bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiorespiratory Effects of Positive End-expiratory Pressure during Progressive Tidal Volume Reduction (Permissive Hypercapnia) in Patients with Acute Respiratory Distress Syndrome
Authors: Ranieri V. Marco , Mascia Luciana , Fiore Tommaso , Bruno Francesco , Brienza Antonio , Giuliani Rocco
Published: August 2004

Background

In patients with acute respiratory distress syndrome (ARDS), the ventilatory approach is based on tidal volume (VT) of 10-15 ml/kg and positive end-expiratory pressure (PEEP). To avoid further pulmonary injury, decreasing VT and allowing PaCO2 to increase (permissive hypercapnia) has been suggested. Effects of 10 cmH2O of PEEP on respiratory mechanics, hemodynamics, and gas exchange were compared during mechanical ventilation with conventional (10-15 ml/kg) and low (5-8 ml/kg) VT.

Methods

Nine sedated and paralyzed patients were studied. VT was decreased gradually (50 ml every 20-30 min). Static volume-pressure (V-P) curves, hemodynamics, and gas exchange were measured.

Results

During mechanical ventilation with conventional VT, V-P curves on PEEP 0 (ZEEP) exhibited an upward convexity in six patients reflecting a progressive reduction in compliance with inflating volume, whereas PEEP resulted in a volume displacement along the flat part of this curve. After VT reduction, V-P curves in the same patients showed an upward concavity, reflecting progressive alveolar recruitment with inflating volume, and application of PEEP resulted in alveolar recruitment. The other three patients showed a V-P curve with an upward concavity; VT reduction increased this concavity, and application of PEEP induced greater alveolar recruitment than during conventional VT. With PEEP, cardiac index decreased by, respectively, 31% during conventional VT and 11% during low VT (P < 0.01); PaO2 increased by 32% and 71% (P < 0.01), respectively, whereas right-to-left venous admixture (Qs/Qt) decreased by 11% and 40%, respectively (P < 0.01). The greatest values of PaO2, static compliance, and oxygen delivery and the lowest values of Qs/Qt (best PEEP) were obtained during application of PEEP with low VT (P < 0.01).

Conclusions

Although PEEP induced alveolar hyperinflation in most patients during mechanical ventilation with conventional VT, at low VT, there appeared to be a significant alveolar collapse, and PEEP was able to expand these units, improving gas exchange and hemodynamics.
Validation of the Alfentanil Canonical Univariate Parameter as a Measure of Opioid Effect on the Electroencephalogram
Authors: Gambus Pedro L. , Gregg Keith M. , Shafer Steven L.
Published: August 2004

Background

Several parameters derived from the multivariate electroencephalographic (EEG) signal have been used to characterize the effects of opioids on the central nervous system. These parameters were formulated on an empirical basis. A new statistical method, semilinear canonical correlation, has been used to construct a new EEG parameter (a certain combination of the powers in the EEG power spectrum) that correlates maximally with the concentration of alfentanil at the effect site. To date, this new canonical univariate parameter (CUP) has been tested only in a small sample of subjects receiving alfentanil.

Methods

The CUP was tested on EEG data from prior studies of the effect of five opioids: alfentanil (n = 5), fentanyl (n = 15), sufentanil (n = 11), trefentanil (n = 5), and remifentanil (n = 8). We compared the CUP to the commonly used EEG parameter spectral edge, SE95%. The comparison was based on the signal to noise ratio, obtained by fitting a nonlinear pharmacodynamic model to both parameters. The pharmacodynamic parameter estimates obtained using both measurements were also compared.

Results

The values for signal-to-noise ratio were significantly greater for the CUP than for SE95% when considering all the opioids at once. The pharmacodynamic estimates were similar between the two EEG parameters and with previously published results. Semilinear canonical correlation coefficients estimated within each drug group showed patterns similar to each other and to the coefficients in the CUP, but different from coefficients for propofol and midazolam.

Conclusions

Although the CUP was originally designed and tested using alfentanil, we have proven it to be a general measure of opioid effect on the EEG.
Fluorine-19 Nuclear Magnetic Resonance Imaging and Spectroscopy of Sevoflurane Uptake, Distribution, and Elimination in Rat Brain
Authors: Xu Yan , Tang Pei , Zhang Weiguo , Firestone Leonard , Winter Peter M.
Published: August 2004

Background

Determination of macroscopic and microscopic distribution of general anesthetics can facilitate identification of anatomic, cellular, and molecular loci of anesthetic action. Previous attempts to measure brain anesthetic distributions with fluorine-19 (19F) nuclear magnetic resonance (NMR) imaging were conducted at magnetic field strengths lower than 2 Tesla. All have produced only silhouettes of brain tissue. Difficulties intrinsic to NMR imaging of anesthetics include higher anesthetic solubility in extracranial tissues and the lower limits to spin-echo delay times that can be used in conventional NMR imaging methods. So far, such methods have been unable to capture rapidly decaying brain 19F NMR signals.

Methods

19F NMR imaging and spectroscopy were conducted at 4.7 Tesla using a specially developed NMR probe and new imaging methods. With the new techniques, it was possible to observe directly the uptake, distribution, and elimination in brain of sevoflurane, a fluorinated general anesthetic with special advantages for NMR investigations.

Results

19F NMR images, acquired at different times after sevoflurane administration, clearly showed the distribution of a fluorinated general anesthetic within the brain. Based on continuous transverse relaxation time measurements, sevoflurane signals could be separated into two components, attributable respectively to sevoflurane in a mobile or immobile microenvironment. During washin, there was a delayed accumulation of anesthetic in the mobile microenvironment. During washout, there was a rapid elimination from the immobile microenvironment.

Conclusions

At anesthetizing concentrations, sevoflurane distributes heterogeneously in the brain. Sevoflurane in the brain tissue contributes mostly to the immobile component of the 19F signal, whereas that in the surrounding adipose and muscle tissues contributes mostly to the mobile component. Imaging and spectroscopic results suggest that the immobile component of sevoflurane is associated with the general anesthetic effects of the agent.
In Vitro Effects of Eltanolone on Rat Myocardium
Authors: Riou Bruno , Ruel Patrick , Hanouz Jean-Luc , Langeron Olivier , Lecarpentier Yves , Viars Pierre
Published: August 2004

Background

Eltanolone is a new short-acting intravenous induction agent. However, its effects on intrinsic myocardial contractility remain unknown.

Methods

The effects of eltanolone and its solvent (soya bean emulsion) on the intrinsic contractility of rat left ventricular papillary muscles were investigated in vitro (Krebs-Henseleit solution, 29 degrees C, pH 7.40, Ca2+ 0.5 mM, stimulation frequency 12 pulses/min). We studied contraction; relaxation; contraction-relaxation coupling under high and low loads; and postrest potentiation.

Results

Eltanolone (0.1, 0.3, 1, 3, and 10 micrograms.ml-1) induced no significant inotropic effect, as shown by the lack of changes in maximum unloaded shortening velocity and active isometric force. Eltanolone did not significantly modify the contraction-relaxation coupling under low load, suggesting that it did not modify calcium uptake by the sarcoplasmic reticulum. Eltanolone did not significantly modify the contraction-relaxation coupling under high load, suggesting that it did not modify calcium myofilament sensitivity. Eltanolone decreased the postrest potentiation in a concentration-dependent manner (from 150 +/- 14% to 118 +/- 9% at 10 micrograms.ml-1, P < 0.001), suggesting a decrease in the maximum capacity of calcium release by the sarcoplasmic reticulum, whereas its solvent did not. However, eltanolone did not slow postrest potentiation recovery, as shown by the absence of significant changes in the recovery slope, tau (4.5 +/- 1.4 vs. 3.8 +/- 1.0 beats; difference not statistically significant).

Conclusions

Eltanolone induced no significant inotropic effect on rat myocardium. It induced a decrease in the calcium release function of the sarcoplasmic reticulum, but this effect was not sufficiently important to modify the inotropic properties.
Inhaled Anesthetics Alter the Determinants of Coronary Collateral Blood Flow in the Dog
Authors: Mignella Ronnie , Buffington Charles W.
Published: August 2004

Background

Whether coronary steal is induced by inhaled anesthetic agents remains controversial in part because multiple factors determine collateral blood flow.

Methods

We used an established model to determine how halothane, isoflurane, and desflurane affect the hemodynamic determinants of coronary collateral blood flow. Twelve dogs were studied 4-5 weeks after ameroid constrictor implantation. Retrograde flow draining from the occluded artery was measured as an index of collateral flow after antegrade embolization. Pressure in the supplying artery at the origin of the collaterals was estimated with a stop-flow technique. These techniques allow calculation of collateral segment resistance and the resistances of the supply artery upstream and downstream from the origin of the collaterals.

Results

None of the inhaled anesthetics affected collateral segment resistance. Downstream (arteriolar) resistance of the supplying artery was decreased by desflurane (-45%), isoflurane (-35%), and halothane (-15%), lowering pressure at the origin of the collaterals, an effect that was partially offset by a decrease in upstream resistance. Retrograde flow was unaffected by isoflurane and halothane but decreased by about 20% during desflurane administration.

Conclusions

Inhaled anesthetics have many effects on segmental resistance and pressure in the coronary circulation. These findings help explain conflicting results from previous studies and provide a useful model for investigating the effects of inhaled agents on small coronary arteries.
Halothane and Isoflurane Inhibit Endothelium-derived Relaxing Factor-dependent Cyclic Guanosine Monophosphate Accumulation in Endothelial Cell-Vascular Smooth Muscle Co-cultures Independent of an Effect on Guanylyl Cyclase Activation
Authors: Johns Roger A. , Tichotsky Alexandra , Muro Michael , Spaeth James P. , Le Cras Timothy D. , Rengasamy Appavoo
Published: August 2004

Background

Interaction of inhalational anesthetics with the nitric oxide signaling pathway and the mechanism of such effects are controversial. The aim of this study was to clarify the sites and mechanism of inhalational anesthetic interaction with the vascular nitric oxide and guanylyl cyclase signaling pathway.

Methods

To specifically study the mechanism of anesthetic interaction with the nitric oxide-guanylyl cyclase pathway, cultured vascular smooth muscle and endothelial cell-vascular smooth muscle (EC-VSM) co-culture models were chosen. Monolayer cultures of VSM with or without cultured endothelial cells grown on microcarrier beads were preequilibrated with anesthetic and stimulated with agonists. The effect of inhalational anesthetics on cyclic guanosine monophosphate (GMP) content of unstimulated VSM and of VSM in which soluble guanylyl cyclase had been activated by the endothelium-independent nitrovasodilators, sodium nitroprusside, nitroglycerin, or nitric oxide was determined. Experiments were also performed to assess the effect of inhalational anesthetics on unstimulated endothelial cell-vascular smooth muscle co-cultures and on co-cultures in which nitric oxide synthase and subsequent cyclic GMP production had been activated by the receptor-mediated agonists bradykinin and adenosine triphosphate and by the non-receptor-mediated calcium ionophore A23187.

Results

Increasing concentrations of halothane and isoflurane from 0.5 to 5% had no effect on basal cyclic GMP concentrations in cultured VSM alone or in endothelial cell-vascular smooth muscle co-cultures, and had no effect on sodium nitroprusside, nitroglycerin, or nitric oxide stimulated cyclic GMP accumulation in cultured VSM. In agonist-stimulated co-cultures, however, halothane and isoflurane significantly (P < 0.05) inhibited increases in cyclic GMP concentration in response to both receptor- and non-receptor-mediated nitric oxide synthase activating agents.

Conclusions

Inhalational anesthetics do not stimulate or inhibit basal cyclic GMP production in co-cultures or VSM, suggesting that inhalational anesthetics do not activate soluble or particulate guanylyl cyclase and do not activate nitric oxide synthase. Inhalational anesthetics do not inhibit nitrovasodilator-induced cyclic GMP formation, suggesting a lack of interference with soluble guanylyl cyclase activation. Inhalational anesthetics inhibit both agonist and calcium ionophore-stimulated nitric oxide-dependent cyclic GMP accumulation in endothelial cell-vascular smooth muscle co-cultures. Consistent with previous vascular ring studies, anesthetics appear to inhibit nitric oxide-guanylyl cyclase signaling distal to receptor activation in the endothelial cell and proximal to nitric oxide activation of guanylyl cyclase.
Characteristics of the Analgesic Effects and Drug Interactions of Intrathecal Carbachol in Rats
Authors: Abram Stephen E. , O'Connor Therese C.
Published: August 2004

Background

Intrathecal carbachol produces consistent analgesia in animals without appreciable adverse effects. Little is known about the ability of this drug to provide analgesia as stimulus intensity is increased. Likewise, there are few data regarding interactions between carbachol and other intrathecal analgesics.

Methods

Using two different noxious radiant heat intensities, one applied to each hind limb, analgesic effects of 1, 3, 10, and 30 micrograms intrathecal carbachol on paw withdrawal latencies were measured. Similar testing was done for intrathecal morphine and clonidine. ED50 fractions (1/2, 1/4, 1/8, 1/16) of drug combinations of carbachol-morphine and carbachol-clonidine were administered, responses to the low intensity stimulus were recorded, and the ED50 of each combination was established and isobolographic analysis of the drug interactions was carried out.

Results

The 30-micrograms dose of carbachol was associated with transient agitation, salivation, and hind limb weakness. No other adverse effects were noted. The ED50 (95% confidence interval) of intrathecal carbachol was 2.34 micrograms (1.34-4.04) for low intensity stimulation and 12.64 micrograms (4.18-38.25) for high intensity. There was no significant difference between high- and low-intensity ED50 values for intrathecal morphine and clonidine. The analgesic effect of the carbachol-morphine and carbachol-clonidine combinations were significantly greater than the calculated additive effects. The ED50 for the carbachol-morphine combination was 12% of the expected additive value and the ED50 for the carbachol-clonidine combination was 30% of the expected additive value.

Conclusions

Intrathecal carbachol provides analgesia to noxious thermal stimulation of the hind paw in rats. It is relatively less effective at providing analgesia than intrathecal morphine or clonidine when stimulus intensity is raised. Intrathecal carbachol is synergistic when combined with intrathecal morphine or clonidine.
Hepatic Heat Shock and Acute-phase Gene Expression Are Induced Simultaneously after Celiotomy in the Anesthetized Pig
Authors: Pannen Benedikt H. J. , Maeda Kaori , Ayuse Takao , Brienza Nicola , Revelly Jean-Pierre , Robotham James L. , Buchman Timothy G.
Published: August 2004

Background

The liver plays a central role in the whole organism's response to injury. Expression of hepatic acute-phase and heat-shock genes likely contributes to the restoration of homeostasis after stressful events. However, after prolonged ischemia, hepatic transcription of heat-shock genes can exclude the simultaneous transcription of acute-phase genes. The issue of whether hepatic 72-kd heat-shock protein (hsp72) gene expression is induced under perioperative conditions that do not result in prolonged liver ischemia and whether this might further affect the expression of the acute-phase reactant inter-alpha-trypsin inhibitor (alpha-Ti) was examined.

Methods

Pigs were anesthetized with sodium pentobarbital and ketamine hydrochloride, tracheally intubated, and their lungs ventilated. After celiotomy, a hepatic biopsy sample was obtained. Arterial blood pressure, cardiac output, and total hepatic blood flow were measured. Subsequent biopsies were obtained at 1, 2, 3, 4, and 6 h after the initial biopsy. Arterial norepinephrine concentrations were measured using high-pressure liquid chromatography. Nuclear runoff (run on) analysis and Northern blotting were applied to estimate changes in hsp72 and alpha-Ti gene transcription rates and RNA levels. Western blotting was used to estimate changes in hsp72 levels.

Results

Hemodynamic parameters did not change significantly over time. Arterial norepinephrine concentrations were increased at all time points. Hepatic hsp72 RNA levels increased up to sixfold while nuclear runoff assays did not detect significant changes in hsp72 gene transcription rates. The increases in hsp72 RNA levels correlated with accumulation of hsp72 (up to sevenfold). Increases in alpha-Ti transcription rates up to 42-fold were associated with respective increases in alpha-Ti RNA levels (up to 17-fold).

Conclusions

These data demonstrate that hepatic expression of hsp72 is not confined to conditions that lead to prolonged liver ischemia but is also part of the response of the liver to surgery under general anesthesia. Furthermore, these conditions are permissive for the simultaneous RNA expression of the acute-phase reactant alpha-Ti.
Parental Presence and a Sedative Premedicant for Children Undergoing Surgery
Authors: Kain Zeev N. , Mayes Linda C. , Wang Shu-Ming , Caramico Lisa A. , Krivutza Dawn M. , Hofstadter Maura B.
Published: August 2004

Background

Although some anesthesiologists use oral sedatives or parental presence during induction of anesthesia (PPIA) to treat preoperative anxiety in children, others may use these interventions simultaneously (e.g., sedatives and PPIA). The purpose of this investigation was to determine whether this approach has advantages over treating children with sedatives alone.

Methods

The child's and the parental anxiety throughout the perioperative period was the primary endpoint of the study. Parental satisfaction was the secondary endpoint. Subjects (n = 103) were assigned randomly to one of two groups: a sedative group (0.5 mg/kg oral midazolam) or a sedative and PPIA group. Using standardized measures of anxiety and satisfaction, the effects of the interventions on the children and parents were assessed. Statistical analysis (varimax rotation) of the satisfaction questionnaire items resulted in two factors that described satisfaction of the separation process and satisfaction of the overall care provided.

Results

Anxiety in the holding area, at entrance to the operating room, and at introduction of the anesthesia mask did not differ significantly between the two groups (F[2,192] = 1.26, P = 0.28). Parental anxiety after separation, however, was significantly lower in the sedative and PPIA group (F[2,93] = 4.46, P = 0.037). Parental satisfaction with the overall care provided (-0.28 +/- 1.2 vs. 0.43 +/- 0.26, P = 0.046) and with the separation process (-0.30 +/- 1.2 vs. 0.47 +/- 0.20, P = 0.03) was significantly higher among the sedative and PPIA group compared with the sedative group.

Conclusions

PPIA in addition to 0.5 mg/kg oral midazolam has no additive effects in terms of reducing a child's anxiety. Parents who accompanied their children to the operating room, however, were less anxious and more satisfied.
Pharmacokinetics and Arteriovenous Differences in Clevidipine Concentration following a Short- and a Long-term Intravenous Infusion in Healthy Volunteers
Authors: Ericsson Hans , Bredberg Ulf , Eriksson Ulf , Jolin-Mellgård Åse , Nordlander Margareta , Regårdh Carl G.
Published: August 2004

Background

Clevidipine is an ultra-short-acting calcium antagonist developed for reduction and control of blood pressure during cardiac surgery. The objectives of the current study were to determine the pharmacokinetics of clevidipine after 20-min and 24-h intravenous infusions, and to determine the relation between the arterial and venous concentrations and the hemodynamic responses to clevidipine in healthy volunteers.

Methods

Four volunteers received clevidipine for 20 min, and eight subjects were administered clevidipine intravenously for 24 h at two different dose rates. Arterial and venous blood samples were drawn for pharmacokinetic evaluation, and blood pressure and heart rate were recorded.

Results

A triexponential disposition model described the pharmacokinetics of clevidipine. The mean arterial blood clearance of clevidipine was 0.069l/kg-1/min-1 and the mean volume of distribution at steady state was 0.19 l/kg. The duration of the infusion had negligible effect on the pharmacokinetic parameters, and the context-sensitive half-time for clevidipine, simulated from the mean pharmacokinetic parameters derived after 24 h infusion at the highest dose, was less than 1 min. The arterial blood levels reached steady state within 2 min of the start of infusion and were about twice as high as those in the venous blood at steady state. The peak response preceded the peak venous concentration and was slightly delayed from the peak arterial blood concentration.

Conclusion

Clevidipine is a high clearance drug with a small volume of distribution, resulting in extremely short half-lives in healthy subjects. The initial rapid increase in the arterial blood concentrations and the short equilibrium time between the blood and the biophase suggest that clevidipine can be rapidly titrated to the desired effect.
Maximum Tolerated Dose of Nalmefene in Patients Receiving Epidural Fentanyl and Dilute Bupivacaine for Postoperative Analgesia
Authors: Dougherty Thomas B. , Porche Vivian H. , Thall Peter F.
Published: August 2004

Background

This study investigated the ability of the modified continual reassessment method (MCRM) to determine the maximum tolerated dose of the opioid antagonist nalmefene, which does not reverse analgesia in an acceptable number of postoperative patients receiving epidural fentanyl in 0.075% bupivacaine.

Methods

In the postanesthetic care unit, patients received a single intravenous dose of 0.25, 0.50, 0.75, or 1.00 microg/kg nalmefene. Reversal of analgesia was defined as an increase in pain score of two or more integers above baseline on a visual analog scale from 0 through 10 after nalmefene administration. Patients were treated in cohorts of one, starting with the lowest dose. The maximum tolerated dose of nalmefene was defined as that dose, among the four studied, with a final mean probability of reversal of anesthesia (PROA) closest to 0.20 (ie., a 20% chance of causing reversal). The modified continual reassessment method is an iterative Bayesian statistical procedure that, in this study, selected the dose for each successive cohort as that having a mean PROA closest to the preselected target PROA of 0.20.

Results

The modified continual reassessment method repeatedly updated the PROA of each dose level as successive patients were observed for presence or absence of ROA. After 25 patients, the maximum tolerated dose of nalmefene was selected as 0.50 microg/kg (final mean PROA = 0.18). The 1.00-microg/kg dose was never tried because its projected PROA was far above 0.20.

Conclusions

The modified continual reassessment method facilitated determination of the maximum tolerated dose ofnalmefene . Operating characteristics of the modified continual reassessment method suggest it may be an effective statistical tool for dose-finding in trials of selected analgesic or anesthetic agents.
Prophylactic Ondansetron in Prevention of Postoperative Nausea and Vomiting following Pediatric Strabismus Surgery
Authors: Sadhasivam Senthilkumar , Shende Dilip , Madan Rashmi
Published: August 2004

Background

This study evaluated the antiemetic effectiveness, dose-response, and clinical usefulness of prophylactic ondansetron in the prevention of postoperative nausea and vomiting (PONV) in children undergoing strabismus repair.

Method

The authors observed 180 children, American Society of Anesthesiologists physical status I or II, 2-12 yr of age, who were undergoing strabismus repair. After induction of anesthesia with halothane and nitrous oxide in oxygen or intravenous thiopental, children received either placebo (saline) or intravenous ondansetron in doses of 25, 50, 75, 100, and 150 /microg/kg (n = 30). The trachea was intubated and ventilation was controlled. Perioperative analgesic and fluid requirements were standardized. Episodes of nausea and vomiting were recorded for the first 24 h postoperatively. Data such as nonsurrogate (parental satisfaction scores and duration of postanesthesia care unit stay) and therapeutic (numbers needed to prevent and harm) outcome measures were collected.

Results

The incidences of PONV in the placebo and 25-, 50-, 75-, 100-, and 150-,microg/kg ondansetron groups were 83, 77, 47, 30, 30, and 27%, respectively. The incidence was less in the 75(P = 0.002), 100- (P = 0.002), and 150-microg/kg (P < 0.001) ondansetron groups compared with placebo. Duration of stay in the postanesthesia care unit was shorter in the 75-, 100-, and 150-microg/kg ondansetron groups (P < 0.002) compared with the placebo group. Parental assessment scores for the child's perioperative experience and the positive number needed to prevent PONV were also better and favorable in the 75-, 100-, and 150-microg/kg ondansetron groups compared with the placebo group. The incidence (P > 0.99) and severity (P = 0.63) of PONV were similar in the 75- and 150-microg/kg ondansetron groups. Surrogate, nonsurrogate, and therapeutic outcome measures revealed that 75 microg/kg ondansetron provided the same benefits as did 100 and 150 microg/kg.

Conclusion

The routine prophylactic use of ondansetron at a dose of 75 microg/kg is as effective as 150 microg/kg in preventing PONV and improving the "true" outcome measures after strabismus repair in children.
Contrasting Synaptic Actions of the Inhalational General Anesthetics Isoflurane and Xenon
Authors: de Sousa Sara L. M. , Dickinson Robert , Lieb William R. , Franks Nicholas P.
Published: August 2004

Background

The mechanisms by which the inhalational general anesthetics isoflurane and xenon exert their effects are unknown. Moreover, there have been surprisingly few quantitative studies of the effects of these agents on central synapses, with virtually no information available regarding the actions of xenon.

Methods

The actions of isoflurane and xenon on gamma-aminobutyric acid-mediated (GABAergic) and glutamatergic synapses were investigated using voltage-clamp techniques on autaptic cultures of rat hippocampal neurons, a preparation that avoids the confounding effects of complex neuronal networks.

Results

Isoflurane exerts its greatest effects on GABAergic synapses, causing a marked increase in total charge transfer (by approximately 70% at minimum alveolar concentration) through the inhibitory postsynaptic current. This effect is entirely mediated by an increase in the slow component of the inhibitory postsynaptic current. At glutamatergic synapses, isoflurane has smaller effects, but it nonetheless significantly reduces the total charge transfer (by approximately 30% at minimum alveolar concentration) through the excitatory postsynaptic current, with the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor-mediated components being roughly equally sensitive. Xenon has no measurable effect on GABAergic inhibitory postsynaptic currents or on currents evoked by exogenous application of GABA, but it substantially inhibits total charge transfer (by approximately 60% at minimum alveolar concentration) through the excitatory postsynaptic current. Xenon selectively inhibits the NMDA receptor-mediated component of the current but has little effect on the AMPA/kainate receptor-mediated component.

Conclusions

For both isoflurane and xenon, the most important targets appear to be postsynaptic. The authors' results show that isoflurane and xenon have very different effects on GABAergic and glutamatergic synaptic transmission, and this may account for their differing pharmacologic profiles.
Effects of Intravenous Anesthetic Agents on Glutamate Release
Authors: Buggy Donal J. , Nicol Beverley , Rowbotham David J. , Lambert David G.
Published: August 2004

Background

Many anesthetic agents are known to enhance the alpha1beta2gamma2S gamma-aminobutyric acid type A (GABAA) chloride current; however, they also depress excitatory neurotransmission. The authors evaluated two hypotheses: intravenous anesthetic agents inhibit glutamate release and any observed inhibition may be secondary to GABAA receptor activation.

Methods

Cerebrocortical slices were prepared from Wistar rats. After perfusion in oxygenated Krebs buffer for 60 min at 37 degrees C, samples for glutamate assay were obtained at 2-nmin intervals. After 6 min, a 2-min pulse of 46 mM K+ was applied to the slices (S1); this was repeated after 30 min (S2). Bicuculline (1-100 microM) was applied when the S1 response returned to basal level, and 10 min later, thiopental (1-300 micro/M), propofol (10 microM), or ketamine (30 microM) were also applied until the end of S2. Perfusate glutamate concentrations were measured fluorometrically, and the area under the glutamate release curves was expressed as a ratio (S2/S1).

Results

Potassium (46 mM) evoked a monophasic release of glutamate during S1 and S2, with a mean control S2/S1 ratio of 1.07 +/- 0.33 (mean +/- SD, n = 96). Ketamine and thiopental produced a concentration-dependent inhibition of K+-evoked glutamate release with half-maximum inhibition of release values of 18.2 and 10.9 /microM, respectively. Release was also inhibited by propofol. Bicuculline produced a concentration dependent reversal of thiopental inhibition of glutamate release with a half-maximum reversal of the agonist effect of 10.3 microM. Bicuculline also reversed the effects of propofol but not those of ketamine.

Conclusions

The authors' data indicate that thiopental, propofol, and ketamine inhibit K+-evoked glutamate release from rat cerebrocortical slices. The inhibition produced by thiopental and propofol is mediated by activation of GABAA receptors, revealing a subtle interplay between GABA-releasing (GABAergic) and glutamatergic transmission in anesthetic action.
Attenuation of Ascending Nociceptive Signals to the Rostroventromedial Medulla Induced by a Novel α2-Adrenoceptor Agonist, MPV-2426, following Intrathecal Application in Neuropathic Rats
Authors: Pertovaara Antti , Wei Hong
Published: August 2004

Background

In the current study, the potency and spread of the antinociception induced by MPV-2426, a novel alpha2-adrenoceptor agonist, was characterized in neuropathic and non-neuropathic animals.

Methods

Neuropathy was induced by unilateral ligation of two spinal nerves in the rat. After lumbar intrathecal or systemic administration of MPV-2426, thermally and mechanically evoked responses of nociceptive neurons of the rostroventromedial medulla were recorded during pentobarbitone anesthesia. To obtain a behavioral correlate of neurophysiologic findings, nocifensor reflex responses evoked by thermal and mechanical stimuli were assessed in unanesthetized neuropathic and control animals.

Results

After intrathecal administration, MPV-2426 and dexmedetomidine produced a dose-related antinociceptive effect, independent of the submodality of the noxious test stimulus or the pathophysiologic condition. This antinociceptive effect was spatially restricted to the inputs from the lower half of the body, and it was reversed by atipamezole, an alpha2-adrenoceptor antagonist. After systemic administration in non-neuropathic animals, MPV-2426 had no antinociceptive effect on responses to rostroventromedial medulla neurons, whereas systemically administered dexmedetomidine produced a dose-related suppression of nociceptive signals to the rostroventromedial medulla, independent of the site of test stimulation. In a behavioral study, intrathecal MPV-2426 produced a dose-dependent suppression of nocifensor responses evoked by noxious mechanical or heat stimuli, whereas systemic administration of MPV-2426 had no effects.

Conclusions

Intrathecal MPV-2426 has spatially limited antinociceptive properties in neuropathic and non-neuropathic conditions because of its action on spinal alpha2-adrenoceptors. These properties may be advantageous when designing therapy for spatially restricted pain problems.
Volatile Anesthetics Differentially Affect Immunostimulated Expression of Inducible Nitric Oxide Synthase
Authors: Tschaikowsky Klaus , Ritter Jörg , Schröppel Klaus , Kühn Matthias
Published: August 2004

Background

Nitric oxide released by inducible nitric oxide synthase (iNOS) plays an important role in immune responses and systemic vasodilation in septic shock. Volatile anesthetics have been reported to interfere with signal transduction and gene expression. We studied the effect of volatile anesthetics on activity and expression of iNOS and potential mechanisms of action.

Methods

Nitrite release and iNOS expression were determined using the Griess reaction and Western and Northern blot techniques, respectively, in J774 murine macrophages stimulated with lipopolysaccharide and gamma-interferon in the absence and presence of various concentrations (0.25-2.0 minimum alveolar concentration [MAC]) of volatile anesthetics (i.e., halothane, enflurane, isoflurane, desflurane). Furthermore, potential interference of volatile anesthetics with specific signal transduction pathways was investigated.

Results

All volatile anesthetics, studied in a time- and dose-dependent manner, suppressed nitrite production and iNOS expression in J774 macrophages stimulated by lipopolysaccharide or gamma-interferon at clinically relevant concentrations. The inhibition was completely antagonized by ionomycin but unaffected by diacylglycerol, phorbol myristate acetate, and C2-ceramide. In contrast, in cells costimulated by lipopolysaccharide plus gamma-interferon, volatile anesthetics significantly increased nitrite production and iNOS expression independent of ionomycin and other mediators studied.

Conclusions

Volatile anesthetics strongly reduced the mRNA and protein levels of iNOS and NOS activity after a single stimulation with lipopolysaccharide or gamma-interferon, most likely by attenuating intracellular calcium increase. Costimnulation with lipopolysaccharide plus gamma-interferon, however, results in maximum iNOS expression and activity, which are no longer inhibited but are potentiated by volatile anesthetics by unidentified mechanisms.
Antiallodynic Effect of Intrathecal Gabapentin and Its Interaction with Clonidine in a Rat Model of Postoperative Pain
Authors: Cheng Jen-Kun , Pan Hui-Lin , Eisenach James C.
Published: August 2004

Background

Systemic administration of gabapentin was shown previously to attenuate mechanical allodynia in a rat model of postoperative pain. Because intrathecal administration of gabapentin is effective in other hypersensitivity states, the authors tested its effect in the postoperative model, its interaction with another antiallodynic agent (clonidine), and a possible mechanism of gabapentin action (entry into sites of action via an L-amino acid transporter).

Methods

Male Sprague-Dawley rats were anesthetized with halothane, and an incision of the plantaris muscle of right hind paw induced punctate mechanical allodynia. Withdrawal threshold to von Frey filament application near the incision site was determined before and 2 h after surgery. Then, an intrathecal injection was performed and thresholds were determined every 30 min for 3 h thereafter.

Results

Paw incision induced a mechanical hypersensitivity (mechanical threshold > 25 g before incision and < 5 g after). Intrathecal gabapentin dose-dependently (10-100 microg) reduced mechanical allodynia. Intrathecal injection of an inhibitor of L-amino acid transporters or a competitor for this transporter, L-leucine, did not reverse the intrathecal effect of gabapentin. The ED50 of intrathecal gabapentin, clonidine, and their combination were 51, 31, and 9 microg, respectively, and isobolographic analysis showed synergy between gabapentin and clonidine.

Conclusions

Intrathecal gabapentin is effective against tactile allodynia that occurs after paw incision, and interacts synergistically with clonidine. Unlike results in vitro, gabapentin does not obligatorily need to enter cells via the L-amino acid transporter mechanism to achieve its effects in vivo.
Subunit-dependent Inhibition of Human Neuronal Nicotinic Acetylcholine Receptors and Other Ligand-gated Ion Channels by Dissociative Anesthetics Ketamine and Dizocilpine
Authors: Yamakura Tomohiro , Chavez-Noriega Laura E. , Harris R. Adron
Published: August 2004

Unlabelled

Background The neuronal mechanisms responsible for dissociative anesthesia remain controversial. N-methyl-D-aspartate (NMDA) receptors are inhibited by ketamine and related drugs at concentrations lower than those required for anesthetic effects. Thus, the authors studied whether ligand-gated ion channels other than NMDA receptors might display a sensitivity to ketamine and dizocilpine that is consistent with concentrations required for anesthesia.

Methods

Heteromeric human neuronal nicotinic acetylcholine receptors (hnAChR channels alpha2beta2, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2 and alpha4beta4), 5-hydroxytryptamine3 (5-HT3), alpha1beta2gamma2S gamma-aminobutyric acid type A (GABAA) and alpha1 glycine receptors were expressed in Xenopus oocytes, and effects of ketamine and dizocilpine were studied using the two-electrode voltage-clamp technique.

Results

Both ketamine and dizocilpine inhibited hnAChRs in a noncompetitive and voltage-dependent manner. Receptors containing beta1 subunits were more sensitive to ketamine and dizocilpine than those containing beta2 subunits. The inhibitor concentration for half-maximal response (IC50) values for ketamine of hnAChRs composed of beta4 subunits were 9.5-29 microM, whereas those of beta2 subunits were 50-92 microM. Conversely, 5-HT3 receptors were inhibited only by concentrations of ketamine and dizocilpine higher than the anesthetic concentrations. This inhibition was mixed (competitive/noncompetitive). GABAA and glycine receptors were very resistant to dissociative anesthetics.

Conclusions

Human nAChRs are inhibited by ketamine and dizocilpine at concentrations possibly achieved in vivo during anesthesia in a subunit-dependent manner, with beta subunits being more critical than alpha subunits. Conversely, 5-HT3, GABAA, and glycine receptors were relatively insensitive to dissociative anesthetics.
Blockade of Adenosine Triphosphate–sensitive Potassium Channels by Thiamylal in Rat Ventricular Myocytes
Authors: Tsutsumi Yasuo , Oshita Shuzo , Kitahata Hiroshi , Kuroda Yasuhiro , Kawano Takashi , Nakaya Yutaka
Published: August 2004

Background

The adenosine triphosphate (ATP)-sensitive potassium (KATP) channels protect myocytes during ischemia and reperfusion. This study investigated the effects of thiamylal on the activities of KATP channels in isolated rat ventricular myocytes during simulated ischemia.

Methods

Male Wistar rats were anesthetized with ether. Single, quiescent ventricular myocytes were dispersed enzymatically. Membrane currents were recorded using patch-clamp techniques. In the cell-attached configuration, KATP channel currents were assessed before and during activation of these channels by 2,4-dinitrophenol and after administration of 25, 50, and 100 mg/l thiamylal. The open probability was determined from current-amplitude histograms. In the inside-out configuration, the current-voltage relation was obtained before and after the application of thiamylal (50 mg/1).

Results

In the cell-attached configuration, 2,4-dinitrophenol caused frequent channel opening. 2,4-Dinitrophenol-induced channel activities were reduced significantly by glibenclamide, suggesting that the channels studied were KATP channels. Open probability of KATP channels was reduced by thiamylal in a concentration-dependent manner. KATP channels could be activated in the inside-out configuration because of the absence of ATP. Thiamylal inhibited KATP channel activity without changing the single-channel conductance.

Conclusions

The results obtained in this study indicate that thiamylal inhibits KATP channel activities in cell-attached and inside-out patches, suggesting a direct action of this drug on these channels.
Modeling the Uncertainty of Surgical Procedure Times
Authors: Strum David P. , May Jerrold H. , Vargas Luis G.
Published: August 2004

Background

Medical institutions are under increased economic pressure to schedule elective surgeries efficiently to contain the costs of surgical services. Surgical scheduling is complicated by variability inherent in the duration of surgical procedures. Modeling that variability, in turn, provides a mechanism to generate accurate time estimates. Accurate time estimates are important operationally to improve operating room utilization and strategically to identify surgeons, procedures, or patients whose duration of surgeries differ from what might be expected.

Methods

The authors retrospectively studied 40,076 surgical cases (1,580 Current Procedural Terminology-anesthesia combinations, each with a case frequency of five or more) from a large teaching hospital, and attempted to determine whether the distribution of surgical procedure times more closely fit a normal or a log-normal distribution. The authors tested goodness-of-fit to these data for both models using the Shapiro-Wilk test. Reasons, in practice, the Shapiro-Wilk test may reject the fit of a log-normal model when in fact it should be retained were also evaluated.

Results

The Shapiro-Wilk test indicates that the log-normal model is superior to the normal model for a large and diverse set of surgeries. Goodness-of-fit tests may falsely reject the log-normal model during certain conditions that include rounding errors in procedure times, large sample sizes, untrimmed outliers, and heterogeneous mixed populations of surgical procedure times.

Conclusions

The authors recommend use of the log-normal model for predicting surgical procedure times for Current Procedural Terminology-anesthesia combinations. The results help to legitimize the use of log transforms to normalize surgical procedure times before hypothesis testing using linear statistical models or other parametric statistical tests to investigate factors affecting the duration of surgeries.
Prediction of Difficult Mask Ventilation
Authors: Langeron Olivier , Masso Eva , Huraux Catherine , Guggiari Michel , Bianchi André , Coriat Pierre , Riou Bruno
Published: August 2004

Background

Maintenance of airway patency and oxygenation are the main objectives of face-mask ventilation. Because the incidence of difficult mask ventilation (DMV) and the factors associated with it are not well known, we undertook this prospective study.

Methods

Difficult mask ventilation was defined as the inability of an unassisted anesthesiologist to maintain the measured oxygen saturation as measured by pulse oximetry > 92% or to prevent or reverse signs of inadequate ventilation during positive-pressure mask ventilation under general anesthesia. A univariate analysis was performed to identify potential factors predicting DMV, followed by a multivariate analysis, and odds ratio and 95% confidence interval were calculated.

Results

A total of 1,502 patients were prospectively included. DMV was reported in 75 patients (5%; 95% confidence interval, 3.9-6.1%), with one case of impossible ventilation. DMV was anticipated by the anesthesiologist in only 13 patients (17% of the DMV cases). Body mass index, age, macroglossia, beard, lack of teeth, history of snoring, increased Mallampati grade, and lower thyromental distance were identified in the univariate analysis as potential DMV risk factors. Using a multivariate analysis, five criteria were recognized as independent factors for a DMV (age older than 55 yr, body mass index > 26 kg/m2, beard, lack of teeth, history of snoring), the presence of two indicating high likelihood of DMV (sensitivity, 0.72; specificity, 0.73).

Conclusion

In a general adult population, DMV was reported in 5% of the patients. A simple DMV risk score was established. Being able to more accurately predict DMV may improve the safety of airway management.
Citrate Storage Affects Thrombelastograph®Analysis
Authors: Camenzind Vladimir , Bombeli Thomas , Seifert Burkhardt , Jamnicki Marina , Popovic Dragoljub , Pasch Thomas , Spahn Donat R.
Published: August 2004

Background

Thrombelastograph analysis (TEG) is used to evaluate blood coagulation. Ideally, whole blood is immediately processed. If impossible, blood may be citrated and assessed after recalcification. No data describe the effect of such treatment and storage on TEG parameters.

Methods

Three studies were performed in 90 surgical patients. In 30 patients, blood was citrated (1:10, 0. 129 M) and recalcified (20 microl 2 M CaCl2 to 340 microl citrated blood), and TEG was performed with native blood and after recalcification after 0, 15, and 30 min of citrate storage. In another 30 patients, TEG was performed with citrated blood recalcified immediately and after 1-72 h storage. In a third study, thrombin-antithrombin complex, prothrombin fragment 1+2, and beta-thromboglobulin were measured (using enzyme-linked immunoabsorbant assay tests) at corresponding time points. Data were compared using repeated-measures analysis of variance and post hocpaired t tests.

Results

TEG parameters were different in recalcified citrated blood compared with native blood (P < 0.05) and changed significantly during 30-min (P < 0.025) and 72-h (P < 0.001) citrate storage. TEG parameters measured between 1 and 8 h of citrate storage were stable. Thrombin-antithrombin complex and prothrombin fragment 1+2 values were not elevated in native blood. After 30 min of citrate storage a gradual thrombin activation was observed, as evidenced by increasing thrombin-antithrombin complex and prothrombin fragment 1+2 values (P < 0.05). beta-Thromboglobulin level was increased after 2 and 8 h of citrate storage (P < 0.01).

Conclusions

Analysis of native blood yields the most reliable TEG results. Should immediate TEG processing not be possible, citrated blood may be used if recalcified after 1-8 h.