Involvement of Fgf2-mediated tau protein phosphorylation in cognitive deficits induced by sevoflurane in aged rats.

OBJECTIVE: Anesthetics have been linked to cognitive alterations, particularly in the elderly. The current research delineates how Fibroblast Growth Factor 2 (Fgf2) modulates tau protein phosphorylation, contributing to cognitive impairments in aged rats upon sevoflurane administration. METHODS: Rats aged 3, 12, and 18 months were subjected to a 2.5% sevoflurane exposure to form a neurotoxicity model. Cognitive performance was gauged, and the GEO database was employed to identify differentially expressed genes (DEGs) in the 18-month-old cohort post sevoflurane exposure. Bioinformatics tools, inclusive of STRING and GeneCards, facilitated detailed analysis. Experimental validations, both in vivo and in vitro, examined Fgf2's effect on tau phosphorylation. RESULTS: Sevoflurane notably altered cognitive behavior in older rats. Out of 128 DEGs discerned, Fgf2 stood out as instrumental in regulating tau protein phosphorylation. Sevoflurane exposure spiked Fgf2 expression in cortical neurons, intensifying tau phosphorylation via the PI3K/AKT/Gsk3b trajectory. Diminishing Fgf2 expression correspondingly curtailed tau phosphorylation, neurofibrillary tangles, and enhanced cognitive capacities in aged rats. CONCLUSION: Sevoflurane elicits a surge in Fgf2 expression in aging rats, directing tau protein phosphorylation through the PI3K/AKT/Gsk3b route, instigating cognitive aberrations.

Dopamine neurons in the ventral periaqueductal gray modulate isoflurane anesthesia in rats.

AIMS: General anesthesia has been applied in surgery for more than 170 years, and there is little doubt that GABAA receptors have an important role as anesthetic molecular targets, but its neural mechanisms remain unclear. Increasing researchers have shown that dopaminergic pathways in the brain are crucial for sleep and wake. General anesthesia-induced unconsciousness and natural sleep share some neural correlates. However, the role of GABAA receptors in ventral periaqueductal gray (vPAG) dopamine (DA) neurons in the isoflurane-induced unconsciousness has yet to be identified. METHODS: In the present study, we used calcium fiber photometry recording to explore that the activity of ventral periaqueductal gray (vPAG) neurons. Then, rats were unilaterally microinjected with 6-hydroxydopamine into the vPAG area to determine the role of vPAG-DA neurons in isoflurane-induced-anesthesia. Furthermore, thirty SD rats were divided into three groups: a GABAA R agonist-muscimol group, a GABAA R antagonist-gabazine group, and a control group. Finally, whole-cell patch clamp was used to examine the effects of isoflurane and GABAA receptor agonist/antagonist on vPAG-DA neurons. RESULTS: The vPAG neurons were markedly inhibited during isoflurane anesthesia induction and that these neurons were activated during emergence from isoflurane anesthesia. Lesion to the vPAG-DA neurons shortened the induction time and prolonged the emergence time while increasing δ power in isoflurane anesthesia. Intracerebral injection of the GABAA receptor agonist (muscimol) into the vPAG accelerated the induction of anesthesia and delayed recovery from isoflurane anesthesia, with a decrease of δ power and an augment of ß power. Injection of GABAA receptor antagonist gabazine generated the opposite effects. Isoflurane enhanced GABAergic transmission, and GABAA receptor agonist partly increased isoflurane-induced inhibition of vPAG-DA neurons, while GABAA receptor antagonist evidently attenuated GABAergic transmission. CONCLUSION: Our results suggest that vPAG-DA neurons are involved in isoflurane anesthesia through activation of the GABAA receptor.

Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins.

Membrane proteins are primary targets for most therapeutic indications in cancer and neurological diseases, binding over 50% of all known small molecule drugs. Understanding how such ligands impact membrane proteins requires knowledge on the molecular structure of ligand binding, a reasoning that has driven relentless efforts in drug discovery and translational research. Binding of small ligands appears however highly complex involving interaction to multiple transmembrane protein sites featuring single or multiple occupancy states. Within this scenario, looking for new developments in the field, we investigate the concentration-dependent binding of ligands to multiple saturable sites in membrane proteins. The study relying on docking and free-energy perturbation provides us with an extensive description of the probability density of protein-ligand states that allows for computation of thermodynamic properties of interest. It also provides one- and three-dimensional spatial descriptions for the ligand density across the protein-membrane system which can be of interest for structural purposes. Illustration and discussion of the results are shown for binding of the general anesthetic sevoflurane against Kv1.2, a mammalian ion channel for which experimental data are available.

Patients Undergoing Orthotopic Liver Transplantation Require Lower Concentrations of the Volatile Anesthetic Sevoflurane.

BACKGROUND: Sevoflurane is a volatile anesthetic commonly used to maintain anesthesia in patients with end-stage liver disease (ESLD) undergoing orthotopic liver transplantation (OLT). Growing evidence suggests that patients with ESLD have decreased anesthetic requirements compared to patients with preserved liver function. The potency of volatile anesthetics is expressed as the minimum alveolar concentration (MAC). In this prospective, blinded study, we compared the MAC of sevoflurane among patients with ESLD undergoing OLT and patients with normal liver function undergoing major abdominal surgery. METHODS: After propofol-induced anesthesia, the MAC of sevoflurane was assessed by evaluating motor response to initial skin incision in patients undergoing OLT and in patients with normal liver function undergoing major abdominal surgery. The MAC was determined using Dixon "up-and-down" method and compared between groups. In addition, the bispectral index was documented immediately before and after skin incision. RESULTS: Twenty patients undergoing OLT and 20 control patients were included in the study. The MAC of sevoflurane in patients undergoing OLT was 1.3% (95% confidence interval [CI], 1.1-1.4). In comparison, the MAC of sevoflurane in patients with normal liver function was 1.7% (95% CI, 1.6-1.9), equal to a relative reduction of the MAC in patients with ESLD of 26% (95% CI, 14-39). The bispectral index was higher in patients with ESLD than in control patients at 3 minutes before (47 [95% CI, 40-53] vs 35 [95% CI, 31-40], P = .011), 1 minute before (48 [95% CI, 42-54] vs 37 [95% CI, 33-43], P = .03), and 1 minute after skin incision (57 [95% CI, 50-64] vs 41 [95% CI, 36-47], P < .001). CONCLUSIONS: Our results suggest that the MAC of sevoflurane is lower in patients with ESLD than in patients with normal liver function after propofol-induced anesthesia. However, as we did not measure propofol concentrations at the time of skin incision, the difference in MAC should be interpreted with caution given that residual propofol may have been present at the time of skin incision.

Pharmacogenomics in Anesthesia.

A significant number of commonly administered medications in anesthesia show wide clinical interpatient variability. Some of these include neuromuscular blockers, opioids, local anesthetics, and inhalation anesthetics. Individual genetic makeup may account for and predict cardiovascular outcomes after cardiac surgery. These interactions can manifest at any point in the perioperative period and may also only affect a specific system. A better understanding of pharmacogenomics will allow for more individually tailored anesthetics and may ultimately lead to better outcomes, decreased hospital stays, and improved patient satisfaction.

Halogenated Ether, Alcohol, and Alkane Anesthetics Activate TASK-3 Tandem Pore Potassium Channels Likely through a Common Mechanism.

The TWIK-related acid-sensitive potassium channel 3 (TASK-3; KCNK9) tandem pore potassium channel function is activated by halogenated anesthetics through binding at a putative anesthetic-binding cavity. To understand the pharmacologic requirements for TASK-3 activation, we studied the concentration-response of TASK-3 to several anesthetics (isoflurane, desflurane, sevoflurane, halothane, α-chloralose, 2,2,2-trichloroethanol [TCE], and chloral hydrate), to ethanol, and to a panel of halogenated methanes and alcohols. We used mutagenesis to probe the anesthetic-binding cavity as observed in a TASK-3 homology model. TASK-3 activation was quantified by Ussing chamber voltage clamp analysis. We mutagenized the residue Val-136, which lines the anesthetic-binding cavity, its flanking residues (132 to 140), and Leu-122, a pore-gating residue. The 2-halogenated ethanols activate wild-type TASK-3 with the following rank order efficacy (normalized current [95% confidence interval]): 2,2,2-tribromo-(267% [240-294]) > 2,2,2-trichloro-(215% [196-234]) > chloral hydrate (165% [161-176]) > 2,2-dichloro- > 2-chloro ≈ 2,2,2-trifluoroethanol > ethanol. Similarly, carbon tetrabromide (296% [245-346]), carbon tetrachloride (180% [163-196]), and 1,1,1,3,3,3-hexafluoropropanol (200% [194-206]) activate TASK-3, whereas the larger carbon tetraiodide and α-chloralose inhibit. Clinical agents activate TASK-3 with the following rank order efficacy: halothane (207% [202-212]) > isoflurane (169% [161-176]) > sevoflurane (164% [150-177]) > desflurane (119% [109-129]). Mutations at and near residue-136 modify TCE activation of TASK-3, and interestingly M159W, V136E, and L122D were resistant to both isoflurane and TCE activation. TASK-3 function is activated by a multiple agents and requires a halogenated substituent between ∼30 and 232 cm3/mol volume with potency increased by halogen polarizeability. Val-136 and adjacent residues may mediate anesthetic binding and stabilize an open state regulated by pore residue Leu-122. Isoflurane and TCE likely share commonalities in their mechanism of TASK-3 activation.

A survey of the dose of inhalational agents used to maintain anaesthesia in infants.

BACKGROUND: Various animal studies suggest that currently used anaesthetics are toxic to the developing brain. Many reviews advise that the total anaesthetic drug exposure should be reduced but the dose usually used in clinical practice has not been clearly elucidated. OBJECTIVES: To provide an overview of the dose ranges currently used in clinical practice during the maintenance phase of anaesthesia in infants undergoing anaesthesia for noncardiac surgery and diagnostic procedures. DESIGN: A two-centre mixed prospective (London) and retrospective (Utrecht) observational cohort study. SETTING: Two independent tertiary paediatric referral centres in March and November 2013; Great Ormond Street Hospital (GOSH), London, United Kingdom and Wilhelmina Children's Hospital, University Medical Center Utrecht (UMCU), The Netherlands. PATIENTS: A total of 76 infants were included in the analysis, 38 infants from each hospital. METHODS: Patients from GOSH were matched by procedure, age and weight with patients from the UMCU. The end-tidal concentrations of the inhalational agents were investigated from anaesthetic charts during the maintenance phase and corrected for the age-specific minimal alveolar concentration (MAC), expressed as a percentage from the MAC (%MAC). RESULTS: Three different types of inhalational anaesthetics were used: sevoflurane, desflurane, isoflurane. The mean %MAC was 0.85. No significant differences in %MAC were found between GOSH and the UMCU (P = 0.329); the mean %MAC in GOSH was 0.87 and in the UMCU was 0.82. There was a significant increase in the %MAC in relation to age (slope = 0.036 MAC month, P < 0.001). Of all patients, 75% had an end-tidal concentration lower than 1 MAC. There was no significant effect of the use of analgesia on the end-tidal concentration of inhalational anaesthetics (P = 0.366). CONCLUSION: The concentration of inhalational anaesthetics in %MAC increased with age and was lowest in neonates. Most young infants received inhalational anaesthetics at a concentration below 1 MAC, which accords with current guidance to minimise anaesthetic drug exposure but may have unintended consequences.

Intraoperative end-tidal concentration of isoflurane in cats undergoing ovariectomy that received tramadol, buprenorphine or a combination of both.

Objectives The aim of the study was to evaluate the end-tidal concentration of isoflurane required to maintain heart and respiratory rate within ± 20% of basal measurement in cats undergoing ovariectomy that received buprenorphine, tramadol or a combination of both. Methods Thirty cats, divided into three groups, were enrolled in a simple operator-blinded, randomised study. Cats received acepromazine (0.03 mg/kg) and one of the following treatments: buprenorphine (0.02 mg/kg), tramadol (2 mg/kg) or a combination of both. Anaesthesia was induced with propofol and maintained with isoflurane titrated in order to maintain heart and respiratory rate within the target values recorded before premedication. Results Groups were similar for age, weight, dose of propofol administered, sedation and recovery scores. Cats receiving tramadol with buprenorphine were extubated earlier after isoflurane discontinuation. No statistical differences were detected in end-tidal fraction of isoflurane between buprenorphine alone or with tramadol. In cats that received tramadol or buprenorphine alone, ovarian pedicle traction caused a statistical increase in end-tidal isoflurane concentration compared with that measured during incision and suture of the skin. In cats that received the combination of tramadol plus buprenorphine no differences among surgical time points were observed. Conclusions and relevance Tramadol added to buprenorphine did not provide any advantage in decreasing the end-tidal fraction of isoflurane compared with buprenorphine alone, although it is speculated there may be an infra-additive interaction between tramadol and buprenorphine in cats.

Inhalational anesthetics disrupt postsynaptic density protein-95, Drosophila disc large tumor suppressor, and zonula occludens-1 domain protein interactions critical to action of several excitatory receptor channels related to anesthesia.

BACKGROUND: The authors have shown previously that inhaled anesthetics disrupt the interaction between the second postsynaptic density protein-95, Drosophila disc large tumor suppressor, and zonula occludens-1 (PDZ) domain of postsynaptic density protein-95 (PSD-95) and the C-terminus of N-methyl-D-aspartate receptor subunits NR2A and NR2B. The study data indicate that PDZ domains may serve as a molecular target for inhaled anesthetics. However, the underlying molecular mechanisms remain to be illustrated. METHODS: Glutathione S-transferase pull-down assay, coimmunoprecipitation, and yeast two-hybrid analysis were used to assess PDZ domain-mediated protein-protein interactions in different conditions. Nuclear magnetic resonance spectroscopy was used to investigate isoflurane-induced chemical shift changes in the PDZ1-3 domains of PSD-95. A surface plasmon resonance-based BIAcore (Sweden) assay was used to examine the ability of isoflurane to inhibit the PDZ domain-mediated protein-protein interactions in real time. RESULTS: Halothane and isoflurane dose-dependently inhibited PDZ domain-mediated interactions between PSD-95 and Shaker-type potassium channel Kv1.4 and between α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA2 and its interacting proteins-glutamate receptor-interacting protein or protein interacting with c kinase 1. However, halothane and isoflurane had no effect on PDZ domain-mediated interactions between γ-aminobutyric acid type B receptor and its interacting proteins. The inhaled anesthetic isoflurane mostly affected the residues close to or in the peptide-binding groove of PSD-95 PDZ1 and PDZ2 (especially PDZ2), while barely affecting the peptide-binding groove of PSD-95 PDZ3. CONCLUSION: These results suggest that inhaled anesthetics interfere with PDZ domain-mediated protein-protein interactions at several receptors important to neuronal excitation, anesthesia, and pain processing.

Involvement of the blood-brain barrier opening in cognitive decline in aged rats following orthopedic surgery and high concentration of sevoflurane inhalation.

The underlying causes of postoperative cognitive decline (POCD) in old patients remained unelucidated, and there are little descriptions on mechanisms associated with the blood-brain barrier (BBB) disruption during POCD. We therefore tested the effects of orthopedic surgery with different concentrations of sevoflurane for 2 h on the behavior test and the BBB permeability in aged rats. 18-month rats were divided into control group and surgical group with propofol anesthesia (0.7 mgkg(-1) min(-1)) and 1.0 MAC, 1.3 MAC, and 1.5 MAC sevoflurane inhalation for 2 h. We assessed their cognitive function via Y-maze and fear conditioning test on day 1, 3, and 7 after experiments. Animals were then assigned to control group, propofol (2 h, 0.7 mgkg(-1) min(-1)) group, surgery plus propofol group and surgery plus 1.5 MAC sevoflurane inhalation for 2h. Their hippocampal BBB permeability was detected with Evans blue quantification. Alterations of tight junctions in hippocampus were measured with occludin and claudin-5 western blot. Then we assessed matrix metalloproteinase-2,9 (MMP-2,9) via western blot and immunohistochemistry staining at day 1, 3, 7, and 14 after experiments. Surgery impaired cognitive function and increased Evans blue leakage into the hippocampus in aged rats while 2 h of 1.5 MAC sevoflurane inhalation potentiated these effects. Surgery induced occludin protein expression decreases and MMP-2,9 proteins increase and these influences can be enhanced by high concentration of sevoflurane inhalation. In conclusion, 1.5 MAC sevoflurane for 2 h exacerbated cognitive impairment induced by orthopedic surgery in aged rats and the breach in BBB may be involved in this process.

Cardioprotection during diabetes: the role of mitochondrial DNA.

BACKGROUND: Diabetes alters mitochondrial bioenergetics and consequently disrupts cardioprotective signaling. The authors investigated whether mitochondrial DNA (mtDNA) modulates anesthetic preconditioning (APC) and cardiac susceptibility to ischemia-reperfusion injury by using two strains of rats, both sharing nuclear genome of type 2 diabetes mellitus (T2DN) rats and having distinct mitochondrial genomes of Wistar and fawn-hooded hypertensive (FHH) rat strains (T2DN(mtWistar) and T2DN(mtFHH), respectively). METHODS: Myocardial infarct size was measured in Wistar, T2DN(mtWistar), and T2DN(mtFHH) rats with or without APC (1.4% isoflurane) in the presence or absence of antioxidant N-acetylcysteine. Flavoprotein fluorescence intensity, a marker of mitochondrial redox state, 5-(and-6)-chloromethyl-2',7'-dichlorofluorescein fluorescence intensity, a marker of reactive oxygen species generation, and mitochondrial permeability transition pore opening were assessed in isolated rat ventricular cardiomyocytes with or without isoflurane (0.5 mmol/l). RESULTS: Myocardial infarct size was decreased by APC in Wistar and T2DN(mtWistar) rats (to 42 ± 6%, n = 8; and 44 ± 7%, n = 8; of risk area, respectively) compared with their respective controls (60 ± 3%, n = 6; and 59 ± 9%, n = 7), but not in T2DN(mtFHH) rats (60 ± 2%, n = 8). N-acetylcysteine applied during isoflurane treatment restored APC in T2DN(mtFHH) (39 ± 6%, n = 7; and 38 ± 5%, n = 7; 150 and 75 mg/kg N-acetylcysteine, respectively), but abolished protection in control rats (54 ± 8%, n = 6). Similar to the data on infarct size, APC delayed mitochondrial permeability transition pore opening in T2DN(mtWistar) but not in T2DN(mtFHH) cardiomyocytes. Isoflurane increased flavoprotein and 5-(and-6)-chloromethyl-2',7'-dichlorofluorescein fluorescence intensity in all rat strains, with the greatest effect in T2DN(mtFHH) cardiomyocytes. CONCLUSION: Differences in the mitochondrial genome modulate isoflurane-induced generation of reactive oxygen species which translates into differential susceptibility to APC and ischemia-reperfusion injury in diabetic rats.

Epileptogenic effect of sevoflurane: determination of the minimal alveolar concentration of sevoflurane associated with major epileptoid signs in children.

BACKGROUND: Sevoflurane has become the gold standard for inhalation induction in children. However in children as in adults, epileptiform electroencephalographic signs have been described under high concentrations of sevoflurane. The aim of this study was to determine the minimal alveolar concentration (MAC) of sevoflurane associated with the occurrence of major epileptiform signs (MES) in 50% children under steady-state conditions. The MAC of MES (MAC MES) was determined in 100% oxygen and with the addition of 50% nitrous oxide or after the injection of alfentanil (ALFENTA). METHODS: Seventy-nine children (3-11 yr), undergoing elective surgery and premedicated with hydroxyzine were included. After induction by inhalation and tracheal intubation, a 10-min period with a stable expired fraction of sevoflurane was obtained. The MES were defined as rhythmic polyspikes or epileptiform discharges. Electroencephalographic recordings were blindly analyzed by two independent experts. The MAC MES were determined by the Dixon method: the concentration of sevoflurane was determined by the result from the previous patient: increase of 0.2% if MES were absent or decrease of 0.2% if MES were present. Three consecutive series were performed: (1) in 100% oxygen (MAC MESO2); (2) in 50% oxygen and 50% nitrous oxide (MAC MESN2O); and (3) in 100% oxygen with a bolus of alfentanil (MAC MESALFENTA). RESULTS: The MAC MESO2 was 4.3±0.1% (mean±SD), the MAC MESN2O and the MAC MESALFENTA were higher, respectively: 4.6±0.2% (P=0.01) and 4.6±0.2% (P=0.02). CONCLUSIONS: In children premedicated with hydroxyzine, the MAC MES of sevoflurane calculated in 100% O2 corresponded to 1.75 surgical MAC. In addition, our results have demonstrated a moderate effect of nitrous oxide and alfentanil in raising the threshold of MES.

Hospital stay and mortality are increased in patients having a "triple low" of low blood pressure, low bispectral index, and low minimum alveolar concentration of volatile anesthesia.

BACKGROUND: Low mean arterial pressure (MAP) and deep hypnosis have been associated with complications and mortality. The normal response to high minimum alveolar concentration (MAC) fraction of anesthetics is hypotension and low Bispectral Index (BIS) scores. Low MAP and/or BIS at lower MAC fractions may represent anesthetic sensitivity. The authors sought to characterize the effect of the triple low state (low MAP and low BIS during a low MAC fraction) on duration of hospitalization and 30-day all-cause mortality. METHODS: Mean intraoperative MAP, BIS, and MAC were determined for 24,120 noncardiac surgery patients at the Cleveland Clinic, Cleveland, Ohio. The hazard ratios associated with combinations of MAP, BIS, and MAC values greater or less than a reference value were determined. The authors also evaluated the association between cumulative triple low minutes, and excess length-of-stay and 30-day mortality. RESULTS: Means (±SD) defining the reference, low, and high states were 87 ± 5 mmHg (MAP), 46 ± 4 (BIS), and 0.56 ± 0.11 (MAC). Triple lows were associated with prolonged length of stay (hazard ratio 1.5, 95% CI 1.3-1.7). Thirty-day mortality was doubled in double low combinations and quadrupled in the triple low group. Triple low duration ≥60 min quadrupled 30-day mortality compared with ≤15 min. Excess length of stay increased progressively from ≤15 min to ≥60 min of triple low. CONCLUSIONS: The occurrence of low MAP during low MAC fraction was a strong and highly significant predictor for mortality. When these occurrences were combined with low BIS, mortality risk was even greater. The values defining the triple low state were well within the range that many anesthesiologists tolerate routinely.

Effect of cuffed and uncuffed endotracheal tubes on the oropharyngeal oxygen and volatile anesthetic agent concentration in children.

BACKGROUND: Over the past 5 years, there has been a change in the clinical practice of pediatric anesthesiology with a transition to the use of cuffed instead of uncuffed endotracheal tubes (ETTs) in infants and children. As the trachea is sealed, one advantage is to eliminate the contamination of the oropharynx with oxygen which should be advantageous during adenotonsillectomy where there is a risk of airway fire. The current study prospectively assesses the oropharyngeal oxygen and volatile anesthetic agent concentration during adenotonsillectomy in infants and children. METHODS: Following the induction of general anesthesia in patients scheduled for adenoidectomy, tonsillectomy or adenotonsillectomy, the trachea was intubated. The use of a cuffed or uncuffed ETT and the use of spontaneous (SV) or positive pressure ventilation (PPV) were at the discretion of the anesthesia team. The oxygen concentration was kept at 100% oxygen until the study was completed. Following placement of the mouth gag, the otolaryngolist placed into the oropharynx a small bore catheter, which was attached to a standard anesthesia gas monitoring device which sampled the gas at 150mL/min. The concentration of the oxygen and the concentration of the anesthetic agent in the oropharynx were measured for 5 breaths. RESULTS: The cohort for the study included 200 patients ranging in age from 1 to 18 years. With the use of a cuffed ETT and either SV or PPV, the oxygen concentration in the oropharynx was 20-21% and the volatile agent concentration was 0% in all 118 patients. With the use of an uncuffed ETT and the administration of 100% oxygen, there was significant contamination of the oropharynx noted during both PPV and SV. The mean oxygen concentration was 71% during PPV with an uncuffed ETT and 65% during SV with an uncuffed ETT. In these patients, the oropharyngeal oxygenation concentration exceeded 30% in 73 of the 82 patients (89%). The oropharyngeal oxygen and agent concentration was greater when the leak around the uncuffed ETT was ≥10cmH(2)O versus less than 10cmH(2)O and when the leak around the uncuffed ETT was ≥15cmH(2)O versus less than 15cmH(2)O. CONCLUSIONS: With the use of an uncuffed ETT and the administration of 100% oxygen, there was significant contamination of the oropharynx noted during both PPV and SV. The oropharyngeal concentration of oxygen is high enough to support combustion in the majority of patients. The use of a cuffed ETT eliminates oropharyngeal contamination with oxygen during the administration of anesthesia and may be useful in limiting the incidence of an airway fire.

Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain.

Postoperative cognitive dysfunction, POCD, afflicts a large number of elderly surgical patients following surgery with general anesthesia. Mechanisms of POCD remain unclear. N-methyl-D-aspartate (NMDA) receptors, critical in learning and memory, that display protein expression changes with age are modulated by inhalation anesthetics. The aim of this study was to identify protein expression changes in NMDA receptor subunits and downstream signaling pathways in aged rats that demonstrated anesthesia-induced spatial learning impairments. Three-month-old and 18-month-old male Fischer 344 rats were randomly assigned to receive 1.8% isoflurane/70% nitrous oxide (N(2)O) anesthesia for 4h or no anesthesia. Spatial learning was assessed at 2weeks and 3months post-anesthesia in Morris water maze. Hippocampal and cortical protein lysates of 18-month-old rats were immunoblotted for activated caspase 3, NMDA receptor subunits, and extracellular-signal regulated kinase (ERK) 1/2. In a separate experiment, Ro 25-6981 (0.5mg/kg dose) was administered by I.P. injection before anesthesia to 18-month-old rats. Immunoblotting of NR2B was performed on hippocampal protein lysates. At 3months post-anesthesia, rats treated with anesthesia at 18-months-old demonstrated spatial learning impairment corresponding to acute and long-term increases in NR2B protein expression and a reduction in phospho-ERK1/2 in the hippocampus and cortex. Ro 25-6981 pretreatment attenuated the increase in acute NR2B protein expression. Our findings suggest a role for disruption of NMDA receptor mediated signaling pathways in the hippocampus and cortex of rats treated with isoflurane/ N(2)O anesthesia at 18-months-old, leading to spatial learning deficits in these animals. A potential therapeutic intervention for anesthesia associated cognitive deficits is discussed.

A gain-of-function mutation in adenylate cyclase confers isoflurane resistance in Caenorhabditis elegans.

BACKGROUND: Volatile general anesthetics inhibit neurotransmitter release by a mechanism not fully understood. Genetic evidence in Caenorhabditis elegans has shown that a major mechanism of action of volatile anesthetics acting at clinical concentrations in this animal is presynaptic inhibition of neurotransmission. To define additional components of this presynaptic volatile anesthetic mechanism, C. elegans mutants isolated as phenotypic suppressors of a mutation in syntaxin, an essential component of the neurotransmitter release machinery, were screened for anesthetic sensitivity phenotypes. METHODS: Sensitivity to isoflurane concentrations was measured in locomotion assays on adult C. elegans. Sensitivity to the acetylcholinesterase inhibitor aldicarb was used as an assay for the global level of C. elegans acetylcholine release. Comparisons of isoflurane sensitivity (measured by the EC50) were made by simultaneous curve-fitting and F test. RESULTS: Among the syntaxin suppressor mutants, js127 was the most isoflurane resistant, with an EC50 more than 3-fold that of wild type. Genetic mapping, sequencing, and transformation phenocopy showed that js127 was an allele of acy-1, which encodes an adenylate cyclase expressed throughout the C. elegans nervous system and in muscle. js127 behaved as a gain-of-function mutation in acy-1 and had increased concentrations of cyclic adenosine monophosphate. Testing of single and double mutants along with selective tissue expression of the js127 mutation revealed that acy-1 acts in neurons within a Gαs-PKA-UNC-13-dependent pathway to regulate behavior and isoflurane sensitivity. CONCLUSIONS: Activation of neuronal adenylate cyclase antagonizes isoflurane inhibition of locomotion in C. elegans.

Minimum alveolar concentrations and hemodynamic effects of two different preparations of sevoflurane in pigs

BACKGROUND: Original sevoflurane (Sevo A) is made with water, while a generic sevoflurane (Sevocris) is produced with propylene glycol as a stabilizing additive. We investigated whether the original and generic sevoflurane preparations differed in terms of their minimum alveolar concentration (MAC) values and hemodynamic effects. METHODS: Sixteen pigs weighing 31.6±1.8 kg were randomly assigned to the Sevo A or Sevocris groups. After anesthesia induction via mask with the appropriate sevoflurane preparation (6 percent in 100 percent oxygen), the MAC was determined for each animal. Hemodynamic and oxygenation parameters were measured at 0.5 MAC, 1 MAC and 1.5 MAC. Histopathological analyses of lung parenchyma were performed. RESULTS: The MAC in the Sevo A group was 4.4±0.5 percent, and the MAC in the Sevocris group was 4.1±0.7 percent. Hemodynamic and metabolic parameters presented significant differences in a dose-dependent pattern as expected, but they did not differ between groups. Cardiac indices and arterial pressures decreased in both groups when the sevoflurane concentration increased from 0.5 to 1 and 1.5 MAC. The oxygen delivery index (DO2I) decreased significantly at 1.5 MAC. CONCLUSION: Propylene glycol as an additive for sevoflurane seems to be as safe as a water additive, at least in terms of hemodynamic and pulmonary effects.

The effect on the recovery profile of a change from enflurane to desflurane during the latter part of anaesthesia.

This study compared emergence and recovery characteristics after either enflurane anaesthesia or crossover from enflurane to desflurane anaesthesia. At an estimated 1 h prior to the end of operation, enflurane was either reduced (group E, n = 23) or replaced with desflurane (group X, n = 23). At the end of the operation, emergence and recovery characteristics of the two groups were compared. The crossover technique accelerated recovery compared with enflurane anaesthesia. The time taken for the eyes to open in response to painful pinching or a verbal command, and to regain awareness of age and name, were significantly shorter after crossover anaesthesia than after enflurane anaesthesia. The digit symbol substitution test and serial seven test scores were significantly better in patients subjected to crossover anaesthesia than in those subjected to enflurane anaesthesia. We conclude that, during surgery, the substitution of enflurane with desflurane in the latter part of anaesthesia can improve recovery.

Experience with remifentanil-sevoflurane balanced anesthesia for abdominal surgery in neonates and children less than 2 years.

BACKGROUND: Few data report remifentanil use in the neonatal population. We described here our experience with remifentanil-sevoflurane balanced anesthesia in neonates and children less than 2 years who underwent general anesthesia for abdominal surgery. METHODS: We retrospectively studied the pattern of remifentanil infusion associated with sevoflurane inhalation in preterm neonates (PTN; n = 18) (born before 37 weeks of gestation and <45 weeks of postmenstrual age), full-term neonates (FTN; n = 21) (born after 37 weeks of gestation and less than 29 days old) and older children up to 2 years (CUT; n = 24). We recorded heart rate (HR), mean arterial pressure (MAP), mean remifentanil dose and sevoflurane concentration before incision and at 5, 10, 20, 30, 45, 60, 90, and 105 min after incision. RESULTS: We observed that remifentanil doses used during surgery were lower in PTN than in both FTN and CUT and lower in FTN than in CUT. This was because of a progressive decrease in remifentanil dose during anesthesia in PTN and FTN. Conversely, remifentanil doses increased in CUT during anesthesia. Sevoflurane concentrations were higher in CUT group than in PTN and FTN groups. MAP and HR did not vary in the three groups during anesthesia. CONCLUSIONS: Remifentanil-sevoflurane anesthesia can be used for general anesthesia in neonates. We observed that anesthetists used lower doses of remifantanil and lower concentrations of sevoflurane in neonates compared with the older children.