Nicholas M. Greene

Distribution of local anesthetic solutions within the subarachnoid space.

Uptake of local anesthetics injected into the subarachnoid space determines which neuronal functions are affected during spinal anesthesia. Elimination of local anesthetics from the subarachnoid space determines the duration of these effects. Distribution of local anesthetics within cerebrospinal fluid (CSF) determines the extent of altered neuronal function. Uptake and elimination have been reviewed previously (1). The present review deals with distribution, the determinant of the level of spinal anesthesia. Studies of drug distribution usually rest upon measurements of concentrations of the drug as a function of time after administration. Technical and ethical considerations make it impossible to take multiple samples of CSF at different levels of the subarachnoid space in patients. Reliance must, therefore, be placed upon estimates of distribution of local anesthetics in CSF not by measuring drug concentrations in CSF but, instead, by measuring the extent of neurologic responses to local anesthetics in CSF. The neurologic response that will be relied upon in this review, for estimation of local anesthetic distribution in CSF, is the spinal segmental level of anesthesia. Anesthesia is defined (for the present purposes only) as loss of pinprick sensation. This definition of anesthesia is employed because it is the definition most widely used by clinicians in determining the level to which local anesthetic solutions have spread. Differences between the levels of anesthesia as thus defined and levels of analgesia, somatic motor paralysis, sympathetic denervation, and other forms of neuronal impairment are not dwelt upon. These other forms of

Uptake and Elimination of Local Anesthetics during Spinal Anesthesia

The pharmacokinetics of spinal anesthesia involves three phenomena: distribution of local anesthetics within cerebrospinal fluid (CSF); uptake of local anesthetics into tissues within the subarachnoid space; and elimination of local anesthetics from the subarachnoid space. The present review considers only uptake and elimination. The object is provision of neither an encyclopedic review nor an annotated bibliography, but rather, selective analysis of published materials for the development of principles and concepts important in clinical anesthesia.

Time-courses of zones of differential sensory blockade during spinal anesthesia with hyperbaric tetracaine or bupivacaine

The purposes of this study were twofold: to compare bupivacaine and tetracaine spinal anesthesia with regard to the zones of differential sensory blockade and to evaluate the time-courses of the widths of the zones of differential sensory blockade during spinal anesthesia. In 51 patients, the most rostral levels of sensory denervation to light touch, pinprick, and temperature discrimination were measured. There was no statistically significant difference in the height of sensory blockade in the 29 patients given bupivacaine and in the 22 patients given equipotent doses of tetracaine. The widths of the zones of differential blockade were also not statistically different between the two groups during onset, maintenance, and regression of anesthesia, except that the light touch-to-pinprick and light touch-to-temperature zones of differential blockade were greater with bupivacaine than with tetracaine 30 min after subarachnoid injection. The width of the zones of differential blockade also remained unchanged within each group during onset, maintenance, and regression of anesthesia. Changes in, and absolute levels of, blood pressure and heart rate were similar with both bupivacaine and tetracaine throughout. We conclude that zones of differential sensory blockade are essentially the same with tetracaine and bupivacaine, that the widths of the zones of differential sensory blockade remain constant during onset, maintenance, and offset of spinal anesthesia, and that bupivacaine and tetracaine are associated with similar changes in heart rate and blood pressure during spinal anesthesia.

Anesthesiology Journals, 1992

he intellectual and professional stature of any branch of human endeavor can be judged by T the quality of the written word that it produces. Within the liberal arts, the written word as it appears in monographs and books may be an especially useful guide in various fields of special interest. Not so in biomedicai areas. In biomedical areas, the written word as it appears in journals more accurately reflects the health, the vigor, and even the scientific validity of a special discipline than does the written word as it appears in monographs and textbooks. This is the case because what appears in peerreviewed biomedical journals (quality of the written word in journals can be assured only by peer review) represents the cutting edge in that specialty. The written word in these journals casts light on what those who are engaged in peer review regard as new, important, and valid in that field. What is published in the journals of a medical specialty defines for better or for worse the standard of contemporary excellence within the discipline. This is as true in anesthesiology as in any other medical discipline. Pausing to reflect on the state of the art of anesthesiology as evidenced by the quality of the written word in its journal thus provides a useful and indeed necessary opportunity for asking ourselves: where do we stand? Where are we going? Measuring something as subjective as quality of the written word is as fraught with dangers as attempting to measure beauty. Perhaps one qualification might be 40 years in the specialty, much of it as an earnest student and observer of medical journals to see what makes them tick and what makes them good, great, or not so good or great. Not just anesthesiology journals either, but all types of medical journals. It also might be helpful in judging the quality of anesthesiology journals to have spent 26 years both as editor and editor-in-chief of Anestlzesiology and as editor-in-chief of Anesthesia and Analgesia,

Anesthesia and the development of surgery (1846-1896).

The hypothesis that the introduction of anesthesia in 1846 accelerated the development of surgery was tested by compiling statistics on the types of operations performed in this country and abroad in the absence of anesthesia (prior to 1846) and over the 50-year period after 1846. Prior to 1846, surgery involved the extremities and superficial parts of the body almost exclusively. The same was generally true for 50 years following 1846. The introduction of anesthesia was necessary before surgery could advance, but control of infection, establishment of the sciences of pathology and physiology, and development of professionalism in clinical medicine and surgery based on research and teaching were also required. Almost a half-century lapsed after the introduction of anesthesia before surgery advanced significantly beyond the stage it was at prior to the introduction of anesthesia in 1846.

Waking up to desflurane: The anesthetic for the '90s?

This issue of the Journal contains a report by Jones et al. (1) that describes the first use of desflurane (1-653) in humans. One is prompted to question whether we truly need a new inhalation anesthetic that, at first glance, appears to be quite similar to isoflurane. The introduction of halothane in the late 1950s certainly marked the beginning of an era of new volatile anesthetics with much sought after properties: a total anesthetic allowing high inspired concentrations of oxygen, not irritating when inhaled, nonexplosive, and with minimal side effects. Halothane provided, however, less than complete surgical relaxation, was said to cause rare but potentially lethal hepatitis, and certainly was associated with sensitization of the myocardium to catecholamines, all of which led to the search for other inhalation anesthetics. Fluroxene, methoxyflurane, enflurane, and isoflurane were products of that search. Some of these anesthetics have fallen by the wayside because of their side effects, but others, e.g., enflurane and isoflurane, have become popular to the point of displacing, in some areas, halothane. In the eyes of some, it is with enflurane, and, perhaps even more so, with isoflurane that that new agent, desflurane, must be compared. As shown in the paper by Jones et al. induction of and emergence from desflurane anesthesia are rapid. This, of course, is not unexpected in view of the low blood/gas partition coefficient (0.424) of desflurane (2). The subjects reported by Jones et al. responded,

Blood Levels of Local Anesthetics during Spinal and Epidural Anesthesia

HYSIOLOGIC responses to spinal anesthesia P have for many years been ascribed solely to block of nerve conduction within the subarachnoid space.’ Particular importance has been attached to the consequences of interruption of nerve impulse transmission within preganglionic sympathetic fibers. Indeed, cardiovascular responses to spinal anesthesia have been said to represent the physiology of sympathetic denervation. Subarachnoid block of somatic motor fibers and at least partial block of superficial tracts within the spinal cord also occur but generally are regarded as being substantially less impottant. Block of somatic sensory fibers, although the raison d’etre of spinal anesthesia, is also devoid of significant physiologic effects. Blood levels of local anesthetics during spinal anesthesia have been assumed to be so low as to be unassociated with any signiicant phannamlogic effects on either the cardiovascular system or any other system. The amounts of local anesthetic injected into the subarachnoid space during spinal anesthesia have been felt to be too modest and their rates of absorption into the vascular system too slow to pmduce plasma concentrations of local anesthetics adequate to elicit systemic respomes. In the absence of measurements of plasma levels of local anesthetics during spinal anesthesia, this concept has been based on theory, not hard data. Physiologic responses to epidural anesthesia, on the other hand, have been explained on the basis of a combination of two factors: sympathetic denervation analogous to that observed during spinal anesthesia, plus plasma levels of local anesthetics (and vasoconstrictors, when used) great enough to exert direct pharmacologic effects on peripheral smooth muscle and the myocardium.2s The fact that equal sensory levels of spinal and epidural anesthesia are associated with quite different cardiovascular responses has been said to be due mainly to differences in plasma levels of local anesthetics (and vasoconstrictors) associated with the two techniques. Equal sensory levels of anesthesia are, of course, accompanied by less extensive sympathetic blockade during epidural anesthesia than during spinal anesthesia because the zone of differential blockade during spinal anesthesia is absent during epidural anesthesia. This, however, is. probably less important in explaining the differences in cardiovascular function during the two types of anesthesia. Classic concepts of the etiology of the cardiovascular responses to spinal anesthesia require reevaluation in view of the data reported by Giasi, DAgostino, and Catino in the present issue of this journal: For the first time data are reported on plasma levels of a local anesthetic during spinal anesthesia. That blood levels of local anesthetics have never before been reported dth a regio~al anesthetic technique that has enjoyed such populhrity for threequarters of a century is remaPkable in itself. Even more remarkable is t k i r finding that peak plasma levels of lidocaine following injection of lidocaine into the lumbar epidural space are no different than they are when an equal amount.of lidocaine is injected into the lumbar subarachnoid space. Blood levels are achieved more rapidiy with epidural than with spinal anesthesia, to be sure, and this is, no doubt, due to differences in vascularity and rates of absorption, as the authors suggest. But there is no statistically significant difference in the maximum plasma concentrations. What are we to make of this important observation? Does it mean, for example, that cardiovascular responses to spinal anesthesia can no longer be ascribed simply and solely to sympathetic denervation? Should we now regard the physiologic effects of spinal an-

Further light on the potencies of local anesthetics.

IL/WATER partition coefficients are commonly 0 used as indices of the potencies of anesthetics. In the case of inhalation anesthetics oil/water partition coefficients can be determined in a relatively straightforward manner as these types of anesthetics are not subject to protonation or dissociation in biologic media. The resulting relationship between lipid solubility and potency is so linear that, knowing either of these two factors, one can with considerable confidence predict the other, a fact known for almost a century and a fact used to explain distribution of inhalation anesthetics in neuronal tissue and perhaps even their mode of action in nerve membranes. The same is not true for local anesthetics. Local anesthetics commonly used in clinical practice are both protonated and dissociated into charged and uncharged forms in biologic fluids at physiologic levels of pH. Anesthetic potencies of local anesthetics depend, therefore, not only upon the oil/water partition coefficients of uncharged molecules, but also on the partition coefficients of charged forms of local anesthetics. Furthermore, it is usually assumed in discussions of the distribution and mode of action of local anesthetics that the dissociation constant, the pKa, of local anesthetics is the same in lipid media as it is in aqueous media. Whether this assumption is, or is not, valid has not been adequately addressed, yet it is critical to our understanding of the mode of action of local anesthetics. As a result, the relationship between lipid solubility and anesthetic potency of local anesthetics is not as clear-cut, linear, predictable, or even accurately determined as it is in the case of inhalation anesthetics. In the present issue Ueda and associates (p 56) evaluate some of the factors involved in determining the distribution of local anesthetics between aqueous media and lipids. They also address the problem of the forms in which local anesthetics exist in lipid media. Their paper may understandably strike some readers as being an arcane exercise in physical chemistry which is neither relevant to nor intelligible to clinicaI anesthesiologists. Unintelligible as it may well be in certain of its details to the majority of us who are not versed in physical chemistry, the results are certainly germane to anyone who would aspire to complete understanding of where and how local anesthetics act and what factors govern their concentrations at their sites of action in pharmacologically active forms and pharmacologically active amounts. The results of this seminal contribution by Ueda and co-workers include demonstration that the coefficient of distribution of local anesthetics in water and in lipids as usually measured represents an apparent partition coefficient, not a true coefficient of distribution which takes into account the form in which the local anesthetic exists in both aqueous and lipid phases. Furthermore, the data emphasize the fact that calculated values of partition coefficients depend in part upon whether concentrations of local anesthetics are given in terms of molarity, molality, or mole fraction. Partition coefficients also depend upon the lipid (oil) solvent employed in such studies, a frequently overlooked matter of substantial importance when attempting to evaluate events that transpire where things count most, i.e., at their site of action in lipid layers of nerve membranes. The possibility that partition coefficients of local anesthetics (and inhalation anesthetics, too, for that matter) may vary in neuronal structures depending on the type of lipid present poses major problems in our understanding of the site of action and the mode of action of anesthetics. Finally, the data of Ueda et a1 demonstrate that dissociation constants of local anesthetics are lower in lipids than in aqueous media, an observation which implies that in lipid media there will be a relative increase in uncharged forms of local anesthetics over charged forms. This in turn alters our understanding of the relationship between oil/water partition coefficients of local anesthetics and their potency since although it is in the uncharged form that local anesthetics cross biologic barriers, including cell membranes, it is generally agreed that it is in the charged form that they act on nerve membrane function. The paper by Ueda et a1 emphasizes the complexities of accurate determinations of oil/water partition