bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Halothane on the Recirculatory Pharmacokinetics of Physiologic Markers
Authors: Avram Michael J. , Krejcie Tom C. , Niemann Claus U. , Klein Cheri , Gentry W. Brooks , Shanks Colin A. , Henthorn Thomas K. 
Published: November 2003

Background
The cardiovascular effects of halothane are well recognized, but little is known of how this affects drug distribution. The effect of halothane anesthesia on physiologic factors that affect drug disposition from the moment of injection was investigated.

Methods
The dispositions of markers of intravascular space and blood flow (indocyanine green), extracellular space and free water diffusion (inulin), and total body water and tissue perfusion (antipyrine) were determined in four purpose-bred coonhounds. The dogs were studied while awake and while anesthetized with 1%, 1.5%, and 2% halothane in a randomized order determined by a repeated measures Latin square experimental design. Marker dispositions were described by recirculatory pharmacokinetic models based on frequent early and less frequent later arterial blood samples. These models characterize the role of cardiac output and its distribution on drug disposition.

Results
Halothane caused a significant and dose-dependent decrease in cardiac output. The disposition of antipyrine was most profoundly affected by halothane anesthesia, which increased both nondistributive intercompartmental clearance and volume while decreasing fast and slow tissue clearances and elimination clearance in a halothane dose-dependent manner.

Conclusions
Halothane-induced changes in blood flow to the compartments of the antipyrine recirculatory model were not proportional to changes in cardiac output. Halothane anesthesia significantly increased (to more than double) the area under the drug concentration versus time curve due to an increase in the apparent peripheral blood flow not involved in drug distribution, despite a dose-dependent cardiac output decrease. Recirculatory pharmacokinetic models include the best aspects of traditional compartmental and physiologic pharmacokinetic models while offering advantages over both.
Effects of the Water Content of Soda Lime on Compound A Concentration in the Anesthesia Circuit in Sevoflurane Anesthesia
Authors: Bito Hiromichi , Ikeuchi Yukako , Ikeda Kazuyuki 
Published: November 2003

Background
Sevoflurane anesthesia is usually performed with fresh gas flow rates greater than 2 l/min due to the toxicity of compound A in rats and limited clinical experience with sevoflurane in low-flow systems. However, to reduce costs, it would be useful to identify ways to reduce compound A concentrations in low-flow sevoflurane anesthesia. This goal of this study was to determine if compound A concentrations can be reduced by using soda lime with water added.

Methods
Low-flow sevoflurane anesthesia (fresh gas flow of 1 l/min) was performed in 37 patients using soda lime with water added (perhydrated soda lime) or standard soda lime as the carbon dioxide (CO2) absorbent. The soda lime was not changed between patients, but rather was used until CO2 rebreathing occurred. The perhydrated soda lime was prepared by spraying 100 ml distilled water onto 1 kg fresh soda lime, and water was added only when a new bag of soda lime was placed into the canister. Compound A concentrations in the circle system, soda lime temperatures, inspired and end-tidal CO2 and end-tidal sevoflurane concentrations, and CO2 elimination by the patient were measured during anesthesia.

Results
Compound A concentrations were significantly lower for the perhydrated soda lime (1.9 +/- 1.8 ppm; means +/- SD) than for the standard soda lime (13.9 +/- 8.2 ppm). No differences were seen between the two types of soda lime with regard to the temperature of the soda lime, end-tidal sevoflurane concentrations, or CO2 elimination. Compound A concentration decreased with the total time of soda lime use for both types of soda lime. The CO2 absorption capacity was significantly less for perhydrated soda lime than for standard soda lime.

Conclusions
Compound A concentrations in the circuit can be reduced by using soda lime with water added. The CO2 absorption capacity of the soda lime is reduced by adding water to it, but this should not be clinically significant.
Blockade of Na+and K+Currents by Local Anesthetics in the Dorsal Horn Neurons of the Spinal Cord
Authors: Olschewski Andrea , Hempelmann Gunter , Vogel Werner , Safronov Boris V. 
Published: November 2003

Background
The dorsal horn of the spinal cord is a pivotal point for transmission of neuronal pain. During spinal and epidural anesthesia, the neurons of the dorsal horn are exposed to local anesthetics. Unfortunately, little is known about the action of local anesthetics on the major ionic conductances in dorsal horn neurons. In this article, the authors describe the effects of bupivacaine, lidocaine, and mepivacaine on voltage-gated Na+ and K+ currents in the membranes of these neurons.

Methods
The patch-clamp technique was applied to intact dorsal horn neurons from laminae I-III identified in 200-microm slices of spinal cord from newborn rats. Under voltage-clamp conditions, the whole-cell Na+ and K+ currents activated by depolarization were recorded in the presence of different concentrations of local anesthetics.

Results
Externally applied bupivacaine, lidocaine, and mepivacaine produced tonic block of Na+ currents with different potencies. Half-maximum inhibiting concentrations (IC50) were 26, 112, and 324 microM, respectively. All local anesthetics investigated also showed a phasic, that is, a use-dependent, block of Na+ channels. Rapidly inactivating K+ currents (KA currents) also were sensitive to the blockers with IC50 values for tonic blocks of 109, 163, and 236 microM, respectively. The block of KA currents was not use dependent. In contrast to Na+ and KA currents, delayed-rectifier K+ currents were almost insensitive to the local anesthetics applied.

Conclusions
In clinically relevant concentrations, local anesthetics block Na+ and KA currents but not delayed-rectifier K+ currents in spinal dorsal horn neurons. The molecular mechanisms of Na+ and K+ channel block by local anesthetics seem to be different. Characterization of these mechanisms could be an important step in understanding the complexity of local anesthetic action during spinal and epidural anesthesia.
Cardiovascular Effects of Propofol in Dogs with Dilated Cardiomyopathy
Authors: Pagel Paul S. , Hettrick Douglas A. , Kersten Judy R. , Lowe Dermot , Warltier David C. 
Published: November 2003

Background
The authors tested the hypothesis that propofol improves left ventricular diastolic function in dogs with dilated cardiomyopathy by reducing left ventricular preload and afterload.

Methods
Seven dogs were instrumented for left ventricular and aortic pressures, aortic blood flow, and subendocardial segment length. Left ventricular afterload and contractility were quantified with aortic input impedance and preload recruitable stroke work, respectively. Diastolic function was evaluated with a time constant of left ventricular relaxation (tau); segment-lengthening velocities and time-velocity integrals during early left ventricular filling (dL/dtE and TVI-E, respectively) and atrial systole (dL/dtA and TVI-A, respectively); and a regional chamber stiffness constant (K). Dogs were paced at 240 beats/min for 18 +/- 3 days, and hemodynamics were recorded in sinus rhythm in the conscious state. Anesthesia was induced with propofol (5 mg/kg) and maintained with propofol infusions at 25, 50, and 100 mg x kg-1 x h-1, and hemodynamics were recorded after 15 min of equilibration at each dose.

Results
Propofol decreased mean arterial pressure, left ventricular end-diastolic pressure, and K but did not change heart rate. Propofol reduced total arterial resistance and increased total arterial compliance derived from aortic input impedance. Propofol also reduced preload recruitable stroke work. The lowest dose of propofol decreased tau. Propofol decreased dL/dtE and TVI-E and reduced the dL/dt-E/A and TVI-E/A ratios.

Conclusions
Propofol reduces left ventricular preload, afterload, and regional chamber stiffness, causes direct negative inotropic effects, and impairs early-diastolic left ventricular filling in dogs with dilated cardiomyopathy.
Selective Pulmonary Vasodilation by Intravenous Infusion of an Ultrashort Half-life Nucleophile/Nitric Oxide Adduct
Authors: Adrie Christophe , Hirani Mona W. , Holzmann Alexandra , Keefer Larry , Zapol Warren M. , Hurford William E. 
Published: November 2003

Background
PROLI/NO (C5H7N3O4Na2 x CH3OH) is an ultrashort-acting nucleophile/NO adduct that generates NO (half-life 2 s at 37 degrees C and pH 7.4). Because of its short half-life, the authors hypothesized that intravenous administration of this compound would selectively dilate the pulmonary vasculature but cause little or no systemic hypotension.

Methods
In eight awake healthy sheep with pulmonary hypertension induced by 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha, the authors compared PROLI/NO with two reference drugs-inhaled NO, a well-studied selective pulmonary vasodilator, and intravenous sodium nitroprusside (SNP), a nonselective vasodilator. Sheep inhaled 10, 20, 40, and 80 parts per million NO or received intravenous infusions of 0.25, 0.5, 1, 2, and 4 microg x kg-1 x min-1 of SNP or 0.75, 1.5, 3, 6, and 12 microg x kg-1 x min-1 of PROLI/NO. The order of administration of the vasoactive drugs (NO, SNP, PROLI/NO) and their doses were randomized.

Results
Inhaled NO selectively dilated the pulmonary vasculature. Intravenous SNP induced nonselective vasodilation of the systemic and pulmonary circulation. Intravenous PROLI/NO selectively vasodilated the pulmonary circulation at doses up to 6 microg x kg-1 x min-1, which decreased pulmonary vascular resistance by 63% (P < 0.01) from pulmonary hypertensive baseline values without changing systemic vascular resistance. At 12 microg x kg-1 x min-1, PROLI/NO decreased systemic and pulmonary vascular resistance and pressure. Exhaled NO concentrations were higher during PROLI/NO infusion than during SNP infusion (P < 0.01 with all data pooled).

Conclusions
The results suggest that PROLI/NO could be a useful intravenous drug to vasodilate the pulmonary circulation selectively.
Skin Vasomotor Reflex Predicts Circulatory Responses to Laryngoscopy and Intubation
Authors: Shimoda Osamu , Ikuta Yoshihiro , Sakamoto Masakatsu , Terasaki Hidenori 
Published: November 2003

Background
An evaluation of autonomic reactivity may help to predict circulatory responses to intubation. The relation between the magnitude of the skin vasomotor reflex (SVmR) immediately before laryngoscopy and the circulatory responses to intubation was examined.

Methods
Forty-four adult patients (classified as American Society of Anesthesiologists physical status I or II) were studied. General anesthesia was induced with fentanyl and thiamylal and maintained with nitrous oxide and sevoflurane. The SVmR was evoked by an electrostimulus to the ulnar nerve, and decreases in skin blood flow were detected using a laser-Doppler flowmeter. In study 1, two groups of patients were studied. In the monitored group (n = 14), laryngoscopy was performed when the SVmR amplitude had decreased to less than 0.1. In the control group (n = 15), intubation was performed regardless of changes in the SVmR amplitude. In study 2, after induction, the end-tidal concentration of sevoflurane was maintained at 1 MAC (n = 9) or 1.3 MAC (n = 6) for 5 min. The SVmR was tested by changing the electric intensity.

Results
In study 1, the blood pressure and heart rate of the control group increased significantly (P < 0.01) after laryngoscopy. The blood pressure of the monitored group did not increase. The SVmR amplitude and the systolic blood pressure changes showed a significant linear correlation (P < 0.001). In study 2, the relation between the electric intensity and the SVmR amplitude showed a weak but significant correlation (P < 0.01) in the 1 MAC group.

Conclusion
The evaluation of the SVmR provides useful information for determining the optimal anesthetic depth for laryngoscopy and intubation in individual patients.
Dose Proportionality and Pharmacokinetics of Oral Transmucosal Fentanyl Citrate
Authors: Streisand James B. , Busch Michael A. , Egan Talmage D. , Smith Barbara Gaylord , Gay Mason , Pace Nathan L. 
Published: November 2003

Background
The pharmacokinetics of a single dose (15 microg/kg) of oral transmucosal fentanyl citrate (OTFC) have been characterized. A range of doses may eventually be used in clinical practice. The goal of this study was to determine if the pharmacokinetics of OTFC are dose proportional for doses ranging from 200 to 1,600 microg.

Methods
Twelve healthy male volunteers were studied on four different occasions, receiving 200, 400, 800, and 1,600 microg OTFC in a double-blind, randomized protocol. Venous blood samples were collected at selected times during and after dosing for a 24-h period and assayed for fentanyl using a radioimmunoassay. Maximum concentration, time to maximum concentration, area under the curve, and elimination half-life were determined for each dose administered. In addition, respiratory rate, need for verbal prompting to breathe, and supplemental oxygen requirements were noted.

Results
Mean fentanyl concentration time curves were similarly shaped with increasing doses. Both peak concentrations and area under the curve increased linearly with an increase in dose, whereas time to reach peak serum concentrations did not vary significantly between doses. Except for the 200-microg dose, the apparent elimination half-life remained relatively constant (358-386 min). The incidence of low respiratory rate, supplemental oxygen requirement, and number of breathing prompts significantly increased with increasing doses.

Conclusions
Oral transmucosal fentanyl citrate exhibits dose-proportional pharmacokinetics over the dose range of 200-1,600 microg.
Role of Fiberoptic Bronchoscopy in Conjunction with the Use of Double-lumen Tubes for Thoracic Anesthesia
Authors: Klein Uwe , Karzai Waheedullah , Bloos Frank , Wohlfarth Mathias , Gottschall Reiner , Fritz Harald , Gugel Michael , Seifert Albrecht 
Published: November 2003

Background
Fiberoptic bronchoscopy has been recommended to verify the position of double-lumen tubes (DLT), but this remains controversial. The authors studied the role of bronchoscopy for placing and monitoring right- and left-sided DLTs after blind intubation and after positioning the patient.

Methods
Two hundred patients having thoracic surgery requiring DLT insertion were prospectively studied. "Blind" tracheal intubations were done with 163 left-sided and 37 right-sided disposable polyvinyl chloride Robertshaw tubes. Bronchoscopy was performed by a different anesthesiologist after intubation and conventional clinical verification of correct placement and after patient positioning for thoracotomy. A DLT was considered malpositioned when it had to be moved >0.5 cm to correct its position. Critical malpositions were those that might have affected patient safety or influenced the surgical procedure if left uncorrected.

Results
After "blind" DLT intubation, clinical evidence of malpositioning was found in 28 patients. This was confirmed by fiberoptic assessment. In 172 patients in whom placement was judged correct by clinical assessment, malpositioning was detected by bronchoscopy in 79 cases, 25 of which were critical. After patient positioning, DLTs were found to be displaced in 93 patients, 48 of which were critical. Right-sided DLTs were significantly more likely to be malpositioned than were left-sided DLTs. Two complications were related to unsatisfactory lung separation in the 200 patients studied.

Conclusions
After blind intubation and patient positioning, more than one third of DLTs required repositioning. Routine bronchoscopy is therefore recommended after intubation and after patient positioning.
Identification of a Genetic Region in Mice that Specifies Sensitivity to Propofol
Authors: Simpson Victoria J. , Rikke Brad A. , Costello Jennifer M. , Corley Robin , Johnson Thomas E. 
Published: November 2003

Background
Long-sleep (LS) and short-sleep (SS) mice, initially selected for differential sensitivity to ethanol, also exhibit differential sensitivity to propofol. By interbreeding LS and SS mice to obtain progeny whose chromosomes are a patchwork of the LS and SS chromosomes, the authors determined whether differential propofol sensitivity cosegregates with any particular chromosomal region(s). Such cosegregation is the essence of genetic linkage mapping and a first step toward isolating a gene that can modulate propofol sensitivity in mammals. A gene underlying a quantitative trait such as anesthetic sensitivity is commonly called a quantitative trait locus (QTL).

Methods
The propofol dose was 20 mg/kg injected retroorbitally. Sensitivity was measured as the duration of the loss of righting reflex (LORR). The LORR and propofol brain levels at awakening were determined for 24 LSXSS recombinant-inbred (RI) strains, derived by intercrossing LS and SS for two generations followed by >20 generations of inbreeding. A genetic linkage between LORR and an albino mutation on chromosome 7 was investigated further using 164 second-generation progeny (F2s) from intercrossing inbred LS and inbred SS mice, similar to the LSXSS RIs except F2s are not inbred. The linkage between propofol sensitivity and the albino locus also was investigated using additional genetic markers on chromosome 7. Statistical significance was assessed by interval mapping using a regression method for RIs and Mapmaker/QTL (Whitehead Institute, Cambridge, MA) for F2s.

Results
Genetic mapping in the LSXSS RIs revealed a QTL tightly linked to the Tyr (albino) locus that accounts for nearly all of the genetic difference in propofol sensitivity between LS and SS mice. Analysis of propofol brain levels at awakening indicated that this QTL results from differential neurosensitivity. Mapping in F2s confirmed the genetic linkage to Tyr. Mice (ISS c/c x C57BL/6 c2j/C) that differed only by an albino mutation at Tyr were not differentially sensitive to propofol.

Conclusions
A single QTL, called Lorp1, underlies most of the genetic difference in propofol neurosensitivity between LS and SS mice. Although this QTL is tightly linked to Tyr, propofol sensitivity is not modulated by albinism. For mapping this QTL, the LSXSS RIs proved to be an especially powerful resource, localizing the candidate-gene region to a 99% confidence interval of only 2.5 centimorgans.
Structure-Activity Relation of N-alkyl Tetracaine Derivatives as Neurolytic Agents for Sciatic Nerve Lesions
Authors: Wang Ging Kuo , Vladimirov Marina , Shi Hao , Mok Wai Man , Thalhammer Johann G. , Anthony Douglas C. 
Published: November 2003

Background
N-butyl tetracaine has local anesthetic and neurolytic properties. An injection of this drug at the rat sciatic notch produces rapid onset and nerve impairment lasting > 1 week. This study aimed to elucidate the structure-activity relation of various tetracaine derivatives to design better neurolytic agents.

Methods
N-alkyl tetracaine salts (n = 2-6) were synthesized, and their ability to elicit sciatic nerve impairment of sensory and motor functions in vivo was tested in rats. A single dose (0.1 ml at 37 mM) was administered close to the sciatic nerve at the sciatic notch. Regeneration was assessed morphologically in transverse sections of treated nerves. Finally, the drug potency in blocking Na+ currents was studied under voltage-clamp conditions.

Results
N-ethyl and N-propyl tetracaine derivatives were non-neurolytic and elicited complete sciatic nerve block lasting 3-7 h. In contrast, N-butyl, N-pentyl, and N-hexyl tetracaine derivatives were strong neurolytic agents and elicited functional impairment of sciatic nerve for > 1 week. All derivatives were strong Na+ channel blockers, more potent than tetracaine if applied intracellularly. External drug application showed marked differences in their wash-in rate: tetracaine > N-hexyl > N-butyl > N-ethyl tetracaine. All derivatives were trapped within the cytoplasm and showed little washout within 7 min.

Conclusions
When n-alkylation is 4-6, n-alkyl tetracaine appeared as a strong neurolytic agent. Neurolytic derivatives retained their local anesthetic activity and elicited rapid onset of nerve block after injection. Such derivatives are potential local anesthetic-neurolytic dual agents for chemical lesions of the sciatic nerve.
Nitrous Oxide-induced Enhancement of γ-Aminobutyric Acid-A-mediated Chloride Currents in Acutely Dissociated Hippocampal Neurons
Authors: Dzoljic Misa , Van Duijn Bert 
Published: November 2003

Background
Because the synaptic inhibition in the human brain is largely mediated by gamma-aminobutyric acid (GABA), the GABA receptor is of primary interest for the study of the working mechanism of general anesthetics. This article examines the interaction between this type of ion channel and nitrous oxide (N2O).

Methods
Patch clamp recording techniques were applied to investigate the effects of N2O on GABA(A) receptor channels in a whole-cell configuration at room temperature. Acutely dissociated rat hippocampal cells from the CA1 region were used. Rapid application of the agonist muscimol and anesthetics (N2O, pentobarbital, and ethanol) was accomplished using a Y tube application system. Peak chloride (Cl-) currents were measured.

Results
Short-term application of muscimol (5-30 microM) with dissolved N2O (80%, approximately 22.5 mM) increased the Cl- current (approximately 140%) compared with muscimol alone. This effect is comparable with results the authors obtained with ethanol (800 mM) and pentobarbital (100 microM). Prolonged exposure (9 min) to N2O further increased Cl- currents by an additional 50%. Concentrations of N2O lower than 12 mM did not show an enhancement of this current, whereas application of N2O alone did not result in any Cl- conductance.

Conclusions
These results indicate that N2O can enhance GABA(A) channel-mediated Cl- currents by modulating the effect of the specific GABA(A) agonist; it is not active by itself.