Davide Cattano

Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain.

Drugs that block N-methyl-d-aspartate glutamate receptors or that promote &ggr;-aminobutyric acid type A inhibition trigger neuroapoptosis in the developing rodent brain. Propofol reportedly interacts with both &ggr;-aminobutyric acid type A and N-methyl-d-aspartate glutamate receptors, but has not been adequately evaluated for its ability to induce developmental neuroapoptosis. Here we determined that the intraperitoneal (i.p.) dose of propofol required to induce a surgical plane of anesthesia in the infant mouse is 200 mg/kg. We then administered graduated doses of propofol (25–300 mg/kg i.p.) and found that doses ≥50 mg/kg induce a significant neuroapoptosis response. We conclude that propofol induces neuroapoptosis at 1/4 the dose required for surgical anesthesia.

Lithium protects against anesthesia-induced developmental neuroapoptosis.

Background:Ethanol and anesthetic drugs trigger neuroapoptosis in the developing mouse brain. Recently, it was found that ethanol-induced neuroapoptosis is preceded by suppressed phosphorylation of extracellular signal-regulated protein kinase (ERK), and lithium counteracts both the phosphorylated ERK suppressant action and ethanol-induced neuroapoptosis. The current study was undertaken to address the following questions. (1) Do ketamine and propofol mimic ethanol in suppressing ERK phosphorylation? (2) If they do, does lithium prevent this suppressant action and also prevent these anesthetic drugs from triggering neuroapoptosis? Method:Postnatal day 5 mice were treated with propofol, ketamine, lithium, a combination of propofol or ketamine with lithium or saline, and their brains were prepared for Western blot analysis or histology. For Western blot, cytosolic lysates of caudate putamen were analyzed for expression of phosphorylated ERK and phosphorylated serine/threonine-specific protein kinase. For histology, brains were stained immunohistochemically with antibodies to activated caspase-3, and the density of activated caspase-3 positive cells was determined. Results:Ketamine and propofol suppressed phosphorylated ERK, and lithium counteracted both the phosphorylated ERK suppressant action and neuroapoptotic action of these anesthetic drugs. Conclusion:If further testing finds lithium to be safe for use in pediatric/obstetric medicine, administration of a single dose of lithium before anesthesia induction may be a suitable means of mitigating the risk of anesthesia-induced developmental neuroapoptosis.

Risk factors assessment of the difficult airway: An Italian survey of 1956 patients

Over the last decade, there has been a heightened awareness and an increase in the amount of literature being published on recognition and prediction of the difficult airway. During the preoperative evaluation of the airway, a thorough history and physical specifically related to the airway should be performed. Various measurements of anatomic features and noninvasive clinical tests can be performed to enhance this assessment. In this study we correlated the Mallampati modified score and several other indexes with the laryngoscopic view to identify anatomical and clinical risk factors related to the difficult airway. We prospectively collected data on 1956 consecutive patients scheduled to receive general anesthesia requiring endotracheal intubation for elective surgery. The Mallampati classification versus the Cormack-Lehane (C-L) linear correlation index was 0.904. A Mallampati Class 3 correlated with a C-L Grade 2 (0.94), whereas a Mallampati Class 4 correlated with a C-L Grade 3 (0.85) and a C-L Grade 4 (0.80). Operator evaluation, performed by a simplified tracheal intubation difficulty scale, showed a linear correlation of 0.96 compared with the C-L groups. Although there is a correlation between oropharyngeal volume and difficult intubation, the Mallampati score by itself is insufficient for predicting difficult endotracheal intubation.

Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain

Purpose: Drugs that suppress neuronal activity, including all general anesthetics that have been tested thus far (ketamine, midazolam, isoflurane, propofol, and a cocktail of midazolam, nitrous oxide and isoflurane), trigger neuroapoptosis in the developing rodent brain. Combinations of nitrous oxide and isoflurane, or ketamine and propofol, cause more severe neuroapoptosis than any single agent by itself, which suggests a positive correlation between increased levels of anesthesia and increased severity of neuroapoptosis. In contrast, there is evidence that the rare gas, xenon, which has anesthetic properties, protects against isoflurane-induced neuroapoptosis in the infant rat brain, while not inducing neuroapoptosis by itself. The present study was undertaken to evaluate the potential of xenon to induce neuroapoptosis or to protect against neuroapoptosis induced by isoflurane in the infant mouse brain.Methods: Seven-day-old C57BL/6 mice were exposed to one of four conditions: air (control); 0.75% isoflurane; 70% xenon; or 0.75% isoflurane +70% xenon for four hours. For histopathological evaluation of the brains, all pups were euthanized two hours later using activated caspase-3 immunohistochemical staining to detect apoptotic neurons. Under each condition, quantitative assessment of the number of apoptotic neurons in the cerebral cortex (CC) and in the caudate/putamen (C/P) was performed by unbiased stereology.Results: The combination of xenon + isoflurane produced a deeper level of anesthesia than either agent alone. Both xenon alone (p<0.003 in CC;p<0.02 in C/P) and isoflurane alone (p<0.001 in both CC and C/P) induced a significant increase in neuroapoptosis compared to controls. The neuroapoptotic response to isoflurane was substantially more robust than the response to xenon. When xenon was administered together with isoflurane, the apoptotic response was reduced to a level lower than that for isoflurane alone (p<0.01 in CP; marginally non-significant in CC).Conclusions: We conclude that xenon, in the infant mouse brain, has paradoxical properties. It triggers neuroapoptosis, and when combined with isoflurane, it increases the depth of anesthesia, and retains its own apoptogenic activity. However, it suppresses, rather than augments, isoflurane’s apoptogenic activity.RésuméObjectif: Les médicaments supprimant l’activité neuronale, y compris tous les anesthésiants généraux testés jusqu’à présent (kétamine, midazolam, isoflurane, propofol, et un cocktail de midazolam, de protoxyde d’azote et d’isoflurane) déclenchent la neuroapoptose dans le cerveau en développement des rongeurs. Des combinaisons de protoxyde d’azote de d’isoflurane, ou de kétamine et de propofol, provoquent une neuroapoptose plus grave que n’importe quel agent administré seul, ce qui suggère une corrélation positive entre des niveaux plus élevés d’anesthésie et une neuroapoptose plus grave. En revanche, il existe des données soutenant que le xénon, un gaz rare qui présente des propriétés anesthésiques, protège de la neuroapoptose induite par l’isoflurane dans le cerveau de rongeurs nourrissons, alors que seul, il n’induit pas de neuroapoptose. Cette étude a été menée dans le but d’évaluer le potentiel du xénon pour induire la neuroapoptose ou de protéger contre la neuroapoptose provoquée par l’isoflurance dans le cerveau de rongeurs nourrissons.Méthode: Des souris C57BL/6 de sept jours ont été exposées à un de quatre états : air (témoin) ; 0,75 % isoflurane ; 70 % xénon ; ou 0,75 % isoflurane + 70 % xénon pendant quatre heures. Afin de réaliser une évaluation histopathologique du cerveau, tous les petits ont été euthanasiés deux heures plus tard à l’aide d’une technique de coloration immunohistochimique de caspase-3 activée pour permettre de détecter les neurones apoptotiques. Dans chaque état, une évaluation quantitative du nombre de neurones apoptotiques dans le cortex cérébral (CC) et dans le noyau caudé / putamen (C/P) a été réalisée par stéréologie non biaisée.Résultats: La combinaison de xénon + isoflurane a provoqué un niveau d’anesthésie plus profond que lorsque les agents ont été administrés seuls. Le xénon seul (p<0,003 dans CC; p<0,02 dans C/P) et l’isoflurane seul (p<0,001 dans le CC et le C/P) ont provoqué une augmentation significative de neuroapoptose par rapport au groupe témoin. La réaction neuroapoptotique à l’isoflurane était considérablement plus puissante que la réaction au xénon. Lorsque le xénon a été administré avec l’isoflurane, la réaction apoptotique a diminué à un niveau plus bas que celui de l’isoflurane seul (p<0,01 dans CP; marginalement non significatif dans CC).Conclusion: Nous concluons que le xénon, dans le cerveau de rongeurs nourrissons, possède des propriétés paradoxales. Il déclenche la neuroapoptose et, lorsqu’il est combiné à l’isoflurane, approfondit l’anesthésie, et retient sa propre activié apoptogène. Toutefois il supprime plutôt qu’augmente l’activité apoptogène de l’isoflurane.

Morphological evidence that xenon neuroprotects against N-methyl-DL-aspartic acid-induced damage in the rat arcuate nucleus: a time-dependent study.

Abstract:u2002 The hyperactivation of glutamate receptors, especially those of the N‐methyl‐d‐aspartate subtype (NMDA), can induce excess calcium entry into cells, leading to neuronal death. Since the anesthetic gas xenon behaves as an NMDA antagonist, the present article investigated, by distinct morphological approaches and after different times, the possible neuroprotectant effects of this gas in a model of neuronal damage induced by N‐methyl‐dl‐aspartic acid (NMA) on rat arcuate nucleus. Rats were assigned to the following groups: controls; xenon exposure; NMA treatment; or xenon exposure + NMA treatment. Animals were placed in an experimental cage and after 10 min a mixture of xenon (or nitrogen) 70% and oxygen 30% was delivered. After 3 h, 1, 2, 5, or 7 days from gas exposure, rats were euthanized and the whole brain was removed and processed for either transmission electron microscopy or light microscopy. In the arcuate nucleus from NMA‐treated animals only 40–60% of cell population survived in all times with several degenerating neurons giving the typical appearance of a “bulls eye.” At ultrastructural level, chromatin margination, nuclear shrinkage, mitochondria with matrix dilution, dilated endoplasmic cisternae, and electrondense cytoplasm were detected. Xenon alone did not induce changes, but reduced of about 50% NMA‐induced cell loss as well as degenerating neurons, with the maximal neuroprotection at 7 days. These results confirm that in the rat arcuate nucleus NMA can induce a severe neuronal damage that is already marked after 3 h. Xenon significantly reduced the neuronal damage at all times and can be then regarded as a promising neuroprotectant agent.

Xenon induces transcription of ADNP in neonatal rat brain

Xenon and other inhalational agents induce cell and organ protection through different and only partially elucidated molecular mechanisms. Anesthesia induced or pharmacologic preconditioning is a recognized mechanism of cell protection. In this study we explored the gene transcription of activity-dependent neuroprotective protein (ADNP) in neonatal rat brain as consequence to xenon exposure, comparing the noble gas to nitrogen. Seven-day-old Sprague Dawley rats were exposed for 120 min to 75% xenon and 25% oxygen or control condition consisting of 75% nitrogen and 25% oxygen (Air). ADNP was found to be differentially expressed by SSH, validated by Relative Real-Time PCR (RT-PCR) and confirmed by western blot and immunohistochemistry. The differential expression of ADNP in the rat neonatal brain may account for the preconditioning and neuroprotective effects exerted by gas xenon.

The use of the laryngeal mask airway during guidewire dilating forceps tracheostomy

Percutaneous tracheostomy has become a common alternative to the classical open tracheostomy because of its convenience, cost effectiveness, and decreased complication rates. We retrospectively reviewed our intensive care practice using a guidewire dilatating forceps percutaneous tracheostomy technique with an endotracheal tube, as compared with the Classic Laryngeal Mask Airway (LMA) for these procedures. From 1998 to 2004, 274 patients underwent a tracheostomy procedure. Two-hundred-fifty-four (92.7%) of these patients underwent a guidewire dilatating forceps tracheostomy and 20 (7.3%) underwent a surgical tracheostomy. In the guidewire dilatating forceps group, 188 (74%) were performed by endoscopy via LMA-guided bronchoscopy, and 66 (26%) were performed through an endotracheal tube. Endoscopic views obtained via the LMA were subjectively better than those obtained with the endotracheal tube. Acute complications were significantly more frequent when using an endotracheal tube as compared with the LMA (6 of 66 versus 4 of 188; P = 0.022 Fishers exact test, odds ratio = 4.6). There was a significant difference in terms of acute (10 of 254 versus 6 of 20; P < 0.001, odds ratio = 10.5) and chronic (0 of 254 versus 4 of 20; P < 0.001) complications between the 2 groups. There were no ventilatory complications or reports of gastric aspiration. The LMA provides a safe and effective alternative to an endotracheal tube for airway management during guidewire dilatating forceps tracheostomies in selected patients.

Percutaneous tracheostomy: prospective practice

1 Gale TCE, Roberts MJ, Sice PJ, et al. Predictive validity of a selection centre testing non-technical skills for recruitment to training in anaesthesia. Br J Anaesth 2010; 105: 603–9 2 Weller JM, Jolly B, Misur MP, et al. Mini-clinical evaluation exercise in anaesthesia training. Br J Anaesth 2009; 102: 633–41 3 Available from http://www.rcoa.ac.uk/docs/A-CEX-Apr2010.doc (accessed November 15, 2010)