bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the Intubation Conditions Provided by Rapacuronium (ORG 9487) or Succinylcholine in Humans during Anesthesia with Fentanyl and Propofol
Authors: Fleming Neal W. , Chung Frances , Glass Peter S. A. , Kitts John B. , Kirkegaard-Nielsen Hans , Gronert Gerald A. , Chan Vincent , Gan Tong. J. , Cicutti Nicholas , Caldwell James E. 
Published: November 2003

Background
Currently, the only approved muscle relaxant with a rapid onset and short duration of action is succinylcholine, a drug with some undesirable effects. Rapacuronium is an investigational nondepolarizing relaxant that also has a rapid onset and short duration and consequently should be compared with succinylcholine in its ability to facilitate rapid tracheal intubation.

Methods
This prospective, randomized clinical trial involved 336 patients. Anesthesia was induced with fentanyl and propofol and either 1.5 mg/kg rapacuronium or 1.0 mg/kg succinylcholine. The goal was to accomplish tracheal intubation by 60 s after administration of the neuromuscular blocking drug. Endotracheal intubation was performed, and conditions were graded by a blinded investigator. Recovery of neuromuscular function was assessed by electromyography.

Results
Intubation conditions were evaluated in 236 patients. Intubation by 60 s after drug administration occurred in 100% of patients with rapacuronium and in 98% with succinylcholine. Intubation conditions were excellent or good in 87% of patients with rapacuronium and in 95% with succinylcholine (P < 0.05). The time (median and range) to the first recovery of the train-of-four response was 8.0 (2.8-20.0) min with rapacuronium and 5.7 (1.8-17.7) min with succinylcholine (P < 0.05). The overall incidence of adverse effects was similar with both drugs.

Conclusions
A 1.5-mg/kg dose of rapacuronium effectively facilitates rapid tracheal intubation. It can be considered a valid alternative to 1.0 mg/kg succinylcholine for this purpose.
Blockade of Glutamate Receptors and Barbiturate Anesthesia
Authors: Joo Daisy T. , Xiong Zhigang , MacDonald John F. , Jia Zhengping , Roder John , Sonner Jim , Orser Beverley A. 
Published: November 2003

Background
Barbiturates enhance gamma-aminobutyric acid type A (GABA(A)) receptor function and also inhibit the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptor. The relative contribution of these actions to the behavioral properties of barbiturates is not certain. Because AMPA receptor complexes that lack the GluR2 subunit are relatively insensitive to pentobarbital inhibition, GluR2 null mutant mice provide a novel tool to investigate the importance of AMPA receptor inhibition to the anesthetic effects of barbiturates.

Methods
GluR2 null allele (-/-), heterozygous (+/-), and wild-type (+/+) mice were injected with pentobarbital (30 and 35 mg/kg intraperitoneally). Sensitivity to anesthetics was assessed by measuring the latency to loss of righting reflex, sleep time, and the loss of corneal, pineal, and toe-pinch withdrawal reflexes. In addition, patch-clamp recordings of acutely dissociated CA1 hippocampal pyramidal neurons from (-/-) and (+/+) mice were undertaken to investigate the effects of barbiturates on kainate-activated AMPA receptors and GABA-activated GABA(A) receptors.

Results
Behavioral tests indicate that sensitivity to pentobarbital was increased in (-/-) mice. In contrast, AMPA receptors from (-/-) neurons were less sensitive to inhibition by pentobarbital (concentrations that produced 50% of the maximal inhibition [IC50], 301 vs. 51 microM), thiopental (IC50, 153 vs. 34 microM), and phenobarbital (IC50, 930 vs. 205 microM) compared with wild-type controls, respectively. In addition, the potency of kainate was greater in (-/-) neurons, whereas no differences were observed for the potentiation of GABA(A) receptors by pentobarbital.

Conclusions
The GluR2 null mutant mice were more sensitive to pentobarbital anesthesia despite a reduced sensitivity of GluR2-deficient AMPA receptors to barbiturate blockade. Our results indicate that the inhibition of AMPA receptors does not correlate with the anesthetic effects of barbiturates in this animal model. We postulate that the increase in the sensitivity to anesthetics results from a global suppression of excitatory neurotransmission in GluR2-deficient mice.
Respiratory Mechanics during Xenon Anesthesia in Pigs
Authors: Calzia Enrico , Stahl Wolfgang , Handschuh Thomas , Marx Thomas , Fröba Gebhardt , Bäder Stefan , Georgieff Michael , Radermacher Peter 
Published: November 2003

Background
Because of its high density and viscosity, xenon (Xe) may influence respiratory mechanics when used as an inhaled anesthetic. Therefore the authors studied respiratory mechanics during xenon and nitrous oxide (N2O) anesthesia before and during methacholine-induced bronchoconstriction.

Methods
Sixteen pentobarbital-anesthetized pigs initially were ventilated with 70% nitrogen-oxygen. Then they were randomly assigned to a test period of ventilation with either 70% xenon-oxygen or 70% N2O-oxygen (n = 8 for each group). Nitrogen-oxygen ventilation was then resumed. Tidal volume and inspiratory flow rate were set equally throughout the study. During each condition the authors measured peak and mean airway pressure (Pmax and Pmean) and airway resistance (R(aw)) by the end-inspiratory occlusion technique. This sequence was then repeated during a methacholine infusion.

Results
Both before and during methacholine airway resistance was significantly higher with xenon-oxygen (4.0 +/- 1.7 and 10.9 +/- 3.8 cm H2O x s(-1) x 1(-1), mean +/- SD) when compared to nitrogen-oxygen (2.6 +/- 1.1 and 5.8 +/- 1.4 cm H2O x s(-1) x l(-1), P < 0.01) and N2O-oxygen (2.9 +/- 0.8 and 7.0 +/- 1.9, P < 0.01). Pmax and Pmean did not differ before bronchoconstriction, regardless of the inspired gas mixture. During bronchoconstriction Pmax and Pmean both were significantly higher with xenon-oxygen (Pmax, 33.1 +/- 5.5 and Pmean, 11.9 +/- 1.6 cm H2O) when compared to N2O-oxygen (28.4 +/- 5.7 and 9.5 +/- 1.6 cm H2O, P < 0.01) and nitrogen-oxygen (28.0 +/- 4.4 and 10.6 +/- 1.3 cm H2O, P < 0.01).

Conclusions
Airway pressure and resistance are increased during xenon anesthesia. This response is moderate and not likely to assume major importance for the general use of xenon in anesthesia.
Relationship between Cardiopulmonary Bypass Flow Rate and Cerebral Embolization in Dogs
Authors: Sungurtekin Hulya , Plöchl Walter , Cook David J. 
Published: November 2003

Background
Cerebral embolization is a primary cause of cardiac surgical neurologic morbidity. During cardiopulmonary bypass (CPB), there are well-defined periods of embolic risk. In theory, cerebral embolization might be reduced by an increase in pump flow during these periods. The purpose of this study was to determine the CPB flow-embolization relation in a canine model.

Methods
Twenty mongrel dogs underwent CPB at 35 degrees C with alpha-stat management and a fentanyl-midazolam anesthetic. In each animal, CPB flow was adjusted to achieve a mean arterial pressure of 65-75 mmHg. During CPB, an embolic load of 1.2 x 10(5) 67 microm fluorescent microspheres was injected into the arterial inflow line. Before and after embolization, cerebral blood flow was determined using 15-microm microspheres. Tissue was taken from 12 brain regions and microspheres were recovered. The relation between pump flow and embolization/g of brain was determined.

Results
The mean arterial pressure at embolization was 67 +/-4 mmHg, and the range of pump flow was 0.9-3.5 l x min(-1)x m(-2). Cerebral blood flow was independent of pump flow. At lower pump flow, the percentage of that flow delivered to the brain increased. There was a strong inverse relation between pump flow and cerebral embolization (r = -0.708, P < 0.000 by Spearman rank order correlation).

Conclusions
Cerebral embolization is determined by the CPB flow. At an unchanged mean arterial pressure, as pump flow is reduced, a progressively greater proportion of that flow is delivered to the brain.
Activation of Spinal N-methyl-D-aspartate Receptors Stimulates a Nitric Oxide/Cyclic Guanosine 3′,5′-monophosphate/Glutamate Release Cascade in Nociceptive Signaling
Authors: Kawamata Tomoyuki , Omote Keiichi 
Published: November 2003

Background
Increasing evidence has suggested the possibility that the activation of N-methyl-D-aspartate (NMDA) receptors modulates spinal nociceptive transmission via a nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway. However, the existence and the role of an NO/cGMP pathway in the modulation of spinal nociceptive transmission has been unclear. The authors hypothesized that the activation of NMDA receptors stimulates an NO/cGMP pathway, and this pathway evokes glutamate release within the spinal cord, modulating spinal nociceptive transmission.

Methods
The authors have examined the effects of an NO synthase inhibitor and a soluble guanylate cyclase inhibitor on the concentrations of NO metabolites (NO2-/NO3-) and glutamate in the cerebrospinal fluid after intrathecal perfusion of NMDA, concomitantly observing pain-related behavior (scratching, biting, and vocalization) in unanesthetized, free-moving rats using an intrathecal microdialysis method. The contents of cGMP in the dorsal horn were also measured using enzyme immunoassay method.

Results
Intrathecal perfusion of NMDA produced pain-related behavior and increased glutamate and NO2-/NO3-concentrations in a dose-dependent manner. A competitive NMDA receptor antagonist, D,L-2-amino-5-phosphonovaleric acid, completely blocked the NMDA-induced responses. An NO synthase inhibitor, N(G)-monomethyl-L-arginine acetate, at a dose that completely blocked the increase in NO2-/NO3-, inhibited both the NMDA-induced pain-related behavior and the increase in glutamate concentration. In addition, a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxaline-1-one, also inhibited significantly NMDA-induced pain-related behavior and the increase in glutamate concentration. NMDA induced an increase in cGMP in the dorsal half of the spinal cord, which was blocked by N(G)-monomethyl-L-arginine acetate.

Conclusions
The results of this study support the hypothesis that the activation of NMDA receptors modulated pain-related behavior via an NO/cGMP/glutamate release cascade within the spinal cord.
Antinociceptive and Hemodynamic Effects of a Novel α2-Adrenergic Agonist, MPV-2426, in Sheep
Authors: Eisenach James C. , Lavand'homme Patricia , Tong Chuanyao , Cheng Jen-Kun , Pan Hui-Lin , Virtanen Raimo , Nikkanen Hanna , James Robert 
Published: November 2003

Background
alpha2-Adrenergic agonists produce analgesia primarily by a spinal action and hypotension and bradycardia by actions at several sites. Clonidine is approved for epidural use in the treatment of neuropathic pain, but its wider application is limited by hemodynamic side effects. This study determined the antinociceptive and hemodynamic effects of a novel alpha2-adrenergic agonist, MPV-2426, in sheep.

Methods
Forty sheep of mixed Western breeds with indwelling catheters were studied. In separate studies, antinociception to a mechanical stimulus, hemodynamic effects, arterial blood gas tensions, cerebrospinal fluid pharmacokinetics, and spinal cord blood flow was determined after epidural, intrathecal, and intravenous injection of MPV-2426.

Results
MPV-2426 produced antinociception with greater potency intrathecally (ED50 = 49 microg) than epidurally (ED50 = 202 microg), whereas intravenous administration had no effect. Intrathecal injection, in doses up to three times the ED95, failed to decrease systemic or central arterial blood pressures or heart rate, whereas larger doses, regardless of route, increased systemic arterial pressure. Bioavailability in cerebrospinal fluid was 7% after epidural administration and 0.17% after intravenous administration. Intrathecal MPV-2426, in an ED95 dose and three times this dose, produced a dose-independent reduction in thoracic and lumbar spinal cord blood flow.

Conclusions
MPV-2426 shares many characteristics of other alpha2-adrenergic agonists examined in sheep, but differs from clonidine and dexmedetomidine by lack of antinociception and minimal reduction in oxygen partial pressure after large intravenous and epidural injections. No hemodynamic depression was observed after intrathecal injection at antinociceptive doses. These results suggest this compound may be an effective spinal analgesic in humans with less hypotension than clonidine, although its relative potency to cause sedation was not tested in this study.
Sex Differences in Cholinergic Analgesia I
Authors: Chiari Astrid , Tobin Joseph R. , Pan Hui-Lin , Hood David D. , Eisenach James C. 
Published: November 2003

Background
Cholinergic agents produce analgesia after systemic and intrathecal administration. A retrospective review showed that intrathecal neostigmine was more potent in women than in men, suggesting a sex difference in this response. The purpose of this study was to determine whether such a sex difference exists in normal rats and to examine the pharmacologic mechanisms that underlie this difference.

Methods
Male and female rats with indwelling intrathecal catheters received injections of neostigmine, bethanechol (muscarinic agonist), or RJR-2403 (neuronal nicotinic agonist) alone or with atropine (muscarinic antagonist), mecamylamine (nicotinic antagonist), or phentolamine alpha-adrenergic antagonist) with antinociception determined to a noxious heat stimulus to the hind paw. Time versus subcutaneous paw temperature relationships were defined for males and females.

Results
Neostigmine produced dose-dependent antinociception with five times greater potency in female than in male rats. Neostigmine-induced antinociception was reversed in male rats by atropine and unaffected by mecamylamine, whereas it was partially reduced by each antagonist alone in females and completely reversed after injection of both. RJR-2403 was more potent in females than in males, whereas there was no sex difference to bethanechol. Phentolamine partially reversed antinociception from RJR-2403 in females. Paw temperature increased more rapidly in females than in males for the same lamp intensity.

Conclusions
These data demonstrate a large sex difference in antinociception to intrathecal neostigmine that is primarily the result of a nicotinic component in females. Phentolamine reversal suggests that part of this nicotinic component may rely on spinal norepinephrine release. A better understanding of this sex difference could lead to development of novel pain therapy for women.
Sex Differences in Cholinergic Analgesia II
Authors: Lavand'homme Patricia M. , Eisenach James C. 
Published: November 2003

Background
Cholinergic agents reduce allodynia after nerve injury in animals and may be useful in the treatment of neuropathic pain. Intrathecally administered neostigmine and neuronal nicotinic agonists are more potent in female than in male rats against acute thermal noxious stimuli. The purpose of this study was to determine whether there is also a sex difference in the antiallodynic effects of intrathecal cholinomimetic agents in two models of allodynia and to test their pharmacologic mechanisms.

Methods
Male and female rats with indwelling intrathecal catheters received injections of neostigmine, bethanechol (muscarinic agonist), RJR-2403 (neuronal nicotinic agonist) alone or with atropine (muscarinic antagonist), mecamylamine (nicotinic antagonist), phentolamine (alpha-adrenergic antagonist), or saline control. The effect of these agents was determined on mechanical allodynia produced by either intraplantar injection of capsaicin or ligation of spinal nerves.

Results
Neostigmine and RJR-2403 but not bethanechol were more potent in female than in male rats in reducing allodynia after nerve injury, and antagonist studies were also consistent with a nicotinic component to explain this sex difference. Phentolamine did not reverse neostigmine's effect. In contrast, for capsaicin-induced allodynia, neostigmine plus mecamylamine but not neostigmine or RJR-2403 was more potent in female than in male rats.

Conclusions
These data demonstrate a sex difference of intrathecal neostigmine after nerve injury-induced allodynia similar to that observed in normal animals that received acute noxious thermal stimulation. However, this sex difference is not universal to all pain models because it was not present after intradermal capsaicin injection, nor is its interaction with spinal noradrenergic mechanisms consistent in all models.
Effects of Propofol and Remifentanil on Phrenic Nerve Activity and Nociceptive Cardiovascular Responses in Rabbits
Authors: Ma Daqing , Chakrabarti Mihir K. , Whitwam James G. 
Published: November 2003

Background
The effects of propofol, remifentanil, and their combination on phrenic nerve activity (PNA), resting heart rate (HR), mean arterial pressure (MAP), and nociceptive cardiovascular responses were studied in rabbits.

Methods
Basal anesthesia and constant blood gas tensions were maintained with alpha-chloralose and mechanical ventilation. PNA, HR, MAP, and maximum changes in HR and MAP (deltaHR, deltaMAP) evoked by electrical nerve stimulation of tibial nerves were recorded. The comparative effects were observed for propofol at infusion rates from 0.05 to 3.2 mg x kg(-1) x min(-1) (group I) and remifentanil from 0.0125 to 12.8 microg x kg(-1) x min(-1) alone (group II), and during constant infusions of propofol at rates of 0.1 and 0.8 mg x kg(-1) x min(-1) (groups III and IV, respectively). Finally, the effect of remifentanil on propofol blood levels was observed (group V).

Results
The infusion rates for 50% depression (ED50) of PNA, deltaHR, and deltaMAP were 0.41, 1.32, and 1.58 mg x kg-(1) x min(-1) for propofol, and 0.115, 0.125, and 1.090 microg x kg(-1) x min(-1) for remifentanil, respectively. The ratios for the ED50 values of deltaHR and deltaMAP to PNA were 3.2 and 3.9 for propofol, and 1.1 and 9.5 for remifentanil, respectively. Analysis of the expected and observed responses and isobologrms showed that although their combined effects on PNA, resting HR, and MAP, and deltaMAP were synergistic for deltaHR, they were merely additive. Remifentanil had no effect on propofol blood levels.

Conclusion
PNA was abolished by propofol and remifentanil, alone and in combination, before significant depression of nociceptive pressor responses occurred. Their combined effects on PNA, HR, MAP, and deltaMAP are greater than additive, ie., synergistic. Unlike propofol, remifentanil obtunded pressor responses more than the resting circulation.
Meperidine and Lidocaine Block of Recombinant Voltage-Dependent Na+Channels
Authors: Wagner Larry E. , Eaton Michael , Sabnis Salas S. , Gingrich Kevin J. 
Published: November 2003

Background
The opioid meperidine induces spinal anesthesia and blocks nerve action potentials, suggesting it is a local anesthetic. However, whether it produces effective clinical local anesthesia in peripheral nerves remains unclear. Classification as a local anesthetic requires clinical local anesthesia but also blockade of voltage-dependent Na+ channels with characteristic features (tonic and phasic blockade and a negative shift in the voltage-dependence of steady-state inactivation) involving an intrapore receptor. The authors tested for these molecular pharmacologic features to explore whether meperidine is a local anesthetic.

Methods
The authors studied rat skeletal muscle mu1 (RSkM1) voltage-dependent Na+ channels or a mutant form heterologously coexpressed with rat brain Na+ channel accessory beta1, subunit in Xenopus oocytes. Polymerase chain reaction was used for mutagenesis, and mutations were confirmed by sequencing. Na+ currents were measured using a two-microelectrode voltage clamp. Meperidine and the commonly used local anesthetic lidocaine were applied to oocytes in saline solution at room temperature.

Results
Meperidine and lidocaine produced tonic current inhibition with comparable concentration dependence. Meperidine caused phasic current inhibition in which the concentration-response relationship was shifted to fivefold greater concentration relative to lidocaine. Meperidine and lidocaine negatively shifted the voltage dependence of steady-state inactivation. Mutation of a putative local anesthetic receptor reduced phasic inhibition by meperidine and lidocaine and tonic inhibition by lidocaine, but not meperidine tonic inhibition.

Conclusions
Meperidine blocks Na+ channels with molecular pharmacologic features of a local anesthetic. The findings support classification of meperidine as a local anesthetic but with less overall potency than lidocaine.
Controlled Airway Pressure Therapy, Nitric Oxide Inhalation, Prone Position, and Extracorporeal Membrane Oxygenation (ECMO) as Components of an Integrated Approach to ARDS
Authors: Ullrich Roman , Lorber Christine , Röder Georg , Urak Georg , Faryniak Barbara , Sladen Robert N. , Germann Peter 
Published: November 2003

Background
Recent years have seen the introduction of innovative additive therapies for acute respiratory distress syndrome. However, because there are no reliable predictors of response to a particular therapy, potential responders to a specific therapeutic intervention may be lost. Therefore, the authors evaluated the effect of a combined therapeutic approach on the survival of patients with acute respiratory distress syndrome, when treated according to a strict algorithm.

Methods
During a 2.5-yr period, 84 patients with acute respiratory distress syndrome were assigned to a standardized treatment protocol. Data analysis was performed by retrospective review of patient charts. Patients were treated using a stepwise treatment algorithm of pressure-controlled ventilation (peak airway pressure < 35 cm H2O), positive end-expiratory pressure (PEEP; 12-15 cm H2O), permissive hypercapnia, inhaled nitric oxide (5-20 ppm), and prone positioning. These interventions were termed "conventional therapy." Response to treatment was defined as a more than 20% increase in arterial oxygen tension (PaO2). Nonresponders were triaged to extracorporeal membrane oxygenation.

Results
The overall survival rate was 80%. All patients received conventional therapy up to 96 h; 71 responded to conventional therapy and 59 survived (83%). Thirteen patients (15%) did not respond to conventional therapy and underwent extracorporeal membrane oxygenation; 8 of these patients (62%) survived. For the group, the mean admission lung injury score was 3.3+/-0.5, the PaO2/fractional inspired oxygen tension (F(I)O2) ratio was 96+/-45, and the Acute Physiology and Chronic Health Evaluation (APACHE) II score was 18+/-6.

Conclusions
The 80% overall survival rate achieved in this group of patients with severe acute respiratory distress syndrome may in part reflect the additive beneficial effects of combined treatment methods, such as airway pressure control, nitric oxide inhalation, prone position, and early triage of nonresponders to extracorporeal membrane oxygenation.