Exposure to halogenated ethers causes neurodegeneration and behavioural changes in young healthy experimental animals: a systematic review and meta analyses.

The FDA issued a warning that repeated and prolonged use of inhalational anaesthetics in children younger than 3 years may increase the risk of neurological damage. Robust clinical evidence supporting this warning is however lacking. A systematic review of all preclinical evidence concerning isoflurane, sevoflurane, desflurane and enflurane exposure in young experimental animals on neurodegeneration and behaviour may elucidate how severe this risk actually is PubMed and Embase were comprehensively searched on November 23, 2022. Based on predefined selection criteria the obtained references were screened by two independent reviewers. Data regarding study design and outcome data (Caspase-3 and TUNEL for neurodegeneration, Morris water maze (MWM), Elevated plus maze (EPM), Open field (OF) and Fear conditioning (FC)) were extracted, and individual effect sizes were calculated and subsequently pooled using the random effects model. Subgroup analyses were predefined and conducted for species, sex, age at anesthesia, repeated or single exposure and on time of outcome measurement. Out of the 19.796 references screened 324 could be included in the review. For enflurane there were too few studies to conduct meta-analysis (n = 1). Exposure to sevoflurane, isoflurane and desflurane significantly increases Caspase-3 levels and TUNEL levels. Further, sevoflurane and isoflurane also cause learning and memory impairment, and increase anxiety. Desflurane showed little effect on learning and memory, and no effect on anxiety. Long term effects of sevoflurane and isoflurane on neurodegeneration could not be analysed due to too few studies. For behavioural outcomes, however, this was possible and revealed that sevoflurane caused impaired learning and memory in all three related outcomes and increased anxiety in the elevated plus maze. For isoflurane, impaired learning and memory was observed as well, but only sufficient data was available for two of the learning and memory related outcomes. Further, single exposure to either sevoflurane or isoflurane increased neurodegeneration and impaired learning and memory. In summary, we show evidence that exposure to halogenated ethers causes neurodegeneration and behavioural changes. These effects are most pronounced for sevoflurane and isoflurane and already present after single exposure. To date there are not sufficient studies to estimate the presence of long term neurodegenerative effects. Nevertheless, we provide evidence in this review of behavioral changes later in life, suggesting some permanent neurodegenerative changes. Altogether, In contrast to the warning issued by the FDA we show that already single exposure to isoflurane and sevoflurane negatively affects brain development. Based on the results of this review use of sevoflurane and isoflurane should be restrained as much as possible in this young vulnerable group, until more research on the long term permanent effects have been conducted.

[Health hazards resulting from occupational exposure to enfluran - overview of tests and analysis of admissible concentration values]. / Zagrozenia zdrowotne wynikajace z narazenia zawodowego na enfluran ­ przeglad badan i próba analizy wartosci dopuszczalnych stezen.

The aim of this work is to analyze the health hazards of enflurane exposure and to analyze the occupational exposure limits (OEL). The method of obtaining evidence based on a review of online databases of scientific journals was used. Enflurane is an inhalation anesthetic. Malignant hyperthermia, seizures, arrhythmias, respiratory depression and hypotension have been observed in patients. Occupational exposure to enflurane may occur in healthcare professionals. The target organ for enflurane is the central nervous system with a critical consequence of deterioration in psychomotor performance. In studies on volunteers recruited from the medical staff of operating rooms exposed to enflurane, a significant deterioration in the results of the Simple Reaction Time Test was shown. World experts' groups assume that the LOAEC (lowest observed adverse effect concentration) value for the deterioration of psychomotor test results is 5-10% of the MAC value (minimal anesthetic concentration), i.e., 6342-12 684 mg/m3. Assessment of the nephrotoxic potential of enflurane has shown that it is unlikely to occur because biotransformation of enflurane in humans results in a low peak serum fluoride concentration of 15 µmol/l. Early reports about liver damage in patients were not be supported. Occupational exposure epidemiological studies have raised concerns about the effects of anesthetic gas mixtures on the abortion rate or on fetal development and birth defects in children, but none of these studies specifically determined the type and concentration of anesthetic gases used. The carcinogenicity and mutagenicity studies were negative. Occupational exposure to enflurane is not monitored in Poland, as no standard value has been established for it in the air of the working environment. It is necessary to quickly introduce this anesthetic along with the applicable limit value to the OEL list. Med Pr. 2022;73(1):51-69.

General inhalational anesthetics - pharmacodynamics, pharmacokinetics and chiral properties.

Since the advent of nitric oxide, diethyl ether, chloroform and cyclopropane, the greatest advancement in the area of general inhalational anesthetics has been achieved by the introduction of fluorinated anesthetics and the relevant chiral techniques. This progress led to marked decrease in mortality rates in anesthesia. In the group of chiral fluorinated compounds, halothane (Fluotan®), isoflurane (Foran®), desflurane (Supran®) and enflurane (Ehran®) are deployed as volatile anesthetics. Chiral anesthetics possess a stereogenic center in their molecules and thus exist as two enantiomers (S)-(+) and (R)-(-). Although these chiral anesthetics are used as racemates, it is crucial to study besides the bioactivities of the racemic compounds also the biological activity and other properties of the particular enantiomers. The present survey discusses the drug category known as inhalational anesthetics in regard to their chiral aspects. These compounds exhibit marked differences between the (R) and (S)-enantiomers in their pharmacodynamics, pharmacokinetics and toxicity. The main analytical technique employed in the enantioseparation of these compounds is gas chromatography (GC). This review lists the individual chiral phases (chiral selectors) used in the enantioseparation as well as in pharmacokinetic studies. The possibilities of preparation of these compounds in their enantiomerically pure form by means of stereoselective synthesis are also mentioned.

[Determination of Sevoflurane, Isoflurane and Enflurane in the air of workplace by gas chromatography].

Objective: To establish a solvent desorption gas chromatographic method for determination of Sevoflurane, Isoflurane and Enflurane in the air of the Workplace. Methods: Sevoflurane, Isoflurane and Enflurane were collected with activated carbon tube and desorbed with dichloromethane, separated with DB-1 capillary columns, and then detected with flame ionization detector. Results: The linearity ranges were 1.9-304.8 µg/ml for Sevoflurane, 2.1-300.4 µg/ml for Isoflurane and 1.7-305.2 µg/ml for Enflurane, The correlation coefficient was both >0.999. Their limits of detection were 0.6 µg/ml, 0.6 µg/ml and 0.5 µg/ml, and Their limits of quatification were 1.9 µg/ml, 2.1 µg/ml and 1.7 µg/ml, and their minimum detectable concentrations were 0.1、0.2 and 0.1 mg/m(3) per 4.5 L of air. Their relative standard deviations (RSD) were 2.5%-3.0%, 2.3%-3.1% and 2.2%-3.0%. The average desorption efficiencies were 101.1%-103.3%, 100.7%-102.7% and 101.0%-102.9%. The sampling efficiency was both 100%. The breakthrough volume of 100 mg actived carbon was 3.7 mg, 3.4 mg and 3.4 mg. Sevoflurane, Isoflurane and Enflurane in activated carbon tube could be kept at least 10 days at room temperature without significant losses. Conclusion: The method shows lower detection limit, high accuracy and precision. It is feasible for determination of Sevoflurane, Isoflurane and Enflurane in the air of workplace.

Minimum alveolar concentration: Key concepts and a review of its pharmacological reduction in dogs. Part 1.

OBJECTIVE: To outline the major components of the minimum alveolar concentration (MAC) and review the literature in regard to pharmacological manipulation of the MAC of halothane, isoflurane, sevoflurane, enflurane, and desflurane in dogs. The pharmacologic agents included are alpha-2 agonists, benzodiazepines, propofol, maropitant, opioids, lidocaine, acepromazine, non-steroidal anti-inflammatory agents, and NMDA antagonists. Part 1 will focus on summarizing the relevance, measurement, and mechanisms of MAC and review the effects of alpha-2 agonists, benzodiazepines, and propofol on MAC. DATABASES USED: PubMed, Google Scholar, CAB Abstracts. Search terms used: minimum alveolar concentration, MAC, dog, canine, inhaled anesthetic potency, isoflurane, sevoflurane, desflurane, enflurane, and halothane. CONCLUSIONS: Many drugs reduce the MAC of inhaled anesthetics in dogs, and allow for a clinically important decrease in inhalant anesthetic use. A decrease in MAC may decrease the adverse cardiovascular and pulmonary effects associated with the use of high concentrations of inhaled anesthetics.

Programmable Peptide-Cross-Linked Nucleic Acid Nanocapsules as a Modular Platform for Enzyme Specific Cargo Release.

Herein we describe a modular assembly strategy for photo-cross-linking peptides into nucleic acid functionalized nanocapsules. The peptides embedded within the nanocapsules form discrete nanoscale populations capable of gating the release of molecular and nanoscale cargo using enzyme-substrate recognition as a triggered release mechanism. Using photocatalyzed thiol-yne chemistry, different peptide cross-linkers were effectively incorporated into the nanocapsules and screened against different proteases to test for degradation specificity both in vitro and in cell culture. By using a combination of fluorescence assays, confocal and TEM microscopy, the particles were shown to be highly specific for their enzyme targets, even between enzymes of similar protease classes. The rapid and modular nature of the assembly strategy has the potential to be applied to both intracellular and extracellular biosensing and drug delivery applications.

Exposición ambiental del sevoflurano en trabajadores sanitarios / Environmental exposure of sevoflurane in healthcare workers

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Lateral Pressure Profile and Free Volume Properties in Phospholipid Membranes Containing Anesthetics.

The effect of four general anesthetics, namely chloroform, halothane, diethyl ether, and enflurane on the free volume fraction and lateral pressure profiles in a fully hydrated dipalmitoylphosphatidylcholime (DPPC) membrane is investigated by means of computer simulation. In order to find changes that can be related to the molecular mechanism of anesthesia as well as its pressure reversal, the simulations are performed both at atmospheric and high (1000 bar) pressures. The obtained results show that the additional free volume occurring in the membrane is localized around the anesthetic molecules themselves. Correspondingly, the fraction of the free volume is increased in the outer of the two membrane regions (i.e., at the outer edge of the hydrocarbon phase) where anesthetic molecules prefer to stay in every case. As a consequence, the presence of anesthetics decreases the lateral pressure in the nearby region of the lipid chain ester groups, in which the anesthetic molecules themselves do not penetrate. Both of these changes, occurring upon introducing anesthetics in the membrane, are clearly reverted by the increase of the global pressure. These findings are in accordance both with the more than 60 years old "critical volume hypothesis" of Mullins, and with the more recent "lateral pressure hypothesis" of Cantor. Our results suggest that if anesthesia is indeed caused by conformational changes of certain membrane-bound proteins, induced by changes in the lateral pressure profile, as proposed by Cantor, the relevant conformational changes are expected to occur in the membrane region where the ester groups are located.

Cardiac Calcium Release Channel (Ryanodine Receptor 2) Regulation by Halogenated Anesthetics.

BACKGROUND: Halogenated anesthetics activate cardiac ryanodine receptor 2-mediated sarcoplasmic reticulum Ca release, leading to sarcoplasmic reticulum Ca depletion, reduced cardiac function, and providing cell protection against ischemia-reperfusion injury. Anesthetic activation of ryanodine receptor 2 is poorly defined, leaving aspects of the protective mechanism uncertain. METHODS: Ryanodine receptor 2 from the sheep heart was incorporated into artificial lipid bilayers, and their gating properties were measured in response to five halogenated anesthetics. RESULTS: Each anesthetic rapidly and reversibly activated ryanodine receptor 2, but only from the cytoplasmic side. Relative activation levels were as follows: halothane (approximately 4-fold; n = 8), desflurane and enflurane (approximately 3-fold,n = 9), and isoflurane and sevoflurane (approximately 1.5-fold, n = 7, 10). Half-activating concentrations (Ka) were in the range 1.3 to 2.1 mM (1.4 to 2.6 minimum alveolar concentration [MAC]) with the exception of isoflurane (5.3 mM, 6.6 minimum alveolar concentration). Dantrolene (10 µM with 100 nM calmodulin) inhibited ryanodine receptor 2 by 40% but did not alter the Ka for halothane activation. Halothane potentiated luminal and cytoplasmic Ca activation of ryanodine receptor 2 but had no effect on Mg inhibition. Halothane activated ryanodine receptor 2 in the absence and presence (2 mM) of adenosine triphosphate (ATP). Adenosine, a competitive antagonist to ATP activation of ryanodine receptor 2, did not antagonize halothane activation in the absence of ATP. CONCLUSIONS: At clinical concentrations (1 MAC), halothane desflurane and enflurane activated ryanodine receptor 2, whereas isoflurane and sevoflurane were ineffective. Dantrolene inhibition of ryanodine receptor 2 substantially negated the activating effects of anesthetics. Halothane acted independently of the adenine nucleotide-binding site on ryanodine receptor 2. The previously observed adenosine antagonism of halothane activation of sarcoplasmic reticulum Ca release was due to competition between adenosine and ATP, rather than between halothane and ATP.

Serotonin, estrus, and social context influence c-Fos immunoreactivity in the inferior colliculus.

A fundamental task of sensory systems is to extract relevant social information from a range of environmental stimuli in the face of changing behavioral contexts and reproductive states. Neuromodulatory pathways that interact with such contextual variables are 1 mechanism for achieving this. In the mouse inferior colliculus (IC), a midbrain auditory region, the neuromodulator serotonin increases in females interacting with courting males, but events downstream of serotonin release have not been investigated. Here, we manipulated serotonin levels in female mice with the serotonin releaser fenfluramine or the serotonin depleter para-chlorophenylalaninemethyl ester (pCPA). Females were then exposed to an empty cage, a male partner, or a playback of courtship vocalizations, and the numbers of neurons in the IC with positive immunoreactivity for the immediate early gene product c-Fos were measured. The effects of drug treatments depended on social context and estrous state. Fenfluramine had greater effects in the nonsocial than in the partner social treatments. Females in proestrus or estrus and given fenfluramine had higher densities of c-Fos immunoreactive neurons, while females in diestrus had fewer immunoreactive neurons. The drug pCPA had the expected opposite effect of fenfluramine, causing a decreased response in pro/estrus females and an increased response in diestrus females. These findings show that the effects of serotonin on c-Fos activity in the IC of females is dependent on both external context and reproductive state, and suggest that these effects occur downstream of serotonin release. (PsycINFO Database Record

Conformational Exploration of Enflurane in Solution and in a Biological Environment.

Enflurane is a fluorinated volatile anesthetic, whose bioactive conformation is not known. Actually, a few studies have reported on the conformations of enflurane in nonpolar solution and gas phase. The present computational and spectroscopic (infrared and NMR) work shows that three pairs of isoenergetic conformers take place in the gas phase, neat liquid, polar, and nonpolar solutions. According to docking studies, a single conformation is largely preferred over its isoenergetic isomers to complex with the active site of Integrin LFA-1 enzyme (PDB code: 3F78 ), where the widely used anesthetic isoflurane (a constitutional isomer of enflurane) is known to bind. Weak hydrogen bonding from an electrostatic interaction between the CHF2 hydrogen and the central CF2 fluorines was not found to rule the conformational isomerism of enflurane. Moreover, intramolecular interactions based on steric, electrostatic, and hyperconjugative effects usually invoked to describe the anomeric effect are not responsible for the possible bioactive conformation of enflurane, which is rather governed by the enzyme induced fit.

Effects of maternal enflurane exposure on NR2B expression in the hippocampus of their offspring

This work aims to study the pathogenesis of learning and memory impairment in offspring rats resulting from maternal enflurane anesthesia by focusing on the expression of the N-methyl-d-aspartic acid receptor subunit 2B (NR2B) in the hippocampus of the offspring. Thirty female Sprague-Dawley rats were randomly divided into three groups: control (C group), 4 h enflurane exposure (E1 group), and 8 h enflurane exposure (E2 group) groups. Eight to ten days after the initiation of pregnancy, rats from the E1 and E2 groups were allowed to inhale 1.7% enflurane in 2 L/min oxygen for 4 h and 8 h, respectively. Rats from the C group were allowed to inhale 2 L/min of oxygen only. The Morris water maze was used to assay the learning and memory function of the offspring on postnatal days 20 and 30. RT-PCR and immunohistochemistry assays were then used to measure the mRNA levels and protein expression of NR2B, respectively. Relative to offspring rats from the C group, those from the E1 and E2 groups exhibited longer escape latencies, lesser number of crossings over the platform, and less time spent in the target quadrant in the spatial exploration test (P < 0.05). In addition, the mRNA and protein expression levels of NR2B in the hippocampus of offspring rats in the E1 and E2 groups were down-regulated (P < 0.05). No significant differences between the E1 and E2 groups were observed (P > 0.05) in terms of mRNA levels and protein expression of NR2B. The cognitive function of the offspring is impaired when maternal rats are exposed to enflurane during early pregnancy. A possible mechanism of this effect is related to the down-regulation of NR2B expression.

Este trabalho objetiva o estudo da patogênese de deficiência no aprendizado e memória de prole de ratos resultante da anestesia maternal por enflurano, por meio da expressão da subunidade 2B do receptor do ácidoN-metil-D-aspártico (NR2B) no hipocampo dos filhotes. Dividiram-se, aleatoriamente, 30 fêmeas de ratos Sprague-Dawley em três grupos: controle (grupo C), exposição ao enflurano por 4 h (grupo E1) e por 8 h (grupo E2). De oito a 10 dias após o início da gravidez, os ratos dos grupos E1 e E2 inalaram enflurano 1,7% em 2 L/min de oxigênio, por 4 h e 8 h, respectivamente. Ratos do grupo C inalaram apenas 2 L/min de oxigênio. O labirinto de água de Morris foi empregado para analisar as funções de aprendizado e memória da cria em 20 e 30 dias após o nascimento. Utilizaram-se ensaios de RT-PCR e de imuno-histoquímica para medir os níveis de mRNA e expressão da proteína do NR2B, respectivamente. Em comparação com os ratos controle do grupo C, aqueles dos grupos E1 e E2 exibiram latências de escape mais longas, menor número de travessias na plataforma e menos tempo gasto no quadrante alvo no teste de exploração espacial (P < 0,05). Adicionalmente, os níveis de expressão de mRNA e de proteína do NR2B no hipocampo dos filhotes nos grupos E1 e E2 estavam reduzidos (P < 0,05). Não se observaram diferenças significativas entre os grupos E1 e E2 (P < 0,05) quanto aos níveis de mRNA e à expressão de proteína de NR2B. A função cognitiva dos filhotes é prejudicada quando as mães são expostas ao enflurano durante o início da gravidez. O mecanismo possível para esse efeito está relacionado à diminuição na expressão de NR2B.

Relationship between gamma-hydroxybutyric acid receptors and the hypnotic and analgesic effects of emulsified inhalation anesthetics.

OBJECTIVES: This study was designed to investigate the role of gamma-hydroxybutyric acid receptors (GHBR) in hypnosis and analgesia induced by emulsified inhalation anesthetics. MATERIALS AND METHODS: After having established the mice model of hypnosis and analgesia by intraperitoneal injections of appropriate doses of enflurane, isoflurane, or sevoflurane, we intracerebroventricularly (i.c.v.) or intrathecally injected different doses of NCS-382 (antagonist of GHBR) and, then, observed the effects on the sleeping time using awaken test and the pain threshold in hot-plate test (HPPT) using HPPT. RESULTS: In the awaken test, 1, 5, and 25 µg of NCS-382 (i.c.v.) significantly decreased the sleeping time of the mice treated with the three emulsified inhalation anesthetics mentioned above (p < 0.05 or 0.01). In the HPPT, 1, 5, and 25 µg of NCS-382 (intrathecally) did not affect the HPPT in conscious mice (p > 0.05); in contrast, 1, 5, and 25 µg of NCS-382 (intrathecally) significantly decreased the HPPT of the mice treated with emulsified inhalation anesthetics (p < 0.05 or 0.01). CONCLUSIONS: The data presented in this study suggest that GHBR may be important targets for the hypnotic and analgesic effects induced by emulsified enflurane, isoflurane, and sevoflurane.

Influence of propofol, isoflurane and enflurance on levels of serum interleukin-8 and interleukin-10 in cancer patients.

OBJECTIVE: To observe the influence of propofol, isoflurane and enflurance on interleukin-8 (IL-8) and IL-10 levels in cancer patients. METHODS: Ninety cancer patients with selective operation from March 2011 to May 2014 were randomly divided into group A (34 cases), group B (28 cases) and group C (28 cases). Intramuscular injections of scopine hydrochloride and phenobarbital sodium were routinely conducted to 3 groups. After general anesthesia was induced, tracheal intubations were given. During the maintenance of anesthesia, 0.5~1.0 mg/ kg propofol was intravenously injected to group A discontinuously, while continuous suctions of isoflurane and enflurance were subsequently performed to group B and C correspondingly. Clinical outcomes, postoperative complications as well as serum IL-8 and IL-10 levels before operation (T0), at the time of skin incision (T1), 3 h after the beginning of the operation (T2) and 24 h (T3) and 72 h (T4) after the operation were observed among 3 groups. RESULTS: Operations in all groups were successfully completed. The rates of surgery associated complications were 8.82% (3/34), 7.14% (2/28) and 7.14% (2/28) in group A, B and C, respectively, and there were no significant differences (P>0.05). Serum IL-8 and IL-10 levels increased gradually from the beginning of the operation and reached the peak at T3, and were evidently higher at each time point than at T0 (P<0.01). At T1, serum IL-8 and IL-10 levels had no significant differences among 3 groups (P<0.05), but the differences were significant at T2, T3 and T4 (P<0.05). Moreover, correlation analysis suggested that serum IL-8 level was in positive relation with IL-10 level (r=0.952, P<0.01). CONCLUSIONS: Propofol, which is better in inhibiting serum IL-8 secretion and improving IL-10 secretion than isoflurane and enflurance, can be regarded as a preferable anesthetic agent in inhibiting traumatic inflammatory responses.

Ventilation/perfusion ratios measured by multiple inert gas elimination during experimental cardiopulmonary resuscitation.

BACKGROUND: During cardiopulmonary resuscitation (CPR) the ventilation/perfusion distribution (VA /Q) within the lung is difficult to assess. This experimental study examines the capability of multiple inert gas elimination (MIGET) to determine VA /Q under CPR conditions in a pig model. METHODS: Twenty-one anaesthetised pigs were randomised to three fractions of inspired oxygen (1.0, 0.7 or 0.21). VA/ Q by micropore membrane inlet mass spectrometry-derived MIGET was determined at baseline and during CPR following induction of ventricular fibrillation. Haemodynamics, blood gases, ventilation distribution by electrical impedance tomography and return of spontaneous circulation were assessed. Intergroup differences were analysed by non-parametric testing. RESULTS: MIGET measurements were feasible in all animals with an excellent correlation of measured and predicted arterial oxygen partial pressure (R(2) = 0.96, n = 21 for baseline; R(2) = 0.82, n = 21 for CPR). CPR induces a significant shift from normal VA /Q ratios to the high VA /Q range. Electrical impedance tomography indicates a dorsal to ventral shift of the ventilation distribution. Diverging pulmonary shunt fractions induced by the three inspired oxygen levels considerably increased during CPR and were traceable by MIGET, while 100% oxygen most negatively influenced the VA /Q. Return of spontaneous circulation were achieved in 52% of the animals. CONCLUSIONS: VA /Q assessment by MIGET is feasible during CPR and provides a novel tool for experimental purposes. Changes in VA /Q caused by different oxygen fractions are traceable during CPR. Beyond pulmonary perfusion deficits, these data imply an influence of the inspired oxygen level on VA /Q. Higher oxygen levels significantly increase shunt fractions and impair the normal VA /Q ratio.

Inhalation anesthesia is preferable for recording rat cardiac function using an electrocardiogram.

The effects of inhalation anesthesia (2% isoflurane, sevoflurane, or enflurane) and intraperitoneal anesthesia with pentobarbital (65 mg/kg) were compared in rats using an electrocardiogram (ECG) and determination of blood oxygen saturation (SPO2) levels. Following inhalation anesthesia, heart rate (HR) and SPO2 were acceptable while pentobarbital anesthesia decreased HR and SPO2 significantly. This indicates that inhalation anesthesia is more preferable than pentobarbital anesthesia when evaluating cardiovascular factors. Additionally, pentobarbital significantly increased HR variability (HRV), suggesting a regulatory effect of pentobarbital on the autonomic nervous system, and resulted in a decreased response of the baro-reflex system. Propranolol or atropine had limited effects on ECG recording following pentobarbital anesthesia. Taken together, these data suggest that inhalation anesthesia is suitable for conducting hemodynamic analyses in the rat.

Comparison of subarachnoid anesthetic effect of emulsified volatile anesthetics in rats.

Spinal cord is an important target of volatile anesthetics in particular for the effect of immobility. Intrathecal injection of volatile anesthetics has been found to produce subarachnoid anesthesia. The present study was designed to compare spinal anesthetic effects of emulsified volatile anesthetics, and to investigate the correlation between their spinal effects and general effect of immobility. In this study, halothane, isoflurane, enflurane and sevoflurane were emulsified by 30% Intralipid. These emulsified volatile anesthetics were intravenously and intrathecally injected, respectively. ED50 of general anesthesia and EC50 of spinal anesthesia were determined. The durations of general and spinal anesthesia were recorded. Correlation analysis was applied to evaluate the anesthetic potency of volatile anesthetics between their spinal and general effects. ED50 of general anesthesia induced by emulsified halothane, isoflurane, enflurane and sevoflurane were 0.41 ± 0.07, 0.54 ± 0.07, 0.74 ± 0.11 and 0.78 ± 0.08 mmol/kg, respectively, with significant correlation to their inhaled MAC (R(2) = 0.8620, P = 0.047). For intrathecal injection, EC50 of spinal anesthesia induced by emulsified halothane, isoflurane, enflurane and sevoflurane were 0.35, 0.27, 0.33 and 0.26 mol/L, respectively, which could be predicted by the product of inhaled MAC and olive oil/gas partition coefficients (R(2) = 0.9627, P = 0.013). In conclusion, potency and efficacy of the four emulsified volatile anesthetics in spinal anesthesia were similar and could be predicted by the product of inhaled MAC and olive oil/gas partition coefficients (MAC × olive oil/gas partition coefficients).

Up-regulation of Alzheimer's disease-associated proteins may cause enflurane anesthesia induced cognitive decline in aged rats.

Isoflurane anesthesia can cause post-operative cognitive dysfunction in elderly patients. As an isomer of isoflurane, enflurane may also account for cognitive dysfunction. However, the mechanism of enflurane-induced cognitive dysfunction remains obscure. In this study, we investigated the effects of enflurane anesthesia on cognitive function and the possible roles of ß-amyloid protein and phosphorylated tau protein in response to enflurane anesthesia in aged rats. After intraperitoneal injection of enflurane, the Morris water maze and the step-down passive avoidance tests were conducted to test the cognitive ability and memory. The enflurane group showed prolonged escape latency, extended space exploration time and increased number of errors at early stage after enflurane anesthesia, suggesting that enflurane should be responsible for the impairment of cognition in aged rats. In addition, we analyzed the expression level of ß-amyloid and phosphorylation level of tau in the hippocampus by immunoblotting. Interestingly, the levels of ß-amyloid and phosphorylated tau in the hippocampus increased significantly at early stage and then restored to pre-anesthetic levels. Taken together, our results suggest that increasing of ß-amyloid and phosphorylation of tau are important to cause cognitive decline in aged rats during initial stage after enflurane anesthesia.

Peripheral nerve injury caused by needle impalement: Synchrotron small-angle X-ray scattering study in ex-vivo rat sciatic nerve

BACKGROUND: Direct puncture by a needle is a risk factor for nerve damage. This study was designed to demonstrate nerve damage caused by a needle using the synchrotron small-angle X-ray scattering (SAXS) technique. METHODS: A 15 mm section of rat (Male Spargue-Dawley, about 250 grams) sciatic nerves were involved in this study. The nerve specimen for the experiment (N = 5) was punctured 5 times by a needle (25 G, 100 beveled) under general anesthesia with enflurane. The needle was placed perpendicular to the nerve and the needle bevel was placed parallel to the nerve. The SAXS patterns of the punctured nerves, extracted about 15 min prior to the experiment, were acquired after 1 week. The SAXS patterns of a normal sciatic nerve (N = 5), extracted about 15 min prior to the experiment, were measured in order to provide a comparison. Experiments were carried out at 4C1 beamline at Pohang Accelerator Laboratory in Korea. Incoming X-rays were monochromatized at 11 keV using a double multilayer (WB4C) monochromator; the beam size was around 0.5 (V) x 0.8 (H) mm2. The exposure time was 60 sec, and 8 to 12 images were acquired per sample with a 0.5 mm interval. RESULTS: In the punctured group, the periodic peaks of myelin sheath and collagen fiber were not changed. However, the periodic peaks of interfibrillar distance of collagen were greatly changed. CONCLUSIONS: Direct needle-nerve impalement did not cause damages in myelin sheath and collagen fibers when the needle was placed perpendicular and the needle bevel paralleled to the nerve fiber. This result can imply that the needle slipped into the interfibrillar packing of collagen fibrils.