bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mixed-effects Modeling of the Intrinsic Ventilatory Depressant Potency of Propofol in the Non-steady State
Authors: Bouillon Thomas , Bruhn Joergen , Radu-Radulescu Lucian , Andresen Corina , Cohane Carol , Shafer Steven L. 
Published: January 2004

Background
Despite the ubiquitous use of propofol for anesthesia and conscious sedation and numerous publications about its effect, a pharmacodynamic model for propofol-induced ventilatory depression in the non-steady state has not been described. To investigate propofol-induced ventilatory depression in the clinically important range (at and below the metabolic hyperbola while carbon dioxide is accumulating because of drug-induced ventilatory depression), the authors applied indirect effect modeling to Paco2 data at a fraction of inspired carbon dioxide of 0 during and after administration of propofol.

Methods
Ten volunteers underwent determination of their carbon dioxide responsiveness by a rebreathing design. The parameters of a power function were fitted to the end-expiratory carbon dioxide and minute ventilation data. The volunteers then received propofol in a stepwise ascending pattern with use of a target-controlled infusion pump until significant ventilatory depression occurred (end-tidal pressure of carbon dioxide > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 microg/ml. Propofol pharmacokinetics and the Paco2 were determined from frequent arterial blood samples. An indirect response model with Bayesian estimates of the pharmacokinetics and carbon dioxide responsiveness in the absence of drug was used to describe the Paco2 time course. Because propofol reduces oxygen requirements and carbon dioxide production, a correction factor for propofol-induced decreasing of carbon dioxide production was included.

Results
The following pharmacodynamic parameters were found to describe the time course of hypercapnia after administration of propofol (population mean and interindividual variability expressed as coefficients of variation): F (gain of the carbon dioxide response), 4.37 +/- 36.7%; ke0, CO2, 0.95 min-1 +/- 59.8%; baseline Paco2, 40.9 mmHg +/- 12.8%; baseline minute ventilation, 6.45 l/min +/- 36.3%; kel, CO2, 0.11 min-1 +/- 34.2%; C50,propofol, 1.33 microg/ml +/- 49.6%; gamma, 1.68 +/- 21.3%.

Conclusion
Propofol at common clinical concentrations is a potent ventilatory depressant. An indirect response model accurately described the magnitude and time course of propofol-induced ventilatory depression. The indirect response model can be used to optimize propofol administration to reduce the risk of significant ventilatory depression.
Children Undergoing Repeated Exposures for Radiation Therapy Do Not Develop Tolerance to Propofol
Authors: Keidan Ilan , Perel Azriel , Shabtai Esther L. , Pfeffer Raphael M. 
Published: January 2004

Background
The purpose of this study was to apply clinical criteria and Bispectral Index monitor data for evaluating the development of tolerance to propofol in children undergoing repeated drug exposure.

Methods
Children undergoing multiple sessions of radiation therapy during anesthesia for various malignancies were given a predetermined dose of propofol at each session. Heart rate, blood pressure, oxygen saturation, respiratory rate, requirement of additional propofol, and time to emergence and discharge were recorded. The Bispectral Index was monitored continuously, and parameters were extracted and averaged for each week of therapy.

Results
Fifteen children (aged 2.5-10 yr) were treated for an average of 5 weeks (24 +/- 6 sessions). There were no significant differences in physiologic parameters or requirements of additional propofol between the weeks of treatment. Bispectral Index data analysis showed that although a nonlinear change with time for each parameter could not be rejected, the differences between the first and last intervals were nonsignificant.

Conclusions
Overall changes with time resulted from random fluctuations without a consistent trend. Combined with clinical data, Bispectral Index parameters showed that tolerance to propofol does not develop in children undergoing repeated exposures to the drug during radiation therapy.
Effects of Two Target-controlled Concentrations (1 and 3 ng/ml) of Remifentanil on MACBARof Sevoflurane
Authors: Albertin Andrea , Casati Andrea , Bergonzi Piercarlo , Fano Greta , Torri Giorgio 
Published: January 2004

Background
The aim of this prospective, randomized, double-blind study was to determine the effects of two different target-controlled concentrations of remifentanil (1 and 3 ng/ml) on the sevoflurane requirement for blunting sympathetic responses after surgical incision (MACBAR).

Methods
Seventy-four patients aged 20-50 yr, with American Society of Anesthesiologists physical status I, were anesthetized with propofol, cisatracurium, and sevoflurane with a mixture of 60% nitrous oxide in oxygen. Then, patients were randomly allocated to receive no remifentanil infusion (n = 27) or a target-controlled plasma concentration of 1 ng/ml (n = 27) or 3 ng/ml remifentanil (n = 20). Sympathetic responses to surgical incision (presence or absence of an increase in either heart rate or mean arterial blood pressure of 15% or more above the mean of the values measured during the 2 min before skin incision) were determined after a 20-min period of stable end-tidal sevoflurane and target-controlled remifentanil concentrations. Predetermined end-tidal sevoflurane concentrations and the MACBAR for each group were determined using an up-and-down sequential-allocation technique.

Results
The MACBAR of sevoflurane was higher in the group receiving no remifentanil (2.8% [95% confidence interval: 2.5-3.0%]) as compared with patients of the groups receiving 1 ng/ml (1.1% [0.9-1.3%]; P = 0.012) and 3 ng/ml remifentanil (0.2% [0.1-0.3%]; P = 0.006). When considering a minimum anesthetic concentration (MAC) value in this age population and the contribution of 60% nitrous oxide (0.55 MAC), the combined MACBAR values, expressed as multiples of the MAC, were 1.95 MAC, 1.1 MAC, and 0.68 MAC, in the three groups, respectively.

Conclusion
A target-controlled concentration of 1 ng/ml remifentanil results in a 60% decrease in the MACBAR of sevoflurane combined with 60% nitrous oxide. Increasing the target concentration of remifentanil to 3 ng/ml produces a further 30% decrease in the MACBAR values of sevoflurane.
Antichemical Protective Gear Prolongs Time to Successful Airway Management
Authors: Flaishon Ron , Sotman Alexander , Ben-Abraham Ron , Rudick Valery , Varssano David , Weinbroum Avi A. 
Published: January 2004

Background
Airway management is the first step in resuscitation. The extraordinary conditions in mass casualty situations impose special difficulties in airway management, even for experienced caregivers. The authors evaluated whether wearing surgical attire or antichemical protective gear made any difference in anesthetists' success of airway control with either an endotracheal tube or a laryngeal mask airway.

Methods
Fifteen anesthetists with 2-5 yr of residency and wearing either full antichemical protective gear or surgical attire intubated or inserted laryngeal masks in 60 anesthetized patients. The study was performed in a prospective, randomized, crossover manner. The duration of intubation/insertion was measured from the time the device was grasped to the time a normal capnography recording was obtained.

Results
Endotracheal tubes were introduced significantly (P < 0.01) faster when the anesthetist wore surgical attire (31 +/- 7 vs. 54 +/- 24 s for protective gear), but the mean times necessary to successfully insert laryngeal masks were similar (44 +/- 20 s for surgical attire vs. 39 +/- 11 s for protective gear). Neither performance failure nor incidences of hypoxemia were recorded.

Conclusions
This first report in humans shows to what extent anesthetists' wearing of antichemical protective gear slows the time to intubate but not to insert a laryngeal mask airway compared with wearing surgical attire. Laryngeal mask airway insertion is faster than tracheal intubation when wearing protective gear, indicating its advantage for airway management when anesthetists wear antichemical protective gear. If chances for rapid and successful tracheal intubation under such chaotic conditions are poor, laryngeal mask airway insertion is a viable choice for airway management until a proper secured airway is obtainable.
An Investigation to Dissociate the Analgesic and Anesthetic Properties of Ketamine Using Functional Magnetic Resonance Imaging
Authors: Rogers Richard , Wise Richard G. , Painter Deborah J. , Longe Sarah E. , Tracey Irene 
Published: January 2004

Background
Anatomic sites within the brain, which activate in response to noxious stimuli, can be identified with the use of functional magnetic resonance imaging. The aim of this study was to determine whether the analgesic effects of ketamine could be imaged.

Methods
Ketamine was administered to eight healthy volunteers with use of a target-controlled infusion to three predicted plasma concentrations: 0 (saline), 50 (subanalgesic), and 200 ng/ml (analgesic, subanesthetic). Volunteers received noxious thermal stimuli and auditory stimuli and performed a motor task within a 3-T human brain imaging magnet. Activation of brain regions in response to noxious and auditory stimuli and during the motor task was compared with behavioral measures.

Results
The analgesic subanesthetic dose of ketamine significantly reduced the pain scores, and this matched a decrease in activity within brain regions that activate in response to noxious stimuli, in particular, the insular cortex and thalamus. A different pattern of activation was observed in response to an auditory task. In comparison, smaller behavioral and imaging changes were found for the motor paradigm. The lower dose of ketamine gave similar but smaller nonsignificant effects.

Conclusion
The analgesic effect can be measured within a more global effect of ketamine as shown by auditory and motor tasks, and the analgesia produced by ketamine occurs with a smaller degree of cortical processing in pain-related regions.
Alterations in Rat Brain Proteins after Desflurane Anesthesia
Authors: Fütterer Carsten D. , Maurer Martin H. , Schmitt Anne , Feldmann Robert E. , Kuschinsky Wolfgang , Waschke Klaus F. 
Published: January 2004

Background
Volatile anesthetics disappear from an organism after the end of anesthesia. Whether changes of protein expression persist in the brain for a longer period is not known. This study investigates the question of whether the expression of proteins is altered in the rat brain after the end of desflurane anesthesia.

Methods
Three groups (n = 12 each) of rats were anesthetized with 5.7% desflurane in air for 3 h. Brains were removed directly after anesthesia, 24 h after anesthesia, or 72 h after anesthesia. Two additional groups (n = 12 each) served as naive conscious controls, in which the brains were removed without previous anesthesia 3 or 72 h after the start of the experiment. Cytosolic proteins were isolated. A proteome-wide study was performed, based on two-dimensional gel electrophoresis and mass spectrometry.

Results
Compared with conscious controls, significant (P < 0.05) increase/decrease was found: 3 h of anesthesia, 5/2 proteins; 24 h after anesthesia, 13/1 proteins; 72 h after anesthesia, 6/4 proteins. The overall changes in protein expression as quantified by the induction factor ranged from -1.67 (decrease to 60%) to 1.79 (increase by 79%) compared with the controls (100%). Some of these regulated proteins play a role in vesicle transport and metabolism.

Conclusion
Desflurane anesthesia produces changes in cytosolic protein expression up to 72 h after anesthesia in the rat brain, indicating yet unknown persisting effects.
Long-term Impairment of Acquisition of a Spatial Memory Task following Isoflurane–Nitrous Oxide Anesthesia in Rats
Authors: Culley Deborah J. , Baxter Mark G. , Yukhananov Rustam , Crosby Gregory 
Published: January 2004

Background
The authors demonstrated previously that isoflurane-nitrous oxide anesthesia attenuates performance improvement on an already-learned spatial memory task and that the effect persists for weeks. This experiment was designed to test the hypothesis that learning of new information is particularly susceptible to prolonged disruption after general anesthesia.

Methods
Six- (n = 5) and 20- (n = 5) month-old male Fischer 344 rats were anesthetized for 2 h with 1.2% isoflurane, 70% nitrous oxide, and 30% oxygen. Age-matched control rats received 30% oxygen and 70% nitrogen (n = 5 per group). Rats breathed spontaneously, and anesthetic and oxygen concentrations were measured. Spatial learning was assessed daily for 21 days on a 12-arm radial maze (RAM) beginning 48 h after anesthesia. In a post hoc experiment to examine locomotion, swim speed was assessed in a separate group of identically treated rats (n = 3 per group) for 4 days beginning 48 h after anesthesia.

Results
Aged rats were slower to complete the maze, made fewer correct choices before first error, and made more errors at baseline than young rats (P < 0.05). Anesthesia worsened maze performance in both age groups, as evidenced by increased time to complete the maze and a decreased number of correct choices before first error (P < 0.05), but there were no statistically significant differences in total number of errors. Interestingly, there were no age-by-anesthesia interactions. Aged rats swam slower than adult rats (P < 0.001), but there were no differences between the control and anesthesia groups.

Conclusions
Isoflurane-nitrous oxide anesthesia is associated with a persistent deficit in RAM performance that is not explained by impaired locomotion. This impairment occurs in adult and aged rats, indicating that it is not an age-specific phenomenon. Thus, RAM performance is altered after general anesthesia for longer than predicted by the pharmacology of the drugs used, which, by inference, suggests a long-term deficit in learning/memory.
Pharmacokinetics of Intrathecal Oligodeoxynucleotides
Authors: Krupp Jennifer L. , Bernards Christopher M. 
Published: January 2004

Background
Intrathecal administration of antisense oligonucleotides is a frequently used technique to alter gene expression for research purposes. However, in the future, antisense oligonucleotides will likely be administered intrathecally to humans for therapeutic purposes. To date, there have been no systematic studies of the pharmacokinetics of intrathecal oligonucleotides. This study was designed to fill that knowledge gap.

Methods
Microdialysis probes were placed intrathecally at the L4, L1, and T11 vertebral levels and epidurally at the L4 vertebral level in pigs. One of the study oligodeoxynucleotides (10-, 18-, or 30-nucleotide-long sequences of the human MDR-1 gene) was injected intrathecally at the L4 level at time 0. Microdialysis samples were obtained for measurement of oligodeoxynucleotide samples at 5-min intervals until 20 min, 10-min intervals until 60 min, and 20-min intervals until 180 min. Noncompartmental pharmacokinetic analysis was performed using PK Solutions software.

Results
Mean residence time and terminal elimination half-life did not differ significantly among the three oligodeoxynucleotides at any sampling site. In contrast, area under the concentration-time curve differed significantly among the oligodeoxynucleotides at all sampling sites and was inversely related to oligodeoxynucleotide length at the L4 and L1 intrathecal sites but not the T11 or epidural sampling sites. Similarly, clearance and volumes of distribution at the L4 level differed significantly among the oligodeoxynucleotides and were directly related to oligodeoxynucleotide length.

Conclusion
The intrathecal pharmacokinetics of oligodeoxynucleotides are largely determined by oligodeoxynucleotide length. This contrasts with smaller drug molecules, such as opioids, for which intrathecal and epidural pharmacokinetics are largely determined by lipid solubility, not size. The potential clinical utility of this information is that oligodeoxynucleotide distribution within the central nervous system may be controllable to some degree by varying oligodeoxynucleotide length.
Hypothermic Preconditioning Increases Survival of Purkinje Neurons in Rat Cerebellar Slices after an In Vitro Simulated Ischemia
Authors: Yuan Hui-Bih , Huang Yueming , Zheng Shuqiu , Zuo Zhiyi 
Published: January 2004

Background
A period of hypothermia before ischemia (hypothermic preconditioning) induces a delayed phase of ischemic tolerance in rat brain. However, whether hypothermic preconditioning induces an acute phase (within a few hours after the hypothermia) of ischemic tolerance remains unknown. This study was designed to determine the time window of the hypothermic preconditioning-induced acute phase of neuroprotection, which is useful information for situations during surgery with anticipated ischemic episodes, and its involved mechanisms.

Methods
Survival of Purkinje cells in rat cerebellar slices was evaluated after a 20-min oxygen-glucose deprivation (OGD, in vitro simulated ischemia) followed by a 4-h recovery. Mild hypothermia (33 degrees C) for 20 min was applied at various times before the OGD.

Results
The hypothermia applied immediately to 3 h before the OGD equally effectively reduced OGD-induced Purkinje cell death/injury. Glibenclamide, a selective KATP channel blocker; 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine A1 receptor antagonist; and farnesyl protein transferase inhibitor III, a selective inhibitor to reduce Ras farnesylation, abolished hypothermic preconditioning-induced neuroprotection when applied during the hypothermia. OGD increased the expression of high-mobility group I(Y) proteins, which are nuclear transcription factors to enhance the expression of putatively damaging proteins such as cyclooxygenase-2, in cerebellar slices. This increase was attenuated by hypothermic preconditioning.

Conclusions
Hypothermic preconditioning induces an acute phase of neuroprotection. This neuroprotection depends on activation of the signaling molecules, adenosine A1 receptors, KATP channels, and Ras. Inhibition of putatively damaging proteins via the effects of hypothermic preconditioning on high-mobility group I(Y) expression may also be involved in hypothermic preconditioning-induced neuroprotection.
Determinants of the Sensitivity of AMPA Receptors to Xenon
Authors: Plested Andrew J. R. , Wildman Scott S. , Lieb William R. , Franks Nicholas P. 
Published: January 2004

Background
There is substantial and growing literature on the actions of general anesthetics on a variety of neurotransmitter-gated ion channels, with the greatest attention being focused on inhibitory gamma-amino butyric acid type A receptors. In contrast, glutamate receptors, the most important class of fast excitatory neurotransmitter-gated receptor channels, have received much less attention, and their role in the production of the anesthetic state remains controversial.

Methods
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors formed from a variety of different subunits were expressed in Xenopus oocytes and HEK-293 cells, and their sensitivities to the inhalational general anesthetics xenon, isoflurane, and halothane were determined using two-electrode voltage clamp and patch clamp techniques. The effects of desensitization on anesthetic sensitivity were investigated using cyclothiazide and site-directed mutagenesis. An ultrarapid application system was also used to mimic rapid high-concentration glutamate release at synapses.

Results
The authors show that xenon can potently inhibit AMPA receptors when assayed using bath application of kainate. However, when the natural neurotransmitter l-glutamate is used under conditions in which the receptor desensitization is blocked and the peak of the glutamate-activated response can be accurately measured, the pattern of inhibition changes markedly. When desensitization is abolished by a single-point mutation (L497Y in GluR1 and the equivalent mutation L505Y in GluR4), the xenon inhibition is eliminated. When AMPA receptors are activated by glutamate using an ultrarapid application system that mimics synaptic conditions, sensitivity to xenon, halothane, and isoflurane is negligible.

Conclusions
AMPA receptors, when assayed in heterologous expression systems, showed a sensitivity to inhalational anesthetics that was minimal when glutamate was applied rapidly at high concentrations. Because these are the conditions that are most relevant to synaptic transmission, the authors conclude that AMPA receptors are unlikely to play a major role in the production of the anesthetic state by inhalational agents.
Paravertebral Analgesia with Levobupivacaine Increases Postoperative Flap Tissue Oxygen Tension after Immediate Latissimus Dorsi Breast Reconstruction Compared with Intravenous Opioid Analgesia
Authors: Buggy Donal J. , Kerin Michael J. 
Published: January 2004

Background
Directly measured tissue oxygen tension (Pto2) reflects the adequacy of local tissue oxygenation and influences surgical wound healing. Epidural analgesia increases Pto2 compared with intravenous morphine analgesia after abdominal surgery. The authors tested the hypothesis that paravertebral regional anesthesia and analgesia would increase Pto2 compared with intravenous opioid-based anesthesia and analgesia.

Methods
Twenty patients scheduled to undergo mastectomy with immediate latissimus dorsi breast reconstruction were randomized to receive either general anesthesia with postoperative intravenous morphine analgesia or combined general-paravertebral anesthesia with continuous paravertebral postoperative analgesia using levobupivacaine in this prospective, cohort study. All patients had a local tissue oxygen sensor implanted in the flap muscle. Data were downloaded continuously for 20 h postoperatively.

Results
The mean Pto2 over the 20-h period was significantly higher in patients receiving paravertebral anesthesia (75 +/- 38 vs. 44 +/- 23 mmHg [mean +/- SD]; P = 0.03). Intraoperative blood loss was less in paravertebral patients (1.2 +/- 0.4 vs. 1.7 +/- 0.5 l; P = 0.04). Dynamic visual analog scale pain scores were significantly lower in paravertebral patients. Intraoperative and postoperative fluids administered, hemoglobin, core temperature, intraoperative end-tidal carbon dioxide, and mean arterial pressure were similar in both groups.

Conclusion
The postoperative latissimus dorsi flap Pto2 was higher for 20 h after breast reconstruction with paravertebral analgesia compared with intravenous morphine analgesia.