios, adultos, machos e fêmeas evitando-se aquelas em estro ou em gestação. Os animais foram separados e protocolados em três grupos de 10 cães cada (G1, G2 e G3). Induziu-se a anestesia geral com administração intravenosa de propofol, na dose de 10±1,3 mg/kg. em seguida procedeu-se à intubação orotraqueal e anestesia geral inalatória pelo desfluorano (G1), sevofluorano (G2) e isofluorano (G3), diluídos em oxigênio a 100,00%, por meio de circuito anestésico tipo semi-fechado, dotado de vaporizadores calibrados para cada agente anestésico. As variáveis estudadas foram Freqüência Respiratória, CO2 ao Final da Expiração, Saturação de Oxihemoglobina, Volume Corrente, Volume Minuto, Pressão Parcial Arterial de O2, Pressão Parcial Arterial de CO2, Excesso de Bases e pH. A avaliação estatística destas variáveis foi realizada pela Análise de Perfil, sendo considerado o nível de significância de 5,00%. Os resultados obtidos permitiram concluir que o desfluorano deprime o sistema respiratório aumentando a pressão parcial arterial de CO2 e o CO2 ao final da expiração; e diminuindo a pressão parcial arterial de O2 e o volume minuto, quando comparado com os outros anestésicos em teste.

Dexmedetomidine Alters the Cardiovascular Response During Infra-Renal Aortic Cross-Clamping in Sevoflurane-Anesthetized Dogs

Some properties of the volatile anesthetics, such as vasodilatation and myocardial depression, combined with the sympathetic inhibition that alpha 2-agonists can produce may determine hemodynamic alterations during aortic, surgery. The interaction between dexmedetomidine (DEX), an alpha 2-agonist, and sevoflurane during aortic surgery is unknown. We studied the effects of DEX on hemodynamics and systemic oxygenation during aortic cross-clamping (Aox) and unclamping (UAox) in sevoflurane-anesthetized dogs Twenty dogs were. anesthetized with sevoflurane and were randomly assigned to two groups prior to Aox and UAox: control, n = 10, received saline infusion only, and DEX (1 mu g.kg(-1) load followed by 1 mu g.kg(-1).h(-1) infusion), n = 10. Hemodynamic and oxygenation variables were measured at baseline, after saline or DEX loading dose, 20 and 40 min after Aox, and 20 and 40 min after UAox. After DEX administration, heart rate, cardiac index l and systemic oxygen transport index (131021) were lower than in control group. Aox increased mean arterial pressure (MAP) and systemic vascular resistance index (SVRI) in both groups, but the effects were greater with DEX. Cl, heart rate, and DO(2)I were lower, while central venous pressure (CVP) and pulmonary artery occlusion pressure were higher in DEX compared to control. After UAox, MAP, CVP and SVRI were maintained higher in DEX in relation to control. We conclude that in sevoflurane-anesthetized dogs DEX alters the cardiovascular response during aortic surgery.

Sevoflurano e desflurano sobre o ritmo cardíaco de cães tratados com infusão contínua de doses crescentes de adrenalina

Os anestésicos inalatórios sensibilizam o miocárdio ou seu sistema de condução à ação das catecolaminas endógenas e/ou exógenas, predispondo o animal às arritmias cardíacas. Dentre os anestésicos voláteis, o sevoflurano e o desflurano são fármacos relativamente recentes e, embora sejam dotados de características relacionadas a não sensibilização do miocárdio às catecolaminas, desconhecem-se estudos que comparem suas eventuais propriedades antiarritmogênicas. Com o objetivo de estudar, comparativamente, o comportamento do ritmo cardíaco e observar eventuais bloqueios atrioventriculares em cães anestesiados pelo sevoflurano e desflurano e submetidos à infusão contínua de adrenalina, foram utilizados 20 animais adultos, os quais foram separados em dois grupos de igual número (G1 e G2). Aos cães do G1, foi administrado propofol, na dose média de 10mmg.kg-1; em seguida os animais receberam sevoflurano, a 1,5CAM. Decorridos 30 minutos do início da administração do anestésico volátil, iniciou-se a infusão de adrenalina na dose de 1mmg.kg-1.min-1. A cada 10 minutos, a dose da catecolamina foi acrescida em uma unidade, cessando-se a administração em 6mmg.kg-1.min-1. Para o G2, empregou-se a mesma metodologia, substituindo-se o sevoflurano pelo desflurano, administrado a 1,5CAM. A cada dose de adrenalina, foi feita contagem de batimentos ventriculares ectópicos, bem como a observação de bloqueios atrioventriculares. Os achados foram tratados pelos métodos estatísticos de Análise de Perfil e Kruskall-Wallis. Os resultados permitiram concluir que o desflurano minimiza de maneira mais eficiente a arritmia induzida pela adrenalina, além de reduzir a incidência de bloqueios atrioventriculares.

Perfil de citocinas inflamatórias em indivíduos submetidos a procedimentos cirúrgicos utilizando propofol ou isoflurano

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Sevoflurano e dexmedetomidina em isquemia e reperfusão renais no rato

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Does occupational exposure to anesthetic gases lead to increase of pro-inflammatory cytokines?

There is great concern about the possible harmful effects of exposure to volatile anesthetics. The current study aimed at evaluating, for the first time, the effects of occupational exposure to anesthetic gases on physicians who work in operating rooms, by determining several inflammatory cytokines. Plasma inflammatory cytokines (IL-1β, -6, -8, -10, -12, TNF-α) were investigated in 30 individuals who were allocated into two groups of 15: the exposed group, consisting of operating room medical personnel exposed to a mixture of anesthetic gases for 3 years, and a control group composed of medical personnel not exposed to anesthetic gases. The concentrations of volatile anesthetics were measured in the operating room by means of an infrared portable analyzer Our findings suggest an increase of the pro-inflammatory IL-8 (p < 0.05) in medical personnel exposed to high concentrations of anesthetic gases, even for a relatively short period.

Efeitos da infusão contínua de Cetamina s(+) em equinos anestesiados pelo Halotano

The horse’s blood pressure is susceptible to changes induced by volatile anesthetics. Because of that, the use of anesthesic techniques which keep stable the horse´s blood pressure is essencial. Ketamine is an important induction and maintenance anesthetic agent used in the horse anesthesia practice mainly to improve the blood pressure. S(+)-ketamine provides the same effects on the blood pressure, with greater analgesic results and less side effects than the normal ketamine. Although some studies have been conducted with ketamine continuous rate infusion during the halothane anesthetized horses, the S(+)-ketamine has not been evaluated yet. Considering the increased use of ketamine, it is important to evaluate its cardiovascular and respiratory effects in halothane anesthetized horses. To conclude, S(+)-ketamine 0.01mg/kg/min. continuous rate infusion did not induce additive cardiovascular and respiratory depression in halothane anesthetized horses.

Alterations of Endothelial Glycocalyx During Orthotopic Liver Transplantation in Patients With End-Stage Liver Disease.

BACKGROUND Endothelial glycocalyx participates in the maintenance of vascular integrity, and its perturbations cause capillary leakage, loss of vascular responsiveness, and enhanced adhesion of leukocytes and platelets. We hypothesized that marked shedding of the glycocalyx core protein, syndecan-1, occurs in end-stage liver disease (ESLD) and that it increases during orthotopic liver transplantation (OLT). We further evaluated the effects of general anesthesia on glycocalyx shedding and its association with acute kidney injury (AKI) after OLT. PATIENTS AND METHODS Thirty consecutive liver transplant recipients were enrolled in this prospective study. Ten healthy volunteers served as a control. Acute kidney injury was defined by Acute Kidney Injury Network criteria. RESULTS Plasma syndecan-1 was significantly higher in ESLD patients than in healthy volunteers (74.3 ± 59.9 vs 10.7 ± 9.4 ng/mL), and it further increased significantly after reperfusion (74.3 ± 59.9 vs 312.6 ± 114.8 ng/mL). The type of general anesthesia had no significant effect on syndecan-1. Syndecan-1 was significantly higher during the entire study in patients with posttransplant AKI stage 2 or 3 compared to patients with AKI stage 0 or 1. The area under the curve of the receiver operating characteristics curve of syndecane-1 to predict AKI stage 2 or 3 within 48 hours after reperfusion was 0.76 (95% confidence interval, 0.57-0.89, P = 0.005). CONCLUSIONS Patients with ESLD suffer from glycocalyx alterations, and ischemia-reperfusion injury during OLT further exacerbates its damage. Despite a higher incidence of AKI in patients with elevated syndecan-1, it is not helpful to predict de novo AKI. Volatile anesthetics did not attenuate glycocalyx shedding in human OLT.

A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans

The molecular mechanisms underlying general anesthesia are unknown. For volatile general anesthetics (VAs), indirect evidence for both lipid and protein targets has been found. However, no in vivo data have implicated clearly any particular lipid or protein in the control of sensitivity to clinical concentrations of VAs. Genetics provides one approach toward identifying these mechanisms, but genes strongly regulating sensitivity to clinical concentrations of VAs have not been identified. By screening existing mutants of the nematode Caenorhabditis elegans, we found that a mutation in the neuronal syntaxin gene dominantly conferred resistance to the VAs isoflurane and halothane. By contrast, other mutations in syntaxin and in the syntaxin-binding proteins synaptobrevin and SNAP-25 produced VA hypersensitivity. The syntaxin allelic variation was striking, particularly for isoflurane, where a 33-fold range of sensitivities was seen. Both the resistant and hypersensitive mutations decrease synaptic transmission; thus, the indirect effect of reducing neurotransmission does not explain the VA resistance. As assessed by pharmacological criteria, halothane and isoflurane themselves reduced cholinergic transmission, and the presynaptic anesthetic effect was blocked by the resistant syntaxin mutation. A single gene mutation conferring high-level resistance to VAs is inconsistent with nonspecific membrane-perturbation theories of anesthesia. The genetic and pharmacological data suggest that the resistant syntaxin mutant directly blocks VA binding to or efficacy against presynaptic targets that mediate anesthetic behavioral effects. Syntaxin and syntaxin-binding proteins are candidate anesthetic targets.

Influence of general anesthetics on a specific neural pathway in Drosophila melanogaster.

The neural pathway that governs an escape response of Drosophila to sudden changes in light intensity can be artificially induced by electrical stimulation of the brain and monitored by electrical recording from the effector muscles. We have refined previous work in this system to permit reliable ascertainment of two kinds of response: (i) a short-latency response that follows from direct excitation of a giant fiber neuron in the interior of the fly brain and (ii) a long-latency response in which electrical stimulation triggers neurons in the optic ganglia that ultimately impinge on the giant fiber neuron. The general anesthetic halothane is reported here to have very different potencies in inhibiting these two responses. The long-latency response is obliterated at concentrations similar to those that cause gross behavioral effects in adult flies, whereas the short-latency response is only partially inhibited at doses that are 10-fold higher. Three other volatile anesthetic agents show a similar pattern. Thus, as in higher organisms, the Drosophila nervous system is differentiated into components of high and low sensitivity to general anesthetics. Moreover, this work shows that one of the sensitive components of the nervous system lies in the optic lobe and is readily assayed by its effect on downstream systems; it should provide a focus for exploring the effects of genetic alteration of anesthetic sensitivity.