bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Mechanisms of Ketamine Blockade of N-methyl-D-aspartate Receptors
Authors: Orser Beverley A. , Pennefather Peter S. , MacDonald John F. 
Published: November 2003

Background
The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is blocked by ketamine, and this action likely contributes to ketamine's anesthetic and analgesic properties. Previous studies suggest that ketamine occludes the open channel by binding to a site located within the channel pore. This hypothesis was examined by investigating the effects of ketamine on single-channel currents from NMDA receptors.

Methods
The cell-attached and outside-out configurations of the patch clamp technique were used to study NMDA-activated currents recorded from cultured mouse hippocampal neurons.

Results
In cell-attached patches, NMDA evoked currents that had an apparent mean open time (tau o) of 3.26 ms. The probability of at least one channel being open (Po') was 0.058. The addition of ketamine (0.1 microM or 1 microM) to the pipette solution decreased Po' to 53% and 24% of control values, respectively. At 1 microM ketamine, this reduction was due to a decrease in both the frequency of channel opening and the mean open time (44% and 68% of control values, respectively). Ketamine did not influence channel conductance and no new components were required to fit the open- or closed-duration distributions. Ketamine (50 microM), applied outside the recording pipette, reduced the opening frequency of channels recorded in the cell attached configuration. This observation suggests that ketamine gained access to a binding site by diffusing across the hydrophobic cell membrane. In outside-out patches, ketamine potency was lower than that observed in cell-attached patches: 1 microM and 10 microM ketamine reduced Po' to 63% and 34% of control values, respectively, and this reduction was due primarily to a decrease in the frequency of channel opening with little change in mean open time.

Conclusions
These observations are consistent with a model whereby ketamine inhibits the NMDA receptor by two distinct mechanisms: (1) Ketamine blocks the open channel and thereby reduces channel mean open time, and (2) ketamine decreases the frequency of channel opening by an allosteric mechanism.
Neurologic Evaluation of Infant and Adult Rats before and after Sciatic Nerve Blockade
Authors: Hu Delphine , Hu Rosa , Berde Charles B. 
Published: November 2003

Background
Only limited data exist comparing differences in sensory function and responses to neural blockade in infant and adult rats. Therefore, the authors sought (1) to compare baseline thermal, proprioceptive, and postural responses in infant, adolescent, and adult rats; and (2) to compare the effects of sciatic nerve blockade on thermal, proprioceptive, and postural responses in infant, adolescent, and adult rats.

Methods
Infant, adolescent, and adult rats were evaluated for proprioceptive, thermal, and mechanical nociceptive and motor function before and after sciatic blockade using a detailed neurologic examination.

Results
Mechanical and thermal nociception were present in all rats, starting from age 1 day. The withdrawal reflex latency to pinch was rapid at all ages, whereas that reaction to thermal stimulus depended on both age and temperature. In contrast, the tactile placing response and hopping response were absent at birth and developed completely during the first 10 days of life. The extensor postural thrust was absent in the first 2 weeks of life and developed variably during the first 50 days of life. Sciatic blockade duration is shorter in infant rats than in adult rats receiving the same dose per kilogram. A brief halothane general anesthetic at the time of sciatic injection in infant or adult rats does not alter the duration of blockade.

Conclusions
Infant rats show increased sensitivity to noxious thermal stimuli and similar response to deep mechanical stimuli compared with adult rats. Their proprioceptive and motor responses develop during the first 2 weeks of life. When doses are scaled by body weight, block duration is shorter in infant than in adult rats.
Bronchoscopy via a Redesigned Combitube(TM) in the Esophageal Position
Authors: Krafft Peter , Roggla Martin , Fridrich Peter , Locker Gottfried J. , Frass Michael , Benumof Jonathan L. 
Published: November 2003

Background
The esophageal-tracheal Combitube (Kendall-Sheridan Catheter Corp., Argyle, NY) is an effective device for providing adequate gas exchange. However, tracheal suctioning is impossible with the Combitube placed in the esophageal position. To eliminate this disadvantage, the Combitube was redesigned by creating an enlarged hole in the pharyngeal lumen that allows fiberoptic access, tracheal suctioning, and tube exchange over a guide wire.

Methods
The two anterior, proximal perforations of regular Combitubes were replaced by a larger, ellipsoid-shaped hole. After the study was approved by the institutional review board, 20 patients with normal airways (Mallampati I or II) were studied. During general anesthesia, patients were esophageally intubated with the Combitube. A flexible bronchoscope was inserted and guided via the modified hole and glottic opening down the trachea. For the replacement procedure, a J tip guide wire was introduced through the bronchoscope. The bronchoscope and the Combitube were removed and a standard endotracheal tube was advanced over a guide catheter.

Results
Bronchoscopic evaluation of the trachea and guided replacement of the Combitube by an endotracheal tube was successful in all 20 study patients. The average time needed to perform airway exchange was 90 +/- 20 s (mean +/- SD). Arterial oxygen saturation and end-tidal carbon dioxide levels remained normal in all patients. No case of laryngeal trauma was observed during intubation or the airway exchange procedure.

Conclusions
The redesigned Combitube enables fiberoptic bronchoscopy, fine-tuning of its position in the esophagus, and guided airway exchange in patients with normal airways. Further studies are warranted to demonstrate its value in patients with abnormal airways.
Alterations in Canine Left Ventricular-arterial Coupling and Mechanical Efficiency Produced by Propofol
Authors: Hettrick Douglas A. , Pagel Paul S. , Warltier David C. 
Published: November 2003

Background
Propofol reduces blood pressure by decreasing left ventricular (LV) afterload and myocardial contractility. This investigation tested the hypothesis that propofol preserves LV-arterial coupling and mechanical efficiency because of these simultaneous hemodynamic actions.

Methods
Experiments were conducted in open-chest dogs (n = 8) instrumented for measurement of aortic and LV pressure, dP/dtmax, and LV volume. Myocardial contractility was assessed with the slope (Ees) of the LV end systolic pressure-volume relationship. Effective arterial elastance (En; the ratio of end systolic arterial pressure to stroke volume), stroke work (SW), and pressure-volume area (PVA) were determined from the LV pressure-volume relationships. Dogs were studied 30 min after instrumentation and after 15-min intravenous infusions of propofol at 5, 10, 20, and 40 mg.kg-1.h-1.

Results
Propofol caused dose-dependent decreases in Ees (4.7 +/- 0.9 during control to 2.7 +/- 0.5 mmHg/ml during the high dosage) and dP/dtmax, indicating a direct negative inotropic effect. Ea increased at the 10 mg.kg-1.h-1 dose of propofol but decreased at higher dosages. Propofol decreased the ratio of Ees to Ea (0.88 +/- 0.13 during control to 0.56 +/- 0.10 during the high dosage), consistent with impairment of LV-arterial coupling. Propofol also reduced the ratio SW to PVA (0.54 +/- 0.03 during control to 0.45 +/- 0.03 during the 20 mg.kg-1.h-1), suggesting a decline in LV mechanical efficiency. SW and PVA recovered toward baseline values at the 40 mg.kg-1.h-1 dose.

Conclusions
Although propofol depresses mechanical matching of the LV to the arterial system and reduces LV efficiency, these alterations plateau at higher dosages of propofol because reductions in afterload begin to offset further declines in myocardial contractile function.
Calcium Concentration-dependent Mechanisms through which Ketamine Relaxes Canine Airway Smooth Muscle
Authors: Pabelick Christina M. , Jones Keith A. , Street Kathleen , Lorenz Robert R. , Warner David O. 
Published: November 2003

Background
Ketamine is a potent bronchodilator that, in clinically used concentrations, relaxes airway smooth muscle in part by a direct effect. This study explored the role of calcium concentration (Ca2+) in this relaxation.

Methods
Canine trachea smooth muscle strips were loaded with the fluorescent probe fura-2 and mounted in a spectro-photometric system to measure force and intracellular calcium concentration ([Ca2+]i) simultaneously. Calcium influx was estimated using a manganese quenching technique. Cyclic nucleotides in the airway smooth muscle strips were measured by radioimmunoassay.

Results
In smooth muscle strips stimulated with submaximal (0.1 microM) and maximal (10 microM) concentrations of acetylcholine, ketamine caused a concentration-dependent decrease in force and [Ca2+]i. The sensitivity of the force response to ketamine significantly decreased as the intensity of muscarinic receptor stimulation increased; the median effective concentration for relaxation induced by ketamine was 59 microM and 850 microM for tissue contracted by 0.1 microM or 10 microM acetylcholine, respectively (P < 0.05). In contrast, the sensitivity of the [Ca2+]i response did not depend on the intensity of muscarinic receptor stimulation. Ketamine at 1 mM significantly inhibited calcium influx. Ketamine did not significantly increase cyclic nucleotide concentrations.

Conclusions
Ketamine-induced relaxation of canine airway smooth muscle is associated with a decrease in [Ca2+]i and calcium influx, effects that are not mediated by an increase in cyclic nucleotides; and the sensitivity of the force response to ketamine decreases as the level of preexisting muscle tone increases, an effect that is not explained by differential effects on [Ca2+]i.
Inhibition of Lysophosphatidate Signaling by Lidocaine and Bupivacaine
Authors: Nietgen Gregor W. , Chan Carrie K. , Durieux Marcel E. 
Published: November 2003

Background
Lidocaine and bupivacaine impair wound healing, but the mechanism of this side effect has not been determined. The phospholipid messenger lysophosphatidate is released from activated platelets and induces fibroblast and smooth muscle proliferation. Because it may play a role in wound healing, the authors studied the effects of local anesthetics on lysophosphatidate signaling in Xenopus oocytes.

Methods
Defolliculated Xenopus oocytes expressing endogenous G protein-coupled lysophosphatidate receptors were voltage clamped and studied in the presence or absence of lidocaine or bupivacaine. Lysophosphatidate-induced Ca(2+)-activated Cl- currents (IC1(Ca)) were measured. To determine the site of action of the local anesthetics on the signaling pathway, the authors studied 1) the effects of local anesthetics on signaling induced by intracellular injection of the second messenger inositoltrisphosphate, and 2) the effects of local anesthetics on functioning of recombinantly expressed angiotensin II receptor signaling through the same pathways as the lysophosphatidate receptor.

Results
Lysophosphatidate signaling was inhibited in the presence of local anesthetics. The half maximal inhibitory concentration (IC50S) for lidocaine and bupivacaine were 29.6 mM and 4.7 mM, respectively. Neither responses induced by inositoltrisphosphate injection nor angiotensin signaling were influenced by local anesthetics.

Conclusions
Lysophosphatidate signaling is inhibited by the extracellular application of lidocaine or bupivacaine. In contrast, inositoltrisphosphate or angiotensin signaling was not affected by local anesthetics. Therefore local anesthetics have a specific, extracellular effect on lysophosphatidate receptor functioning. As the local anesthetic concentrations used were similar to those observed after injection around surgical wounds, LP inhibition may play a role in the observed detrimental effects of local anesthetics on wound healing.
Pharmacokinetics of Rocuronium during the Three Stages of Liver Transplantation
Authors: Fisher Dennis M. , Ramsay Michael A. E. , Hein H. A. Tillmann , Marcel Randy J. , Sharma Manohar , Ramsay Kirsten J. , Miller Ronald D. 
Published: November 2003

Background
Little is known about the influence of liver transplantation on the pharmacokinetics of most anesthetic drugs. The authors determined the pharmacokinetics of rocuronium during liver transplantation and examined whether variability in pharmacokinetics could explain variability in recovery of neuromuscular function.

Methods
Twenty patients undergoing liver transplantation were given rocuronium, 600 microg/kg, after induction of anesthesia and again after perfusion of the transplanted liver. Plasma was sampled to determine rocuronium concentrations. Pharmacokinetic models were fit to rocuronium concentrations versus time data using a mixed-effects population approach. Various models permitted changes in clearance (Cl) or central compartment volume to account for changes in hepatic function and circulatory status during the paleohepatic, anhepatic, and neohepatic periods. Time to initial recovery of four twitches of the orbicularis oculi was determined.

Results
During the paleohepatic and anhepatic periods, the typical value of Cl was 2.47 ml x kg(-1) x min(-1) and was not influenced by the magnitude of preexisting liver disease (as evidenced by prothrombin time, bilirubin, serum albumin, alanine transaminase [ALT], and aspartate transaminase [AST]). During the neohepatic period, the typical value of Cl varied as a function of the duration of warm ischemia of the hepatic allograft and was 2.72 ml x kg(-1) x min(-1) for a patient with an average 60-min period of warm ischemia; time to neuromuscular recovery varied as a function of Cl.

Conclusions
Despite prolonged hypothermic ischemia, the newly transplanted liver eliminates rocuronium as well as the diseased native liver (and comparably with historical control values). However, some patients had decreased rocuronium Cl during the neohepatic period, apparently a result of prolonged graft warm ischemia. The authors' finding of preservation of hepatic drug elimination in the hepatic allograft is consistent with limited data for other drugs evaluated during anesthesia.
Inhibition of Airway Constriction by Opioids Is Different down the Isolated Bovine Airway
Authors: Zappi Lucia , Song Pingfong , Nicosia Siriana , Nicosia Francesco , Rehder Kai 
Published: November 2003

Background
Opioid agonists attenuate in isolated airways contractile responses to electrical field stimulation (EFS), and this attenuation is mediated by opioid receptors. Differences exist in the density of muscarinic and beta-adrenergic receptors between large and small airways. The authors hypothesized that the density of opioid receptors may also be different down the airway.

Methods
The effects of three selective opioid agonists (mu, kappa, delta) on EFS-induced contractions were compared between isolated bovine sublobar (4- or 5-mm inner diameter) and segmental (2- or 3-mm inner diameter) bronchial rings and between trachealis strips and bronchial rings.

Results
D-Ala2-N-MePhe4-Gly-ol5 enkephalin (DAMGO; 10(-5) M), a mu-opioid agonist, attenuated EFS-induced contractions of isolated sublobar and segmental bronchial rings at low stimulating frequencies of 0.5 Hz (P < 0.001), 2 Hz (P < 0.001), and 8 Hz (P < 0.001), but not at 32 Hz (P = 0.071). The inhibitory effect of DAMGO was antagonized by naloxone (10(-5) M) (P = 0.025). The selective kappa-opioid agonist U-50488 H (10(-5) m) attenuated EFS-induced contractions at 32 Hz (P = 0.008) and 8 Hz (P = 0.045), but not at 2-Hz (P = 0.893) or 0.5-Hz (P = 0.145) contractions. The inhibitory effects of 10(-5) M U-50488 H were not antagonized by the highly selective kappa-antagonist 2,2'-[1,1'-biphenyl] 4,4'-diyl-bis [2-hydroxy-4,4-dimethyl]-morpholinium (nor-BNI; 10(-5) M; P = 0.216) or naloxone (10[-5]) M; P = 0.065). The selective delta-agonist D-penicillamine2-D-penicillamine5-enkephalin (DPDPE) (10(-5) M) had no inhibitory effects (P = 0.256). The inhibitory effects of the selective mu-opioid agonist DAMGO were smaller (P < 0.001) and those of U-50488 H larger (P < 0.001) in trachealis strips compared with bronchial rings.

Conclusions
The attenuation of EFS-induced contractions by DAMGO in isolated bovine bronchi was mediated by prejunctional opioid receptors. In contrast, the inhibitory effect of U-50488 H was probably not mediated by opioid receptors in the bronchi.
Permissive Hypercapnia with and without Expiratory Washout in Patients with Severe Acute Respiratory Distress Syndrome
Authors: Kalfon Pierre , Rao G. S. Umamaheswara , Gallart Lluis , Puybasset Louis , Coriat Pierre , Rouby Jean-Jacques 
Published: November 2003

Background
Permissive hypercapnia is a ventilatory strategy aimed at avoiding lung volutrauma in patients with severe acute respiratory distress syndrome (ARDS). Expiratory washout (EWO) is a modality of tracheal gas insufflation that enhances carbon dioxide removal during mechanical ventilation by reducing dead space. The goal of this prospective study was to determine the efficacy of EWO in reducing the partial pressure of carbon dioxide (PaCO2) in patients with severe ARDS treated using permissive hypercapnia.

Methods
Seven critically ill patients with severe ARDS (lung injury severity score, 3.1 +/- 0.3) and no contraindications for permissive hypercapnia were studied. On the first day, hemodynamic and respiratory parameters were measured and the extent of lung hyperdensities was assessed using computed tomography. A positive end-expiratory pressure equal to the opening pressure identified on the pressure-volume curve was applied. Tidal volume was reduced until a plateau airway pressure of 25 cm H2O was reached. On the second day, after implementation of permissive hypercapnia, EWO was instituted at a flow of 15 l/min administered during the entire expiratory phase into the trachea through the proximal channel of an endotracheal tube using a ventilator equipped with a special flow generator. Cardiorespiratory parameters were studied under three conditions: permissive hypercapnia, permissive hypercapnia with EWO, and permissive hypercapnia.

Results
During permissive hypercapnia, EWO decreased PaCO2 from 76 +/- 4 mmHg to 53 +/- 3 mmHg (-30%; P < 0.0001), increased pH from 7.20 +/- 0.03 to 7.34 +/- 0.04 (P < 0.0001), and increased PaO2 from 205 +/- 28 to 296 +/- 38 mmHg (P < 0.05). The reduction in PaCO2 was accompanied by an increase in end-inspiratory plateau pressure from 26 +/- 1 to 32 +/- 2 cm H2O (P = 0.001). Expiratory washout also decreased cardiac index from 4.6 +/- 0.4 to 3.7 +/- 0.3 l.min-1.m-2 (P < 0.01), mean pulmonary arterial pressure from 28 +/- 2 to 25 +/- 2 mmHg (P < 0.01), and true pulmonary shunt from 47 +/- 2 to 36 +/- 3% (P < 0.01).

Conclusions
Expiratory washout is an effective and easy-to-use ventilatory modality to reduce PaCO2 and increase pH during permissive hypercapnia. However, it significantly increases airway pressures and lung volume through expiratory flow limitation, reexposing some patients to a risk of lung volutrauma if the extrinsic positive end-expiratory pressure is not substantially reduced.
Improvement in Oxygenation by Phenylephrine and Nitric Oxide in Patients with Adult Respiratory Distress Syndrome
Authors: Doering Elana B. , Hanson C. William , Reily Daniel J. , Marshall Carol , Marshall Bryan E. 
Published: November 2003

Background
Inhaled nitric oxide (NO), a selective vasodilator, improves oxygenation in many patients with adult respiratory distress syndrome (ARDS). Vasoconstrictors may also improve oxygenation, possibly by enhancing hypoxic pulmonary vasoconstriction. This study compared the effects of phenylephrine, NO, and their combination in patients with ARDS.

Methods
Twelve patients with ARDS (PaO2/FIO2 <le> 180; Murray score <me> 2) were studied. Each patient received three treatments in random order: intravenous phenylephrine, 50-200 micrograms/min, titrated to a 20% increase in mean arterial blood pressure; inhaled NO, 40 ppm; and the combination (phenylephrine+NO). Hemodynamics and blood gas measurements were made during each treatment and at pre- and posttreatment baselines.

Results
All three treatments improved PaO2 overall. Six patients were "phenylephrine-responders" (delta PaO2 > 10 mmHg), and six were "phenylephrine-nonresponders." In phenylephrine-responders, the effect of phenylephrine was comparable with that of NO (PaO2 from 105 +/- 14 to 132 +/- 14 mmHg with phenylephrine, and from 110 +/- 14 to 143 +/- 19 mmHg with NO), and the effect of phenylephrine+NO was greater than that of either treatment alone (PaO2 from 123 +/- 13 to 178 +/- 23 mmHg). In phenylephrine-nonresponders, phenylephrine did not affect PaO2, and the effect of phenylephrine+NO was not statistically different from that of NO alone (PaO2 from 82 +/- 12 to 138 +/- 28 mmHg with NO; from 84 +/- 12 to 127 +/- 23 mmHg with phenylephrine+NO). Data are mean +/- SEM.

Conclusions
Phenylephrine alone can improve PaO2 in patients with ARDS. In phenylephrine-responsive patients, phenylephrine augments the improvement in PaO2 seen with inhaled NO. These results may reflect selective enhancement of hypoxic pulmonary vasoconstriction by phenylephrine, which complements selective vasodilation by NO.
Assessment of Cytochrome P450 3A4 Activity during the Menstrual Cycle Using Alfentanil as a Noninvasive Probe
Authors: Kharasch Evan D. , Russell Michael , Garton Kyle , Lentz Gretchen , Bowdle T. Andrew , Cox Kathy 
Published: November 2003

Background
Gender-dependent differences in cytochrome P450 activity, drug metabolism, drug elimination, and their clinical consequences are increasingly apparent. P450 3A4 is the most abundant P450 isoform in the human liver and is responsible for metabolizing a vast and diverse assortment of therapeutic agents, including opioids, benzodiazepines, and local anesthetics. P450, 3A4 activity is higher in women, influenced by steroid hormone levels, and is speculated to vary during the menstrual cycle. This investigation tested the hypothesis that P450 3A4 activity varies during the menstrual cycle. Alfentanil clearance was used as a metabolic probe for P450 3A4 activity.

Methods
Alfentanil (20 micrograms/kg bolus) was administered to nine nonsmoking, nonpregnant female volunteers (age, 26 +/- 5 yr) with normal menstrual cycles on three separate occasions during the same menstrual cycle: days 2 (menstrual phase), 13 (estrogen peak), and 21 (progesterone peak). Venous plasma alfentanil concentrations were determined by gas chromatography-mass spectrometry. Alfentanil clearance was determined by noncompartmental methods and by a three-compartment model with both pooled population and two-stage analysis.

Results
There was no significant difference in any measure of alfentanil clearance. Noncompartmental clearances (mean +/- SD) were 3.62 +/- 0.76, 3.81 +/- 0.96, and 3.60 +/- 0.84 ml/kg/ min, respectively, on days 2, 13, and 21 of the menstrual cycle.

Conclusions
Alfentanil clearances were not different on menstrual cycle days 2, 13, and 21, strongly suggesting no change in P450 3A4 activity. Menstrual cycle differences in alfentanil clearances do not contribute to interindividual variability in alfentanil disposition in women. If other P450 3A4 substrates are comparable, then menstrual cycle variability in their metabolism may not be a consideration in dosing or in the design of pharmacokinetic investigations.