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PubMed2002

Benefit and risks of local anesthetics in infants and children.

Regional anesthesia has become a routine part of the practice of anesthesiology in infants and children. Local anesthetic toxicity is extremely rare in infants and children; however, seizures, dysrhythmias, cardiovascular collapse, and transient neuropathic symptoms have been reported. Infants and children may be at increased risk from local anesthetics compared with adults. Larger volumes of local anesthetics are used for epidural anesthesia in infants and children than in adults. Metabolism and elimination of local anesthetics can be delayed in neonates, who also have decreased plasma concentrations of alpha(1)-acid glycoprotein, leading to increased concentrations of unbound bupivacaine. Most regional anesthetic procedures in infants and children are performed with the patient heavily sedated or anesthetized; because of this, and because a test dose is not a particularly sensitive marker of intravenous injection in the anesthetized patient, detection of intravascular local anesthetic injection is extremely difficult. The same local anesthetics used in adult anesthetic practice are also used in infants and children. Because of its extremely short duration of action, chloroprocaine has been used primarily for continuous epidural techniques in infants and children. The use of tetracaine has generally been limited to spinal and topical anesthesia. Lidocaine (lignocaine) has been used extensively in infants and children for topical, regional, plexus, epidural and spinal anesthesia. The association between prilocaine and methemoglobinemia has generally restricted prilocaine use in infants and children to the eutectic mixture of local anesthetics (EMLA). Because of its greater degree of motor block compared with other long-acting local anesthetics, etidocaine has generally been limited to plexus blocks in infants and children. Mepivacaine has been used for both plexus and epidural anesthesia in infants and children. Because postoperative analgesia is often the primary justification for regional anesthesia in infants and children, bupivacaine, a long-acting local anesthetic, is the most commonly reported local anesthetic for pediatric regional anesthesia. Given the lower toxic threshold of bupivacaine compared with other local anesthetics, the risk-benefit ratio of bupivacaine may be greater than that of other local anesthetics. Two new enantiomerically pure local anesthetics, ropivacaine and levobupivacaine, offer clinical profiles comparable to that of bupivacaine but without its lower toxic threshold. The extreme rarity of major toxicity from local anesthetics suggests that widespread replacement of bupivacaine with ropivacaine or levobupivacaine is probably not necessary. However, there are clinical situations, including prolonged local anesthetic infusions, use in neonates, impaired hepatic metabolic function, and anesthetic techniques requiring a large mass of local anesthetic, where replacement of bupivacaine with ropivacaine, levobupivacaine or (for continuous techniques) chloroprocaine appears prudent.

Anesthesia, Conduction↗
PubMed1994

Local anesthetics destabilize lipid membranes by breaking hydration shell: infrared and calorimetry studies.

Differential scanning calorimetry (DSC) showed that local anesthetics decreased the pretransition (L beta'-->P beta') temperature of dipalmitoylphosphatidylcholine (DPPC) vesicle membranes four- to five-fold more than the main transition (P beta'-->L alpha) temperature. Because pretransition is mainly a change in the hydrophilic head property (tilted-rippled), the stronger effect on the pretransition suggests that the primary action site of local anesthetics is the lipid-water interface. The interfacial effect was analyzed by Fourier-transform infrared spectroscopy (FTIR) in water-in-oil (CCl4) reversed micelles. FTIR showed that the local anesthetics released hydrogen-bonded water molecules from the phosphate (P = O bands) and glycerol (sn-2 C = O) moieties. The N-H stretching band of the local anesthetics was deconvoluted into two bands: hydrogen bonded to the phosphate moiety of the lipid and free (unbound to lipid). The formation constants between lipid P = O and anesthetic N-H were estimated in CCl4 from the spectral changes: 110 M-1 for lidocaine and 250 M-1 for dibucaine. This small difference in the formation constants cannot explain the ten-fold stronger effect on the phase-transition temperature of dibucaine over lidocaine. By comparing the local anesthetic adsorption to the air/water interface in the presence and absence of lipid monolayers, we have previously shown (Lin et al. (1980) Biochim. Biophys. Acta 598, 51-65) that lipid-anesthetics interaction involves three forces: lipophilic effect, hydrophobic effect, and anesthetic-anesthetic interaction. The anesthetic potency depends mainly on the hydrophobic effect (the difference in the standard molar free energies of local anesthetics in water and at the interface) and anesthetic-anesthetic interaction energy. The anesthetic-anesthetic interaction means cooperativity of local anesthetics for the interfacial density: local anesthetics condense at the membrane surface when there are enough anesthetic molecules present at the interface to attract more anesthetics. The present data suggest that anesthetic action is directed to the interface between water and macromolecule, whether it is lipid membranes or proteins.

Anesthetics, Local↗
PubMed2006

Interactions of anesthetics with their targets: non-specific, specific or both?

What makes a general anesthetic a general anesthetic? We shall review first what general anesthesia is all about and which drugs are being used as anesthetics. There is neither a unique definition of general anesthesia nor any consensus on how to measure it. Diverse drugs and combinations of drugs generate general anesthetic states of sometimes very different clinical quality. Yet the principal drugs are still considered to belong to the same class of 'general anesthetics'. Effective concentrations of inhalation anesthetics are in the high micromolar range and above, and even for intravenous anesthetics they do not go below the micromolar range. At these concentrations, many molecular and higher level targets are affected by inhalation anesthetics, fewer probably by intravenous anesthetics. The only physicochemical characteristic shared by anesthetics is the correlation of their anesthetic potencies with hydrophobicity. These correlations depend on the group of general anesthetics considered. In this review, anesthetic potencies for many different targets are plotted against octanol/water partition coefficients as measure of hydrophobicity. Qualitatively, similar correlations result, suggesting several but weak interactions with proteins as being characteristic of anesthetic actions. The polar interactions involved are weak, being roughly equal in magnitude to hydrophobic interactions. Generally, intravenous anesthetics are noticeably more potent than inhalation anesthetics. They differ considerably more between each other in their interactions with various targets than inhalation anesthetics do, making it difficult to come to a decision which of these should be used in future studies as representative 'prototypical general anesthetics'.

Action Potentials↗
PubMed1996

Measuring the performance of anesthetic depth indicators.

BACKGROUND: An appropriate measure of performance is needed to identify anesthetic depth indicators that are promising for use in clinical monitoring. To avoid misleading results, the measure must take into account both desired indicator performance and the nature of available performance data. Ideally, anesthetic depth indicator value should correlate perfectly with anesthetic depth along a lighter-deeper anesthesia continuum. Experimentally, however, a candidate anesthetic depth indicator is judged against a "gold standard" indicator that provides only quantal observations of anesthetic depth. The standard anesthetic depth indicator is the patient's response to a specified stimulus. The resulting observed anesthetic depth scale may consist only of patient "response" versus "no response," or it may have multiple levels. The measurement scales for both the candidate anesthetic depth indicator and observed anesthetic depth are no more than ordinal; that is, only the relative rankings of values on these scales are meaningful. METHODS: Criteria were established for a measure of anesthetic depth indicator performance and the performance measure that best met these criteria was found. RESULTS: The performance measure recommended by the authors is prediction probability PK, a rescaled variant of Kim's dy.x measure of association. This performance measure shows the correlation between anesthetic depth indicator value and observed anesthetic depth, taking into account both desired performance and the limitations of the data. Prediction probability has a value of 1 when the indicator predicts observed anesthetic depth perfectly, and a value of 0.5 when the indicator predicts no better than a 50:50 chance. Prediction probability avoids the shortcomings of other measures. For example, as a nonparametric measure, PK is independent of scale units and does not require knowledge of underlying distributions or efforts to linearize or to otherwise transform scales. Furthermore, PK can be computed for any degree of coarseness or fineness of the scales for anesthetic depth indicator value and observed anesthetic depth; thus, PK fully uses the available data without imposing additional arbitrary constraints, such as the dichotomization of either scale. And finally, PK can be used to perform both grouped- and paired-data statistical comparisons of anesthetic depth indicator performance. Data for comparing depth indicators, however, must be gathered via the same response-to-stimulus test procedure and over the same distribution of anesthetic depths. CONCLUSIONS: Prediction probability PK is an appropriate measure for evaluating and comparing the performance of anesthetic depth indicators.

Anesthesia↗
PubMedDate not supplied

Understanding allergic reactions to local anesthetics.

OBJECTIVE: To review the pharmacology and mechanisms by which local anesthetics cause allergic reactions. Recommendations concerning appropriate use of local anesthetics and alternative therapies in patients with documented local anesthetic allergies are given. DATA SOURCE: A MEDLINE search of English-language literature identified pertinent clinical studies, case reports, and reviews. The periods of review were Med1, 1990-present, and Med2, 1985-1989, using the MeSH terms drug hypersensitivity and anesthetics. References from the selected studies, case reports, and reviews were reviewed. STUDY SELECTION: Controlled and uncontrolled prospective studies and case reports pertaining to local anaesthetic allergies were reviewed. The selection focused on information pertaining to the etiology and diagnosis of allergic reactions to local anesthetics and alternative therapies for patients with local anesthetic allergies. DATA SYNTHESIS: Local anesthetics are classified as either ester or amide compounds. Esters are associated with a higher incidence of allergic reactions, due to a p-aminobenzoic acid (PABA) metabolite. Amide agents do not undergo such metabolism. However, preservative compounds (methylparaben) used in the preparation of amide-type agents are metabolized to PABA. Patients who are allergic to ester local anesthetics should be treated with a preservative-free amide local anesthetic. If the patient is not allergic to ester local anesthetics, these agents may be used in amide-sensitive patients. In the rare instance that hypersensitivity to both ester and amide local anesthetics occurs, or if skin testing cannot be performed, than alternative therapies including diphenhydramine, opioids, general analgesia, or hypnosis can be used. CONCLUSIONS: A true immunologic reaction to a local anesthetic is rare. Intradermal skin testing of local anesthetic compounds, methylparaben, and metabisulfite should be performed in patients when a thorough history does not rule out a possible allergic reaction to local anesthetics and future local anesthesia is necessary. Skin testing enables the clinician to identify autonomic responses to minor surgical procedures and toxic reactions to anesthetics so that patients are not incorrectly labeled as "caine" allergic. Diphenhydramine can be used as an alternative to ester and amide local anesthetics in minor procedures of short duration.

Anesthesia, Local↗