General anesthetics and long-term neurotoxicity

We do not know how general anesthetics cause their desired effects. Contrary to what has been thought until relatively recently, the clinical state of anesthesia consists of multiple components that are mediated via interaction of the anesthetic drugs with different targets on the molecular-cellular, the network, and the structural-anatomical levels. The molecular targets by which some of these drugs induce the different components of "anesthesia" may be rather specific: discrete mutations of single amino acids in specific proteins profoundly affect the ability of certain anesthetics to achieve specific endpoints. Despite this potential specificity, inhalational anesthetics are present in the body at very high concentrations during surgical anesthesia. Due to their lipid solubility, general anesthetics dissolve in every membrane, penetrate into every organelle, and can interact with numerous cellular structures in multiple ways. A priori, it is therefore not unreasonable to assume that these drugs have the potential to cause insidious changes in the body other than those acute and readily apparent ones that we routinely monitor. Some changes may wane within a short time after removal of the drug (e.g., the suppression of immune cell function). Others may persist after complete removal of the drug and even become self-propagating [e.g., beta-oligomerization of proteins (Eckenhoff et al. 2004)], still others may be irreversible [e.g., the induction of apoptosis in the CNS (Jevtovic-Todorovic et al. 2003)] but of unclear significance. This article will focus on evidence for anesthetic toxicity in the central nervous system (CNS). The CNS appears to be susceptible to anesthetic neurotoxicity primarily at the extremes of ages, possibly via different pathways: in the neonate, during the period of most intense synaptogenesis, anesthetics can induce excessive apoptosis; in the aging CNS subtle cognitive dysfunction can persist long after clearance of the drug, and processes reminiscent of neurodegenerative disorders may be accelerated (Eckenhoff et al. 2004). At all ages, anesthetics affect gene expression-regulating protein synthesis in poorly understood ways. While it seems reasonable to assume that the vast majority of our patients completely restore homeostasis after general anesthesia, it is also time to acknowledge that exposure to these drugs has more profound and longer lasting effects on the brain than heretofore imagined.     

Effects on synaptic inhibition in the hippocampus do not underlie the amnestic and convulsive properties of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane

BACKGROUND: Although it does not suppress movement in response to noxious stimuli, the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6, also known as 2N) does cause amnesia and seizures. These occur at 0.48 and 1.3 times, respectively, the concentrations that are predicted from its lipid solubility to cause immobility. The molecular and cellular basis of these effects is not known. The ionotropic gamma-aminobutyric acid type A (GABAA) receptor is modulated strongly by anesthetics, and it plays an important role in many seizure models. Also, the hippocampus is a structure central to the formation of memory and is susceptible to seizure generation. The authors therefore investigated the effect of F6 on GABAA receptor- mediated inhibition in hippocampal neurons. METHODS: Transverse hippocampal slices were prepared from young (12- to 21-day-old) Sprague-Dawley rats. Inhibitory postsynaptic currents were recorded from hippocampal CA1 pyramidal cells in the presence of ionotropic glutamate receptor antagonists. F6 was applied with the bath solution. The concentration of F6 achieved during the experiment at the location of synaptic inhibition was derived using a diffusion model. RESULTS: At tissue concentrations of up to 75 microm (approximately 5 x predicted minimal alveolar concentration), F6 had no discernible effect on either the amplitude or the kinetics of GABA-mediated synaptic currents. Isoflurane, by contrast, prolonged the decay time constant of these currents at 100 microm (approximately 0.3 x minimal alveolar concentration). CONCLUSIONS: At concentrations that bracket the in vivo amnestic and seizure-inducing range, F6 has no discernible effect on fast synaptic GABAA receptors in hippocampal CA1 pyramidal neurons. Synaptic GABAA receptors sharply discriminate between volatile anesthetics and a prototype nonimmobilizer. Similar in vivo effects of anesthetics and nonimmobilizers may be mediated by different cellular mechanisms.     

Aeromonas hydrophila myonecrosis accompanying mucormycosis five years after bone marrow transplantation

A 36-year-old man, five years after bone marrow transplantation for aplastic anemia, was admitted with myonecrosis of the forearm after he had immersed his hand in sewage water several days prior to his admission. Blood cultures and specimens taken from the necrotic tissue of the arm all grewAeromonas hydrophila. Following extension of the infection, the patient underwent amputation of the arm but ultimately died of cerebral mucormycosis. The epidemiology ofAeromonas infections is discussed and the literature ofAeromonas myonecrosis is reviewed.     

Effect of haemofiltration on pathological fibrinolysis due to severe sepsis: a case report.

Bleeding due to coagulopathy is a frequent complication of severe sepsis, especially in burn patients. The primary treatment is aimed at the underlying cause but additional supportive measures, consisting mainly of coagulation factor replacement, are frequently necessary. We describe the salutary effect of continuous veno-venous haemofiltration (CVVH) with predilution on diffuse haemorrhage in a patient with severe septic shock and renal failure. The diffuse haemorrhage was initially treated with replacement of coagulation factors. Prothrombin time and partial thromboplastin time became normal while diffuse bleeding continued and the thrombelastogram showed evidence of fibrinolysis. A short period of CVVH lead to the cessation of bleeding which was reflected by a normal thrombelastogram.     

Is GABA release modulated by presynaptic excitatory amino acid receptors?

The purely GABAergic nature of spontaneous synaptic activity in cultures from the neonatal rat superior colliculus (SC) is of great advantage in investigations aimed at characterizing presynaptic factors regulating GABAergic synaptic transmission. Using SC-derived cultures it was confirmed that excitatory amino acids (EAA) can induce a marked increase in the frequency of spontaneous synaptic Cl- currents (ICl(GABA)SYN). However, this tetrodotoxin-resistant facilitation of Ca2(+)-dependent GABA release required application of EEA to several neurons (multiple cell superfusion). In contrast, no frequency increase of Icl(GABA)SYN was seen with restricted access of EAA to only one neuron and the presynaptic axonal terminals (single cell superfusion). It is therefore concluded that the strong facilitatory effect of glutamate (Glu) and kainate (KA) on GABAergic synaptic activity, as observed under the condition of multiple cell superfusion, is mediated via somatodendritic excitatory amino acid receptors (EAARs).     

The Quest for a Unified Model of Anesthetic Action: A Century in Claude Bernard's Shadow

An accepted truism among clinicians and researchers attributes the persistence of the quest for a unitary mechanism of anesthetic action to the lasting influence of Hans Meyer and Ernest Overton. This article presents a different view: the experiments that led to the Meyer-Overton rule were the consequence-not the source-of a unitary paradigm that was formulated by Claude Bernard a quarter of a century earlier. Bernard firmly believed that the sensitivity to anesthesia was a fundamental criterion that separated 'true life' from 'mere chemistry.' Bernard's scientific authority in the context of 19 century natural philosophy is responsible for establishing a unified (i.e., unitary mechanism and universality across life forms) paradigm of anesthetic action. Meyer and Overton's work was targeted at systematizing and solidifying existing knowledge within this paradigm, not at discovering novelty, and its publication did not substantially affect contemporary research. Claude Bernard's paradigm, by contrast, still influences investigations of mechanisms of anesthetic action.     

Separation of quisqualate- and kainate-selective glutamate receptors in cultured neurons from the rat superior colliculus

The aim of the present study was to identify and characterize the receptors and ionic channels mediating the compound response of tectal neurons to exogenous L-glutamate (Glu). Particular attention was paid to the question of whether separate receptors and channels exist for quisqualate (QA) and kainate (KA) and, if so, whether binding to one of these receptors would modify the response elicited through the other. Neurons were dissociated from the superficial gray layer of the superior colliculus from E21 or P1 rats. Between days 14 and 21 in vitro, responsiveness of tectal neurons to Glu and related substances was tested by recording the whole-cell currents induced by rapid superfusion with drug-containing salt solutions. Our experiments showed that tectal neurons express at least 3 distinct types of receptors for acidic amino acids. KA-activated currents (I(KA)) differ from QA-activated currents (I(QA)) in their dose-response characteristics, desensitization patterns, selective blockade with kynurenic acid and suppression by elevated [Ca2+]o, I(KA), but not I(QA), is significantly reduced by low levels of [Cl-]o, and the [Cl-]o-dependent shift of the reversal potential for I(KA) suggests that KA promotes a conductance decrease for Cl-. Such an effect has been ascribed to APB-receptors, but L-2-amino-4-phosphonobutyrate (APB) itself failed to induce current responses in tectal neurons. KA was without effect when administered together, and in equimolar concentrations, with QA. The block of I(KA) was, however, surmounted by applying KA at considerably higher concentrations. It is concluded that QA acts as a low-affinity competitive antagonist at the KA site and as a high-affinity agonist at its own receptor. The response to the endogenous ligand Glu reflects properties of all receptors. QA and KA receptors account for 20-30% (QA) and 49-82% (KA) of the compound current elicited with 100 microM Glu. These results indicate that binding of Glu does not, in contrast to QA, produce any significant suppression of the KA-receptor-mediated current component.