bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isoflurane Reduces Ischemia-induced Glutamate Release in Rats Subjected to Forebrain Ischemia
Authors: Patel Piyush M. , Drummond John C. , Cole Daniel J. , Goskowicz Randall L. 
Published: November 2003

Background
The release of excitatory neurotransmitters during ischemia is thought to contribute to ischemic neuronal injury. Volatile anesthetics have been shown to reduce excitatory neurotransmission in vitro, and it is conceivable that they reduce ischemia-induced neurotransmitter release. The current investigation was conducted to evaluate the effect of isoflurane and N2O-fentanyl anesthesia on ischemia-induced glutamate release in the rat and to compare it with that of mild hypothermia, an intervention known to reduce glutamate release significantly.

Methods
Microdialysis probes were implanted into the parietal cortex and dorsal hippocampus of four groups of anesthetized rats (n = 5 per group). The hypothermic group was anesthetized with 1.2% halothane. The two isoflurane groups were anesthetized with 0.5 minimum alveolar concentration or electroencephalographic burst-suppression doses of isoflurane (approximately 2 minimum alveolar concentration). The control group was anesthetized with 70% N2O-30% O2 and fentanyl. The pericranial temperature was maintained at 34 degrees C in the hypothermic group and at 38 degrees C in the remaining groups. Ischemia was induced by bilateral carotid artery occlusion with simultaneous hypotension to 35 mmHg for 10 min, followed by a reperfusion period of 70 min. Dialysate was collected before, during, and after ischemia. The concentrations of glutamate and glycine in the dialysate were measured by high-performance liquid chromatography.

Results
Preischemic glutamate and glycine concentrations in the dialysate were similar among the groups. Ischemia resulted in a significant increase in glutamate and glycine concentrations in the N2O-fentanyl groups in the parietal cortex and in the hippocampus. This increase in neurotransmitter concentrations did not occur in the hypothermic group in either structure. Isoflurane reduced glutamate concentrations in both structures and glycine concentrations in the hippocampus. In the parietal cortex, glycine concentrations did not increase in either isoflurane group.

Conclusions
Hypothermia inhibits ischemia-induced excitatory neurotransmitter release in the rat. Isoflurane, in comparison with a N2O-fentanyl-anesthetized state, significantly attenuates excitatory neurotransmitter release in the hippocampus. This effect of isoflurane is comparable to that of mild hypothermia.
Pharmacokinetics of Rocuronium in Children Aged 4–11 Years
Authors: Vuksanaj Dila , Fisher Dennis M. 
Published: November 2003

Background
Rocuronium is a new nondepolarizing muscle relaxant with a rapid onset and intermediate duration of action. Although the pharmacokinetics of rocuronium have been determined in adults and the elderly, similar data are lacking in children. Accordingly, rocuronium's pharmacokinetics were determined in children aged 4-11 yr.

Methods
Rocuronium (600 micrograms/kg) was administered to 20 children aged 4-11 yr anesthetized with nitrous oxide and < or = 1% halothane, and four plasma samples were obtained over 4 h to determine rocuronium concentrations. The pharmacokinetics of rocuronium were determined using two sparse-sampling population approaches, mixed-effects modeling, and naive pooled data analysis.

Results
With mixed-effects modeling, weight-normalized plasma clearance varied with weight (P < 0.01), being 79.4 ml.min-1 + 3.13 ml.kg-1.min-1. Neither weight-normalized distributional clearance (2.67 ml.kg-1.min-1), weight-normalized central compartment volume (106 ml/kg), nor weight-normalized volume of distribution at steady-state (224 ml/kg) varied with weight, height, or age. Similar results were obtained with the naive pooled data approach.

Conclusions
Maturational changes were observed in rocuronium's weight-normalized clearance but not in its weight-normalized distributional clearance or volume of distribution. Assuming that the duration of rocuronium's neuromuscular effects is influenced by its pharmacokinetics, repeated administration or continuous infusion of rocuronium should result in larger dose requirements and more rapid recovery in younger, compared to older, children.
Effect of Halothane Anesthesia on Glucose Utilization and Production in Adolescents
Authors: Sbai Dounia , Jouvet Philippe , Soulier Anne , Penicaud Luc , Merckx Jacques , Bresson Louis J. 
Published: November 2003

Background
It should be possible to avoid variations in plasma glucose concentration during anesthesia by adjusting glucose infusion rate to whole-body glucose uptake. To study this hypothesis, we measured glucose utilization and production, before and during halothane anesthesia.

Methods
After an overnight fast, six adolescents between 12 and 17 yr of age were infused with tracer doses of [6,6-2H2]glucose for 2 h before undergoing anesthesia, and the infusion was continued after induction, until the beginning of surgery. Plasma glucose concentration was monitored throughout, and free fatty acids, lactate, insulin, and glucagon concentrations were measured before and during anesthesia.

Results
Despite the use of a glucose-free maintenance solution, plasma glucose concentration increased slightly but significantly 5 min after induction (5.3 +/- 0.4 vs. 4.5 +/- 0.4 mmol.l-1, P < 0.05). This early increase corresponded to a significant increase in endogenous glucose production over basal conditions (4.1 +/- 0.4 vs. 3.6 +/- 0.2 mg.kg-1.min-1, P < 0.05), with no concomitant change in peripheral glucose utilization. Fifteen minutes after induction, both glucose utilization and production rates decreased steadily and were 20% less than basal values by 35 min after induction (2.9 +/- 0.3 vs. 3.6 +/- 0.2 mg.kg-1.min-1, P < 0.05). Similarly, glucose metabolic clearance rate decreased by 25% after 35 min. Despite the increase in blood glucose concentration, anesthesia resulted in a significant decrease in plasma insulin concentration.

Conclusions
These data suggest that halothane anesthesia per se affects glucose metabolism. The decrease in peripheral glucose utilization and metabolic clearance rates and the blunted insulin release question the relevance of glucose infusion in these clinical settings.
Touch-evoked Agitation Produced by Spinally Administered Phospholipid Emulsion and Liposomes in Rats
Authors: Yanez Aladino M. , Wallace Mark , Ho Rodney , Shen Danny , Yaksh Tony L. 
Published: November 2003

Background
Phospholipid-based liposomes can alter the kinetics of spinally administered agents. We have observed that spinal delivery of these preparations results in an unexpected touch-evoked agitation, a state in which light touch evokes vocalization by the rat. In the current study we characterized this agitated state induced by various liposome preparations.

Methods
Rats prepared with lumbar intrathecal catheters received a variety of phospholipids delivered spinally as emulsions or as liposomes. Before and after injection, the animal's hot-plate latency (52.5 degrees C surface), spontaneous mobility, and spontaneous and evoked pain behavior were assessed.

Results
Spinal delivery of L-alpha-phosphatidylcholine of egg yolk (L-EPC) and the phospholipase hydrolysis product (lyso-L-alpha-phosphatidylcholine [lyso-L-EPC]) produced dose-dependent touch-evoked agitation; the order of potency and rapidity of onset was lyso-L-EPC > L-EPC, with no difference in activity whether administered as an emulsion or as a liposome preparation. Examination of the activity of a series of pure phospholipids revealed the ordering of touch-evoked agitation potency (where PC = phosphatidylcholine) to be L-monopalmitoyl-PC (lyso product of L-dipalmitoyl-PC) > L-dipalmitoyl-PC > L-distearoyl-PC, L-dioleoyl-PC > L-dilauroyl-PC > L-dimyristoyl-PC; D-dipalmitoyl-PC = 0. The effect of unsaturation on touch-evoked agitation cannot be predicted because dioleoyl-PC and dioleoyl phosphatidylglycerol produced touch-evoked agitation but dipalmitoleoyl-PC did not. Substitution of glycerol for choline as the head group had no influence on touch-evoked agitation. Spinal treatment with an inhibitor of phospholipase (mepacrine) or a cyclooxygenase (ketorolac) blocked the touch-evoked agitation of L-EPC but not that of lyso-L-EPC.

Conclusions
These results emphasize that certain L-isomeric phospholipids with their gel-transition temperatures near body temperature can produce prominent touch-evoked agitation after spinal delivery, an effect likely mediated by a phospholipase hydrolysis product. This touch-evoked agitation, which is consistent with neurotoxicity reported in the early literature on lysophospholipids, suggests that the choice of lipids for the formulation of liposomes intended for spinal drug delivery should be carefully considered.
Nitric Oxide Modulation of Pulmonary Blood Flow Distribution in Lobar Hypoxia
Authors: Freden Filip , Wei Shao Z. , Berglund Jan E. , Frostell Claes , Hedenstierna Goran 
Published: November 2003

Background
Nitric oxide, endogenously produced or inhaled, has been shown to play an important role in the regulation of pulmonary blood flow. The inhalation of nitric oxide reduces pulmonary arterial pressure in humans, and the blockade of endogenous nitric oxide production increases the pulmonary vascular response to hypoxia. This study was performed to investigate the hypothesis that intravenous administration of an nitric oxide synthase inhibitor and regional inhalation of nitric oxide can markedly alter the distribution of pulmonary blood flow during regional hypoxia.

Methods
Hypoxia (5% O2) was induced in the left lower lobe of the pig, and the blood flow to this lobe was measured with transit-time ultrasound. Nitric oxide was administered in the gas ventilating the hypoxic lobe and the hyperoxic lung regions with and without blockade of endogenous nitric oxide production by means of N omega-nitro-L-arginine methyl ester (L-NAME).

Results
Hypoxia in the left lower lobe reduced blood flow to that lobe to 27 +/- 3.9% (mean +/- SEM) of baseline values (P < 0.01). L-NAME caused a further reduction in lobar blood flow in all six animals to 12 +/- 3.5% and increased arterial oxygen tension (PaO2) (P < 0.01). Without L-NAME, the inhalation of nitric oxide (40 ppm) to the hypoxic lobe increased lobar blood flow to 66 +/- 5.6% of baseline (P < 0.01) and, with L-NAME, nitric oxide delivered to the hypoxic lobe resulted in a lobar blood flow that was 88 +/- 9.3% of baseline (difference not significant). When nitric oxide was administered to the hyperoxic lung regions, after L-NAME infusion, the blood flow to the hypoxic lobe decreased to 2.5 +/- 1.6% of baseline and PaO2 was further increased (P < 0.01).

Conclusions
By various combinations of nitric oxide inhalation and intravenous administration of an nitric oxide synthase inhibitor, lobar blood flow and arterial oxygenation could be markedly altered during lobar hypoxia. In particular, the combination of intravenous L-NAME and nitric oxide inhalation to the hyperoxic regions almost abolished perfusion of the hypoxic lobe and resulted in a PaO2 that equalled the prehypoxic values. This possibility of adjusting regional blood flow and thereby of improving PaO2 may be of value in the treatment of patients undergoing one-lung ventilation and of patients with acute respiratory failure.
Oral Clonidine Prolongs Lidocaine Spinal Anesthesia in Human Volunteers
Authors: Liu Spencer MD , Chiu Andrew A. , Neal Joseph M. , Carpenter Randall L. , Bainton Bruce G. , Gerancher J. C. 
Published: November 2003

Background
Premedication with oral clonidine may improve the quality and duration of lidocaine spinal anesthesia, but this effect has not been examined in a quantitative fashion.

Methods
Eight volunteers received 50 mg lidocaine (1.5% dextrose free) both with and without 0.2 mg oral clonidine 1.5 h before spinal anesthesia in a randomized, double-blind, placebo-controlled, crossover fashion. Sensory block was assessed by pinprick, transcutaneous electric stimulation equivalent to surgical incision, and duration of tolerance to pneumatic thigh tourniquet. Motor block at the quadriceps and gastrocnemius muscles was assessed by isometric force dynamometry. Episodes of bradycardia, hypotension, and sedation were recorded.

Results
Regression of pinprick was unchanged with clonidine. However, duration of tolerance to electric stimulation was increased at the knee (28 +/- 24 min) and ankle (31 +/- 28 min) with clonidine (P < 0.05). The duration of tolerance to tourniquet-induced pain was increased with clonidine (14 +/- 12 min; P < 0.05). The duration of motor block was increased at the quadriceps (20 +/- 13 min) and gastrocnemius (33 +/- 24 min) muscle groups with clonidine (P < 0.05). Although clonidine decreased systolic blood pressure (13 +/- 4 mmHg, P < 0.003) and heart rate (13 +/- 5 beats/min; P = 0.02), no subjects had hypotension or bradycardia. The incidence of sedation was greater with clonidine than with plain lidocaine (50% vs. 0%, P < 0.04).

Discussion
Premedication with oral clonidine prolonged sensory and motor block from lidocaine spinal anesthesia. The exact mechanism whereby oral clonidine prolongs spinal anesthesia remains to be determined.
Postpartum Changes in the Minimum Alveolar Concentration of Isoflurane
Authors: Chan Matthew T. V. , Gin Tony 
Published: November 2003

Background
Minimum alveolar concentration (MAC) is decreased in pregnancy, but it is not known how quickly after delivery MAC returns to normal. We measured the MAC of isoflurane in a group of women undergoing elective tubal ligation after delivery.

Methods
After delivery, 20 patients underwent inhalational induction of anesthesia with isoflurane and tracheal intubation. MAC was determined in each patient by observing the response to a 10-s, 50-Hz, 80-mA transcutaneous tetanic electric stimulus to the ulnar nerve at various concentrations of isoflurane. The end-tidal concentration of isoflurane was kept constant for at least 10 min before each stimulus, and the concentration of isoflurane was ultimately varied in steps of 0.05 vol% until we obtained a sequence of three alternate responses: move-not move-move or not move-move-not move. The MAC for each subject was taken as the mean of the two concentrations just permitting and just preventing movement. A venous blood sample was taken immediately before induction of anesthesia for measurement of progesterone concentration. MAC was compared with time after delivery and plasma progesterone concentrations by Kendall's rank correlation.

Results
There was a positive correlation between MAC and the time after delivery (P < 0.001). The median MAC of isoflurane was 0.775 vol% (range 0.675-0.775 vol%) in five women 24-36 h postpartum. MAC was more variable, 0.825 vol% (0.675-0.975 vol%) in nine women 36-72 h postpartum, whereas six patients more than 72 h postpartum had a MAC of 1.125 vol% (1.025-1.175 vol%). The correlation between MAC and plasma progesterone concentration was almost statistically significant (P = 0.060).

Conclusions
The MAC of isoflurane was reduced in women 24-36 h postpartum and gradually increased to normal values by 72 h postpartum.
Clinical Sevoflurane Metabolism and Disposition
Authors: Kharasch Evan D. , Karol Michael D. , Lanni Carmine , Sawchuk Ronald 
Published: November 2003

Background
Sevoflurane has low blood and tissue solubility and is metabolized to free fluoride and hexafluoroisopropanol (HFIP). Although sevoflurane uptake and distribution and fluoride formation have been described, the pharmacokinetics of HFIP formation and elimination are incompletely understood. This investigation comprehensively characterized the simultaneous disposition of sevoflurane, fluoride, and HFIP.

Methods
Ten patients within 30% of ideal body weight who provided institutional review board-approved informed consent received sevoflurane (2.7% end-tidal, 1.3 MAC) in oxygen for 3 h after propofol induction, after which anesthesia was maintained with propofol, fentanyl, and nitrous oxide. Sevoflurane and unconjugated and total HFIP concentrations in blood were determined during anesthesia and for 8 h thereafter. Plasma and urine fluoride and total HFIP concentrations were measured during and through 96 h after anesthetic administration. Fluoride and HFIP were quantitated using an ion-selective electrode and by gas chromatography, respectively.

Results
The total sevoflurane dose, calculated from the pulmonary uptake rate, was 88.8 +/- 9.1 mmol. Sevoflurane was rapidly metabolized to the primary metabolites fluoride and HFIP, which were eliminated in urine. HFIP circulated in blood primarily as a glucuronide conjugate, with unconjugated HFIP < or = 15% of total HFIP concentrations. In blood, peak unconjugated HFIP concentrations were less than 1% of peak sevoflurane concentrations. Apparent renal fluoride and HFIP clearances (mean +/- SE) were 51.8 +/- 4.5 and 52.6 +/- 6.1 ml/min, and apparent elimination half-lives were 21.4 +/- 2.8 and 20.1 +/- 2.6 h, respectively. Renal HFIP and net fluoride excretion were 4,300 +/- 540 and 3,300 +/- 540 mumol. Compared with the estimated sevoflurane uptake, 4.9 +/- 0.5% of the dose taken up was eliminated in the urine as HFIP. For fluoride, 3.7 +/- 0.4% of the sevoflurane dose taken up was eliminated in the urine, which, because a portion of fluoride is sequestered in bone, corresponded to approximately 5.6% of the sevoflurane dose metabolized to fluoride.

Conclusions
Sevoflurane was rapidly metabolized to fluoride and HFIP, which was rapidly glucuronidated and eliminated in the urine. The overall extent of sevoflurane metabolism was approximately 5%.
Clinical Sevoflurane Metabolism and Disposition
Authors: Kharasch Evan D. , Armstrong Andrew S. , Gunn Kerry , Artru Alan , Cox Kathy , Karol Michael D. 
Published: November 2003

Background
Sevoflurane is metabolized to free fluoride and hexafluoroisopropanol (HFIP). Cytochrome P450 2E1 is the major isoform responsible for sevoflurane metabolism by human liver microsomes in vitro. This investigation tested the hypothesis that P450 2E1 is predominantly responsible for sevoflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1.

Methods
Twenty-one patients within 30% of ideal body weight, who provided institutional review board-approved informed consent and were randomized to receive disulfiram (500 mg oral, n = 11) or nothing (control, n = 10) the night before surgery, were evaluated. All patients received sevoflurane (2.7% end-tidal, 1.3 MAC) in oxygen for 3 h after propofol induction. Thereafter, sevoflurane was discontinued, and anesthesia was maintained with propofol, fentanyl, and nitrous oxide. Blood sevoflurane concentrations during anesthesia and for 8 h thereafter were measured by gas chromatography. Plasma and urine fluoride and total (unconjugated plus glucuronidated) HFIP concentrations were measured by an ion-selective electrode and by gas chromatography, respectively, during anesthesia and for 96 h postoperatively.

Results
Patient groups were similar with respect to age, weight, sex, case duration, and intraoperative blood loss. The total sevoflurane dose, measured by cumulative end-tidal sevoflurane concentrations (3.7 +/- 0.1 MAC-h; mean +/- SE), total pulmonary uptake, and blood sevoflurane concentrations, was similar in both groups. In control patients, plasma fluoride and HFIP concentrations were increased compared to baseline values intraoperatively and postoperatively for the first 48 and 60 h, respectively. Disulfiram treatment significantly diminished this increase. Plasma fluoride concentrations increased from 2.1 +/- 0.3 microM (baseline) to 36.2 +/- 3.9 microM (peak) in control patients, but only from 1.7 +/- 0.2 to 17.0 +/- 1.6 microM in disulfiram-treated patients (P < 0.05 compared with control patients). Peak plasma HFIP concentrations were 39.8 +/- 2.6 and 14.4 +/- 1.1 microM in control and disulfiram-treated patients (P < 0.05), respectively. Areas under the plasma fluoride- and HFIP-time curves also were diminished significantly to 22% and 20% of control patients, respectively, by disulfiram treatment. Urinary excretion of fluoride and HFIP was similarly significantly diminished in disulfiram-treated patients. Cumulative 96-h fluoride and HFIP excretion in disulfiram-treated patient was 1,080 +/- 210 and 960 +/- 240 mumol, respectively, compared to 3,950 +/- 560 and 4,300 +/- 540 mumol in control patients (P < 0.05).

Conclusions
Disulfiram, an effective P450 2E1 inhibitor, substantially decreased fluoride ion and HFIP production during and after sevoflurane anesthesia. These results suggest that P450 2E1 is a predominant P450 isoform responsible for human sevoflurane metabolism in vivo.
Effect of 7.2% Hypertonic Saline/6% Hetastarch on Left Ventricular Contractility in Anesthetized Humans
Authors: Goertz Axel W. , Mehl Tobias , Lindner Karl H. , Rockemann Michael G. , Schirmer Uwe , Schwilk Bernhard , Georgieff Michael 
Published: November 2003

Background
Although a positive inotropic effect of hypertonic saline has been demonstrated in isolated cardiac tissue as well as in animal preparations, no information exists about a possible positive inotropic action of hypertonic saline in humans. The aim of this investigation was to determine whether a clinically relevant positive inotropic effect can be demonstrated in humans.

Methods
Twenty-six patients without cardiovascular disease were randomized to receive 4 ml/kg of either 7.2% hypertonic saline/6% hetastarch or 6% hetastarch (control) at a rate of 1 ml.kg-1.min-1 while under general endotracheal anesthesia. Transesophageal echocardiography was used to evaluate left ventricular function. Arterial pressure, heart rate, and left ventricular end-systolic and end-diastolic diameter, area, and wall thickness were measured immediately before and after administration of either solution. Fractional area change, end-systolic wall stress, and the area under the end-systolic pressure-length relationship curve (ESPLRarea) were calculated. ESPLRarea was used to assess left ventricular contractility.

Results
Administration of hypertonic saline/hetastarch resulted in a significant decrease of mean arterial pressure and end-systolic wall stress from 77 +/- 14 (mean +/- SD) to 64 +/- 17 mmHg (P < 0.01) and from 52 +/- 14 to 32 +/- 11 10(3) dyne/cm2 (P > 0.01), respectively. End-diastolic area and fractional area change increased from 16.5 +/- 2.9 to 21.7 +/- 3.3 cm2 (P < 0.01) and from 0.53 +/- 0.07 to 0.70 +/- 0.06 (P < 0.01), respectively, whereas there was only a minor change of ESPLRarea from 38 +/- 13 to 44 +/- 13 mmHg.cm (P < 0.05).

Conclusions
The apparent improvement of left ventricular systolic function in response to hypertonic saline/hetastarch is caused mainly by the combined effect of increased left ventricular preload and reduced left ventricular afterload. A possible positive inotropic action of hypertonic saline/hetastarch is not likely to be clinically relevant.