bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparation of the Siemens KION Anesthetic Machine for Patients Susceptible to Malignant Hyperthermia
Authors: Petroz Guy C. , Lerman Jerrold
Published: August 2004

Background

Preparation of anesthetic machines for use with malignant hyperthermia-susceptible (MHS) patients requires that the machines be flushed with clean fresh gas. We investigated the washout of inhalational anesthetics from the KION anesthetic machine.

Methods

In part 1, halothane was circulated through KION anesthetic machines for either 2 or 12 h using a test lung. The times to washout halothane (to 10 parts per million [ppm]) first, from the internal circuitry and second, from the ventilator-patient cassette (without the carbon dioxide absorber) were determined at 5 and 10 l/min fresh gas flow (FGF). In part 2, the rates of washout of halothane or isoflurane from either the KION or Ohmeda Excel 210 machines were compared. The effluent gases were analyzed using calibrated Datex Capnomac Ultima (Helsinki, Finland) and a Miran LB2 Portable Ambient Air Analyzer (Foxboro, Norwalk, CT).

Results

Halothane was washed out of the internal circuitry of the KION within 5 min at 10 l/min FGF. Halothane was eliminated from the ventilator-patient cassette in 22 min at the same FGF. The times to reach 10 ppm concentration of halothane and isoflurane in the KION at 10 l/min FGF, 23 to 25 min, was four-fold greater than those in the Ohmeda Excel 210, 6 min.

Conclusions

To prepare the KION anesthetic machine for MHS patients, the machine without the carbon dioxide absorber must be flushed with 10 l/min FGF for at least 25 min to achieve 10 ppm anesthetic concentration. This FGF should be maintained throughout the anesthetic to avoid increases in anesthetic concentration in the FGF.
Effects of Halothane and Sevoflurane on Inhibitory Neurotransmission to Medullary Expiratory Neurons in a Decerebrate Dog Model
Authors: Stucke Astrid G. , Stuth Eckehard A. E. , Tonkovic-Capin Viseslav , Tonkovic-Capin Mislav , Hopp Francis A. , Kampine John P. , Zuperku Edward J.
Published: August 2004

Background

In canine expiratory bulbospinal neurons, 1 minimum alveolar concentration (MAC) halothane and sevoflurane reduced the glutamatergic excitatory drive at a presynaptic site and enhanced the overall gamma-aminobutyric acid (GABA)-mediated inhibitory input. The authors investigated if this inhibitory enhancement was mainly caused by postsynaptic effects.

Methods

Two separate anesthetic studies were performed in two sets of decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC halothane or sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline. Complete blockade of GABAA-mediated inhibition with bicuculline was used to assess the prevailing overall inhibitory input to the neuron. The neuronal response to muscimol was used to estimate the anesthetic effect on postsynaptic GABAA receptor function.

Results

Halothane at 1 MAC depressed the spontaneous activity of 12 expiratory neurons 22.2 +/- 14.8% (mean +/- SD) and overall glutamatergic excitation 14.5 +/- 17.9%. Overall GABA-mediated inhibition was enhanced 14.1 +/- 17.9% and postsynaptic GABAA receptor function 74.2 +/- 69.2%. Sevoflurane at 1 MAC depressed the spontaneous activity of 23 neurons 20.6 +/- 19.3% and overall excitation 10.6 +/- 21.7%. Overall inhibition was enhanced 15.4 +/- 34.0% and postsynaptic GABAA receptor function 65.0 +/- 70.9%. The effects of halothane and sevoflurane were not statistically different.

Conclusion

Halothane and sevoflurane at 1 MAC produced a small increase in overall inhibition of expiratory premotor neuronal activity. The increase in inhibition results from a marked enhancement of postsynaptic GABAA receptor function that is partially offset by a reduction in presynaptic inhibitory input by the anesthetics.
An Isolated, Antegrade, Perfused, Peroneal Nerve Anterior Tibialis Muscle Model in the Rat
Authors: De Haes Ann , Houwertjes Martin C. , Proost Johannes H. , Wierda J. Mark K. H.
Published: August 2004

Background

A model of an antegrade, perfused, isolated rat peroneal nerve anterior tibial muscle was developed to study potentially important factors governing the time course of action of (nondepolarizing) neuromuscular blocking agents such as concentration, blood flow, and temperature. The model allows observation of the effects of selective changes in these factors.

Methods

The authors isolated the anterior tibial muscle and cannulated the anterior tibial artery and vein, providing a way for single-pass perfusion with blood from a donor rat. A force transducer was connected to the tibialis anterior muscle and a stimulator was connected to the tibial nerve. The influence of intrinsic potency (EC90) and muscle blood flow rate on the time course of pancuronium and rocuronium was investigated.

Results

The model remained stable for at least 4 h with respect to twitch height, muscle structure and function, and blood chemistry. Doubling the muscle-blood flow resulted in a significantly faster onset and offset for both pancuronium and rocuronium. Trebling the intrinsic potency (EC90) was not associated with significant changes in the time course of action of the relaxants.

Conclusion

The authors developed and validated a model that allows us to study biophase kinetics of neuromuscular blocking agents in the anterior tibial muscle of the rat. In this model, muscle-blood flow rather than EC90 appears to predominantly determine the onset and offset time of nondepolarizing muscle relaxants.
Does the Immobilizing Effect of Thiopental in Brain Exceed That of Halothane?
Authors: Antognini Joseph F. , Carstens Earl , Atherley Richard
Published: August 2004

Background

Recent studies suggest that anesthetics such as isoflurane act in the spinal cord to suppress movement that occurs during noxious stimulation. The authors examined the effect of halothane and thiopental on suppression of noxious-evoked movement using a model of differential anesthetic delivery. They hypothesized that halothane and thiopental, similar to isoflurane, would suppress movement primarily via an action in spinal cord.

Methods

Goats were anesthetized and prepared for differential anesthetic delivery. Anesthesia was maintained with halothane (n = 5) or thiopental (n = 5). Anesthetic requirements were determined (noxious clamp on a dewclaw for 1 min) during halothane or thiopental (via infusion) delivery to the whole body and delivery only to the head.

Results

Control (whole body) halothane requirement was 0.9 +/- 0.2%; halothane requirement in the head during differential delivery was 3.4 +/- 1% (P < 0.01). During selective halothane delivery, the electroencephalogram was greatly depressed or was isoelectric even though the animals moved during noxious stimulation. Control (whole body) plasma thiopental requirement was 20 +/- 10 microg/ml. When thiopental was selectively delivered to the head, the electroencephalogram was active in all five animals, and cranial thiopental requirement was 42 +/- 6 microg/ml (P < 0.01).

Conclusion

These data suggest that halothane and thiopental, like isoflurane, act in spinal cord to suppress movement occurring with noxious stimulation. However, halothane appears to be less potent in the brain as evidenced by the electroencephalogram data, suggesting that action in spinal cord plays a more significant role for halothane than for thiopental.
Droperidol Inhibits GABAAand Neuronal Nicotinic Receptor Activation
Authors: Flood Pamela , Coates Kristen M.
Published: August 2004

Background

Droperidol is used in neuroleptanesthesia and as an antiemetic. Although its antiemetic effect is thought to be caused by dopaminergic inhibition, the mechanism of droperidol's anesthetic action is unknown. Because gamma-aminobutyric acid type A (GABAA) and neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as putative targets of other general anesthetic drugs, the authors tested the ability of droperidol to modulate these receptors.

Methods

gamma-Aminobutyric acid type A alpha1beta1gamma2 receptor, alpha7 and alpha4beta2 nAChRs were expressed in Xenopus oocytes and studied with two-electrode voltage clamp recording. The authors tested the ability of droperidol at concentrations from 1 nm to 100 microm to modulate activation of these receptors by their native agonists.

Results

Droperidol inhibited the GABA response by a maximum of 24.7 +/- 3.0%. The IC50 for inhibition was 12.6 +/- 0.47 nm droperidol. At high concentrations, droperidol (100 microm) activates the GABAA receptor in the absence of GABA. Inhibition of the GABA response is significantly greater at hyperpolarized membrane potentials. The activation of the alpha7 nAChR is also inhibited by droperidol, with an IC50 of 5.8 +/- 0.53 microm. The Hill coefficient is 0.95 +/- 0.1. Inhibition is noncompetitive, and membrane voltage dependence is insignificant.

Conclusions

Droperidol inhibits activation of both the GABAA alpha1beta1gamma2 and alpha7 nAChR. The submaximal GABA inhibition occurs within a concentration range such that it might be responsible for the anxiety, dysphoria, and restlessness that limit the clinical utility of high-dose droperidol anesthesia. Inhibition of the alpha7 nAChR might be responsible for the anesthetic action of droperidol.
Non–steady State Analysis of the Pharmacokinetic Interaction between Propofol and Remifentanil
Authors: Bouillon Thomas , Bruhn Joergen , Radu-Radulescu Lucian , Bertaccini Edward , Park Sang , Shafer Steven
Published: August 2004

Background

The pharmacokinetics of both propofol and remifentanil have been described extensively. Although they are commonly administered together for clinical anesthesia, their pharmacokinetic interaction has not been investigated so far. The purpose of the current investigation was to elucidate the nature and extent of pharmacokinetic interactions between propofol and remifentanil.

Methods

Twenty healthy volunteers aged 20-43 yr initially received either propofol or remifentanil alone in a stepwise incremental and decremental fashion a target controlled infusion. Thereafter, the respective second drug was infused to a fixed target concentration in the clinical range (0-4 microg/ml and 0-4 ng/ml for propofol and remifentanil, respectively) and the stepwise incremental pattern repeated. Frequent blood samples were drawn for up to 6 h for propofol and 40 min for remifentanil after the end of administration and assayed for the respective drug concentrations with gas chromatography-mass spectrometry. The time courses of the measured concentrations were fitted to standard compartmental models. Calculations were performed with NONMEM. After having established the individual population models for both drugs and an exploratory analysis for hypothesis generation, pharmacokinetic interaction was identified by including an interaction term into the population model and comparing the value of the objective function in the presence and absence of the respective term.

Results

The concentration-time courses of propofol and remifentanil were described best by a three- and two-compartment model, respectively. In the concentration range examined, remifentanil does not alter propofol pharmacokinetics. Coadministration of propofol decreases the central volume of distribution and distributional clearance of remifentanil by 41% and elimination clearance by 15%. This effect was not concentration-dependent in the examined concentration range of propofol.

Conclusions

Coadministration of propofol decreases the bolus dose of remifentanil needed to achieve a certain plasma-effect compartment concentration but does not alter the respective maintenance infusion rates and recovery times to a clinically significant degree.
Propofol
Authors: Ludbrook Guy L. , Visco Elizabeth , Lam Arthur M.
Published: August 2004

Background

The potential benefit of propofol dose regimens that use physiologic pharmacokinetic modeling to target the brain has been demonstrated in animals, but no data are available on the rate of propofol distribution to the brain in humans. This study measured the brain uptake of propofol in humans and the simultaneous effects on electroencephalography, cerebral blood flow velocity (V(mca)), and cerebral oxygen extraction.

Methods

Seven subjects had arterial and jugular bulb catheters placed before induction. Electroencephalography and V(mca) were recorded during induction with propofol while blood samples were taken from both catheters for later propofol analysis. Brain uptake of propofol was calculated using mass balance principles, with effect compartment modeling used to quantitate the rate of uptake.

Results

Bispectral index (electroencephalogram) values decreased to a minimum value of approximately 4 at around 7 min from the onset of propofol administration and then slowly recovered. This was accompanied by decreases in V(mca), reaching a minimum value of approximately 40% of baseline. Cerebral oxygen extraction did not change, suggesting parallel changes in cerebral metabolism. There was slow equilibrium of propofol between the blood and the brain (t(1/2keo) of 6.5 min), with a close relation between brain concentrations and bispectral index, although with considerable interpatient variability. The majority of the decreases in V(mca), and presumably cerebral metabolism, corresponded with bispectral index values reaching 40-50 and the onset of burst suppression.

Conclusion

Description of brain distribution of propofol will allow development of physiologic pharmacokinetic models for propofol and evaluation of dose regimens that target the brain.
Validation Study of Two-microphone Acoustic Reflectometry for Determination of Breathing Tube Placement in 200 Adult Patients
Authors: Raphael David T. , Benbassat Maxim , Arnaudov Dimiter , Bohorquez Alex , Nasseri Bita
Published: August 2004

Background

Acoustic reflectometry allows the construction of a one-dimensional image of a cavity, such as the airway or the esophagus. The reflectometric area-distance profile consists of a constant cross-sectional area segment (length of endotracheal tube), followed either by a rapid increase in the area beyond the carina (tracheal intubation) or by an immediate decrease in the area (esophageal intubation).

Methods

Two hundred adult patients were induced and intubated, without restrictions on anesthetic agents or airway adjunct devices. A two-microphone acoustic reflectometer was used to determine whether the breathing tube was placed in the trachea or esophagus. A blinded reflectometer operator, seated a distance away from the patient, interpreted the acoustic area-distance profile alone to decide where the tube was placed. Capnography was used as the gold standard.

Results

Of 200 tracheal intubations confirmed by capnography, the reflectometer operator correctly identified 198 (99% correct tracheal intubation identification rate). In two patients there were false-negative results, patients with a tracheal intubation were interpreted as having an esophageal intubation. A total of 14 esophageal intubations resulted, all correctly identified by reflectometry, for a 100% esophageal intubation identification rate.

Conclusions

Acoustic reflectometry is a rapid, noninvasive method by which to determine whether breathing tube placement is correct (tracheal) or incorrect (esophageal). Reflectometry determination of tube placement may be useful in airway emergencies, particularly in cases where visualization of the glottic area is not possible and capnography may fail, as in patients with cardiac arrest.
Pharmacodynamics and Pharmacokinetics of Propofol in a Medium-Chain Triglyceride Emulsion
Authors: Ward Denham S. , Russell Norton J. , Guivarc'h Pol-Henri , Litman Ronald S. , Bailey Peter L.
Published: August 2004

Background

Because propofol is water insoluble, current formulations of propofol use a soybean oil emulsion. These soybean emulsions cause elevated plasma triglycerides and support bacterial growth. This study compares an alternative formulation of propofol as a 2% emulsion in a medium-chain triglyceride solution (IDD-D Propofol) with Diprivan.

Methods

This double-blind, crossover, phase 1 study compared IDD-D Propofol with Diprivan using two consecutive protocols of 12 subjects each. Subjects in protocol 1 received a single bolus of 2.5 mg/kg, and those in protocol 2 received the same induction dose followed by a 30-min infusion at 0.2 mg. kg(-1).min(-1). Venous samples were taken for propofol concentration and biochemical measurements. Induction and emergence times were measured by termination of voluntary counting and responding to command, respectively.

Results

Plasma concentrations were not different between the two formulations. Induction time was 14% longer with IDD-D Propofol than with Diprivan (N = 24, protocols 1 and 2 combined, 53.3 +/- 12.1 s and 46.9 +/- 7.8 s, respectively; P = 0.002). Emergence time was not significantly different for protocol 1 but was marginally longer (P = 0.04) for IDD-D Propofol in protocol 2 (1,197 +/- 445 s [n = 11] and 1,254 +/- 468 s [n = 12], respectively). As expected because of the inherent characteristics of the formulations, plasma triglycerides were elevated for Diprivan but not for IDD-D Propofol; octanoate, a metabolite of medium-chain triglycerides, was elevated only with IDD-D Propofol. Octanoate was elevated to concentrations below those considered toxic. Plasma concentrations of other biochemical markers of medium-chain triglyceride metabolism, ketones, showed no significant changes. Interestingly, there were significant differences between male and female subjects in the propofol plasma concentrations and time to awakening with both drugs.

Conclusions

Differences between the two propofol formulations were slight and not clinically significant. Similar gender differences in plasma concentrations and awaking times were found for both formulations.
Changes of Electroencephalographic Bicoherence during Isoflurane Anesthesia Combined with Epidural Anesthesia
Authors: Hagihira Satoshi , Takashina Masaki , Mori Takahiko , Mashimo Takashi , Yoshiya Ikuto
Published: August 2004

Background

The authors previously reported that, during isoflurane anesthesia, electroencephalographic bicoherence values changed in a fairly restricted region of frequency versus frequency space. The aim of the current study was to clarify the relation between electroencephalographic bicoherence and the isoflurane concentration.

Methods

Thirty elective abdominal surgery patients (male and female, aged 34-77 yr, American Society of Anesthesiologists physical status I-II) were enrolled. After electroencephalogram recording with patients in an awake state, anesthesia was induced with 3 mg/kg thiopental and maintained with oxygen and isoflurane. Continuous epidural anesthesia with 80-100 mg/kg 1% lidocaine was also administered. Using software they developed, the authors continuously recorded the FP1-A1 lead of the electroencephalographic signal and expired isoflurane concentration to an IBM-PC compatible computer. After confirming the steady state of each isoflurane (end-tidal concentration at 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, and 1.5%), electroencephalographic bicoherence values were calculated.

Results

In a light anesthetic state, electroencephalographic bicoherence values were low (generally < or = 15.0%). At increased concentrations of isoflurane, two peaks of electroencephalographic bicoherence emerged along the diagonal line (f1=f2). The peak emerged at around 4.0 Hz and grew higher as isoflurane concentration increased until it reached a plateau (43.8 +/- 3.5%, mean +/- SD) at isoflurane 0.9%. The other peak, at about 10.0 Hz, also became significantly higher and reached a plateau (32.6 +/- 9.2%) at isoflurane 0.9%; at isoflurane 1.3%, however, this peak slightly decreased.

Conclusion

Changes in the height of two electroencephalographic bicoherence peaks correlated well with isoflurane concentration.
Propofol and Sevoflurane in Subanesthetic Concentrations Act Preferentially on the Spinal Cord
Authors: Kammer Thomas , Rehberg Benno , Menne Dieter , Wartenberg Hans-Christian , Wenningmann Ingobert , Urban Bernd W.
Published: August 2004

Background

Animal experiments in recent years have shown that attenuation of motor responses by general anesthetics is mediated at least partly by spinal mechanisms. Less is known about the relative potency of anesthetic drugs in suppressing cortical and spinal electrophysiological responses in vivo in humans, particularly those, but not only those, connected with motor responses. Therefore, we studied the effects of sevoflurane and propofol in humans using multimodal electrophysiological assessment.

Methods

We studied nine healthy volunteers in two sessions during steady state sedation with 0.5, 1.0, and 1.5 microg/l (targeted plasma concentration) propofol or 0.2 and 0.4 vol% (end-tidal) sevoflurane. Following a 15-min equilibration period, motor responses to transcranial magnetic stimulation and peripheral (H-reflex, F-wave) stimulation were recorded, while electroencephalography and auditory evoked responses were recorded in parallel.

Results

At concentrations corresponding to two thirds of C(50 awake), motor responses to transcranial magnetic stimulation were reduced by approximately 50%, H-reflex amplitude was reduced by 22%, F-wave amplitude was reduced by 40%, and F-wave persistence was reduced by 25%. No significant differences between sevoflurane and propofol were found. At this concentration, the Bispectral Index was reduced by 7%, and the middle-latency auditory evoked responses were attenuated only mildly (N(b) latency increased by 11%, amplitude P(a)N(b) did not change). In contrast, the postauricular reflex was suppressed by 77%.

Conclusions

The large effect of both anesthetics on all spinal motor responses, compared with the small effect on electroencephalography and middle-latency auditory evoked responses, assuming that they represent cortical modulation, may suggest that the suppression of motor responses to transcranial magnetic stimulation is largely due to submesencephalic effects.
Conventional Mechanical Ventilation Is Associated with Bronchoalveolar Lavage-induced Activation of Polymorphonuclear Leukocytes
Authors: Zhang Haibo , Downey Gregory P. , Suter Peter M. , Slutsky Arthur S. , Ranieri V. Marco
Published: August 2004

Background

Protective ventilatory strategies have resulted in a decreased mortality rate in acute respiratory distress syndrome, but the underlying mechanisms remain unclear. The authors hypothesized that (1) mechanical ventilation modulates activation of polymorphonuclear leukocytes (PMNs), (2) the consequent release of proteinases is correlated with a systemic inflammatory response and with multiple organ dysfunction, and (3) these deleterious effects can be minimized by a protective ventilatory strategy.

Methods

Human PMNs were incubated with bronchoalveolar lavage fluid obtained from patients at entry or 36 h after randomization to ventilation with either a conventional (control) or a lung-protective strategy. PMN oxidant production and surface expression of adhesion molecules and granule markers, including CD18, CD63, and L-selectin, were measured by flow cytometry. Extracellular elastase activity was quantified using a fluorescent substrate.

Results

Bronchoalveolar lavage obtained from both groups of patients at entry showed similar effects on PMN oxidant production and expression of surface markers. At 36 h, exposure of PMNs to bronchoalveolar lavage fluid from the control group resulted in increased PMN activation as manifested by a significant increase in oxidant production, CD18, and CD63 surface expression, and shedding of L-selectin. By contrast, these variables were unchanged at 36 h in the lung-protective group. There was a significant correlation between the changes of the variables and changes in interleukin-6 level and the number of failing organs.

Conclusions

Polymorphonuclear leukocytes can be activated by mechanical ventilation, and the consequent release of elastase was correlated with the degree of systemic inflammatory response and multiple organ failure. This result may possibly explain the decreased mortality in acute respiratory distress syndrome patients treated with a lung-protective strategy.
Inhibition of Mammalian Gq Protein Function by Local Anesthetics
Authors: Hollmann Markus W. , McIntire William E. , Garrison James C. , Durieux Marcel E.
Published: August 2004

Background

Local anesthetics have been shown to selectively inhibit functioning of Xenopus laevis Gq proteins. It is not known whether a similar interaction exists with mammalian G proteins. The goal of this study was to determine whether mammalian Gq protein is inhibited by local anesthetics.

Methods

In Xenopus oocytes, the authors replaced endogenous Gq protein with mouse Gq (expressed in Sf9 cells using baculovirus vectors). Cells endogenously expressing lysophosphatidic acid or recombinantly expressing muscarinic m3 receptors were injected with phosphorothioate DNA antisense (or sense as control) oligonucleotides against Xenopus Gq. Forty-eight hours later, oocytes were injected with purified mouse Gq (5 x 10(-8) M) or solvent as control. Two hours later, the authors injected either lidocaine, its permanently charged analog QX314 (at IC50, 50 nl), or solvent (KCl 150 mM) as control and measured Ca-activated Cl currents in response to lysophosphatidic acid or methylcholine (one tenth of EC50).

Results

Injection of anti-Gq reduced the mean response size elicited by lysophosphatidic acid to 33 +/- 7% of the corresponding control response. In contrast, responses were unchanged (131 +/- 29% of control) in cells in addition injected with mouse Gq protein. Injection of mouse Gq protein "rescued" the inhibitory effect of intracellularly injected QX314: whereas QX314 was without effect on Gq-depleted oocytes, responses to lysophosphatidic acid after QX314 injection were inhibited to 44 +/- 10% of control response in cells in addition injected with mouse Gq protein (5 x 10(-8) M). Similar results were obtained for m3 signaling and intracellularly injected lidocaine.

Conclusion

Inhibition of Gq function by local anesthetics is not restricted to Xenopus G proteins. Therefore, Gq should be considered as one additional intracellular target site for local anesthetics, especially relevant for those effects not explainable by sodium channel blockade (e.g., antiinflammatory effects).
Evidence for the Involvement of Spinal Cord α1Adrenoceptors in Nitrous Oxide–induced Antinociceptive Effects in Fischer Rats
Authors: Orii Ryo , Ohashi Yoko , Guo Tianzhi , Nelson Laura E. , Hashimoto Toshikazu , Maze Mervyn , Fujinaga Masahiko
Published: August 2004

Background

In a previous study, the authors found that nitrous oxide (N2O) exposure induces c-Fos (an immunohistochemical marker of neuronal activation) in spinal cord gamma-aminobutyric acid-mediated (GABAergic) neurons in Fischer rats. In this study, the authors sought evidence for the involvement of alpha1 adrenoceptors in the antinociceptive effect of N2O and in activation of GABAergic neurons in the spinal cord.

Methods

Adult male Fischer rats were injected intraperitoneally with alpha1 adrenoceptor antagonist, alpha2 adrenoceptor antagonist, opioid receptor antagonist, or serotonin receptor antagonist and, 15 min later, were exposed to either air (control) or 75% N2O. In some animals, nociception was investigated with the plantar test after 30 min of exposure, while in other animals, gas exposure was continued for 90 min and the spinal cord was examined for c-Fos immunostaining. In a separate experiment, animals were exposed to the above gases alone, after which the spinal cords were examined immunohistochemically for c-Fos and alpha1 adrenoceptor by double-staining methods.

Results

The antinociceptive effect of N2O was attenuated by prazosin (an alpha1 adrenoceptor antagonist), yohimbine (an alpha2 adrenoceptor antagonist), and naloxone (an opioid receptor antagonist) but not by methysergide and tropisetron (serotonin receptor antagonists). N2O exposure induced c-Fos expression in the spinal cord, which was blocked by prazosin and naloxone but not by other drugs. N2O-induced c-Fos expression was colocalized with alpha1 adrenoceptor immunoreactivity in laminae III-IV.

Conclusions

These findings support the hypothesis that N2O activates GABAergic interneurons through alpha1 adrenoceptors to produce its antinociceptive effect.
Clonidine and Dexmedetomidine Potently Inhibit Peristalsis in the Guinea Pig Ileum In Vitro
Authors: Herbert Michael K. , Roth-Goldbrunner Susanne , Holzer Peter , Roewer Norbert
Published: August 2004

Background

Inhibition of intestinal peristalsis is a major side effect of drugs used for anesthesia or for analgesia and sedation of patients in the intensive care unit. This in vitro study examined the effect of clonidine and dexmedetomidine on intestinal peristalsis and analyzed some of their mechanisms of action.

Methods

In isolated segments of the guinea pig small intestine, peristalsis was triggered by a perfusion-induced rise of the intraluminal pressure. The peristaltic pressure threshold to elicit a peristaltic wave was used to quantify drug effects on peristalsis. Vehicle (Tyrode's solution), clonidine (10 nM-100 microm), or dexmedetomidine (0.1-100 nM) were added extraserosally to the organ bath. In other series of experiments, clonidine or dexmedetomidine was administered after pretreatment with yohimbine, prazosin, apamin, naloxone, or vehicle. Clonidine was also tested after blockade of NO synthase with L-NAME and in the presence of the inactive enantiomer D-NAME.

Results

Clonidine and dexmedetomidine concentration-dependently increased peristaltic pressure threshold and inhibited peristalsis (clonidine: EC50 = 19.6 microm; dexmedetomidine: EC50 = 12.0 nM). The inhibition caused by clonidine could be prevented by pretreatment with yohimbine, naloxone, and apamin, but not by prazosin, L-NAME, or D-NAME. Inhibition caused by dexmedetomidine was prevented by yohimbine only.(50) (50)

Conclusions

The results reveal that clonidine and, much more potently, dexmedetomidine inhibit peristalsis of the guinea pig ileum. The inhibition is caused by interaction with alpha2 adrenoceptors and, in the case of clonidine, also involves activation of small conductance Ca2+ -activated potassium channels and endogenous opioidergic pathways.
Nonhalogenated Alkanes Cyclopropane and Butane Affect Neurotransmitter-gated Ion Channel and G-protein–coupled Receptors
Authors: Hara Koji , Eger Edmond I. , Laster Michael J. , Harris R. Adron
Published: August 2004

Background

Anesthetic mechanisms of nonhalogenated alkanes cyclopropane and butane are not understood. This study was designed to look at which neurotransmitter receptors are possible targets for these anesthetics.

Methods

Effects of cyclopropane and butane on eight recombinant receptors expressed in Xenopus oocytes were examined electrophysiologically. To address molecular mechanisms of interaction with glycine and gamma-aminobutyric acid type A (GABA(A)) receptors, cyclopropane was further tested on alpha1(S267C) glycine receptor and alpha2(S270X)beta1 GABA(A) receptors that were mutated to amino acids with larger side chains.

Results

Cyclopropane (1, 2, and 5 minimum alveolar concentration [MAC]) potentiated glycine responses by 39, 62, and 161%, respectively, and butane (1 MAC) potentiated by 64% with an increase in apparent affinity for glycine, but yielded barely detectable potentiation of GABA(A) receptors. The efficacy of cyclopropane for glycine receptors was less than isoflurane and halothane. The potentiation by cyclopropane was eliminated for the alpha1(S267C) glycine receptor. Mutant GABA(A) receptors in which the corresponding amino acid was substituted with larger amino acids did not produce significant potentiation. Cyclopropane and butane inhibited nicotinic acetylcholine and N-methyl-D-aspartate receptors, potentiated G-protein-coupled inwardly rectifying potassium channels, and did not change 5-hydroxytryptamine(3A) or muscarinic(1) receptor function. Only cyclopropane markedly inhibited alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors.

Conclusions

Glycine, nicotinic acetylcholine, and N-methyl-D-aspartate receptors are sensitive to nonhalogenated alkanes, and the authors propose that glycine and N-methyl-D-aspartate receptors are good candidates for anesthetic immobility. The authors also suggest that the distinct effects on glycine and GABA(A) receptors are not due to the small volumes of these anesthetics.
Effects of Delayed Administration of Low-dose Lidocaine on Transient Focal Cerebral Ischemia in Rats
Authors: Lei Baiping , Popp Susanna , Capuano-Waters Christine , Cottrell James E. , Kass Ira S.
Published: August 2004

Background

The authors' previous study demonstrated that a clinical antiarrhythmic dose of lidocaine, when given before ischemia, is neuroprotective in a rat model of transient focal cerebral ischemia. In this study, the authors investigated whether the administration of this dose of lidocaine, when delayed until 45 min after the onset of ischemia, also reduces ischemic brain injury.

Methods

Lidocaine was administered as an intravenous bolus (1.5 mg/kg) followed by an intravenous infusion (2 mg. kg(-1).h(-1)) for 165 min, beginning 45 min after the onset of a 90-min period of transient focal cerebral ischemia. Control animals were given the same volume of saline. Focal cerebral ischemia was induced by occluding the right middle cerebral artery using an intraluminal suture. Neurologic outcome and body weight loss were quantified 7 days later. The brain was fixed 7 days after ischemia and brain sections were stained with hematoxylin and eosin for assessment of infarct size and the number of intact neurons. In separate experiments, local cerebral blood flow and the electroencephalogram were measured during ischemia and 180 min into the reperfusion period. Infarct size was assessed after 24 h.

Results

Infarct size, at either 24 h or 7 days after ischemia, was not significantly reduced in the lidocaine group. However, the number of intact neurons was significantly increased in both the ischemic penumbra and core of the lidocaine group 7 days after ischemia, compared with the vehicle group. Rats treated with lidocaine demonstrated better neurologic outcome and less weight loss (P < 0.05). Lidocaine treatment had no significant influence on local cerebral blood flow and electroencephalogram during ischemia and reperfusion.

Conclusions

Administration of a clinical antiarrhythmic dose of lidocaine, beginning 45 min after the onset of ischemia, reduces ischemic brain injury after transient focal cerebral ischemia in the rat. This indicates that delayed administration of neuroprotective agents may reduce brain damage resulting from ischemia.
Inhibitory Effects of Isoflurane and Nonimmobilizing Halogenated Compounds on Neuronal Nicotinic Acetylcholine Receptors
Authors: Matsuura Takayuki , Kamiya Yoshinori , Itoh Hideki , Higashi Tomoko , Yamada Yoshitsugu , Andoh Tomio
Published: August 2004

Background

Neuronal nicotinic acetylcholine receptors (nAchRs) are inhibited by low concentrations of volatile anesthetics. However, it is not clear whether this phenomenon contributes to the anesthetic effects of volatile anesthetics. Effects of a volatile anesthetic (isoflurane) and structurally related nonimmobilizers (F6: 1,2-dichlorohexafluorocyclobutane, F8: 2,3-dichlorooctafluorobutane) on the current mediated through neuronal nAchRs were studied.

Method

This study investigated neuronal nAchRs in PC12 cells and acutely dissociated rat medial habenula (MHb) neurons. Whole cell currents elicited by 30 microm nicotine were recorded in the absence and presence of the halogenated agents. The minimum alveolar concentrations (MACs) for F6 and F8 were predicted from Meyer-Overton correlation.

Results

All halogenated compounds inhibited the nicotine-induced current in a concentration-dependent manner in PC12 cells. In MHb neurons, while isoflurane and F6 significantly inhibited the nicotine-induced peak current, F8 failed to inhibit it. The peak currents in the presence of isoflurane at 1.7 MAC, of F6 at 2.4 MAC, and of F8 at 2.2 MAC were 12, 31, and 97% of control, respectively.

Conclusions

Isoflurane, F6, and F8 inhibited ganglion-type nAchRs in PC12 cells independent from their abilities to produce the anesthetic state. In MHb neurons, isoflurane and F6, which lack the immobilizing effect but has the amnesic effect, inhibited nAchRs. Native brain nicotinic receptors in MHb neurons were almost insensitive to F8, which lacks both the immobilizing and the amnesic effect. These results are consistent with the hypothesis that inhibition of nAchRs in MHb neurons is not important for the anesthetic effect but may contribute to the amnesic effect of these agents.
Investigation of Systemic Bupivacaine Toxicity using the In situ Perfused Working Heart-Brainstem Preparation of the Rat
Authors: Pickering Anthony E. , Waki Hidefumi , Headley P. Max , Paton Julian F.R.
Published: August 2004

Background

The inadvertent systemic administration of bupivacaine has been associated with fatal cardiovascular collapse. Systemic bupivacaine may affect neural control of the cardiovascular system in addition to having toxic actions on the heart. The study tested the hypothesis that systemic bupivacaine has toxic effects on brainstem cardiorespiratory control.

Methods

The working heart-brainstem preparation (WHBP) of rat was used to examine the actions of bupivacaine administered either by arterial injection or brainstem microinjection. The WHBP is a decerebrate rostral-half of a bisected rat, which is artificially perfused with a carbogenated Ringer solution via the aorta. Phrenic nerve activity, perfusion pressure, and electrocardiographic results were recorded.

Results

Systemic bupivacaine (3 microg/ml) evoked a prolonged pressor response (10.5 +/- 5 mmHg) associated with marked bradycardia (-45 +/- 22 beats/min) and prolonged the PR and QRS intervals of the electrocardiogram. The amplitude of respiratory sinus arrhythmia was attenuated (64 +/- 15%) by bupivacaine without affecting activity recorded from the phrenic nerve. Bupivacaine selectively attenuated the baroreflex gain (55 +/- 19%) but had no effect on the peripheral chemoreflex-evoked bradycardia. The bradycardia elicited by stimulation of the aortic depressor nerve was inhibited by bupivacaine, indicating baroreflex inhibition within the brainstem. Furthermore, bilateral microinjections of bupivacaine in the nucleus of the solitary tract reversibly inhibited the baroreflex.

Conclusions

These results demonstrate that arterial concentrations of bupivacaine that previously were shown to be cardiotoxic can selectively affect key cardiovascular control processes within the brainstem. Such impairment of neural cardiovascular control may contribute to the cardiovascular collapse associated with systemic bupivacaine.
Postural Stability following Ambulatory Regional Analgesia for Labor
Authors: Davies Jeremy , Fernando Roshan , McLeod Andrew , Verma Sonia , Found Philip
Published: August 2004

Background

The safety of mobilization following low-dose regional analgesia in parturients remains controversial. Previous studies have demonstrated preserved balance function despite clinically elicited sensory deficits. The aim of this study was to use the Balance Master 6.1, a device capable of real-time analysis of ambulation, to score the performance of basic maneuvers following initiation of low-dose combined spinal-epidural analgesia in laboring women compared with pregnant and nonpregnant controls.

Methods

Using the Balance Master, balance function during the performance of several simple tasks, including walking and standing up from a sitting position, was evaluated in a prospective, controlled, observational study with 50 laboring women after combined spinal-epidural analgesia compared with 50 pregnant and 50 nonpregnant controls.

Results

Nonpregnant women scored significantly better results in 6 of the 13 measured balance function parameters compared with both the combined spinal-epidural and pregnant control groups. Compared with the nonpregnant subjects, the pregnant groups generated less force standing up from the sitting position (P < 0.0001), walked more slowly (P = 0.0067), and took shorter steps (P < 0.0001). They also took longer to step up onto and over a 20-cm-high obstacle (P < 0.0001), and they generated less force while stepping up. Initial spinal analgesia in laboring women did not significantly affect performance in comparison to the pregnant controls. Thirty-four percent of women in the combined spinal-epidural group required supplemental epidural analgesia following the initial spinal injection (n = 17) before testing; they had significantly impaired balance function in four tests compared with those receiving a spinal injection only (n = 33).

Conclusions

Being pregnant at term significantly affects balance function, although initial low-dose spinal-epidural analgesia does not impair function further. Subsequent supplemental epidural analgesia may have a detrimental effect on balance, but properly designed studies are awaited to confirm this. This study supports the practice of allowing laboring women with initial low-dose spinal-epidural analgesia to ambulate, but indicates that further studies need to be conducted on the effects of subsequent epidural supplementation.
Microinjection of an Adenosine A1Agonist into the Medial Pontine Reticular Formation Increases Tail Flick Latency to Thermal Stimulation
Authors: Tanase Diana , Baghdoyan Helen A. , Lydic Ralph
Published: August 2004

Background

Both pain and the pharmacologic management of pain can cause the undesirable effect of sleep disruption. One goal of basic and clinical neuroscience is to facilitate rational drug development by identifying the brain regions and neurochemical modulators of sleep and pain. Adenosine is thought to be an endogenous sleep promoting substance and adenosinergic compounds can contribute to pain management. In the pontine brain stem adenosine promotes sleep but the effects of pontine adenosine on pain have not been studied. This study tested the hypothesis that an adenosine agonist would cause antinociception when microinjected into pontine reticular formation regions that regulate sleep.

Methods

The tail flick latency (TFL) test quantified the time in seconds for an animal to move its tail away from a thermal stimulus created by a beam of light. TFL measures were used to evaluate the antinociceptive effects of the adenosine A1 receptor agonist N6-p-sulfophenyladenosine (SPA). Pontine microinjection of SPA (0.1 microg/0.25 microl, 0.88 mm) was followed by TFL measures as a function of time after drug delivery and across the sleep-wake cycle.

Results

Compared with saline (control), pontine administration of the adenosine agonist significantly increased latency to tail withdrawal (P < 0.0001). The increase in antinociceptive behavior evoked by the adenosine agonist SPA was blocked by pretreatment with the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 0.75 ng/0.25 microl, 10 microm).

Conclusions

These preclinical data encourage additional research on the cellular mechanisms by which adenosine in the pontine reticular formation contributes to the supraspinal modulation of pain.
Missed Opportunities in Addressing Drinking Behavior in Medical and Mental Health Services
Authors: Weisner Constance , Matzger Helen
Published: August 2004

Background: Epidemiological and clinical literature point to the importance of screening for alcohol problems in medical and psychiatric settings. However, little is known about which problem drinkers seek help from those services or about the characteristics of those who have their drinking addressed.

Methods: We interviewed a probability sample of adult dependent and problem drinkers in the general population (n= 672) and consecutive admissions to chemical dependency programs in a northern California county (n= 926). We reinterviewed them 1 year later and measured medical and mental health visits and whether their drinking was addressed during the visit.

Results: Almost two‐thirds of problem drinkers had a medical visit, and approximately one‐third had a mental health visit, yet drinking was not often discussed, especially during medical visits. Many of those more likely to have a visit were not more likely to have their drinking addressed. Women and individuals older than 40 years had more medical and mental health visits [odds ratio (OR), 1.71; p < 0.001 and OR, 1.55; p < 0.001, respectively, for women; OR, 1.57; p < 0.05 and OR, 1.64; p < 0.05, respectively, for age ≥40 years], but were not more likely to have their drinking addressed in either setting, and women were less likely than men to have their drinking addressed in mental health settings (OR, 0.62; p < 0.05). Those with higher alcohol severity and those who had attended chemical dependency treatment during the previous year were more likely to have their drinking addressed in each setting. Insurance status predicted medical, but not mental health, visits and was not related to having drinking addressed in either setting.

Conclusions: Drinking behavior was not routinely addressed by medical and mental health practitioners for dependent and problem‐drinking men and women who presented in public and private medical and mental health settings.
Cardiac Overexpression of Alcohol Dehydrogenase Exacerbates Cardiac Contractile Dysfunction, Lipid Peroxidation, and Protein Damage After Chronic Ethanol Ingestion
Authors: Hintz Kadon K. , Relling David P. , Saari Jack T. , Borgerding Anthony J. , Duan Jinhong , Ren Bonnie H. , Kato Kosai , Epstein Paul N. , Ren Jun
Published: August 2004

Background: Alcoholic cardiomyopathy is manifested as ventricular dysfunction, although its specific toxic mechanism remains obscure. This study was designed to examine the impact of enhanced acetaldehyde exposure on cardiac function via cardiac‐specific overexpression of alcohol dehydrogenase (ADH) after alcohol intake.

Methods: ADH transgenic and wild‐type FVB mice were placed on a 4% alcohol or control diet for 8 weeks. Mechanical and intracellular Ca2+ properties were evaluated in cardiac myocytes. Levels of acetaldehyde, lipid peroxidation, and protein carbonyl formation were determined.

Results: FVB and ADH mice consuming ethanol exhibited elevated blood ethanol/acetaldehyde, cardiac acetaldehyde, and cardiac hypertrophy compared with non‐ethanol‐consuming mice. However, the levels of cardiac acetaldehyde and hypertrophy were significantly greater in ADH ethanol‐fed mice than FVB ethanol‐fed mice. ADH transgene itself did not affect mechanical and intracellular Ca2+ properties with the exception of reduced resting intracellular Ca2+ and Ca2+ re‐sequestration at low pace frequency. Myocytes from ethanol‐fed mice showed significantly depressed peak shortening, velocity of shortening/relengthening, rise of intracellular Ca2+ transients, and sarco(endo)plasmic reticulum Ca2+ load associated with similar duration of shortening/relengthening compared with myocytes from control mice. Strikingly, the ethanol‐induced mechanical and intracellular Ca2+ defects were exacerbated in ADH myocytes compared with the FVB group except velocity of shortening/relengthening. The lipid peroxidation end products malondialdehyde and protein carbonyl formation were significantly elevated in both livers and hearts after chronic ethanol consumption, with the cardiac lipid and protein damage being exaggerated by ADH transgene.

Conclusion: These data suggest that increased cardiac acetaldehyde exposure due to ADH transgene may play an important role in cardiac contractile dysfunctions associated with lipid and protein damage after alcohol intake.