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PubMed2005

Comparative efficacy and costs of various topical anesthetics for repair of dermal lacerations: a systematic review of randomized, controlled trials.

STUDY OBJECTIVES: To compare the efficacy of infiltrated local anesthesia with topical anesthesia for repair of dermal laceration, to analyze the efficacy of single or multicomponent topical anesthetics, and to identify topical formulations that are potentially less costly and equally efficacious as cocaine-containing topical anesthetics. DESIGN: Systematic review of randomized controlled trials. SETTING: University-affiliated hospital. PATIENTS: Pediatric and adult subjects. MEASUREMENTS AND MAIN RESULTS: Twenty-two trials that randomized more than 3000 patients were identified. The majority of studies demonstrated equivalent or superior analgesic efficacy for topical formulations compared with conventional intradermal infiltration. We found that cocaine is not a mandatory component of topical anesthesia. The literature discloses no significant difference in anesthetic efficacy between topical tetracaine-epinephrine-cocaine and each of the following 6 cocaine-free formulations: lidocaine-epinephrine-tetracaine, lidocaine-epinephrine, tetracaine-phenylephrine, tetracaine-lidocaine-phenylephrine, bupivicaine-norepinephrine, or prilocaine-phenylephrine. CONCLUSION: Topical anesthetics are an efficacious, noninvasive means of providing analgesia before suturing of dermal lacerations. The use of cocaine-containing topical anesthetics can no longer be justified in light of its high cost and potential adverse effects. We have summarized the evidence, mostly favorable, supporting the use of various non-cocaine-containing topical anesthetics.

Anesthetics, Local↗

PubMed1992

Interactive effects of volatile anesthetics, verapamil, and ryanodine on contractility and calcium homeostasis of isolated pregnant rat myometrium.

OBJECTIVE: Both volatile anesthetics and Ca2+ antagonists decrease uterine contractility. The interactive effects of anesthetics, verapamil, and ryanodine on myometrial muscular activity and on intracellular Ca2+ availability were examined. STUDY DESIGN: The effects of minimum alveolar concentrations of 0.5, 1.0, and 2.0 of halothane, enflurane, and isoflurane on electrically stimulated isometric mechanical activity of isolated longitudinal myometrium strips from 45 pregnant rats (15 to 21 days), superfused with Krebs' solution with or without 5.0 mmol/L Ca2+, 10(-7) and 10(-6) mol/L verapamil, and 10(-6) mol/L ryanodine, were compared. Analysis was performed by analysis of variance and Duncan test. RESULTS: All three anesthetics and verapamil produced dose-dependent depression of contractility. Increasing the Ca2+ concentration from 2.5 to 5.0 mmol/L in the superfusate partly reversed the depression. An additive effect of verapamil and anesthetics, especially enflurane, on contractile force was observed. Ryanodine had no effect on contractility, but it could partly counteract the depressant effect of anesthetics. CONCLUSION: Clinically used concentrations of volatile anesthetics modify Ca2+ availability and depress uterine contractility. General anesthesia, especially by enflurane, in patients being treated with calcium antagonists may represent a higher risk.

Anesthetics↗

PubMed2000

The quantitative analysis of three action modes of volatile anesthetics on purple membrane.

We quantitatively assessed the spectroscopic changes of purple membrane in relation to the concentrations of a volatile anesthetic. As reported previously, volatile anesthetics show three modes of action on purple membrane. By using an anesthetic for which the concentration in solution could be determined spectroscopically and by applying modified analytical methods regarding the M-intermediate lifetime, we were able to clarify the quantitative relation between anesthetic concentration and each mode of action, a relation which in the past has only been described qualitatively. We also determined through the measurement of transient pH changes with pyranine that the proton pump efficiency per photochemical cycle in an action mode induced with low concentrations of anesthetic does not change from that of the native state. Moreover, we dynamically obtained the individual M-bacteriorhodopsin difference spectrum of each state at room temperature using our flash photolysis system equipped with a wavelength-tunable dye laser. These results demonstrated again that we should clearly distinguish different action modes of anesthetics according to their concentrations.

Anesthetics↗

PubMed2000

General anesthetic binding to gramicidin A: the structural requirements.

There is a distinct possibility that general anesthetics exert their action on the postsynaptic receptor channels. The structural requirements for anesthetic binding in transmembrane channels, however, are largely unknown. High-resolution (1)H nuclear magnetic resonance and direct photoaffinity labeling were used in this study to characterize the volatile anesthetic binding sites in gramicidin A (gA) incorporated into sodium dodecyl sulfate (SDS) micelles and into dimyristoylphosphatidylcholine (DMPC) bilayers, respectively. To confirm that the structural arrangement of the peptide side chains can affect anesthetic binding, gA in nonchannel forms in methanol was also analyzed. The addition of volatile anesthetic halothane to gA in SDS with a channel conformation caused a concentration-dependent change in resonant frequencies of the indole amide protons of W9, W11, W13, and W15, with the most profound changes in W9. These frequency changes were observed only for gA carefully prepared to ensure a channel conformation and were absent for gA in methanol. For gA in DMPC bilayers, direct [(14)C]halothane photolabeling and microsequencing demonstrated dominant labeling of W9, less labeling of W11 and W13, and no significant labeling of W15. In methanol, gA showed much less labeling of any residues. Inspection of the 3-D structure of gA suggests that the spatial arrangements of the tryptophan residues in the channel form of gA, combined with the amphiphilic regions of lipid, create a favorable anesthetic binding motif.

Amino Acid Sequence↗

PubMed2001

Ion selectivity filter regulates local anesthetic inhibition of G-protein-gated inwardly rectifying K+ channels.

The weaver mutation (G156S) in G-protein-gated inwardly rectifying K+ (GIRK) channels alters ion selectivity and reveals sensitivity to inhibition by a charged local anesthetic, QX-314, applied extracellularly. In this paper, disrupting the ion selectivity in another GIRK channel, chimera I1G1(M), generates a GIRK channel that is also inhibited by extracellular local anesthetics. I1G1(M) is a chimera of IRK1 (G-protein-insensitive) and GIRK1 and contains the hydrophobic domains (M1-pore-loop-M2) of GIRK1 (G1(M)) with the N- and C-terminal domains of IRK1 (I1). The local anesthetic binding site in I1G1(M) is indistinguishable from that in GIRK2(wv) channels. Whereas chimera I1G1(M) loses K+ selectivity, although there are no mutations in the pore-loop complex, chimera I1G2(M), which contains the hydrophobic domain from GIRK2, exhibits normal K+ selectivity. Mutation of two amino acids that are unique in the pore-loop complex of GIRK1 (F137S and A143T) restores K+ selectivity and eliminates the inhibition by extracellular local anesthetics, suggesting that the pore-loop complex prevents QX-314 from reaching the intrapore site. Alanine mutations in the extracellular half of the M2 transmembrane domain alter QX-314 inhibition, indicating the M2 forms part of the intrapore binding site. Finally, the inhibition of G-protein-activated currents by intracellular QX-314 appears to be different from that observed in nonselective GIRK channels. The results suggest that inward rectifiers contain an intrapore-binding site for local anesthetic that is normally inaccessible from extracellular charged local anesthetics.

Anesthetics, Local↗

PubMed1997

Different distribution of fluorinated anesthetics and nonanesthetics in model membrane: a 19F NMR study.

Despite their structural resemblance, a pair of cyclic halogenated compounds, 1-chloro-1,2,2-trifluorocyclobutane (F3) and 1,2-dichlorohexafluorocyclobutane (F6), exhibit completely different anesthetic properties. Whereas the former is a potent general anesthetic, the latter produces no anesthesia. Two linear compounds, isoflurane and 2,3-dichlorooctofluorobutane (F8), although not a structural pair, also show the same anesthetic discrepancy. Using 19F nuclear magnetic spectroscopy, we investigated the time-averaged submolecular distribution of these compounds in a vesicle suspension of phosphatidylcholine lipids. A two-site exchange model was used to interpret the observed changes in resonance frequencies as a function of the solubilization of these compounds in membrane and in water. At clinically relevant concentrations, the anesthetics F3 and isoflurane distributed preferentially to regions of the membrane that permit easy contact with water. The frequency changes of these two anesthetics can be well characterized by the two-site exchange model. In contrast, the nonanesthetics F6 and F8 solubilized deeply into the lipid core, and their frequency change significantly deviated from the prediction of the model. It is concluded that although anesthetics and nonanesthetics may show similar hydrophobicity in bulk solvents such as olive oil, their distributions in various regions in biomembranes, and hence their effective concentrations at different submolecular sites, may differ significantly.

Anesthetics↗

PubMed1997

The action of local anesthetics on myelin structure and nerve conduction in toad sciatic nerve.

X-ray scattering and electrophysiological experiments were performed on toad sciatic nerves in the presence of local anesthetics. In vitro experiments were performed on dissected nerves superfused with Ringer's solutions containing procaine, lidocaine, tetracaine, or dibucaine. In vivo experiments were performed on nerves dissected from animals anesthesized by targeted injections of tetracaine-containing solutions. In all cases the anesthetics were found to have the same effects on the x-ray scattering spectra: the intensity ratio of the even-order to the odd-order reflections increases and the lattice parameter increases. These changes are reversible upon removal of the anesthetic. The magnitude of the structural changes varies with the duration of the superfusion and with the nature and concentration of the anesthetic molecule. A striking quantitative correlation was observed between the structural effects and the potency of the anesthetic. Electron density profiles, which hardly showed any structural alteration of the unit membrane, clearly indicated that the anesthetics have the effect of moving the pairs of membranes apart by increasing the thickness of the cytoplasmic space. Electrophysiological measurements performed on the very samples used in the x-ray scattering experiments showed that the amplitude of the compound action potential is affected earlier than the structure of myelin (as revealed by the x-ray scattering experiments), whereas conduction velocity closely follows the structural alterations.

Action Potentials↗

PubMed1997

Inhibitory effects of anesthetics and ethanol on muscarinic receptors expressed in Xenopus oocytes.

Anesthetics (and ethanol) are known to produce amnesia as well as immobilization. Recent identification of a nonimmobilizing (nonanesthetic) agent (F6 or 1,2-dichlorohexafluorocyclobutane) that impairs learning and memory suggests that distinct mechanisms may be responsible for these two actions of anesthetic agents. Muscarinic receptors are believed to play a role in memory and learning, and we asked if a specific subtype of these receptors is affected by anesthetics as well as the new nonanesthetic. We investigated the effects of halothane, a novel halogenated anesthetic compound F3 (1-chloro-1,2,2-trifluorocyclobutane) and ethanol on acetylcholine-induced current mediated by a muscarinic m1 receptor expressed in Xenopus oocytes. We also studied the effects of halogenated nonanesthetic compounds, F6 and F8 (2,3-chlorooctafluorobutane) on muscarinic m1 receptors. Halothane, F3, F6 and ethanol inhibited muscarinic m1 receptor-induced Ca2+-dependent Cl- currents at pharmacologically relevant concentrations. F8 had no effect on acetylcholine-induced muscarinic m1 receptor function. The protein kinase C inhibitor, bisindolylmaleimide I (GF109203X), enhanced the acetylcholine-induced current and the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), inhibited this current. GF109203X abolished the inhibitory effects of halothane, F3 and ethanol on muscarinic m1 receptors but had no effect on actions of F6. These results demonstrate that anesthetics and a nonanesthetic inhibit the function of muscarinic m1 receptors and suggest activation of protein kinase C as the mechanism of action of anesthetics and ethanol on these receptors.

Anesthetics, Inhalation↗

PubMed2002

Tryptophan scanning mutagenesis in TM4 of the GABA(A) receptor alpha1 subunit: implications for modulation by inhaled anesthetics and ion channel structure.

Previous studies have shown that amino acid residues in trans-membrane (TM) segments 1, 2 and 3 of the alpha subunit are critical for the enhancement of GABA(A) receptor function by inhaled anesthetics. In this study we used tryptophan (Trp) scanning mutagenesis between Ile 406 and Asn 417 in the alpha1 subunit to determine the effects of Trp substitution in the fourth transmembrane segment (TM4) on receptor gating and anesthetic modulation. Wild-type and mutant alpha1 subunits were transiently expressed in HEK 293 cells with wild-type beta2 and gamma2s subunits and GABA-activated currents were recorded using whole-cell voltage clamp. The potentiation by three inhaled anesthetics (isoflurane, halothane and chloroform) of responses elicited by a submaximal concentration of GABA were also examined.EC(50) values for GABA at the mutant receptors were in the range 4-60 microM (wild-type=20 microM), indicating that Trp substitution can alter the apparent affinity of the receptor for GABA positively or negatively, dependent on position. The variation of the calculated EC(50) value for GABA exhibited an interesting periodicity, with the cycle length for each repeat corresponding to approximately 3.6 amino acids. These data are consistent with an alpha-helical structure for the TM4 segment of the alpha subunit. Several of these Trp point mutations altered the ability of one or more of the three inhaled anesthetics to modulate receptor function; four of the 12 mutations abolished receptor modulation by one or more of the anesthetics tested. These data are consistent with a role for these residues at the extracellular end of TM4 in anesthetic modulation of GABA(A) receptors.

Amino Acid Sequence↗

PubMed2002

Local anesthetics for facial plastic procedures.

The use of local anesthetic in facial plastic surgical procedures is well established as an effective and safe mode of anesthesia delivery. Local infiltration of anesthesia may be used alone for minor surgical procedures, or it may be used with general anesthesia or intravenous sedation and analgesia for more complex, lengthy procedures. When considered independently, the use of local anesthetic agents has undeniable limitations. Local anesthetics can cause toxicity and side effects. Injection of local anesthetics for subcutaneous infiltration frequently is painful until sensory anesthesia occurs. Local anesthetics have limited efficacy with respect to the intensity and duration of sensory blockade that can be achieved. In some situations, use of local anesthesia with the maintenance of an awake patient also may be undesirable for the surgeon and impractical for the patient. Despite these shortcomings, local anesthetics are fundamentally ideal for use in facial plastic surgery.

Anesthetics, Local↗

PubMed1995

Intranasal anesthetic effects of lidocaine and tetracaine compared.

The quality of nasal anesthesia obtained with two local anesthetic solutions (2% lidocaine in oxymetazoline and 1% tetracaine in oxymetazoline) was evaluated in this double-blind, randomized study. Each local anesthetic mixture was applied to the nasal septum of healthy volunteers with medication-soaked pledgets. Measurements of anesthetic effect (sensation threshold and pain perception) were made with Semmes-Weinstein monofilaments (North Coast Medical, San Jose, Calif.). Measurements were performed before local anesthetic application and at 10 and 70 minutes after local anesthetic application. Subjects had greater increases in sensation threshold with tetracaine than with lidocaine at both 10 and 70 minutes (p = 0.0005 and p = 0.0001, respectively). Subjects had greater decreases in pain perception with tetracaine than with lidocaine at both time intervals (p = 0.0003 and p < 0.0001, respectively). Tetracaine mixed with oxymetazoline appears to be a superior topical anesthetic for nasal procedures.

Administration, Intranasal↗

PubMed1997

The relationship among brain, spinal cord and anesthetic requirements.

The spinal cord is a crucial site wherein anesthetics suppress movement in response to noxious stimuli. The balance of excitatory and inhibitory influences on the spinal cord likely determines the extent of motor response, and is thus important to anesthetic requirements. When the volatile anesthetic isoflurane is selectively delivered to the in situ goat brain (with low concentrations in the torso), anesthetic requirements increase dramatically, but when low isoflurane concentrations are delivered to the brain, anesthetic requirements decrease in the torso. When high, supraclinical concentrations of isoflurane (6-10%) are delivered to the brain and not to the torso, spontaneous movement occurs. These results are best explained by a differential effect of anesthetics on spinal cord neurons and cerebral neurons (midbrain reticular formation). Examination of neurons in the dorsal horn and midbrain reticular formation, and the electromyogram, during differential delivery of isoflurane to brain and spinal cord, will test this hypothesis.

Anesthesia, General↗

PubMed1998

Macroscopic sites of anesthetic action: brain versus spinal cord.

1. General anesthesia is achieved by anesthetic action in the central nervous system (CNS). 2. Whereas amnesia and unconsciousness are due to anesthetic action in the brain, recent evidence suggests that immobility in response to a noxious stimulus is achieved by anesthetic effects in the spinal cord. The putative spinal cord site(s) include dorsal horn cells and motor neurons. 3. The extent to which anesthetic action in the brain influences the spinal cord probably varies among anesthetics. Furthermore, anesthetics can indirectly influence the brain by their actions within the spinal cord, i.e. by modulating ascending transmission of sensory information.

Anesthesia↗

PubMed2001

Simultaneous determination of fluorinated inhalation anesthetics in blood by gas chromatography-mass spectrometry combined with a headspace autosampler.

Although the fluorinated inhalation anesthetics, including desflurane, sevoflurane, isoflurane, enflurane, and halothane are commonly used, fatal cases resulting from their abuse or misuse have been reported. To date, gas chromatography (GC) equipped with different kinds of detectors has been utilized to analyze inhalation anesthetics. However, none of them can detect desflurane reliably or analyze all five common anesthetics simultaneously. The purpose of the present work is to further modify the previously developed headspace (HS) GC-MS method for blood isoflurane determination to analyze and distinguish five common clinical inhalation anesthetics, simultaneously. The modified HS-GC-MS method adopts a 60 m x 0.25 mm I.D., 0.25 microm film thickness DB-5 capillary column along with an adequate GC temperature program, which gives the five inhalation anesthetics, including isoflurane and its isomer, enflurane, a high resolution. The method also takes both the volatility and the influence of the top space on the obtained concentration into consideration and therefore keeps the sample loss acceptable even for analyzing the highly volatile desflurane. Within a certain concentration range of the calibration standard (about 20-300 microg/ml), this method shows a good linearity with correlation coefficients greater than 0.999. In addition, both within- and between-run precision and accuracy results meet the validation requirements as well as the tested results of practical blood samples of desflurane. In summary, this is a reliable analytical method to simultaneously determine the concentration of five common inhalation anesthetics in blood. Such a method is very practical for both clinical and occupational monitoring, as well as for analytical toxicology.

Anesthetics, Inhalation↗

PubMed2000

Relationship between potency and boiling point of general anesthetics: a thermodynamic consideration.

The most important group of nonspecific drugs is that of the general anesthetics. These nonspecific compounds vary greatly in structure, from noble gases such as Ar or Xe to complex steroids. Since the development of clinical anesthesia over a century ago, there has been a vast amount of research and speculation concerning the mechanism of action of general anesthetics. Despite these efforts, the exact mechanism remains unknown. Many theories of narcosis do not explain how unconsciousness is produced at a molecular level, but instead relate some physicochemical property of anesthetic agents to their anesthetic potencies. In this paper, we address some of those physicochemical properties, with more emphasis on correlating the anesthetic potency of volatile anesthetics to their boiling points based on thermodynamic principles.

Anesthetics, General↗

PubMed1997

The effects of intravenous anesthetics on intracranial pressure and cerebral perfusion pressure in two feline models of brain edema.

PURPOSE: The purpose of this study was to investigate the effects of various intravenous anesthetics on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in two models of brain edema in a prospective study in a Pediatric critical care animal laboratory in a university hospital. MATERIALS AND METHODS: Intraparenchymal ICP monitors were inserted in 30 anesthetized adult cats. In 15 cats, an intraparenchymal balloon-tipped catheter was placed and inflated to create a space-occupying lesion (SOL) to mimic vasogenic brain edema (VBE). In the other 15 cats, cytotoxic brain edema (CBE) was created by an acute reduction in blood osmolality. We used continuous hemodiafiltration (CAVH-D) and replaced the ultrafiltrate with hypotonic solution to maintain euvolemia. At predetermined points, each cat in each model received multiple intravenous (i.v.) injections of one of the following medications: methohexital 1.5 mg/kg, propofol 2 mg/kg, or ketamine 2 mg/kg. ICP and mean arterial pressure (MAP) were continuously monitored in all animals. RESULTS: In the SOL model, all three anesthetic agents decreased ICP after each administration (P < .05). Ketamine administration also resulted in an increase in CPP in this model (P < .05). In the CBE model, none of these agents resulted in a significant change in either ICP or CPP. CONCLUSIONS: Our results indicate that i.v. anesthetics decrease ICP caused by SOL but have no significant effect on ICP due to CBE. We postulate that in the SOL model, and similarly in VBE, some brain tissue is viable and remains responsive to anesthetics. In contrast, in the CBE model, diffuse intracellular damage occurs, the cerebral metabolic rate may be severely depressed, autoregulation of the cerebral vasculature may be impaired, and unresponsiveness to i.v. anesthetics may occur.

Analysis of Variance↗

PubMed1997

Drug interactions: volatile anesthetics and opioids.

Multiple drugs are used to provide anesthesia. Volatile anesthetics are commonly combined with opioids. Several studies have demonstrated that small doses of opioid (i.e., within the analgesic range) result in a marked reduction in minimum alveolar concentration (MAC) of the volatile anesthetic that will prevent purposeful movement in 50% of patients at skin incision). Further increases in opioid dose provide only a further small reduction in MAC. Thus, a ceiling effect of the opioid is observed at a MAC value of the volatile anesthetic equal to its MAC awake. Recovery from anesthesia when an opioid is combined with a volatile anesthetic is dependent on the rate of decrease of both drugs to their respective concentrations that are associated with adequate spontaneous ventilation and awakening. Through an understanding of the pharmacodynamic interaction of volatile anesthetics with opioids and the pharmacokinetic processes responsible for the recovery from drug effect, optimal dosing schemes can thus be developed. A review of these pharmacodynamic and pharmacokinetic principles that will allow clinicians to administer drugs to provide a more optimal anesthetic is provided.

Alfentanil↗

PubMed2002

Role of aromatic side chains in the binding of volatile general anesthetics to a four-alpha-helix bundle.

Currently, the mechanism by which anesthesia occurs is thought to involve the direct binding of inhaled anesthetics to ligand-gated ion channels. This hypothesis is being studied using four-alpha-helix bundles as model systems for the transmembrane domains of the natural "receptor" proteins. This study concerns the role in anesthetic binding played by aromatic side chains in the binding cavity of a four-alpha-helix bundle designed to assume a Rop-like fold. Specifically, the effect of the substitution W15Y on bundle structure, stability, and anesthetic binding energetics was investigated. No appreciable effect of substituting W for Y on the secondary structure or the thermodynamic stability of the four-alpha-helix bundle was identified. However, the substitution W15Y resulted in about 6- and 3-fold decreases in halothane and chloroform binding affinities, respectively. This effect may reflect weaker dipole-aromatic quadrupole interactions between the aromatic side chain and the anesthetic in the tyrosine-containing species, which possesses the smaller aromatic ring system. For these anesthetic binding proteins, this class of interaction occurs when the permanent nonspherical distribution of electrons in the aromatic ring systems interact with the weakly acidic CH group of the anesthetics.

Anesthetics, General↗