bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Cardiovascular Effects and Histamine-releasing Properties of 51W89 in Patients Receiving Nitrous Oxide/Opioid/Barbiturate Anesthesia
Authors: Lien Cynthia A. , Belmont Matthew R. , Abalos Amy , Eppich Larissa , Quessy Steve , Abou-Donia Martha M. , Savarese John J. 
Published: November 2003

Background
Atracurium consists of a mixture of ten stereoisomers. One of these isomers, 51W89, is a potent intermediate-acting nondepolarizing neuromuscular blocking agent. Its ED95 is 0.05 mg.kg-1 in patients receiving nitrous oxide/opioid anesthesia. In preclinical trials, 51W89 did not show evidence of histamine release in cats at doses up to 80 times the human ED95. This study was undertaken to determine the cardiovascular effects and histamine-releasing properties of 51W89 in patients undergoing elective surgical procedures.

Methods
Sixty patients, ASA physical status 1 or 2, anesthetized with nitrous oxide/fentanyl/thiopental were studied. Patients received either 2 times the ED95 of atracurium or 51W89 or 4 or 8 times the ED95 of 51W89 as a rapid intravenous bolus under stable anesthesia, before surgical stimulation. Blood pressure and heart rate were measured by oscillometry and the electrocardiogram in patients receiving 2 times the ED95 of 51W89 or atracurium and by an intraarterial catheter and a tachograph triggered by the arterial pulse waveform in patients receiving 4 or 8 times the ED95 of 51W89. Maximal blood pressure and heart rate changes during the 5 min after administration of the muscle relaxant were recorded. Venous blood samples were obtained before the administration of relaxant and at 2 and 5 min after the administration of relaxant for determination of plasma histamine concentrations by radioenzymatic assay.

Results
Maximal blood pressure and heart rate changes in all groups of patients receiving 51W89 were small and similar to those observed in patients receiving 2 times the ED95 of atracurium. The mean maximum percent changes (+/- SE) in heart rate and mean arterial pressure were -0.6 +/- 1.5 and 0.4 +/- 2.5, respectively, in the group receiving 2 times the ED95 atracurium; -1.3 +/- 3.3 and 2.3 +/- 4.4, respectively, in the group receiving 2 times the ED95 51W89; -2.6 +/- 1.0 and 2.6 +/- 1.5, respectively, in the group receiving 4 times the ED95 51W89; and -2.4 +/- 1.5 and -1.0 +/- 1.3, respectively, in the group receiving 8 times the ED95 51W89. No patient developed a decrease in blood pressure > or = 20% or an increase in heart rate > or = 20% that was attributable to muscle relaxant administration. There was no dose-related change in plasma histamine concentration associated with the administration of 51W89. One patient in the study developed transient facial flushing after the administration of atracurium.

Conclusions
51W89 is a benzylisoquinolinium-type, nondepolarizing muscle relaxant that does not affect plasma histamine concentrations. No cutaneous flushing or clinically important cardiovascular effects were noted after rapid injection of doses up to and including 8 times its ED95 (0.4 mg.kg-1) in healthy patients undergoing elective surgical procedures.
The Iontophoresis of Fentanyl Citrate in Humans
Authors: Ashburn M. A. , Streisand J. , Zhang J. , Love G. , Rowin M. , Niu S. , Kievit J. K. , Kroep J. R. , Mertens M. J. 
Published: November 2003

Background
Iontophoresis is a method of transdermal administration of ionizable drugs in which the electrically charged components are propelled through the skin by an external electric field. This study was designed to determine whether iontophoresis could be used to deliver clinically significant doses of fentanyl in humans and whether there is a charge-dose relation in the delivery of fentanyl by iontophoresis.

Methods
Five adult volunteers were tested three times on separate days, once receiving passive treatment of 0.0 mA for 2 h (0 mA.min), iontophoresis 1.0 mA for 2 h (120 mA.min), and iontophoresis 2.0 mA for 2 h (240 mA.min) in an open, randomized, crossover design. Respiratory rate, heart rate, blood pressure, and hemoglobin oxygen saturation were monitored throughout the study. Plasma fentanyl concentrations were measured several times before, during, and after iontophoresis. Plasma fentanyl concentrations were measured by radioimmunoassay.

Results
No fentanyl was detected after passive (0.0-mA) fentanyl delivery. The following results were obtained for the 1.0- and 2.0-mA deliveries, respectively. Mean times to detectable concentrations of plasma fentanyl were 33 and 19 min; mean times to maximum concentration were 122 and 119 min; maximum concentrations were 0.76 and 1.59 ng/ml (P = 0.010); mean areas under the curve of the plasma fentanyl concentration versus time relation were 233 and 474 ng.ml-1.min (P = 0.003); and mean elimination half-lives were 354 and 413 min (P = 0.326). Only minor adverse side effects related to iontophoresis occurred. However, typical opioid-related effects occurred frequently in the 1.0- and 2.0-mA administration groups.

Conclusions
Clinically significant doses of fentanyl can be administered by iontophoresis for delivery periods of 2 h. A charge-dose relation exists after administration with currents of 1.0 and 2.0 mA. Future research into the iontophoresis of fentanyl as a method of potent opioid administration is indicated.
Inhibition of Sodium/Calcium Exchange and Calcium Channels of Heart Cells by Volatile Anesthetics
Authors: Haworth Robert A. , Goknur Atilla B. 
Published: November 2003

Background
Volatile anesthetics exert profound effects on the heart, probably through their effect on Ca2+ movements during the cardiac cycle. Ca2+ movements across the sarcolemma are thought to involve mainly Ca2+ channels and the Na+/Ca2+ exchanger. We have therefore investigated the action of halothane, isoflurane, and enflurane on Na+/Ca2+ exchange and Ca2+ channel activity to assess the contribution of these pathways to the observed effect of the anesthetics on the myocardium.

Methods
Sarcolemmal ion fluxes were investigated using radioisotope uptake by isolated adult rat heart cells in suspension. Na+/Ca2+ exchange activity was measured from 45Ca2+ uptake by Na(+)-loaded cells. Ca2+ channel activity was measured from verapamil-sensitive trace 54Mn2+ uptake during electric stimulation.

Results
Halothane, isoflurane, and enflurane inhibited Na+/Ca2+ exchange completely, with similar potency when concentrations were expressed in millimolar units in aqueous medium but not when expressed as minimum alveolar concentration (MAC). The inhibition by enflurane was particularly strong, > 50%, at 2 MAC. In contrast, the three anesthetics inhibited Ca2+ channels with similar potency when concentrations were expressed as MAC but not when expressed in millimolar units in aqueous medium. Hill plots of pooled data with all three anesthetics showed a slope of -3.87 +/- 0.50 for inhibition of Na+/Ca2+ exchange and -1.73 +/- 0.19 for inhibition of Ca2+ channels.

Conclusions
Halothane, isoflurane, and enflurane inhibit both Na+/Ca2+ exchange and Ca2+ channels at concentrations relevant to anesthesia, although they exhibit differences in potency and number of sites of action. At 1.5 MAC, halothane inhibits Ca2+ channels more than Na+/Ca2+ exchange, whereas enflurane inhibits Na+/Ca2+ exchange more than Ca2+ channels. Isoflurane inhibited both systems equally. The inhibition of Ca2+ influx by these agents is likely to contribute to their negative inotropic effect in the heart. The inhibition of Na+/Ca2+ exchange by enflurane may account for its observed action of delaying relaxation in species lacking sarcoplasmic reticulum.
Inferences about Respiratory Muscle Use after Cardiac Surgery from Compartmental Volume and Pressure Measurements
Authors: Clergue F. , Whitelaw W. A. , Charles J. C. , Gandjbakhch I. , Pansard J. L. , Derenne J.-P. , Viars P. 
Published: November 2003

Background
After upper abdominal surgery, patients have been observed to have alterations in respiratory movements of the rib cage and abdomen and respiratory shifts in pleural and abdominal pressure that suggest dysfunction of the diaphragm. The validity of making such deductions about diaphragm function from these observations is open to discussion.

Methods
In eight adult patients, American Society of Anesthesiologists physical status 2, scheduled for elective cardiac surgery, we measured respiratory rate, tidal volume, rib cage and abdominal cross-section changes, and esophageal (Pes) and gastric (Pga) pressures preoperatively, 1 day postoperatively, and 5 days postoperatively. These data were analyzed in detail by following the variables through each respiratory cycle.

Results
Mean delta Pga/delta Pes decreased from 0.73 preoperatively to -0.56 1 day postoperatively and recovered to 0.47 5 days postoperatively. Plots of Pes against Pga and rib cage against abdominal expansion (Konno-Mead diagrams) were constructed. Six patients showed a postoperative pattern of breathing similar to that seen in patients who have undergone abdominal surgery: a decrease in the ratio of delta Pga/delta Pes and a shift toward rib cage expansion, with an increase in breathing rate and a decrease in tidal volume. This change was accomplished in most cases by the use of abdominal muscles in expiration with an increase in inspiratory intercostal muscle action without an increase in diaphragm activation, that is, a shift in the normal balance of respiratory muscle use in favor of muscles other than the diaphragm. A different ventilatory pattern was observed in the other two patients, consisting of minimal rib cage excursion and a large abdominal excursion. In these cases tidal volume was generated largely by contraction and relaxation of abdominal muscles with probable reduction in diaphragm activity. In addition, five patients exhibited positive changes in Pes at the end of inspiration that corresponded to closure of the upper airway, relaxation of inspiratory muscles, and subsequent opening of the airway with sudden exhalation, producing a grunt.

Conclusions
Indirect measurements of respiratory muscle action based on pressure and chest wall motion are easier than are assessments based on implanted electromyogram electrodes and sonomicrometers that measure electric activity and muscle length, respectively, directly. Interpretation requires numerous assumptions and detailed analysis of phase relations among the variables. In patients after thoracic surgery, however, these measurements strongly point to a shift in the distribution of motor output toward muscles other than the diaphragm.
The Minimum Alveolar Concentration of Isoflurane in Patients Undergoing Bilateral Tubal Ligation in the Postpartum Period
Authors: Zhou Henry H. , Norman Patricia , DeLima Luiz G.R. , Mehta Mahesh , Bass David 
Published: November 2003

Background
The minimum alveolar concentration (MAC) of volatile anesthetics is decreased during pregnancy, but MAC in the early postpartum period has not been reported. The aim of this study was to determine the MAC of isoflurane and to evaluate the relation between MAC and serum progesterone and beta-endorphin in patients after delivery.

Methods
Eight patients undergoing elective bilateral tubal ligation during general anesthesia in the early postpartum period (< 12 h postpartum) and eight patients undergoing this procedure in the late postpartum period (12-25 h postpartum) were studied. Eight patients undergoing bilateral tubal ligation more than 6 weeks after delivery served as control subjects. Anesthesia was induced with propofol and maintained with isoflurane in oxygen to a steady end-tidal concentration of 0.8-1.0 vol% for 10 min. Reaction to a standardized electric stimulation applied to the forearm was graded as positive (gross or delayed movement) or negative. By using the bracketing technique, the concentration of isoflurane was increased or decreased by 0.1 vol%, depending on the positive or negative responses.

Results
The MAC (mean +/- SD) in patients in the early postpartum period was significantly less (0.75 +/- 0.17 vol%) than that in control subjects (1.04 +/- 0.12 vol%; P < 0.01) and that in patients in the late postpartum period (0.95 +/- 0.2 vol%; P < 0.05). The difference in MAC values between late postpartum and control was not significant (P > 0.05). There was an inverse correlation between progesterone concentration postpartum and time after delivery (r = -0.527; P = 0.036), but P = 0.744). There was no correlation between plasma progesterone or beta-endorphin and MAC by multiple regression (r = 0.166; P = 0.950).

Conclusions
Isoflurane MAC remains 28% less than normal within the 1st 12 h postpartum and then returns to normal 12-25 h after delivery.
Methohexital Impairs Osmoregulation
Authors: Kasner Maieli , Grosse Jochen , Krebs Martin , Kaczmarczyk Gabriele 
Published: November 2003

Background
Anesthetic agents influence central regulations. This study investigated the effects of methohexital anesthesia on renal and hormonal responses to acute sodium and water loading in dogs in the absence of surgical stress.

Methods
Fourteen experiments (two in each dog) were performed in seven well-trained, chronically tracheotomized beagle dogs kept in highly standardized environmental and dietary conditions (2.5 mmol sodium and 91 ml water/kg body weight daily). Experiments lasted 3 h, while the dogs were conscious (7 experiments) or, after 1 h control, while they were anesthetized (7 experiments) with methohexital (initial dose 6.6 mg/kg body weight and maintenance infusion 0.34 mg.min-1.kg-1 body weight) over a period of 2 h. In both experiments, extracellular volume expansion was performed by intravenous infusion of a balanced isoosmolar electrolyte solution (0.5 ml.min-1.kg-1 body weight). Normal arterial blood gases were maintained by controlled mechanical ventilation. In another five dogs the same protocol was used, and vasopressin (0.05 mU.min-1.kg-1 body weight) was infused intravenously during methohexital anesthesia.

Results
Values are given as means. During methohexital anesthesia, mean arterial pressure decreased from 108 to 101 mmHg, and heart rate increased from 95 to 146 beats/min. Renal sodium excretion decreased; urine volume increased; and urine osmolarity decreased from 233 to 155 mosm/l, whereas plasma osmolarity increased from 301 to 312 mosm/l because of an increase in plasma sodium concentration from 148 to 154 mmol/l. Plasma renin activity, plasma aldosterone concentration, plasma atrial natriuretic peptide, and plasma antidiuretic hormone concentrations (range 1.8-2.8 pg/ml) did not change in either protocol. In the presence of exogenous vasopressin (antidiuretic hormone 3.3 pg/ml), water diuresis did not occur, and neither plasma osmolarity nor the plasma concentration of sodium changed.

Conclusions
Methohexital may impair osmoregulation by inhibiting adequate pituitary antidiuretic hormone release in response to an osmotic challenge.
Ketamine Has Stereospecific Effects in the Isolated Perfused Guinea Pig Heart
Authors: Graf Bernhard M. , Vicenzi Martin N. , Martin Eike , Bosnjak Zeljko J. , Stowe David F. 
Published: November 2003

Background
S(+)-Ketamine is judged to produce more potent anesthesia than either the racemate or the R(-) ketamine isomer because of differential activation of specific cerebral receptors. Other than central nervous system effects, the most important side effects of ketamine occur in the cardiovascular system. We examined the direct cardiac effects of the isomers and the racemate of ketamine in the isolated perfused guinea pig heart.

Methods
Twenty-three guinea pig hearts were perfused by the Langendorff technique with modified 37 degrees C Krebs-Ringer's solution (97% oxygen and 3% carbon dioxide) at a constant perfusion pressure. Eight animals were pretreated with reserpine to deplete hearts of catecholamines. These pretreated hearts were also perfused with Krebs-Ringer's solution containing propranolol, phenoxybenzamine, and atropine to block any remaining effects of catecholamines and of acetylcholine. Five additional hearts were perfused with naloxone to block cardiac opioid receptors. Ten hearts were not treated. All 23 hearts were then exposed to four increasing equimolar concentrations of each isomer and the racemate of ketamine for 10 min. Heart rate, atrioventricular conduction time (AVCT), left ventricular pressure, coronary flow, and inflow and outflow oxygen tensions were measured. Percentage oxygen extraction, oxygen delivery, and oxygen consumption were calculated.

Results
Both isomers and the racemate caused a concentration-dependent depression of systolic left ventricular pressure and an increase in AVCT. In the untreated hearts, S(+)-ketamine decreased heart rate and left ventricular pressure and, at higher concentrations, oxygen consumption and percentage oxygen extraction significantly less than R(-)-ketamine independent of blocked or unblocked opioid receptors. Racemic ketamine depressed cardiac function to a degree intermediate to that produced by the isomers. Coronary flow and AVCT were equally affected by the isomers and by the racemic mixture. In the catecholamine-depleted hearts both isomers and the racemate caused equipotent depression of all variables. In these hearts cardiac depression was greater, and AVCT, coronary flow, and oxygen delivery were significantly greater than in untreated and opioid receptor-blocked hearts.

Conclusions
Lesser cardiac depression by the S(+) isomer is attributable to an increased availability of catecholamines, because previous depletion of catecholamine stores and autonomic blockade completely inhibited these differences. The inability of cardiac tissue to reuptake released catecholamines into neuronal or extraneuronal sites during exposure to ketamine is stereoselective and caused predominantly by the S(+) isomer. Cardiac opioid receptors are apparently not involved in this phenomenon.
Halothane Restores the Altered Force-Frequency Relationship in Failing Human Myocardium
Authors: Schmidt Ulrich , Schwinger Robert H. G. , Bohm Michael 
Published: November 2003

Background
The terminally failing human myocardium exerts a negative force-frequency relationship (FFR), whereas a positive FFR occurs in nonfailing myocardium. To study the possibility of pharmacologically influencing this defect of the failing human heart, the effect of halothane on the basal FFR and the FFR in the presence of isoproterenol and ouabain was investigated.

Methods
Experiments were performed on isolated, electrically driven (0.5-2 Hz, 37 degrees C, Ca2+ 1.8 mmol/l) ventricular preparations. Myocardium from human failing and nonfailing hearts was obtained at cardiac surgery. To further characterize the studied myocardium, the positive inotropic effect of isoproterenol and the density of beta-adrenoceptors were measured using the radioligand 125I-CYP.

Results
Halothane produced a negative inotropic effect. The anesthetic (0.38 mmol/l) reversed the negative FFR in failing myocardium, antagonized the effect of isoproterenol (0.1 mumol/l) on FFR, and restored the FFR in the presence of ouabain.

Conclusions
Halothane restores the FFR in human failing myocardium possibly by influencing the intracellular Ca2+ homeostasis. These findings provide evidence that pharmacologic interventions, e.g., during anesthesia, may influence contractility also as a result of a depressed or enhanced FFR.
The Local Anesthetic n-Butyl-p-Aminobenzoate Selectively Affects Inactivation of Fast Sodium Currents in Cultured Rat Sensory Neurons
Authors: Van den Berg R. J. , Van Soest P. F. , Wang Z. , Grouls R. J. E. , Korsten H. H. M. 
Published: November 2003

Background
Aqueous suspensions of the local anesthetic n-butyl-p-aminobenzoate (BAB), epidurally applied in terminal cancer patients, resulted in a sensory blockade, lasting up to several months. To investigate the mechanism of action on the cellular level, the effect of 100 microM BAB on Na+ action potentials and on Na+ currents in dorsal root ganglion neurons from neonatal rats was studied.

Methods
Small neurons grown in cell culture were selected for patch-clamp measurements. Both Na+ action potentials, evoked by current pulses of increasing amplitude (current clamp) and Na+ currents, activated at different membrane potentials (voltage clamp), were investigated in the absence and presence of 100 microM BAB. The local anesthetic was applied by external perfusion for 2 or 10 min.

Results
In the presence of 100 microM BAB, either the firing threshold was raised or the action potential was abolished. The maximal peak conductances, underlying the fast sodium current INa,F and the slow sodium current INa,5, were not changed. However, the inactivation of INa,F was increased by BAB. The sigmoid inactivation curve shifted 12 mV toward hyperpolarizing membrane voltages, whereas no changes were found for the inactivation of the slow Na+ current. Only at short exposure times of 2 min, the effects of BAB could be reversed during a 10-min wash-out.

Conclusions
BAB dramatically increased the firing threshold, and in part of the sensory neurons, it blocked the action potential. The inactivation of the fast Na+ channels, but not of the slow Na+ channels, was increased by BAB. Thus, the block of fast Na+ channels by BAB may contribute to epidural analgesia. At exposure times of 10 min, the effect of BAB was not reversible. This probably originates from its high lipid-solubility, which may be an important factor in determining the duration of the block in vivo.
Computer-controlled Epidural Infusion to Targeted Cerebrospinal Fluid Concentrations in Humans
Authors: Eisenach James C. , Hood David D. , Tuttle Robin , Shafer Steven , Smith Thomas , Tong Chuanyao 
Published: November 2003

Background
Pharmacokinetically designed infusions have been demonstrated to achieve rapidly and maintain desired concentrations of drug in plasma after intravenous administration. In this study we tested whether a similar approach, targeting concentrations in cerebrospinal fluid (CSF), could be used with epidural administration of the alpha 2-adrenergic analgesic clonidine.

Methods
After institutional review board approval and informed consent had been obtained, seven healthy volunteers received a clonidine infusion through a lower lumbar epidural catheter. Infusion of clonidine (10 micrograms/ml) was controlled by the STANPUMP program for sequential 75-min periods to targeted CSF clonidine concentrations of 25, 50, 75, and 150 ng/ml. Before reprogramming to the next higher targeted concentration, mean arterial blood pressure and heart rate were measured; blood was obtained for clonidine and catecholamine assays; and visual analog score for sedation and pain to immersion of foot and hand in ice water were obtained. CSF was collected during infusion with an indwelling lumbar intrathecal catheter and was analyzed for clonidine, catecholamines, and acetylcholine.

Results
CSF clonidine concentrations rapidly increased and were maintained at steady values with the stepped infusion, although observed concentrations were consistently greater than targeted. The relation between CSF clonidine concentration and analgesia in the foot was similar to that previously observed after epidural bolus administration. Clonidine also was associated with concentration-dependent sedation; decreased mean arterial blood pressure, heart rate, and CSF norepinephrine concentration; and increased CSF acetylcholine concentration.

Conclusions
This study suggests that pharmacokinetically designed infusions of drugs in the epidural space in humans can maintain steady concentrations of drug in CSF. In addition to providing a useful tool for investigation of mechanisms of action and drug interactions, this technique may improve analgesia and diminish side effects from epidurally administered analgesics.