bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade and Activation of the Human Neuronal Nicotinic Acetylcholine Receptors by Atracurium and Laudanosine
Authors: Chiodini Florence , Charpantier Eric , Muller Dominique , Tassonyi Edomer , Fuchs-Buder Thomas , Bertrand Daniel 
Published: November 2003

Background
Curaremimetic nondepolarizing muscle relaxants are widely used in clinical practice to prevent muscle contraction either during surgery or during intensive care. Although primarily acting at the neuromuscular junction, these compounds can cause adverse effects, including modification of cardiac rhythm, arterial blood pressure, and in the worst cases, triggering of seizures. In this study, we assessed the interaction of atracurium and its metabolite, laudanosine, with neuronal nicotinic receptors.

Methods
The human neuronal nicotinic receptors alpha4beta2, alpha3beta4, alpha3alpha5beta4, and alpha7 are heterologously expressed in Xenopus laevis oocytes, and the effect of atracurium and its degradation product, laudanosine, were studied on these receptors.

Results
Atracurium and laudanosine inhibited in the micromolar range the major brain alpha4beta2 receptor and the ganglionic alpha3beta4 or alpha3beta4alpha5 and the homomeric alpha7 receptors. For all four receptors, inhibition was rapid and readily reversible within less than 1 min. Atracurium blockade was competitive at alpha4beta2 and alpha7 receptors but displayed a noncompetitive blockade at the alpha3beta4 receptors. Inhibition at this receptor subtype was not modified by alpha5. Laudanosine was found to have a dual mode of action; first, it competes with acetylcholine and, second, it blocks the ionic pore by steric hindrance. At low concentrations, these two drugs are able to activate both the alpha4beta2 and the alpha3beta4 receptors.

Conclusion
Adverse effects observed during atracurium administration may be attributed, at least partly, to an interaction with neuronal nicotinic receptors.
Tissue Injury and the Inflammatory Response to Pediatric Cardiac Surgery with Cardiopulmonary Bypass
Authors: Chew Michelle S. , Brandslund Ivan , Brix-Christensen Vibeke , Ravn Hanne B. , Hjortdal Vibeke E. , Pedersen Jens , Hjortholm Kirsten , Hansen Ole K. , Tønnesen Else 
Published: November 2003

Background
There are few detailed descriptions of the inflammatory response to cardiac surgery with cardiopulmonary bypass (CPB) in children beyond 24 h postoperatively. This is especially true for the antiinflammatory cytokines and the extent of tissue injury. The aim of the current study was to describe the inflammatory and injury responses in uncomplicated pediatric cardiac surgery with CPB, where methylprednisolone and modified ultrafiltration (MUF) were used.

Methods
Blood samples were collected up to 48 h postoperatively. Cytokines (tumor necrosis factor-alpha and interleukin-6, -1beta, -10, and -1ra), complement (C3d and C4d) and coagulation system (prothrombin activation fragments 1 and 2 and antithrombin III) activation, neutrophil elastase, and the resulting tissue injury (creatine kinase, lactate dehydrogenase, alanine transaminase, amylase, and gamma-glutamyl transferase) were measured.

Results
The proinflammatory cytokine release varied widely, in contrast to a clear-cut antiinflammatory response. Cytokine concentrations did not decrease immediately after MUF, and no rebound increases later in the postoperative period were observed. The coagulation system, but not complement, was activated. There was a late release of C-reactive protein. Tissue injury could be quantified biochemically without evidence of hepatic or pancreatic dysfunction.

Conclusion
In this group of uncomplicated subjects, the antiinflammatory cytokine and tissue injury responses were well defined, in contrast to a variable proinflammatory cytokine release. This was accompanied by activation of the coagulation system but not of complement. Concentrations of inflammatory mediators did not decrease immediately after MUF, and there was no evidence for rebound release later in the postoperative period.
Dose–Response Study of Epidural Ropivacaine for Labor Analgesia
Authors: Lee Bee Beng , Ngan Kee Warwick D. , Wong Eliza L. Y. , Liu Justina Y. W. 
Published: November 2003

Background
Ropivacaine has been introduced for use in epidural analgesia in labor. However, there have been few formal dose-response studies of ropivacaine in this setting.

Methods
The authors performed a prospective, randomized, double-blind study examining the effectiveness of five different doses of ropivacaine (10, 20, 30, 40, and 50 mg) administered epidurally in a volume of 10 ml to establish analgesia in 66 parturients who were in active labor with cervical dilatation less than 4 cm. A dose was considered effective when the visual analog scale pain score decreased by 50% or more from baseline.

Results
A sigmoid dose-response curve and a probit log dose-response plot (linear regression coefficient, r = 0.84; coefficient of determination, r2 = 0.71) were obtained. The ED50 (median effective dose) obtained based on the maximum likelihood estimation was 18.4 mg (95% confidence interval, 13.4-25.4 mg). Time to onset of analgesia, duration of analgesia, time to two-segment regression of sensory block level, and incidence of motor block were not affected by the dosage of ropivacaine administered (P = 0.93, 0.12, 0.55, and 0.39, respectively). However, the upper level of sensory block was dose-related (P < 0.01).

Conclusion
In a traditional dose-response study, the ED50 of ropivacaine required to initiate epidural analgesia in early labor was found to be 18.4 mg (95% confidence interval, 13.4-25.4 mg).
The Midlatency Auditory Evoked Potentials Predict Responsiveness to Verbal Commands in Patients Emerging from Anesthesia with Xenon, Isoflurane, and Sevoflurane but Not with Nitrous Oxide
Authors: Goto Takahisa , Nakata Yoshinori , Saito Hayato , Ishiguro Yoshiki , Niimi Yoshinari , Morita Shigeho 
Published: November 2003

Background
It has recently been demonstrated that the approximately 40-Hz spectral power of the midlatency auditory evoked potential (MLAEP) correlates well with wakefulness during desflurane or propofol anesthesia. The aim of this study was to characterize how other inhalational anesthetics affects the MLAEP as the patients regain responsiveness to simple verbal command during emergence from anesthesia.

Methods
Sixty patients were randomly assigned to receive xenon, isoflurane, sevoflurane, or nitrous oxide (N2O) supplemented with epidural anesthesia. During emergence, the concentration of an anesthetic was decreased in 0.1-minimum alveolar concentration (MAC) decrements from 0.8 MAC or from 70% in the case of N2O, and each new concentration was maintained for 15 min. Every 5 min during each equilibration period, the MLAEP was recorded and the patients were asked to open their eyes and squeeze and release the investigator's hand. This process was repeated until the first response to either of these commands was observed.

Results
Thirteen patients were excluded because of technical reasons. The preanesthetic MLAEP showed a periodic waveform, where the Na-Pa-Nb complex was the most prominent component contributing to the high energy around 29-39 Hz in the power spectrum. Emergence from xenon, isoflurane, and sevoflurane anesthesia produced similar changes in the MLAEP. The spectral power for the frequency 29 Hz or greater was severely suppressed at 0.8 MAC but significantly recovered between the concentration only 0.1 MAC higher that permitting the first response to command and that associated with the first response. In contrast, N2O hardly affected the MLAEPs, even at the concentrations producing unresponsiveness. Two patients did not lose responsiveness even at the highest concentration tested (70%).

Conclusions
The MLAEP is closely associated with responsiveness to verbal command during emergence from anesthesia with xenon, isoflurane, and sevoflurane but not with N2O.
Epidural Lidocaine Decreases Sevoflurane Requirement for Adequate Depth of Anesthesia as Measured by the Bispectral Index ® Monitor
Authors: Hodgson Peter S. , Liu Spencer S. 
Published: November 2003

Background
Epidural anesthesia potentiates sedative drug effects and decreases minimum alveolar concentration (MAC). The authors hypothesized that epidural anesthesia also decreases the general anesthetic requirements for adequate depth of anesthesia as measured by Bispectral Index (BIS).

Methods
After premedication with 0.02 mg/kg midazolam and 1 microg/kg fentanyl, 30 patients aged 20-65 yr were randomized in a double-blinded fashion to receive general anesthesia with either intravenous saline placebo or intravenous lidocaine control (1-mg/kg bolus dose; 25 microg x kg(-1) x min(-1)). A matched group was prospectively assigned to receive epidural lidocaine (15 ml; 2%) with intravenous saline placebo. All patients received 4 mg/kg thiopental and 1 mg/kg rocuronium for tracheal intubation. After 10 min of a predetermined end-tidal sevoflurane concentration, BIS was measured. The ED50 of sevoflurane for each group was determined by up-down methodology based on BIS less than 50 (MAC(BIS50)). Plasma lidocaine concentrations were measured.

Results
The MAC(BIS50) of sevoflurane (0.59% end tidal) was significantly decreased with lidocaine epidural anesthesia compared with general anesthesia alone (0.92%) or with intravenous lidocaine (1%; P < 0.0001). Plasma lidocaine concentrations in the intravenous lidocaine group (1.9 microg/ml) were similar to those in the epidural lidocaine group (2.0 microg/ml).

Conclusions
Epidural anesthesia reduced by 34% the sevoflurane required for adequate depth of anesthesia. This effect was not a result of systemic lidocaine absorbtion, but may have been caused by deafferentation by epidural anesthesia or direct rostral spread of local anesthetic within the cerebrospinal fluid. Lower-than-expected concentrations of volatile agents may be sufficient during combined epidural-general anesthesia.
Effects of Isoflurane on Intracellular Calcium and Myocardial Crossbridge Kinetics in Tetanized Papillary Muscles
Authors: Hannon James D. , Cody Mark J. , Housmans Philippe R. 
Published: November 2003

Background
Isoflurane depresses the intracellular Ca2+ transient and force development during a twitch, but its effects on crossbridge cycling rates are difficult to predict because of the transient nature of the twitch. Measurements of the effects of isoflurane on crossbridge cycling kinetics during tetanic contractions, which provide a steady state level of activation in intact cardiac muscle, have not been previously reported.

Methods
Ferret right ventricular papillary muscles were isolated, and superficial cells were microinjected with the bioluminescent photoprotein aequorin to monitor the intracellular Ca2+ concentration. The rate of tension redevelopment (kTR) was measured during steady state isometric activation (tetanic stimulation, frequency 20 Hz, 1 microM ryanodine, temperature = 30 degrees C) in the absence of isoflurane (2, 6, and 12 mM extracellular [Ca2+]) and in the presence of 0.5, 1.0, and 1.5 minimum alveolar concentration isoflurane (12 mM extracellular [Ca2+]).

Results
Intracellular [Ca2+], isometric force, and kTR all increased when the extracellular [Ca2+] increased. Isoflurane (0.5, 1.0, and 1.5 minimum alveolar concentration) caused intracellular [Ca2+], isometric force, and kTR to decrease in a dose-dependent manner in the presence of 12 mM extracellular [Ca2+]. In the presence of increasing concentrations of isoflurane, the relation between intracellular [Ca2+] and force remained unchanged, whereas the relation between intracellular [Ca2+] and kTR was shifted toward higher [Ca2+].

Conclusions
These results indicate that isoflurane depresses myocardial crossbridge cycling rates. It appears that this effect is partially mediated by a decrease in the intracellular [Ca2+]. However, additional mechanisms must be considered to explain the shift of the relation between intracellular [Ca2+] and kTR toward higher [Ca2+].
Body Morphology and the Speed of Cutaneous Rewarming
Authors: Szmuk Peter , Rabb Mary F. , Baumgartner James E. , Berry James M. , Sessler Andrew M. , Sessler Daniel I. 
Published: November 2003

Background
Infants and children cool quickly because their surface area (and therefore heat loss) is large compared with their metabolic rate, which is mostly a function of body mass. Rewarming rate is a function of cutaneous heat transfer plus metabolic heat production divided by body mass. Therefore, the authors tested the hypothesis that the rate of forced-air rewarming is inversely related to body size.

Methods
Isoflurane, nitrous oxide, and fentanyl anesthesia were administered to infants, children, and adults scheduled to undergo hypothermic neurosurgery. All fluids were warmed to 37 degrees C and ambient temperature was maintained near 21 degrees C. Patients were covered with a full-body, forced-air cover of the appropriate size. The heater was set to low or ambient temperature to reduce core temperature to 34 degrees C in time for dural opening. Blower temperature was then adjusted to maintain core temperature at 34 degrees C for 1 h. Subsequently, the forced-air heater temperature was set to high (approximately 43 degrees C). Rewarming continued for the duration of surgery and postoperatively until core temperature exceeded 36.5 degrees C. The rewarming rate in individual patients was determined by linear regression.

Results
Rewarming rates were highly linear over time, with correlations coefficients (r2) averaging 0.98+/-0.02. There was a linear relation between rewarming rate (degrees C/h) and body surface area (BSA; m2): Rate (degrees C/h) = -0.59 x BSA (m2) + 1.9, r2 = 0.74. Halving BSA thus nearly doubled the rewarming rate.

Conclusions
Infants and children rewarm two to three times faster than adults, thus rapidly recovering from accidental or therapeutic hypothermia.
The Corrugator Supercilii, Not the Orbicularis Oculi, Reflects Rocuronium Neuromuscular Blockade at the Laryngeal Adductor Muscles
Authors: Plaud Benoît , Debaene Bertrand , Donati François 
Published: November 2003

Background
Some studies suggest that the orbicularis oculi is resistant to neuromuscular blocking drugs and behaves like laryngeal muscles. Others report little or no difference between the orbicularis oculi and the adductor pollicis. These discrepancies could be related to the exact site of recording. The purpose of this study was to compare two monitoring sites around the eye with the adductor pollicis and the laryngeal adductor muscles.

Methods
After institutional approval and informed consent, the evoked response to train-of-four stimulation was measured in 12 patients by acceleromyography at the thumb (adductor pollicis), the eyelid (orbicularis oculi), and the superciliary arch (corrugator supercilii) after 0.5 mg/kg rocuronium during propofol-fentanyl-nitrous oxide anesthesia. In 12 other patients, laryngeal adductor neuromuscular blockade was assessed via the cuff of the tracheal tube and compared with the adductor pollicis and the corrugator supercilii after 0.6 mg/kg rocuronium.

Results
After 0.5 mg/kg, maximum blockade (%T1, mean +/- SD) was less at the corrugator supercilii (80+/-20%) than at the adductor pollicis (100+/-1%) and the orbicularis oculi (93+/-8%) (P < 0.01). Clinical duration (25%T1) was shorter at the corrugator supercilii (12+/-7 min) than at the adductor pollicis (25+/-4 min) and orbicularis oculi (24+/-10 min) (P < 0.01). After 0.6 mg/kg, maximum blockade was similar at the corrugator supercilii (88+/-8%) and the laryngeal adductor muscles (89+/-11%). Clinical duration at the corrugator supercilii and the laryngeal adductors was 17+/-7 and 17+/-10 min, respectively.

Conclusions
Muscles around the eye vary in their response to rocuronium. The response of the superciliary arch (corrugator supercilii) reflects blockade of laryngeal adductor muscles. However, the eyelid (orbicularis oculi) and thumb (adductor pollicis) have similar sensitivities.
Pulmonary Vasoconstriction during Regional Nitric Oxide Inhalation
Authors: Hambraeus-Jonzon Kristina , Chen Luni , Fredén Filip , Wiklund Peter , Hedenstierna Göran 
Published: November 2003

Background
Inhaled nitric oxide (INO) is thought to cause selective pulmonary vasodilation of ventilated areas. The authors previously showed that INO to a hyperoxic lung increases the perfusion to this lung by redistribution of blood flow, but only if the opposite lung is hypoxic, indicating a more complex mechanism of action for NO. The authors hypothesized that regional hypoxia increases NO production and that INO to hyperoxic lung regions (HL) can inhibit this production by distant effect.

Methods
Nitric oxide concentration was measured in exhaled air (NO(E)), NO synthase (NOS) activity in lung tissue, and regional pulmonary blood flow in anesthetized pigs with regional left lower lobar (LLL) hypoxia (fraction of inspired oxygen [FIO2] = 0.05), with and without INO to HL (FIO2 = 0.8), and during cross-circulation of blood from pigs with and without INO.

Results
Left lower lobar hypoxia increased exhaled NO from the LLL (NO(E)LLL) from a mean (SD) of 1.3 (0.6) to 2.2 (0.9) parts per billion (ppb) (P < 0.001), and Ca2+-dependent NOS activity was higher in hypoxic than in hyperoxic lung tissue (197 [86] vs. 162 [96] pmol x g(-1) x min(-1), P < 0.05). INO to HL decreased the Ca2+-dependent NOS activity in hypoxic tissue to 49 [56] pmol x g(-1) x min(-1) (P < 0.01), and NO(E)LLL to 2.0 [0.8] ppb (P < 0.05). When open-chest pigs with LLL hypoxia received blood from closed-chest pigs with INO, NO(E)LLL decreased from 2.0 (0.6) to 1.5 (0.4) ppb (P < 0.001), and the Ca2+-dependent NOS activity in hypoxic tissue decreased from 152 (55) to 98 (34) pmol x g(-1) x min(-1) (P = 0.07). Pulmonary vascular resistance increased by 32 (21)% (P < 0.05), but more so in hypoxic (P < 0.01) than in hyperoxic (P < 0.05) lung regions, resulting in a further redistribution (P < 0.05) of pulmonary blood flow away from hypoxic to hyperoxic lung regions.

Conclusions
Inhaled nitric oxide downregulates endogenous NO production in other, predominantly hypoxic, lung regions. This distant effect is blood-mediated and causes vasoconstriction in lung regions that do not receive INO.
The γ Subunit Determines Whether Anesthetic-induced Leftward Shift Is Altered by a Mutation at α1S270 in α1β2γ2LGABAAReceptors
Authors: Scheller Michaela , Forman Stuart A. 
Published: November 2003

Background
A major action of volatile anesthetics is enhancement of gamma-aminobutyric acid receptor type A (GABA(A)R) currents. In recombinant GABA(A)Rs consisting of several subunit mixtures, mutating the alpha1 subunit serine at position 270 to isoleucine [alpha1(S270I)] was reported to eliminate anesthetic-induced enhancement at low GABA concentrations. In the absence of studies at high GABA concentrations, it remains unclear whether alpha1(S270I) affects enhancement versus inhibition by volatile anesthetics. Furthermore, the majority of GABA(A)Rs in mammalian brain are thought to consist of alpha1, beta2, and gamma2 subunits, and the alpha1(S270I) mutation has not been studied in the context of this combination.

Methods
Recombinant GABA(A)Rs composed of alpha1beta2 or alpha1beta2gamma2L subunit mixtures were studied electrophysiologically in whole Xenopus oocytes in the voltage clamp configuration. Currents elicited by GABA (0.03 microM to 1 mM) were measured in the absence and presence of isoflurane or halothane. Anesthetic effects on GABA concentration responses were evaluated for individual oocytes.

Results
In wild-type alpha1beta2gamma2L GABA(A), anesthetics at approximately 2 minimum alveolar concentration (MAC) shifted GABA concentration response curves to the left approximately threefold, decreased the Hill coefficient, and enhanced currents at all GABA concentrations. The alpha1(S270I) mutation itself rendered the GABA(A)R more sensitive to GABA and reduced the Hill coefficient. At low GABA concentrations (EC5), anesthetic enhancement of peak current was much smaller in alpha1(S270I)beta2gamma2L versus wild-type channels. Paradoxically, the leftward shift of the whole GABA concentration-response relation by anesthetics was the same in both mutant and wild-type channels. At high GABA concentrations, volatile anesthetics reduced currents in alpha1(S270I)beta2gammaL GABA(A)Rs. In parallel studies on alpha1beta2 (gamma-less) GABA(A)Rs, anesthetic-induced leftward shifts in wild-type receptors were more than eightfold at 2 MAC, and the alpha1(S270I) mutation nearly eliminated anesthetic-induced leftward shift.

Conclusions
The results support a role for alpha1S270 in alpha1beta2gamma2L GABA(A)R gating and sensitivity to inhibition by volatile anesthetics. The alpha1S270 locus also modulates anesthetic enhancement in alpha1beta2 GABA(A)R. The presence of the gamma2L subunit reduces anesthetic-induced left shift of wild-type GABA(A)R and nullifies the impact of the alpha1(S2701) mutation on anesthetic modulation. Thus, the gamma2L subunit plays a significant role in GABA(A)R modulation by volatile anesthetic compounds.
Enflurane Actions on Spinal Cords from Mice That Lack the β3Subunit of the GABAAReceptor
Authors: E. Wong Shirley M. , Cheng Gong , Homanics Gregg E. , Kendig Joan J. 
Published: November 2003

Background
Gamma-aminobutyric acid type A (GABA(A)) receptors are considered important in mediating anesthetic actions. Mice lacking the beta3 subunit of this receptor (beta3-/-) have a higher enflurane minimum alveolar concentration (MAC) than wild types (+/+). MAC is predominantly determined in spinal cord.

Methods
The authors measured three population-evoked responses in whole spinal cords, namely, the excitatory postsynaptic potential (pEPSP), the slow ventral root potential (sVRP), and the dorsal root potential. Synaptic and glutamate-evoked currents from motor neurons in spinal cord slices were also measured.

Results
Sensitivity of evoked responses to enflurane did not differ between +/+ and -/- cords. The GABA(A) receptor antagonist bicuculline significantly (P < 0.05) attenuated the depressant effects of enflurane on pEPSP, sVRP and glutamate-evoked currents in +/+ but not -/- cords. The glycine antagonist strychnine elevated the pEPSP to a significantly greater extent in -/- than in +/+ cords, but the interactions between strychnine and enflurane did not differ between -/- and +/+ cords.

Conclusions
Similar enflurane sensitivity in spinal cords from -/- and +/+ mice was coupled with a decreased role for GABA(A) receptors in mediating the actions of enflurane in the former. This finding implies that other anesthetic targets substitute for GABA(A) receptors. Increase in glycine receptor-mediated inhibition was found in -/- cords, but the glycine receptor does not appear to be a substitute anesthetic target. This mutation thus led to a quantitative change in the molecular basis for anesthetic depression of spinal neurotransmission in a fashion not predicted by the mutation itself. The results argue against an immutable dominant role for GABA(A) receptors in mediating spinal contributions to MAC.