bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Nitric Oxide in the Development of Thermal Hyperesthesia Induced by Sciatic Nerve Constriction Injury in the Rat
Authors: Yamamoto Tatsuo , Shimoyama Naohito
Published: November 2003

Background

Nitric oxide (NO) has been shown to be involved in mediating nociceptive information transmission in the spinal cord. It is known that the N-methyl-D-aspartate receptor plays an important role in the development of the spinal facilitation evoked by a protracted small afferent input and that this effect is mediated at least in part by NO. Recently, it has been found that N-methyl-D-aspartate receptor-mediated spinal facilitation is crucial in the development of thermal hyperesthesia evoked by a nerve constriction injury. In the current study, we investigated the role of NO in the development of thermal hyperesthesia after a nerve constriction injury.

Methods

The Bennett and Xie model (four loose chromic gut ligations around the rat sciatic nerve) was used to examine the development of thermal hyperesthesia. An NO synthase inhibitor (N omega-nitro-L-arginine or N omega-nitro-L-arginine methyl ester hydrochloride), rat hemoglobin, or L-arginine was administered intrathecally 10 min before the nerve injury (pretreatment study) or 15 min after the nerve injury (posttreatment study).

Results

Pretreatment but not posttreatment administration of NO synthase inhibitor significantly delayed the development of thermal hyperesthesia. The effect of NO synthase inhibitor was reversed by the coadministration of L-arginine but not by the coadministration of D-arginine. Pretreatment with rat hemoglobin also delayed the development of thermal hyperesthesia. L-Arginine itself had no effect on the development of thermal hyperesthesia.

Conclusions

NO may play an important role in the development of N-methyl-D-aspartate receptor-mediated spinal facilitation after a nerve constriction injury.
Effects of Propofol on Calcium sup 2+ Regulation by Malignant Hyperthermia-susceptible Muscle Membranes
Authors: Fruen Bradley R. , Mickelson James R. , Roghair Timothy J. , Litterer Lynn A. , Louis Charles F.
Published: November 2003

Background

The effects of inhalation anesthetics on Ca2+ regulation in malignant hyperthermia-susceptible skeletal muscle are considered to be responsible for triggering malignant hyperthermia. The intravenous anesthetic propofol does not trigger malignant hyperthermia in susceptible patients or experimental animals, suggesting that there are important differences between the effects of propofol and the effects of inhalation anesthetics on Ca2+ regulation in malignant hyperthermia-susceptible muscle. Understanding these differences may help to clarify the mechanisms responsible for triggering malignant hyperthermia.

Methods

To investigate the effects of propofol on Ca2+ regulation by malignant hyperthermia-susceptible skeletal muscle, we determined its effects on the membrane channels and pumps that control myoplasmic Ca2+ concentrations: the sarcoplasmic reticulum ryanodine receptor, the transverse tubule dihydropyridine receptor, and the sarcoplasmic reticulum Ca(2+)-adenosine triphosphatase (Ca(2+)-ATPase). Terminal cisternae-derived sarcoplasmic reticulum vesicles enriched in the junctional proteins of the sarcoplasmic reticulum and the transverse tubule membranes were isolated from the muscle of malignant hyperthermia-susceptible and normal pigs. Ca2+ flux, Ca(2+)-ATPase, and ligand binding measurements on these isolated vesicle preparations were performed in the presence of varying propofol concentrations.

Results

Propofol (10-500 microM) had no effect on ryanodine receptor-mediated Ca2+ efflux from muscle membrane vesicles. Propofol (1-100 microM) also had no effect on sarcoplasmic reticulum vesicle [3H]ryanodine binding, whereas higher concentrations (200-300 microM) slightly inhibited [3H]ryanodine binding. Binding of the dihydropyridine receptor Ca2+ channel blocker [3H]PN200-110 to these preparations was inhibited by propofol (10-300 microM). Ca(2+)-ATPase activity was stimulated by 10-100 microM propofol but was inhibited by higher concentrations. In all cases, the effects of propofol on malignant hyperthermia-susceptible and normal membrane preparations were similar.

Conclusions

In contrast to malignant hyperthermia-triggering inhalation anesthetics, propofol does not stimulate malignant hyperthermia-susceptible or normal ryanodine receptor channel activity, even at > 100 times clinical concentrations. Effects on dihydropyridine receptor and Ca(2+)-ATPase function, however, are similar to the effects of inhalation anesthestics and require much lower concentrations of propofol. These findings, demonstrating that propofol does not activate ryanodine receptor Ca2+ channels, suggest a plausible explanation for why propofol does not trigger malignant hyperthermia in susceptible persons.
An Enkephalinase Inhibitor, SCH 32615, Augments Analgesia Induced by Surgery in Mice
Authors: Jayaram Ashok , Singh Parvinder , Carp Harvey M.
Published: November 2003

Background

Stress-induced analgesia is a well recognized phenomenon in animals and humans in which endogenous opioids have been implicated. However, analgesia induced by surgical stress has not been reported. The purpose of this study was to determine whether surgery evokes analgesia and to examine the effect of SCH 32615, an inhibitor of one of the enzymes (enkephalinase) responsible for the degradation of enkephalins, on this analgesia, in mice.

Methods

Analgesia was tested using the hot-plate test. Animals were tested before any procedure was done and then at hourly intervals thereafter. Under halothane anesthesia, the anterior abdominal wall was incised, and the abdominal aorta was compressed against the vertebral column for 1 s. This was repeated for a total of three times at 5-s intervals. At the end of the procedure, the following drug(s) were administered subcutaneously to different groups of animals: (1) no drugs, only surgery (n = 15); (2) 5 mg/kg naloxone (n = 15); (3) 150 mg/kg SCH 32615 (n = 14); (4) 150 mg/kg SCH 32615 plus 5 mg/kg naloxone (n = 15); and (5) SCH 32615 vehicle (0.9% methylcellulose; n = 13). Two more groups of animals were included as controls and were anesthetized, but no surgical procedure was performed. One control group (n = 13) received 0.9% methylcellulose and the other 150 mg/kg SCH 32615 (n = 12).

Results

Hot-plate latency was significantly longer after surgery (hot-plate latency at 4 h after surgery 29.3 +/- 3.2 (SE) s and at 5 h 30.7 +/- 5 s versus baseline 15.8 +/- 7 s; P < 0.05). Naloxone (5 mg/kg) inhibited this analgesic effect of surgery. SCH 32615 significantly enhanced this analgesia (percentage of maximal possible effect (%MPE) at 4 h 33.7 +/- 8.7%, at 5 h 27.5 +/- 4.7%, and at 6 h 23.2 +/- 4.7%; P < 0.05 compared to all other groups), and naloxone antagonized its effect. Anesthesia without surgery did not evoke subsequent analgesia, and SCH 32615 was not analgesic in the absence of antecedent surgery.

Conclusions

Surgery activated endogenous analgesia, the development of which was prevented by naloxone. SCH 32615, an enkephalinase inhibitor, significantly enhanced this analgesia.
Anesthetics and Automaticity of Dominant and Latent Pacemakers in Chronically Instrumented Dogs
Authors: Woehlck Harvey J. , Vicenzi Martin N. , Bajic Jurica , Sokolyk Stephen M. , Bosnjak Zeljko J. , Atlee John L. III
Published: November 2003

Background

Subsidiary atrial pacemakers assume control after sinoatrial (SA) node excision, and anesthetic-catecholamine interactions can produce severe bradycardia during isoflurane anesthesia. We hypothesized that epinephrine enhances atrial, atrioventricular junctional, and ventricular dysrhythmias after SA node excisions in dogs and that inhalation anesthetics would facilitate such dysrhythmias.

Methods

In eight dogs, SA nodes were excised and epicardial electrodes implanted at the atrial appendages, at the His bundle, and along the sulcus terminalis. Site of the earliest atrial activation and incidences of nonatrial beats were determined in the conscious state, with methylatropine, with epinephrine, and during halothane, isoflurane, or enflurane anesthesia.

Results

After SA node excision, a stable, regular subsidiary atrial pacemaker rhythm resulted. Epinephrine and halothane shifted the site of earliest activation to more remote atrial sites. Epinephrine-induced ventricular escape was increased by all anesthetics tested, but atropine prevented ventricular escape. Epinephrine-induced His bundle (atrioventricular junctional) and premature ventricular beats were increased by halothane and enflurane. After SA node excision, ventricular escape occurred as a result of epinephrine-anesthetic interactions, especially during anesthesia with isoflurane.

Conclusions

In dogs with excised SA nodes, anesthetic-catecholamine interaction facilitates ventricular escape, His bundle dysrhythmias, and premature ventricular beats. In addition, halothane and enflurane, more than isoflurane, facilitate ectopic ventricular tachydysrhythmias with epinephrine. Compared to intact dogs, dogs with excised SA nodes may be more susceptible to epinephrine anesthetic dysrhythmias. If findings can be extrapolated to humans, intrinsic SA node dysfunction may facilitate severe cardiac dysrhythmias with inhalation anesthetics and catecholamines.
Effects of Halothane on Glutamate Receptor-mediated Excitatory Postsynaptic Currents
Authors: Perouansky Misha , Baranov Dimitri , Salman Michael , Yaari Yoel
Published: November 2003

Background

The effects of halothane on excitatory synaptic transmission in the central nervous system of mammals have been studied in vivo and in vitro in several investigations with partially contradicting results. Direct measurements of the effects of halothane on isolated glutamate receptor-mediated (glutamatergic) excitatory postsynaptic currents (EPSCs), however, have not been reported to date.

Methods

The effects of halothane on glutamatergic EPSCs were studied in vitro by using tight-seal, whole-cell recordings from CA1 pyramidal cells in thin slices from the adult mouse hippocampus. The EPSCs were pharmacologically isolated into their non-N-methyl-D-aspartate (non-NMDA) and NMDA receptor-mediated components by using selective antagonists. The effects of halothane on EPSC amplitude and kinetics were analyzed at various membrane potentials and were compared with its effects on currents evoked by exogenously applied glutamatergic agonists.

Results

Halothane (0.2-5.1%; 0.37-2.78 mM) reversibly blocked non-NMDA and NMDA EPSCs. This effect was voltage independent; concentrations producing 50% inhibition were 0.87% (0.66 mM) and 0.69% (0.57 mM), respectively. Currents induced by bath-applied glutamatergic agonists were not affected even by the high concentrations of halothane.

Conclusions

Halothane depresses glutamatergic EPSCs irrespective of receptor subtype, most likely by inhibition of glutamate release.
Halothane and Isoflurane Alter the Calcium sup 2+ Binding Properties of Calmodulin
Authors: Levin Aaron , Blanck Thomas J. J.
Published: November 2003

Background

Ca2+ plays an important role in signal transduction and anesthetic mechanisms. To date, no one has observed a direct effect of volatile anesthetics on a Ca(2+)-binding protein. We therefore examined the effects of halothane and isoflurane on the Ca(2+)-binding properties of bovine brain calmodulin.

Methods

The fluorescence emission of calmodulin was obtained over a range of Ca2+ concentrations (10(-7)-10(-4)M) in the presence and absence of halothane and isoflurane. The intrinsic tyrosine fluorescence of calmodulin was measured at an excitation wavelength of 280 nm and an emission wavelength of 320 nm. Fluorescence measurements were carried out in 50 mM hydroxyethylpiperazineethane sulfonic acid, 100 mM KC1, and 2 mM ethyleneglycol-bis-(beta-aminoethyl ether) tetraacetic acid at pH 7.0 and 37 degrees C. Experiments were performed in polytetrafluorethylene-sealed cuvettes so that the volatile anesthetic concentrations remained constant. The titration data were analyzed in two ways. The data were fit to the Hill equation by using nonlinear regression analysis to derive the Hill coefficient and the dissociation constant. The data were also analyzed by two-way analysis of variance with multiple comparisons to determine statistically significant effects. Volatile anesthetic concentrations were measured by gas chromatography.

Results

The presence of volatile anesthetics altered the Ca(2+)-binding affinity of calmodulin in a dose-dependent fashion. At 0.57% (0.25 mM) halothane and 1.7% (0.66 mM) isoflurane, the affinity of calmodulin for Ca2+ relative to control was decreased. However, at higher concentrations of both anesthetics, the affinity for Ca2+ was increased. When the volatile anesthetics were allowed to evaporate from the experimental solutions, the observed rightward shift of the calmodulin-Ca2+ binding curve for Ca2+ at low concentrations of the anesthetics returned to the control position. The leftward shift seen at high concentrations of the anesthetics was irreversible after evaporation of 8.7% (3.3 mM) isoflurane and 5.7% (2.5 mM) halothane.

Conclusions

These data demonstrate a complex interaction of two hydrophobic volatile anesthetics with calmodulin. A biphasic effect was observed both for halothane and for isoflurane. Calmodulin, an EF-hand Ca(2+)-binding protein, undergoes a conformational shift when binding Ca2+, exposing several hydrophobic residues. These residues may be sites at which the anesthetics act.
The Changing Pharmacodynamics of Metocurine Identify the Onset and Offset of Canine Gastrocnemius Disuse Atrophy
Authors: Fung D. L. , White D. A. , Gronert G. A. , Disbrow E.
Published: November 2003

Background

Immobilization of skeletal muscle results in disuse atrophy and resistance to nondepolarizing muscle relaxants. We studied the pharmacodynamics of metocurine (MTC) to identify the development and recovery of disuse-related resistance to MTC.

Methods

Nineteen dogs underwent cast immobilization of a hind limb for as long as 3 weeks. Before, during, and after casting, dogs were intermittently anesthetized with thiamylal-N2O-fentanyl. The blood concentration of MTC and the corresponding degree of paralysis after a brief infusion were recorded and were used to characterize the pharmacokinetics and pharmacodynamics of MTC.

Results

Pharmacodynamic study of the response to MTC demonstrated resistance by the 4th day of casting. The effect-site concentration associated with 50% paralysis of twitch increased after 3 weeks from approximately 250 to 750 ng/ml. After cast removal, resistance persisted for 2 more weeks. Six weeks after cast removal, the effect-site concentration associated with 50% paralysis of twitch was normal in every dog.

Conclusions

Within the context of this study of immobilization disuse atrophy, pharmacokinetic and pharmacodynamic characterization of antagonist responses can be used to infer muscle disuse-related changes in acetylcholine receptors.
Effect of Continuous Arteriovenous Hemofiltration Combined with Systemic Vasopressor Therapy on Depressed Left Ventricular Contractility and Tissue Oxygen Delivery in Canine Escherichia coli Sepsis
Authors: Mink S. N. , Jha P. , Wang R. , Yang J. , Bose D. , Jacobs H. , Light R. B.
Published: November 2003

Background

In a previous study, we showed that continuous arteriovenous hemofiltration (CAVH) reversed the depression in left ventricular (LV) contractility in canine Escherichia coli sepsis by the removal of a circulating substance the molecular weight of which is less than 30,000. Despite the normalization of LV contractility, however, we were unable to demonstrate an improvement in systemic arterial blood pressure (BP), presumably because the mechanisms underlying the depression in LV contractility and the decrease in BP are different in sepsis. In the current study, we examined the effect of combined treatment with CAVH and the alpha-adrenergic agonist phenylephrine on LV mechanics and tissue oxygen delivery in our canine E. coli model.

Methods

Measurements were obtained at baseline (condition B), after 4 h of sepsis (condition S), and after 2 h of CAVH and phenylephrine (condition P) (total of 6 h of sepsis). During P, phenylephrine was infused to restore BP to that found at baseline. The slope of the end-systolic pressure-dimension relation was used as the index of LV contractility; LV anterior-posterior dimensions were measured by sonomicrometry.

Results

During combined CAVH and phenylephrine treatment, the decrease in the slope of the end-systolic pressure-dimension relation otherwise observed at S was reversed. The slope (mean +/- SD) was 57.5 +/- 32 mmHg/mm at B versus 22.2 +/- 8 mmHg/mm at S (P < 0.05, B vs. S) versus 62 +/- 37 mmHg at P (P < 0.05 S vs. P) (analysis of variance). Mean BP was restored to that found at B (123 +/- 19 mmHg versus 82 +/- 14 mmHg (P < 0.05 B vs. S) versus 116 +/- 27 mmHg (P < 0.05 S vs. P). Combination treatment with CAVH and phenylephrine also improved stroke volume (39.3 +/- 13.5 versus 32 +/- 8 versus 44 +/- 12 ml) and tissue oxygen delivery during P compared with results obtained when phenylephrine was given alone.

Conclusions

Our study offers a rationale for the combined use of phenylephrine and CAVH in the reversal of cardiac depression and hypotension in sepsis.
Multivariate Determinants of Early Postoperative Oxygen Consumption in Elderly Patients
Authors: Frank Steven M. , Fleisher Lee A. , Olson Krista F. , Gorman Randolph B. , Higgins Michael S. , Breslow Michael J. , Sitzmann James V. , Beattie Charles
Published: November 2003

Background

Previous investigators have proposed that postoperative shivering may be poorly tolerated by patients with cardiopulmonary disease because of the associated significant increase in total-body oxygen consumption. However, the often-quoted 300-400% increase in oxygen consumption with shivering was derived from relatively few studies performed in a small number of younger persons specifically selected on the basis of clinically recognizable shivering. We hypothesized that the average elderly postoperative patient has a shivering response that is associated with a relatively small increase in total-body oxygen consumption.

Methods

One hundred eleven elderly patients (age > 60 yr) undergoing surgery were studied to assess the determinants of shivering and total-body oxygen consumption in the early postoperative period. Anesthetic technique, postoperative analgesia, and thermal management were controlled by protocol. The clinical variables associated with shivering and increased total-body oxygen consumption were determined by univariate and multivariate analyses.

Results

Mean total-body oxygen consumption in shivering patients was 38% greater than in nonshivering patients. Regardless of whether data from shivering patients were included in the analysis, oxygen consumption was directly proportional to mean body temperature. Despite similar core temperatures, men had a greater incidence of clinically recognizable shivering and greater total-body oxygen consumption than did women.

Conclusions

The metabolic demands associated with postoperative shivering in elderly patients are less than those reported previously in younger persons. These findings suggest that if hypothermia predisposes to cardiovascular complications in the postoperative period, these complications are not likely to be mediated by shivering and increased metabolism.
Improved Amplitude of Myogenic Motor Evoked Responses after Paired Transcranial Electrical Stimulation during Sufentanil/Nitrous Oxide Anesthesia
Authors: Kalkman Cor J. , Ubags Leon H. , Been Henk D. , Swaan Astrid , Drummond John C.
Published: November 2003

Background

Measurement of motor evoked responses to transcranial stimulation (tc-MER) is a technique for intraoperative monitoring of motor pathways in the brain and spinal cord. However, clinical application of tc-MER monitoring is hampered because most anesthetic techniques severely depress the amplitude of motor evoked responses. Because paired electrical stimuli increase tc-MER responses in awake subjects, we examined their effects in anesthetized patients undergoing surgery. METHODS. Eleven patients whose neurologic condition was normal and who were undergoing spinal or aortic surgery were anesthetized with sufentanil-N20-ketamine. Partial neuromuscular blockade (single-twitch height 25% of baseline) was maintained with vecuronium. Single and paired electrical stimuli were delivered to the scalp, and compound action potentials were recorded from the tibialis anterior muscle. The amplitude and latency of the tc-MERs were measured as the interval between paired stimuli was varied between 0 (single stimulus) and 10 ms. All recordings were completed before spinal manipulation or aortic clamping.

Results

Median amplitude of the tc-MER after a single stimulus was 106 microV (10th-90th percentiles: 23-1,042 microV), and the latency to onset was 33.2 +/- 1.4 ms (SD). With paired stimuli (interstimulus interval 2-3 ms), tc-MER amplitudes increased to 285 (79-1,605) microV, or 269% of the single-pulse response (P < 0.01). Reproducibility of individual responses increased with paired stimulation. Onset latency decreased to 31.4 +/- 3.2 ms (P < 0.05). Maximum amplitude augmentation was observed with interstimulus intervals between 2 and 5 ms and in patients with low-amplitude responses after single-pulse stimulation.

Conclusions

Application of paired transcranial electrical stimuli increases amplitudes and reproducibility of tc-MERs during anesthetic-induced depression of the motor system. The effect may represent temporal summation of stimulation at cortical or spinal sites. The results of this study warrant further clinical evaluation of paired transcranial stimulation.
Pharmacokinetics of Inhaled Liposome-encapsulated Fentanyl
Authors: Hung Orlando R. , Whynot Sara C. , Varvel John R. , Shafer Stephen L. , Mezei Michael
Published: November 2003

Background

Pulmonary administration of fentanyl solution can provide satisfactory but brief postoperative pain relief. Liposomes are microscopic phospholipid vesicles that can entrap drug molecules. Liposomal delivery of fentanyl has the potential to control the uptake of fentanyl by the lungs and thus provide sustained drug release. To demonstrate that inhalation of a mixture of free and liposome-encapsulated fentanyl can provide a rapid increase and sustained plasma fentanyl concentrations (CfenS), this study determined the pharmacokinetic profiles after the inhalation of free and liposome-encapsulated fentanyl in healthy volunteers.

Methods

After obtaining institutional approval and informed consent, ten healthy volunteers (five men, five women) were studied. Each subject received 200 micrograms intravenous fentanyl and inhaled 2,000 micrograms of free (50%) and liposome-encapsulated fentanyl (50%) on separate occasions. Frequent venous blood samples were collected, and CfenS were determined by radioimmunoassay. The pharmacokinetics and absorption characteristics of the inhaled mixture of free and liposome-encapsulated fentanyl were determined using moment analysis and least-squares numeric deconvolution.

Results

The mean (+/- SD) volume of distribution at steady-state and clearance of fentanyl after the intravenous administration were comparable to previous studies: 435 +/- 1821 and 0.584 +/- 0.209 l.min-1, respectively. The mean (+/- SD) peak Cfen was significantly greater for the intravenous administration compared to the aerosol mixture of free and liposome-encapsulated fentanyl (4.67 +/- 1.87 vs. 1.15 +/- 0.36 ng.ml-1). However, CfenS at 8 and 24 h after aerosol administration were greater compared to intravenous (0.25 +/- 0.14 and 0.12 +/- 0.16 ng.ml-1 for aerosol versus 0.16 +/- 0.10 and 0.05 +/- 0.06 ng.ml-1 for intravenous). The peak absorption rate, time to peak absorption, and bioavailability after inhalation were 7.02 (+/- 2.34) micrograms.min, -1(16) (+/- 8.0) min, and 0.12 (+/- 0.11), respectively.

Conclusions

The data suggest that this analgesic method offers a simple and noninvasive route of administration with a rapid increase of Cfen and a prolonged therapeutic fentanyl concentration. Future studies are required to determine the optimal liposome composition that would produce a sustained stable Cfen within analgesic therapeutic concentrations.
Alfentanil Slightly Increases the Sweating Threshold and Markedly Reduces the Vasoconstriction and Shivering Thresholds
Authors: Kurz Andrea , Go Janice C. , Sessler Daniel I. , Kaer Klaus , Larson Merlin D. , Bjorksten Andrew R.
Published: November 2003

Background

Hypothermia is common in surgical patients and victims of major trauma; it also results from environmental exposure and drug abuse. In most cases, hypothermia results largely from drug-induced inhibition of normal thermoregulatory control. Although opioids are given to a variety of patients, the thermoregulatory effects of opioids in humans remain unknown. Accordingly, the hypothesis that opioid administration impairs thermoregulatory control was tested.

Methods

Eight volunteers were studied, each on 3 days: (1) a target total plasma alfentanil concentration of 100 ng/ml, (2) control (no drug), and (3) a target alfentanil concentration of 300 ng/ml. Each day, skin and core temperatures were increased sufficiently to provoke sweating. Temperatures subsequently were reduced to elicit peripheral vasoconstriction and shivering. Mathematical compensations were made for changes in skin temperature using the established linear cutaneous contributions to control of sweating (10%) and to vasoconstriction and shivering (20%). From the calculated thresholds (core temperatures triggering responses at a designated skin temperature of 34 degrees C) and unbound plasma alfentanil concentrations, the individual concentration-response relationship was determined. The concentration-response relationship for all the volunteers was determined similarly using total alfentanil concentrations.

Results

In terms of unbound concentration, alfentanil increased the sweating threshold (slope = 0.021 +/- 0.016 degrees C.ng-1.ml; r2 = 0.92 +/- 0.06). Alfentanil also significantly decreased the vasoconstriction (slope = -0.075 +/- 0.067 degrees C.ng-1.ml; r2 = 0.92 +/- 0.07) and shivering thresholds (slope = -0.063 +/- -0.037 degrees C.ng-1.ml; r2 = 0.98 +/- 0.04). In terms of total alfentanil concentration (degrees C.ng-1.ml), the sweating threshold increased according to the equation: threshold (degrees C) = 0.0014[alfentanil] + 37.2 (r2 = 0.33). In contrast, alfentanil produced a linear decrease in the core temperature, triggering vasoconstriction: threshold (degrees C) = -0.0049[alfentanil] + 36.7 (r2 = 0.64). Similarly, alfentanil linearly decreased the shivering threshold: threshold (degrees C) = -0.0057[alfentanil] + 35.9 (r2 = 0.70).

Conclusions

The observed pattern of thermoregulatory impairment is similar to that produced by most general anesthetics: a slight increase in the sweating threshold and a substantial, linear decrease in the vasoconstriction and shivering thresholds.
d-Tubocurarine Accentuates the Burn-induced Upregulation of Nicotinic Acetylcholine Receptors at the Muscle Membrane
Authors: Kim C. , Hirose M. , Martyn J. A. J.
Published: November 2003

Background

Increases in acetylcholine receptors (AChRs) at the muscle membrane, induced by burn injury, have been associated with a hyperkalemic response to succinylcholine and resistance to d-tubocurarine-like drugs. Muscle relaxants often are administered to burn-injured patients in the intensive care unit to facilitate mechanical ventilation. This study in rats tested whether continuous administration of d-tubocurarine in subparalytic doses exaggerates the upregulation of AChRs induced by burn trauma. Subparalytic doses were used to avoid the confounding effects of immobilization.

Methods

Three days after an approximate 50% body surface area burn or sham injury, the animals received an infusion of 3.03 +/- 0.05 micrograms/h of d-tubocurarine or equal volume of saline directly to the left gastrocnemius muscle via catheter connected to a subcutaneously implanted osmotic pump. After 7 days of d-tubocurarine or saline infusion, the AChRs were quantitated using 125I-alpha-bungarotoxin. The AChRs on the d-tubocurarine or saline-infused left gastrocnemius were compared to the contralateral gastrocnemius in the same group. The right or left gastrocnemius AChRs were compared to the ipsilateral muscles between groups. These intra- and intergroup comparisons allowed the delineation of the effects of catheter irritation, burns, or d-tubocurarine on AChRs.

Results

Daily examination of the withdrawal response to toe-pinch revealed no evidence of paralysis. Weight loss in the burn-injury animals receiving d-tubocurarine or saline was similar, confirming that the infusion of d-tubocurarine did not impair the mobility of the animals to move and feed. The plasma d-tubocurarine concentration after 7 days of infusion was 26.0 +/- 12 ng/ml (mean +/- SE). Regardless of burn or sham injury or of d-tubocurarine or saline infusion, the concentration of AChRs on the left was consistently greater than in the contralateral right gastrocnemius muscles within the same group, indicating that manipulation of the area alone can result in upregulation of AChRs. The AChRs in the right gastrocnemius of burn-injured animals were greater than those in the same muscle of sham-injured animals, regardless of saline (7.24 +/- 0.9 vs. 5.7 +/- 0.5 fmoles/mg protein, P = 0.06) or d-tubocurarine (7.3 +/- 0.4 vs. 5.7 +/- 0.5, P < 0.05) infusion to the burn-injury groups. AChRs in the left gastrocnemius of burn-injury animals receiving d-tubocurarine were significantly greater than those in burn- or sham-injury animals receiving saline (13.9 +/- 1.1 vs. 9.8 +/- 1.2 and 7.1 +/- 0.5 fmoles/mg protein, respectively, P < 0.05).

Conclusions

Burn-induced upregulation of AChRs is accentuated by infusion of subparalytic doses of d-tubocurarine. Concomitant administration of d-tubocurarine to burn-injured patients may result in further exaggeration of the aberrant responses to neuromuscular relaxants.
Frequency-dependent Effects of Propofol on Atrioventricular Nodal Conduction in Guinea Pig Isolated Heart
Authors: Alphin Robert S. , Martens Jeffrey R. , Dennis Donn M.
Published: November 2003

Background

The use of propofol has been associated with episodes of bradycardias. The mechanism(s) underlying these phenomena are not well defined. Therefore we investigated (1) the chronotropic and dromotropic effects of propofol, (2) the frequency-dependent effects of propofol on the atrioventricular (AV) node, and (3) the physiologic mechanism(s) underlying propofol's effects on AV nodal conduction.

Methods

Guinea pig isolated, perfused hearts were instrumented for measurement of atrial rate and AV nodal conduction time in spontaneously beating hearts, or stimulus-to-His bundle (S-H) intervals in atrially paced hearts. In addition, the Wenckebach cycle length, effective refractory period and S-H interval prolongation to an abrupt increase in pacing rate were measured to further define propofol's dromotropic effects and frequency-dependent behavior.

Results

Propofol, in a concentration-dependent manner, (1) slowed atrial rate and AV nodal conduction time in spontaneously beating hearts, (2) prolonged the S-H interval in atrially paced hearts, and (3) prolonged Wenckebach cycle length and effective refractory period. The negative dromotropic effect of propofol was greater during atrial pacing than in spontaneously beating hearts. Furthermore, this effect was enhanced at faster pacing rates, indicating frequency-dependent behavior. Atropine significantly antagonized propofol-induced S-H interval prolongation. The results of competition binding studies also supported a M2-muscarinic receptor-mediated mechanism.

Conclusions

We conclude that in the isolated guinea pig heart, propofol slows atrial rate and depresses AV nodal conduction in a concentration-dependent manner. The negative dromotropic effect of propofol shows frequency dependence and is predominantly mediated by M2-muscarinic receptors. Given the marked rate dependence of propofol's AV nodal actions, this anesthetic agent may impart antidysrhythmic protection to those patients susceptible to supraventricular tachycardias.
Halothane, Enflurane, and Isoflurane Do Not Affect the Basal or Agonist-stimulated Activity of Partially Isolated Soluble and Particulate Guanylyl Cyclases of Rat Brain
Authors: Zuo Zhiyi , Johns Roger A.
Published: November 2003

Background

Evidence suggests that inhalational anesthetics interact with the nitric oxide-guanylyl cyclase signaling pathway in the central nervous system and that the inhibitation of this pathway in brain may result in an anesthetic, analgesic, or sedative effect. The mechanism of the effects inhalational anesthetics on this signaling pathway is not clear. This study attempted to determine whether inhalational anesthetics directly affect soluble or particulate guanylyl cyclase activity in a partially isolated enzyme system.

Methods

The effects of halothane (0.44-4.4%), enflurane (1.34-6.7%), and isoflurane (0.6-5.0%) on basal or stimulated soluble or particulate guanylyl cyclase activity were examined. Soluble guanylyl cyclase was isolated from whole rat brain and was stimulated by sodium nitroprusside or nitric oxide. Particulate guanylyl cyclase was isolated from rat olfactory bulb and was stimulated by rat atrial natriuretic peptide(1-28). Cyclic guanosine monophosphate content was measured by radiommunoassay. The concentrations of anesthetics in the incubation solution were confirmed by gas chromatography methods.

Results

None of the three anesthetics affected the activity of basal or stimulated soluble or particulate guanylyl cyclase at the concentrations examined in the current experimental conditions.

Conclusions

These results suggest that halothane, enflurane, and isoflurane do not directly interact with soluble or particulate guanylyl cyclases of rat brain.
Effect of Fentanyl on the Minimum Alveolar Concentration of Isoflurane in Swine
Authors: Moon Paula F. , Scarlett Janet M. , Ludders John W. , Conway Teresea A. , Lamb Steven V.
Published: November 2003

Background

Fentanyl is used in anesthetic protocols for swine, but there are no reports on its potency in this species. This study measured the extent to which fentanyl reduces the minimum alveolar concentration of isoflurane (MACISO) in swine.

Methods

Sixteen swine were randomly assigned to four groups. For each group, baseline MACISO was determined, and three groups received two of three fentanyl infusions as follows: 50 micrograms.kg-1.h-1 intravenously followed by 100 micrograms.kg-1.h-1, 50 micrograms.kg-1.h-1 followed by 200 micrograms.kg-1.h-1, or 100 micrograms.kg-1.h-1 followed by 200 micrograms.kg-1.h-1 (n = 8 for each dosage). A loading dose of fentanyl preceded each infusion. Each infusion was maintained for 60 min before initiating minimum alveolar concentration determination. The infusions were maintained throughout the period of minimum alveolar concentration determination. Plasma fentanyl samples were obtained after 30 min of each infusion, and plasma fentanyl and hemodynamic parameters were obtained immediately before stimulating swine for the final isoflurane concentration used in determining minimum alveolar concentration. A fourth group, control animals, received saline infusions. After each infusion, the MACISO was redetermined. Minimum alveolar concentration was determined using incremental changes in isoflurane concentrations until gross purposeful movement resulted when using a hemostat stimulus applied for 1 min to a rear dewclaw.

Results

MACISO for controls was 2.19 +/- 0.17% (mean +/- SEM) and changed minimally over time (-0.13 +/- 4.77%). MACISO decreased significantly (P < or = 0.01) 24.5 +/- 3.2%, 29.9 +/- 4.8%, and 45.9 +/- 5.5% with fentanyl dosages of 50, 100, and 200 micrograms.kg-1.h-1, respectively. Corresponding plasma fentanyl concentrations were 14 +/- 1 ng/ml, 26 +/- 3 ng/ml, and 59 +/- 5 ng/ml, respectively. A ceiling effect on reduction of MACISO was not observed. Changes over time or between groups were not observed for arterial blood gas tensions, blood pressure, heart and respiratory rate, or body temperature.

Conclusions

These fentanyl dosages are larger than those commonly used in humans and other species. Anesthetic protocols using fentanyl for swine should be designed with the knowledge that a fentanyl infusion of 200 micrograms.kg-1.h-1 contributes approximately a 50% MACISO equivalent.
Region of Epidural Blockade Determines Sympathetic and Mesenteric Capacitance Effects in Rabbits
Authors: Hogan Quinn H. , Stekiel Thomas A. , Stadnicka Anna , Bosnjak Zeljko J. , Kampine John P.
Published: November 2003

Background

The mechanisms producing hemodynamic changes during epidural anesthesia are incompletely understood. The role of capacitance changes in the splanchnic venous bed can be clarified by comparing blocks of differing segmental distributions. Specifically, we speculated that blocks that include the innervation to the mesenteric circulation alter hemodynamics, sympathetic activity, and venous capacitance to a greater extent than blocks without blockade of sympathetic nerves to this critical vascular bed.

Methods

Rabbits were studied during alpha-chloralose anesthesia and mechanical ventilation. Sympathetic efferent nerve activity to the mesenteric vessels was measured by surgically placed electrodes, and mesenteric vein diameter was measured by videomicroscopy. Heart rate and mean arterial pressure were monitored by intraarterial cannulation. Responses were compared after administration of epidural lidocaine using a dose and catheter level that limited anesthetic to lumbar levels (lumbar group) or thoracic levels (thoracic group). In addition, hemodynamic responses were recorded after thoracolumbar block in animals receiving alpha-chloralose but breathing spontaneously (spontaneous ventilation group) and in awake animals (awake group).

Results

Mean arterial pressure decreased 38.3 +/- 5.8% in the thoracic group but only 16.5 +/- 2.8 in the lumbar group. Sympathetic efferent nerve activity decreased in the thoracic group but increased in the lumbar group. An increase in vein diameter followed thoracic epidural anesthesia, but venoconstriction was observed after lumbar epidural block. The addition of intravenous sedation with alpha-chloralose did not increase the hypotensive effect of epidural anesthesia in this model.

Conclusions

Block of sympathetic fibers to the splanchnic circulation with thoracic epidural lidocaine produces mesenteric venodilatation that contributes to hypotension in rabbits. A lesser decrease in blood pressure follows blocks limited to lower segments, because baroreceptor stimulation produces increased splanchnic sympathetic activity and mesenteric venoconstriction. Responses in this model are comparable with and without general anesthesia and mechanical ventilation. To minimize hemodynamic consequences, epidural blockade should ideally be confined to the fewest necessary segments, avoiding splanchnic innervation if possible.
Cardiovascular Effects of Sevoflurane Compared with Those of Isoflurane in Volunteers
Authors: Malan Jr. Philip T. , DiNardo James A. , Isner Joseph R. , Frink Jr. Edward J. , Goldberg Mark , Fenster Paul E. , Brown Elizabeth A. , Depa Raymond , Hammond Leslie C. , Mata Heriberto
Published: November 2003

Background

Sevoflurane is a new inhalational anesthetic with desirable clinical properties. In some clinical situations, an understanding of the detailed cardiovascular properties of an anesthetic is important, so the authors evaluated the hemodynamic effects of sevoflurane in healthy volunteers not undergoing surgery.
Dose-Response Curves of Inhaled Nitric Oxide with and without Intravenous Almitrine in Nitric Oxide-responding Patients with Acute Respiratory Distress Syndrome
Authors: Lu Qin , Mourgeon Eric , Law-Koune Jean Dominique , Roche Sabine , Vezinet Corinne , Abdennour Lamine , Vicaut Eric , Puybasset Louis , Diaby Mohamed , Coriat Pierre , Rouby Jean-Jacques
Published: November 2003

Background

Inhaled nitric oxide, a selective pulmonary vasodilator, in combination with intravenous almitrine, a selective pulmonary vasoconstrictor, markedly improves arterial oxygenation in 50–60% of patients with acute lung injury. The goal of this study was to assess dose response of inhaled nitric oxide with and without almitrine in patients with acute respiratory distress syndrome responding to nitric oxide.
Analysis of Halothane Effects on Myocardial Force-Interval Relationships at Anesthetic Concentrations Depressing Twitches but Not Tetanic Contractions
Authors: Vogel Stephen M. , Weinberg Guy L. , Djokovic Andreja , Miletich David J. , Albrecht Ronald F.
Published: November 2003

Background

Tetanic contractions in rat myocardium depend solely on cellular Calcium2+ uptake, whereas twitches depend on Calcium2+ release from the sarcoplasmic reticulum. Because halothane may cause loss of sequestered Calcium2+, the anesthetic was tested for its differential effects on twitch and tetanic forces. The in vitro effects of halothane on the twitch force-interval relationship were then evaluated, using a mathematical model that relates twitch contractile force to the Calcium2+ content of intracellular compartments.
Evaluation of a Double-lumen Multiorifice Catheter for Resuscitation of Swine from Lethal Venous Air Embolism
Authors: Mongan Paul D. , Hinman Jon A.
Published: November 2003

Background

A double-lumen multiorifice catheter has been developed to potentially enhance accurate electrocardiographic central venous localization and resuscitation from a massive venous air embolism (VAE). This double-lumen multiorifice catheter was compared to a Bunegin-Albin multiorifice catheter for flow characteristics, air aspiration efficiency, and efficacy in resuscitating swine from a lethal VAE.
Premedication with Famotidine Augments Core Hypothermia during General Anesthesia
Authors: Hirose Munetaka , Hara Yumi , Matsusaki Masahiko
Published: November 2003

Background

Animal studies have provided considerable evidence to support a role of histamine in the central nervous system in thermoregulation, and premedication with a histamine Hydrogen2receptor antagonist before general anesthesia is used to reduce the risk of acid aspiration. The authors investigated whether premedication with famotidine had an effect on thermoregulation during general anesthesia.
Volatile and Intravenous Anesthetics Decrease Glutamate Release from Cortical Brain Slices during Anoxia
Authors: Bickler Philip E. , Buck Leslie T. , Feiner John R.
Published: November 2003

Background

Extracellular accumulation of the excitatory neurotransmitter L-glutamate during cerebral hypoxia or ischemia contributes to neuronal death. Anesthetics inhibit release of synaptic neurotransmitters but it is unknown if they alter net extrasynaptic glutamate release, which accounts for most of the glutamate released during hypoxia or ischemia. The purpose of this study was to determine if different types of anesthetics decrease hypoxia-induced glutamate release from rat brain slices.
Diaspirin Cross-linked Hemoglobin Does Not Increase Brain Oxygen Consumption during Hypothermic Cardiopulmonary Bypass in Rabbits
Authors: Hindman Bradley J. , Dexter Franklin , Cutkomp Johann , Smith Tom
Published: November 2003

Background

Decreased erythrocyte deformability due to cardiopulmonary bypass (CPB) and/or hypothermia, may result in brain capillary beds that have decreased erythrocyte transit, resulting in a generalized impairment of brain oxygenation during CPB. Because brain capillary plasma flow continues even when erythrocyte flow is absent, the authors' hypothesized augmentation of plasma oxygen content with a non-erythrocyte-associated oxygen transport molecule would increase brain oxygen uptake during hypothermic CPB.
Vasomotor Responses of Rat Coronary Arteries to Isoflurane and Halothane Depend on Preexposure Tone and Vessel Size
Authors: Park K. W. , Dai H. B. , Lowenstein E. , Sellke F. W.
Published: November 2003

Background

The authors previously reported that in rabbits, isoflurane exhibited a heterogeneous vasomotor effect, constricting small resistance coronary arteries and dilating larger conductance arteries. The novelty of isoflurane-induced constriction of small coronary arteries raised the question of whether the finding depended on the unique experimental setup or species used. The purpose of this study was to address these questions. Therefore, a second species was studied, namely rats, as well as a second volatile anesthetic, halothane. In addition, the dependence of the vasomotor effect on the preexisting tone of the vessels was examined.
Cardiac Outcome after Peripheral Vascular Surgery
Authors: Bode Robert H. , Lewis Keith P. , Zarich Stuart W. , Pierce Eric T. , Roberts Mark , Kowalchuk Glen J. , Satwicz Paul R. , Gibbons Gary W. , Hunter Jennifer A. , Espanola Cynthia C. , Nesto Richard W.
Published: November 2003

Background

Despite evidence that regional anesthesia may be associated with fewer perioperative complications than general anesthesia, most studies that have compared cardiac outcome after general or regional anesthesia alone have not shown major differences. This study examines the impact of anesthetic choice on cardiac outcome in patients undergoing peripheral vascular surgery who have a high likelihood of associated coronary artery disease.

Methods

Four hundred twenty-three patients, between 1988 and 1991, were randomly assigned to receive general (n = 138), epidural (n = 149), or spinal anesthesia (n = 136) for femoral to distal artery bypass surgery. All patients were monitored with radial artery and pulmonary artery catheters. Postoperatively, patients were in a monitored setting for 48-72 h and had daily electrocardiograms for 4-5 days and creatine phosphokinase/isoenzymes every 8 h x 3, then daily for 4 days. Cardiac outcomes recorded were myocardial infarction, angina, and congestive heart failure.

Results

Baseline clinical characteristics were not different between anesthetic groups. Overall, the patient population included 86% who were diabetic, 69% with hypertension, 36% with a history of a prior myocardial infarction, and 41% with a history of smoking. Cardiovascular morbidity and overall mortality were not significantly different between groups when analyzed by either intention to treat or type of anesthesia received. In the intention to treat analysis, incidences of cardiac event or death for general, spinal, and epidural groups were 16.7%, 21.3%, and 15.4%, respectively. The absolute risk difference observed between general and all regional anesthesia groups for cardiac event or death was -1.6% (95% confidence interval -9.2%, 6.1%) This reflected a nonsignificant trend for lower risk of postoperative events with general anesthesia.

Conclusions

The choice of anesthesia, when delivered as described, does not significantly influence cardiac morbidity and overall mortality in patients undergoing peripheral vascular surgery.