bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anesthesia Sensitivity in Mice that Lack the β3 Subunit of the γ-Aminobutyric Acid Type A Receptor
Authors: Quinlan Joseph J. , Homanics Gregg E. , Firestone Leonard L. 
Published: November 2003

Background
The mammalian gamma-aminobutyric acid type A (GABA(A)) receptor, a likely target of anesthetic action, exhibits remarkable subunit heterogeneity. In vitro expression studies suggest that there is subunit specificity to anesthetic responses at the GABA(A) receptor. The authors tested whether genetically engineered mice that lack the beta3 subunit of the GABA(A) receptor differed in their sensitivities to several general anesthetic agents.

Methods
Median effective concentrations for loss-of-righting reflex and tail clamp/withdrawal for enflurane and halothane were determined in mice with and without the beta3 gene and gene product. Sleep time was measured after intraperitoneal injection of pentobarbital, ethanol, etomidate, and midazolam.

Results
Null allele mice (beta3 -/-) did not differ from wild-type mice (beta3 +/+) in the obtunding response to enflurane and halothane but were significantly more resistant to enflurane (null allele half-effect concentrations [EC50] of 2.59 +/- 0.10 vs. wild-type EC50 of 2.06 +/- 0.12 atm %, P < 0.001) and halothane (null allele EC50 of 1.73 +/- 0.04 vs. wild-type EC50 of 1.59 +/- 0.05 atm %, P = 0.01) as determined by tail clamp response. Wild-type and null allele mice exhibited divergent responses to other sedative agents active at the GABA(A) receptor. No differences were noted in sleep times after administration of pentobarbital and ethanol, but null allele mice were more resistant to etomidate (null allele EC50 of 17.8 +/- 1.9 min vs. wild-type EC50 of 26.2 +/- 2.4 min, P < 0.02) and midazolam (null allele EC50 of 14.2 +/- 7.8 min vs. wild-type EC50 of 41.3 +/- 10.4 min, P < 0.05).

Conclusions
The beta3 subunit of the GABA(A) receptor appears to be important in the mediation of the immobilizing (tail clamp) but not obtunding (loss-of-righting reflex) effects of the volatile anesthetic agents enflurane and halothane. These data support the hypotheses that separate components of the anesthetic state are mediated via different central nervous system loci; that the GABA(A) receptor is a likely target for the immobilizing response to volatile anesthetic agents; and that the beta3 subunit plays a direct or indirect role in the mediation of this response. Absence of the beta3 subunit appears to attenuate the obtunding effect of midazolam and etomidate but appears not to alter the obtunding effect of pentobarbital, enflurane, and halothane, suggesting that these anesthetic agents produce hypnosis by different specific molecular mechanisms.
Propofol and Ketamine Only Inhibit Intracellular Ca2+Transients and Contraction in Rat Ventricular Myocytes at Supraclinical Concentrations
Authors: Kanaya Noriaki , Murray Paul A. , Damron Derek S. 
Published: November 2003

Background
The cellular mechanisms that mediate the cardiodepressant effects of intravenous anesthetic agents remain undefined. The objective of this study was to elucidate the direct effects of propofol and ketamine on cardiac excitation-contraction coupling by simultaneously measuring intracellular calcium concentration ([Ca2+]i) and shortening in individual, field-stimulated ventricular myocytes.

Methods
Freshly isolated rat ventricular myocytes were loaded with the Ca2+ indicator, fura-2, and placed on the stage of an inverted fluorescence microscope in a temperature-regulated bath. [Ca2+]i and myocyte shortening (video edge detection) were monitored simultaneously in individual cells that were field-stimulated at 0.3 Hz.

Results
Baseline [Ca2+]i (mean +/- SEM) was 80 +/- 12 nM, and resting cell length was 112 +/- 2 microm. Field stimulation increased [Ca2+]i to 350 +/- 23 nM, and the myocytes shortened by 10% of diastolic cell length. Both intravenous anesthetic agents caused dose-dependent decreases in peak [Ca2+]i and shortening. At 300 microM, propofol prolonged time to peak concentration and time to 50% recovery for [Ca2+]i and shortening. In contrast, changes in time to peak concentration and time to 50% recovery in response to ketamine were observed only at the highest concentrations. Neither agent altered the amount of Ca2+ released from intracellular stores in response to caffeine. Propofol but not ketamine, however, caused a leftward shift in the dose-response curve to extracellular Ca2+ for shortening, with no concomitant effect on peak [Ca2+]i.

Conclusions
These results indicate that both intravenous anesthetic agents have a direct negative inotropic effect, which is mediated by a decrease in the availability of [Ca2+]i. Propofol but not ketamine may also alter sarcoplasmic reticulum Ca2+ handling and increase myofilament Ca2+ sensitivity. The effects of propofol and ketamine are primarily apparent at supraclinical concentrations, however.
Isoflurane Alters Shivering Patterns and Reduces Maximum Shivering Intensity
Authors: Ikeda Takehiko , Kim Jin-Soo , Sessler Daniel I. , Negishi Chiharu , Turakhia Minang , Jeffrey Renee 
Published: November 2003

Background
Shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core hypothermia), and maximum response intensity. Isoflurane produces a clonic muscular activity that is not a component of normal shivering. To the extent that clonic activity is superimposed on normal thermoregulatory shivering, the gain of shivering might be increased during isoflurane anesthesia. Conversely, volatile anesthetics decrease systemic oxygen consumption and peripherally inhibit skeletal muscle strength, which might limit maximum intensity despite central activation. The purpose of the present study was, therefore, to evaluate the effect of isoflurane shivering patterns and the gain and maximum intensity of shivering.

Methods
Ten volunteers were each studied in two separate protocols: (1) control (no drug) and (2) 0.7% end-tidal isoflurane. On each day, the mean skin temperature was maintained at 31 degrees C. Core temperature was then reduced by infusion of cold fluid until shivering intensity no longer increased. The core temperature triggering the initial increase in oxygen consumption defined the shivering threshold. The gain of shivering was defined by the slope of the core temperature versus oxygen consumption regression. Pectoralis and quadriceps electromyography was used to evaluate anesthetic-induced facilitation of clonic (5-7 Hz) muscular activity.

Results
Isoflurane significantly decreased the shivering threshold from 36.4 +/- 0.3 to 34.2 +/- 0.8 degrees C. The increase in oxygen consumption was linear on the control day and was followed by sustained high-intensity activity. During isoflurane administration, shivering was characterized by bursts of intense shivering separated by quiescent periods. Isoflurane significantly increased the gain of shivering (as calculated from the initial increase), from -684 +/- 266 to -1483 +/- 752 ml x min(-1) x degrees C(-1). However, isoflurane significantly decreased the maximum intensity of shivering, from 706 +/- 144 to 489 +/- 80 ml/min. Relative electromyographic power in frequencies associated with clonus increased significantly when the volunteers were given isoflurane.

Conclusions
These data indicate that isoflurane anesthesia markedly changes the overall pattern of shivering during progressive hypothermia from a linear increase to an unusual saw-tooth pattern. They further suggest that clonic muscular activity combines with shivering to increase the initial gain of shivering during isoflurane anesthesia, but that isoflurane peripherally inhibits the maximum expression of shivering.
Correlation of Regional Cerebral Blood Flow with Ischemic Electroencephalographic Changes during Sevoflurane-Nitrous Oxide Anesthesia for Carotid Endarterectomy
Authors: Grady Robert E. , Weglinski Margaret R. , Sharbrough Frank W. , Perkins William J. 
Published: November 2003

Background
Carotid endarterectomy necessitates temporary unilateral carotid artery occlusion. Critical regional cerebral blood flow (rCBF) has been defined as the rCBF below which electroencephalographic (EEG) changes of ischemia occur. This study determined the rCBF50, the rCBF value at which 50% of patients will not demonstrate EEG evidence of cerebral ischemia with carotid cross-clamping.

Methods
Fifty-two patients undergoing elective carotid endarterectomy were administered 0.6-1.2% (0.3-0.6 minimum alveolar concentration) sevoflurane in 50% nitrous oxide (N2O). A 16-channel EEG was used for monitoring. The washout curves from intracarotid 133Xenon injections were used to calculate rCBF before and at the time of carotid occlusion by the half-time (t(1/2)) technique. The quality of the EEG with respect to ischemia detection was assessed by an experienced electroencephalographer.

Results
Ischemic EEG changes developed in 5 of 52 patients within 3 min of carotid occlusion at rCBFs of 7, 8, 11, 11, and 13 ml x 100 g(-1) x min(-1). Logistic regression analysis was used to calculate an rCBF50 of 11.5 +/- 1.4 ml x 100 g(-1) x min(-1) for sevoflurane. The EEG signal demonstrated the necessary amplitude, frequency, and stability for the accurate detection of cerebral ischemia in all patients within the range of 0.6-1.2% sevoflurane in 50% N2O.

Conclusions
The rCBF50 of 0.6-1.2% sevoflurane in 50% N2O, as determined using logistic regression analysis, is 11.5 +/- 1.4 ml 100 g(-1) x min(-1). Further, in patients anesthetized in this manner, ischemic EEG changes due to carotid occlusion were accurately and rapidly detected.
Inhibition of Presynaptic Sodium Channels by Halothane
Authors: Ratnakumari Lingamaneni , Hemmings Hugh C. 
Published: November 2003

Background
Recent electrophysiologic studies indicate that clinical concentrations of volatile general anesthetic agents inhibit central nervous system sodium (Na+) channels. In this study, the biochemical effects of halothane on Na+ channel function were determined using rat brain synaptosomes (pinched-off nerve terminals) to assess the role of presynaptic Na+ channels in anesthetic effects.

Methods
Synaptosomes from adult rat cerebral cortex were used to determine the effects of halothane on veratridine-evoked Na+ channel-dependent Na+ influx (using 22Na+), changes in intrasynaptosomal [Na+] (using ion-specific spectrofluorometry), and neurotoxin interactions with specific receptor sites of the Na+ channel (by radioligand binding). The potential physiologic and functional significance of these effects was determined by measuring the effects of halothane on veratridine-evoked Na+ channel-dependent glutamate release (using enzyme-coupled spectrofluorometry).

Results
Halothane inhibited veratridine-evoked 22Na+ influx (IC50 = 1.1 mM) and changes in intrasynaptosomal [Na+] (concentration for 50% inhibition [IC50] = 0.97 mM), and it specifically antagonized [3H]batrachotoxinin-A 20-alpha-benzoate binding to receptor site two of the Na+ channel (IC50 = 0.53 mM). Scatchard and kinetic analysis revealed an allosteric competitive mechanism for inhibition of toxin binding. Halothane inhibited veratridine-evoked glutamate release from synaptosomes with comparable potency (IC50 = 0.67 mM).

Conclusions
Halothane significantly inhibited Na+ channel-mediated Na influx, increases in intrasynaptosomal [Na+] and glutamate release, and competed with neurotoxin binding to site two of the Na+ channel in synaptosomes at concentrations within its clinical range (minimum alveolar concentration, 1-2). These findings support a role for presynaptic Na+ channels as a molecular target for general anesthetic effects.
Volatile Anesthetic Agents and Vascular Communication in the Microcirculation of the Hamster Cheek Pouch
Authors: Satitpunwaycha Patricia , Rivers Richard J. 
Published: November 2003

Background
There is communication between tissue and the vascular network involved in regulating distribution of blood flow. Signals generated by the tissue are communicated upstream to create a coordinated network response in unison with other controllers of blood flow, such as myogenic and flow-dependent responses.

Methods
This vascular communication was modeled with the microapplication of methacholine (10(-4) M) or potassium chloride solution (KCl; 100 mM) to arterioles (40-60 microm in diameter) of the cheek pouch of anesthetized hamsters and viewed with videomicroscopy. Local and conducted (500 microm upstream) responses were measured. Halothane or isoflurane (1%, 2%, and 3%) was equilibrated with the superfusion solution and applied to the entire tissue. Responses to KCl and methacholine were then repeated in the presence of an anesthetic agent.

Results
Halothane and isoflurane increased the resting diameter of the arterioles. They also decreased the methacholine-initiated dilations. To test for the effects of increased resting diameter on the dilations, 0%, 5% and 10% oxygen alone was applied to the pouch to alter the tone, and the methacholine responses were repeated. The dilations decreased with oxygen-induced increases in resting diameter, but the conducted dilation decreased to a lesser extent than was seen with the volatile anesthetic agents. Neither halothane nor isoflurane decreased constrictions caused by KCl.

Conclusions
Decreased methacholine-initiated conducted dilations caused by halothane and isoflurane were not due to decreases in cell-cell communication because KCl conducted responses persisted. Therefore, cell-cell vascular communication appears intact in the presence of clinical concentrations of halothane and isoflurane.
TOK1 Is a Volatile Anesthetic Stimulated K+Channel
Authors: Gray Andrew T. , Winegar Bruce D. , Leonoudakis Dmitri J. , Forsayeth John R. , Yost Spencer C. 
Published: November 2003

Background
Volatile anesthetic agents can activate the S channel, a baseline potassium (K+) channel, of the marine mollusk Aplysia. To investigate whether cloned ion channels with electrophysiologic properties similar to the S channel (potassium selectivity, outward rectification, and activation independent of voltage) also are modulated by volatile anesthetic agents, the authors expressed the cloned yeast ion channel TOK1 (tandem pore domain, outwardly rectifying K+ channel) in Xenopus oocytes and studied its sensitivity to volatile agents.

Methods
Standard two-electrode voltage and patch clamp recording methods were used to study TOK1 channels expressed in Xenopus oocytes.

Results
Studies with two-electrode voltage clamp at room temperature showed that halothane, isoflurane, and desflurane increased TOK1 outward currents by 48-65% in barium Frog Ringer's perfusate. The concentrations at which 50% potentiation occurred (EC50 values) were in the range of 768-814 microM (0.016-0.044 atm) and had a rank order of potency in atm in which halothane > isoflurane > desflurane. The potentiation of TOK1 by volatile anesthetic agents was rapid and reversible (onset and offset, 1-20 s). In contrast, the nonanesthetic 1,2-dichlorohexafluorocyclobutane did not potentiate TOK1 currents in concentrations up to five times the MAC value predicted by the Meyer-Overton hypothesis based on oil/gas partition coefficients. Single TOK1 channel currents were recorded from excised outside-out patches. The single channel open probability increased as much as twofold in the presence of isoflurane and rapidly returned to the baseline values on washout. Volatile anesthetic agents did not alter the TOK1 single channel current-voltage (I-V) relationship, however, suggesting that the site of action does not affect the permeation pathway of the channel.

Conclusion
TOK1 is a potassium channel that is stimulated by volatile anesthetic agents. The concentrations over which potentiation occurred (EC50 values) were higher than those commonly used in clinical practice (approximately twice MAC).
Desflurane Reduces the Febrile Response to Administration of Interleukin-2
Authors: Negishi Chiharu , Lenhardt Rainer , Sessler Daniel I. , De Witte Jan , Ikeda Takehiko , Kurz Andrea , Lobo Errol 
Published: November 2003

Background
Intraoperative fever is relatively rare considering how often pyrogenic causes are likely to be present and how common fever is postoperatively. This low incidence suggests that general anesthesia per se inhibits the normal response to pyrogenic stimulation. The authors therefore tested the hypothesis that desflurane-induced anesthesia produces a dose-dependent inhibition of the febrile response.

Methods
Eight volunteers were studied, each on 3 study days. Each was given an intravenous injection of 50,000 IU/ kg of interleukin-2 (elapsed time, 0 h), followed 2 h later by 100,000 IU/kg. One hour after the second dose, the volunteers were assigned randomly to three doses of desflurane to induce anesthesia: (1) 0.0 minimum alveolar concentration (MAC; control), (2) 0.6 MAC, and (3) 1.0 MAC. Anesthesia continued for 5 h. Core temperatures were recorded from the tympanic membrane. Thermoregulatory vasoconstriction was evaluated using forearm-minus-fingertip skin temperature gradients; shivering was evaluated with electromyography. Integrated and peak temperatures during anesthesia were compared with repeated-measures analysis of variance and Scheffé's F tests.

Results
Values are presented as mean +/- SD. Desflurane reduced the integrated (area under the curve) febrile response to pyrogen, from 7.7 +/- 2.0 degrees C x h on the control day to 2.1 +/- 2.3 degrees C x h during 0.6 MAC and to -1.4 +/- 3.1 degrees C x h during 1.0 MAC desflurane-induced anesthesia. Peak core temperature (elapsed time, 5-8 h) decreased in a dose-dependent fashion: 38.6 +/- 0.5 degrees C on the control day, 37.7 +/- 0.7 degrees C during 0.6 MAC and 37.2 +/- 1.0 degrees C during 1.0 MAC desflurane anesthesia. Rising core temperature was always associated with fingertip vasoconstriction and often with shivering.

Conclusions
Desflurane-induced anesthesia produced a dose-dependent decrease in integrated and peak core temperatures after administration of pyrogen, with 1.0 MAC essentially obliterating fever. Anesthetic-induced inhibition of the pyrogenic response is therefore one reason that fever is an inconsistent clinical response to inflammation during surgery.
A Bronchoscopic, Computer-assisted Examination of the Changes in Dimension of the Infant Tracheal Lumen with Changes in Head Position
Authors: Wheeler Melissa , Roth Andrew G. , Dunham Michael E. , Rae Bronwyn , Cote Charles J. 
Published: November 2003

Background
Resuscitation guidelines caution against extreme extension or flexion of an infant's head because tracheal obstruction may occur. No data support this recommendation. The authors therefore examined the dimensions of the tracheal lumen in neutral, extended, and flexed head positions in infants undergoing general endotracheal anesthesia for elective surgery.

Methods
Eighteen healthy full-term infants were studied. A flexible fiberoptic bronchoscope was passed through a previously inserted endotracheal tube and positioned above the cricoid cartilage. Video recordings were taken in each of three head positions. Recordings were analyzed by an investigator blinded to head position. A computer-digitized technique was used to measure anterior-posterior and lateral dimensions and cross-sectional area. Data were analyzed using paired t tests and sign tests.

Results
No significant differences in mean tracheal dimensions with changes in head position were found. No infant had complete tracheal obstruction. Infants were equally as likely to have a small increase as they were to have a small decrease in tracheal dimension with changes in head position.

Conclusions
Despite the belief that infants and neonates have obstruction at the level of the trachea with extreme positions of the head, the authors were unable to demonstrate this phenomenon.
Effects of Ketamine on the Contractility of Failing and Nonfailing Human Heart Muscles In Vitro
Authors: Sprung Juraj , Schuetz Shannon M. , Stewart Robert W. , Moravec Christine S. 
Published: November 2003

Background
Induction of anesthesia with ketamine may decrease cardiac output in critically ill patients. The direct effects of ketamine on the failing human myocardium are unknown. This study examined the effects of ketamine on contractility of human failing and nonfailing myocardium in vitro.

Methods
Trabecular muscles were obtained from the left ventricles and right atria of 10 patients with heart failure undergoing transplantation and from the right atria of 14 patients undergoing coronary artery bypass surgery. Muscles were dissected and mounted in a 37 degrees C bath and stimulated at 1 Hz. Isometric contraction variables were recorded before and after addition of ketamine (concentrations between 0.44 and 440.0 microM) to the bath. The effects of ketamine were compared with those of buffer. To test muscle contractility, at the end of each experiment, 1 microM isoproterenol was added.

Results
Ketamine caused a significant dose-dependent decrease in developed tension in nonfailing atrial and failing atrial and ventricular muscles (P < 0.01 for all). In vehicle-treated muscles, developed tension remained stable, and isoproterenol increased developed tension 136% (nonfailing atrial muscles) and 178% (failing atrial and ventricular muscles; P < 0.01). In nonfailing atrial muscle, isoproterenol restored the ketamine-induced decrease in developed tension toward the baseline value. In failing atrial and ventricular muscles exposed to ketamine, isoproterenol did not counteract the ketamine.

Conclusions
Ketamine exerts a direct dose-dependent negative inotropic effect in human heart muscles. The failing myocardium exposed to ketamine has reduced ability to increase contractility even in the presence of increased beta-adrenergic stimulation.
Interactions between Hypothermia and the Latency to Ischemic Depolarization
Authors: Bart Robert D. , Takaoka Seiji , Pearlstein Robert D. , Dexter Franklin , Warner David S. 
Published: November 2003

Background
The authors postulated that hypothermic neuroprotection can be attributed to a delayed onset of ischemic depolarization.

Methods
Halothane-anesthetized rats were prepared for near-complete forebrain ischemia. Direct current (DC) potential microelectrodes were placed in hippocampal CA1. The pericranial temperature was maintained at 31 degrees C, 33 degrees C, 35 degrees C, or 37 degrees C (n = 6 per group). Bilateral carotid occlusion with systemic hypotension was initiated for 10 min. The time to onset of the DC shift was recorded. In a second experiment, rats were assigned to 37 degrees C or 31 degrees C for 10 min of ischemia, or to 31 degrees C for 14 min of ischemia (n = 8 per group). These durations of ischemia were defined to allow 9 min of ischemic depolarization in the 37 degrees C-10 min and 31 degrees C-14 min groups. Neurologic and histologic outcomes were examined 7 days later.

Results
Hippocampal CA1 time to depolarization increased with decreasing temperature (P < 0.0001). Time to depolarization was increased by approximately 4 min in the rats maintained at 31 degrees C compared with those at 37 degrees C. Time to repolarization during reperfusion was not affected by temperature. Increasing the duration of ischemia from 10 min to 14 min with the pericranial temperature maintained at 31 degrees C resulted in a duration of depolarization that was equivalent in the 37 degrees C-10 min and 31 degrees C-14 min groups. However, hippocampal CA1 damage was not increased (31 degrees C-10 min = 4 +/- 1% dead neurons; 31 degrees C-14 min = 6 +/- 1% dead neurons, 95% CI, -1% to 3%; 37 degrees C-10 min = 90 +/- 17% dead neurons).

Conclusions
Despite similar durations of DC depolarization, outcome in hypothermic rats was markedly improved compared with normothermic rats. This indicates that hypothermic neuroprotection can be attributed to mechanisms other than the delay in time to onset of ischemic depolarization.