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M W Kalichman

Publications and source records attributed to M W Kalichman.

16 recordsLinked to original sources
PubMed1992

Local anesthetic-induced conduction block and nerve fiber injury in streptozotocin-diabetic rats.

Patients with diabetes may have peripheral neuropathy, which may have clinical implications for the use of regional nerve block. The effects of local anesthetics on nerve conduction and nerve fiber injury were tested in control rats and at 4 weeks after the onset of diabetes in rats injected with streptozotocin (50 mg/kg intraperitoneally). Nerve conduction was assessed by recording evoked electrical activity in hindpaw muscles following ipsilateral electrical stimulation of the sciatic nerve near the hip. Block of motor nerve conduction was quantified by recording the amplitude of the evoked response at 1-min intervals for up to 15 min after the injection of 500 microliters 1% lidocaine HCl or procaine HCl into the midthigh next to the sciatic nerve. In control animals, procaine was much less effective than lidocaine in producing conduction block. The rate and magnitude of lidocaine-induced conduction block were not significantly different between control and diabetic groups. However, conduction block due to procaine was sufficiently enhanced in diabetic rats to become comparable to that of lidocaine-treated control nerves. Long-lasting injury was assessed in sciatic nerve harvested 2 days after the extraneural injection of saline or 2 or 4% lidocaine HCl. Using a light microscope with a superimposed grid, nerve edema was quantified as the proportion of intersection points falling on extracellular space. Lidocaine induced edema in both control and diabetic nerves, but 4% lidocaine induced significantly more edema in diabetic nerves than in controls. Nerve fiber injury, based on light microscopic scoring of axonal degeneration and demyelination, was not observed in saline-treated nerves.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

A pilot study of biomedical trainees' perceptions concerning research ethics.

The authors surveyed 2,010 biomedical trainees in the fall of 1990 at the University of California, San Diego, regarding their perceptions about unethical practices in research and the extent of their training exposure to the ethics of scientific investigation; 549 responded, representing both clinical and basic science departments and including graduate students and postdoctoral fellows in addition to medical students, residents, and fellows. Of the 549 trainees, 129 (23%) responded that they had received no training in research ethics; 195 (36%), that they had observed some kind of scientific misconduct (although not necessarily in the sense of research fraud defined in federal regulations); and 81 (15%), that they would be willing to select, omit, or fabricate data to win a grant or publish a paper. The trainees planning an academic career were more likely to report having been aware of others' scientific misconduct. Reported exposure to ethics training was not associated with a difference in past or potential unethical behavior. The authors conclude that while the apparent ineffectiveness of past ethics instruction does not preclude the possibility that more systematic training may be useful, it does underscore the need to assess the efficacy of training activities.

California↗
PubMed1991

Experimental nerve ischemia and injury produced by cocaine and procaine.

The effects of ethanol, glycerol, procaine, and cocaine were tested on rat sciatic nerve blood flow. Blood flow measurements were made using a laser Doppler blood perfusion monitor with a 1 mm diameter probe. The local anesthetics procaine and cocaine produced a dose-dependent and time-dependent decrease in nerve blood flow, but 80% ethanol, 80% glycerol, and 0.9% saline did not significantly alter nerve blood flow either acutely (10 min) or for up to 4 h. For histopathologic studies, the same nerves were removed at 2 days after blood flow tests. Evidence of nerve injury (edema and nerve fiber pathology) was observed for the neurolytic agents ethanol and glycerol and for both local anesthetics. No relationship between nerve blood flow and injury was seen for either ethanol or glycerol; however, both local anesthetics exhibited a highly significant negative correlation (P less than 0.01) between blood flow at 4 h and injury at 2 days. These data provide additional evidence that local anesthetics can decrease nerve blood flow; and these results are consistent with an ischemic mechanism for local anesthetic-induced nerve injury.

Analysis of Variance↗
PubMed1991

Transperineurial vessel constriction in an edematous neuropathy.

The hypothesis that the accumulation of endoneurial edema can exert forces sufficient to occlude transperineurial vessels was tested using light microscopy and computer-assisted morphometry in rat sciatic nerve. Experimental nerves were exposed to a concentration of 10% procaine HCl, which from previous studies has been demonstrated to routinely produce an edematous neuropathy. For each vessel, a "constriction ratio" was defined by dividing its minimum intraperineurial lumen area by the average for minimum endoneurial and epineurial lumen cross-sectional areas. Constriction ratios were 0.91 +/- 0.26 (mean +/- SD) for control vessels and 0.28 +/- 0.25 for vessels in the procaine group (p less than 0.005). In addition, a strong negative correlation was observed between the morphologic demonstration of nerve edema and the transperineurial vessel constriction ratio (r = -0.85; p less than 0.002). It is concluded that in neuropathies characterized by widespread edema and increased endoneurial fluid pressures, the concomitant constriction of transperineurial vessels could diminish nerve blood flow and facilitate nerve injury.

Animals↗
PubMed1990

The nonlinear potency of sub-MAC concentrations of nitrous oxide in decreasing the anesthetic requirement of enflurane, halothane, and isoflurane in rats.

The effect of nitrous oxide (N2O) on the MAC of enflurane, halothane, and isoflurane was determined in male rats. Each rat received either enflurane, halothane, or isoflurane, along with 0%, 15%, or 75% N2O. Anesthetic equilibration was verified by mass spectrometry sampling of end-tidal gases. MAC was determined at each N2O concentration by the standard tail clamp method. The N2O dose-response data for each animal were fit by a second-order polynomial equation to estimate the value of a second-order coefficient. A linear dose-response would result in a value of zero, whereas the extent to which the data deviate from nonlinearity would be reflected by an increase in the value of this coefficient. The null hypothesis, that the second-order coefficient should be zero, was tested by a one-sample two-tailed t test. The volatile anesthetic requirement decreased as the N2O concentration increased; however, it did not do so linearly. For each of the three volatile anesthetic groups, the second-order coefficients were consistently greater than zero (P less than 0.05). These data are not consistent with the accepted presumption that the summation of N2O with volatile anesthetics is linear.

Anesthesia, Inhalation↗
PubMed1990

Role of the blood-nerve barrier in experimental nerve edema.

Nerve edema is a common response to the nerve injury seen in many peripheral neuropathies and is an important component of Wallerian degeneration. However, independent pathologic effects of nerve edema that aggravate or induce nerve injury extend the role of edema beyond that of an epiphenomenon of injury. New insights into the mechanism and impact of nerve edema come largely from animal models. In the following review, we discuss the cause and consequences of nerve edema with particular reference to endoneurial fluid pressure and its relevance to the nerve microenvironment. Experimental models of nerve edema include conditions with increased vascular permeability such as lead poisoning, experimental allergic neuritis, and murine globoid leukodystrophy. Increased perineurial permeability induced by local anesthetics and neurolytic drugs can also induce nerve edema sufficient to increase endoneurial fluid pressure. Both perineurial and vascular permeability are increased after damage induced by crush, freeze, or laser injury. One of the most important forms of nerve edema is induced by external compression; the significance of this change is that edema has local compressive effects that persist after the external pressure has been relaxed. Nerve edema and increased endoneurial fluid pressure also occur in conditions in which vascular permeability appears to be unchanged such as experimental diabetic neuropathy and in hexachlorophene intoxication. In both of these conditions, reduced nerve blood flow has been demonstrated in rats and is viewed as a consequence of increased endoneurial fluid pressure. Whatever its mechanism, endoneurial edema has important structural and functional consequences for nerve fibers. A clear understanding of the underlying pathology of the nerve microenvironment may provide useful insights into treatment of clinical neuropathies.

Animals↗
PubMed1989

The nonlinear contribution of nitrous oxide at sub-MAC concentrations to enflurane MAC in rats.

The presumed linear relationship describing the contribution of nitrous oxide (N2O) to the enflurane requirement necessary to achieve a 1.0 MAC level of anesthesia was tested in rats (N = 84). Each rat received one of six different concentrations of N2O, and enflurane was adjusted to attain 1.0 MAC with the use of a standard tail clamp method. The resultant group MAC anesthetic concentrations were Group I-N2O = 0.0%, enflurane = 2.30%; Group II-N2O = 10.4%, enflurane = 2.19%; Group III-N2O = 30.7%, enflurane = 1.85%; Group IV-N2O = 61.8%, enflurane = 1.75%; Group V-N2O = 70.9%, enflurane = 1.56%; and Group VI-N2O = 80.3%, enflurane = 1.54%. Increasing the N2O concentration from 0-10%, from 30-60%, or 70-80% did not significantly decrease the enflurane requirement; however, increasing the N2O concentration from 10-30% or 60-70% produced a significant decrease (P less than 0.05) in the concentration of enflurane required for 1.0 MAC of anesthesia. Thus, in rats, increasing the concentration of N2O in sub-MAC ranges did not produce a linear decrease in the enflurane concentration required to add up to 1.0 MAC of anesthesia. These results are consistent with a dose-dependent interaction between N2O and the excitatory properties of enflurane; this interaction could represent synergism at low concentrations or antagonism at higher concentration of N2O.

Animals↗
PubMed1989

Quantitative histologic analysis of local anesthetic-induced injury to rat sciatic nerve.

Quantitative measurements of endoneurial edema, cytoplasmic lipid droplets, nerve fiber injury and Schwann cell damage were used to elucidate the pathogenesis of local anesthetic-induced injury to sciatic nerve in the rat. All histopathologic measurements were conducted on rat sciatic nerves removed at 48 hr after the extraneural injection of one of three concentrations of the local anesthetic 2-chloroprocaine, procaine, etidocaine or lidocaine. All four drugs produced a concentration-dependent increase in every measure of injury assessed by light microscopy with computer-assisted morphometry of transverse 1-mu thick sections. Edema, lipid inclusions and fiber injury were seen predominantly in the subperineurial region and to a lesser degree in the central areas of nerve fascicles. Quantitative electron microscopic evaluation of Schwann cell injury indicated that the Schwann cells of unmyelinated fibers were more likely to undergo lysis after exposure to local anesthetics, whereas those of myelinated fibers were more likely to accumulate cytoplasmic lipid droplets. These quantitative data on the specificity of the regional distribution of nerve injury and of Schwann cell effects are consistent with a direct cellular toxicity of the local anesthetics; however, these results do not preclude a role for toxicity mediated indirectly by changes in the endoneurial environment.

Anesthetics, Local↗
PubMed1988

Pathology of local anesthetic-induced nerve injury.

Nerve fiber injury and endoneurial edema were induced by the injection of the local anesthetic 2-chloroprocaine, tetracaine, procaine, etidocaine or mepivacaine into the soft tissue and fascia surrounding the sciatic nerve of Sprague-Dawley rats. Light microscopy demonstrated that the perineurial barrier was not mechanically damaged by the surgical procedure but, at 48 h post-injection, perineurial permeability was increased. Previous observations of leakage of horseradish peroxidase and the present report of neutrophils and eosinophils in the endoneurium indicate a disruption of blood-nerve barrier systems. Endoneurial edema was observed in the subperineurial, interstitial and perivascular regions. Axonal degeneration and demyelination occurred; the latter associated with accumulation of large lipid droplets in Schwann cells. Degranulation of mast cells, proliferation of fibroblasts and macrophage activity were noteworthy in affected areas. The findings are remarkable in that this is the first model of endoneurial edema by a neurotoxin which penetrates the perineurium, disrupting barrier system and inducing nerve fiber injury.

Anesthetics, Local↗
PubMed1988

Selective vulnerability of unmyelinated fiber Schwann cells in nerves exposed to local anesthetics.

When peripheral nerves of experimental rats are exposed to local anesthetics, distinctive and reproducible pathologic changes occur involving the perineurial sheath and endoneurial contents. Application of intermediate strength concentrations of the local anesthetics, 2-chloroprocaine, lidocaine, etidocaine, and intermediate or high concentrations of procaine to the surface of rat sciatic nerves resulted in the following changes. By 48 hours, the perineurial sheath exposed to the drug was disrupted and became permeable to granulocytes which infiltrated the subjacent endoneurium in conjunction with edema formation in the endoneurial interstitium. Application of 10% procaine to exposed nerve resulted in extensive demyelination. The most striking pathologic change occurring with either intermediate or high doses was accumulation of lipid droplets in Schwann cells, a phenomenon that occurred often in myelin-producing Schwann cells but much less frequently in unmyelinated fiber Schwann Cells. Lipid accumulation appears to be one of several reactive changes that affect Schwann cells of myelinated fibers and is dose-dependent. On the other hand, while reactive changes were infrequently seen in unmyelinated fiber Schwann cells, these cells appeared more susceptible to injury as shown by electron microscopy. Injury to Schwann cells by local anesthetics is temporary because these cells can replicate quickly. Autoradiographic studies of thymidine incorporation 1 week after procaine administration to the sciatic nerve showed intense proliferation of Schwann cells, but no such activity in controls. These findings support the view that their neurotoxic properties may account in some part for the function of local anesthetics, that Schwann cells of small unmyelinated fibers are more vulnerable to these agents than those of myelinated fibers, and that destruction of their supporting cells is followed by vigorous mitotic activity in the endoneurium.

Anesthetics, Local↗
PubMed1987

Behavioral and electrophysiological recovery following cryogenic nerve injury.

Postthoracotomy pain can be reduced by cryoanalgesia of intercostal nerves. The technique involves focal freezing of peripheral nerves to interrupt pain pathways, producing immediate functional changes that recover as the nerves regenerate. To assess the time-course of functional changes that follow nerve injury, unilateral freeze lesions of sciatic nerve were induced in rats with a cryosurgical unit. The contralateral nerves were used as sham-operated controls. Following nerve injury, behavioral and electrophysiologic tests were repeated to 90 days. The acute effect of nerve injury was a decrease in behavioral measures of hind limb function (P less than 0.05), an increase in electrical threshold to elicit hind limb contraction (P less than 0.005), and an absence of stimulus-evoked compound action potential (P less than 0.005). Morphologic changes included substantial endoneurial edema associated with Wallerian degeneration. Remyelination occurred subsequently during the following 35 days. Although all physiologic measures returned toward normal, nerve conduction velocities were still much slower in the experimental group. In a second study, the long-term effects of cryogenic injury were compared with neurolytic injury with 10% procaine HCl, both of which produced a conduction velocity deficit that persisted at least 90 days after the initial injury. These behavioral and electrophysiologic results complement previous reports of morphologic deficits in the nerves including incomplete recovery of nerve fiber diameter and increased thickness of the perineurial sheath.

Action Potentials↗
PubMed1986

The role of 2-chloroprocaine and sodium bisulfite in rat sciatic nerve edema.

In order to evaluate the possible mechanisms of local anesthetic toxicity, the rat sciatic nerve was exposed to various solutions including Nesacaine (containing the antioxidant sodium bisulfite), 2-chloroprocaine in the Nesacaine vehicle (0.2% sodium chloride), 0.2% sodium bisulfite in 0.2% sodium chloride, or 0.2% sodium chloride alone. All solutions were pH balanced between 2.9 and 3.2. Forty-eight hours (h) following extraneural administration of 1 ml volumes, significant edema was produced by all solutions containing 3% 2-chloroprocaine, but not with 0.2% bisulfite in sodium chloride or with sodium chloride alone. Intrafascicular administration of five to ten microliter volumes of these solutions produced edema at 48 h in all cases, but the highest levels were observed with Nesacaine and the lowest levels with 0.2% bisulfite. The results of this study implicate the local anesthetic 2-chloroprocaine in the production of nerve edema, which is inconsistent with other reports that the toxicity of Nesacaine-CE can be attributed to the antioxidant bisulfite.

Anesthetics, Local↗
PubMed1986

Neurotoxicity of local anesthetics: altered perineurial permeability, edema, and nerve fiber injury.

A quantitative, in situ experimental method was developed employing the rat sciatic nerve to study the neurotoxicity of local anesthetic solutions applied directly to an intact peripheral nerve bundle. One-milliliter volumes of 2-chloroprocaine, 3%; tetracaine, 1%; lidocaine, 2%; bupivacaine, 0.75%; or sodium chloride, 0.2%; were injected with a 30-gauge needle beneath the mesoneurium but exterior to the epineurium. The wound was closed and the animals were normally maintained until the nerves were reexposed for quantitative biophysical and morphologic testing 24 h to 4 weeks later. The results indicate that topically applied 2-chloroprocaine and tetracaine produce significant endoneurial edema 48 h after treatment. Horseradish peroxidase was used to verify increased permeability of the perineurium. Endoneurial fluid pressure was significantly increased in edematous nerves. Electron microscopy revealed abnormal mast cells and proliferation of endoneurial fibroblasts in addition to Schwann cell injury and axonal dystrophy. This study shows that extrafascicular administration of clinically used concentrations of local anesthetic solutions can alter perineurial permeability, producing changes in the endoneurial environment that are associated with neurotoxic injury. Perineurial and endoneurial fibrotic changes may be a late consequence of peripheral nerve injury with anesthetic solutions producing altered perineurial permeability with endoneurial edema.

Anesthetics, Local↗
PubMed1985

Anticonvulsant and convulsant properties of flurazepam.

The anticonvulsant efficacy of the benzodiazepine flurazepam was tested in rats treated with a convulsant dose of either picrotoxin or 3-mercaptopropionic acid. Against picrotoxin, a significant anticonvulsant effect was observed in the range of 30-60 mg/kg, i.p. Epileptogenicity increased as doses of flurazepam were increased from 60 to 200 mg/kg, and at a dose of 400 mg/kg all subjects died. In similar tests, the benzodiazepines clonazepam and triazolam produced only dose-dependent increases in anticonvulsant efficacy. Flurazepam also proved to be an effective anticonvulsant in tests against 3-mercaptopropionic acid. The results of this study provide further evidence that benzodiazepines have varying degrees of epileptogenicity.

3-Mercaptopropionic Acid↗
PubMedDate not supplied

Differential antiepileptic sensitivity between cortical sites in the rat.

The relative efficacies of phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), and valproic acid (VPA) in the suppression of focal and generalized seizures produced by electrical stimulation of two different cortical sites (areas 3 and 10) were evaluated in the rat. The two cortical sites were distinguished by significantly different dose-response curve slopes for the suppression of afterdischarge duration by PHT, CBZ and VPA, which suggests more than one mechanism of action for these drugs. The dose-response curve slopes for PB, on the contrary, were not significantly different, although its potency was significantly greater in area 10. For suppression of generalized convulsions, dose-response curve slopes were not significantly different for any of the drugs. Potencies of PHT, CBZ and VPA were equivalent in the two areas, but PB was significantly more potent in the suppression of generalized convulsions triggered from area 10. It is concluded that focal seizures elicited by the stimulation of different cortical sites are differentially refractory to antiepileptic drugs.

Animals↗