bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacodynamic Modeling of Vecuronium-induced Twitch Depression
Authors: Fisher Dennis M. , Szenohradszky Janos , Wright Peter M. C. , Lau Marie , Brown Ronald , Sharma Manohar
Published: November 2003

Background

After bolus doses of nondepolarizing muscle relaxants, the adductor pollicis recovers from paralysis more slowly than the diaphragm and the laryngeal adductors, suggesting that the adductor pollicis is more sensitive than the respiratory muscles to effects of those drugs. In contrast, during onset, the respiratory muscles are paralyzed more rapidly than the adductor pollicis, suggesting that the respiratory muscles are more sensitive than the adductor pollicis. To reconcile these apparently conflicting findings, we determined vecuronium's pharmacokinetics and its pharmacodynamics at both the adductor pollicis and the laryngeal adductors.

Methods

Six volunteers were studied on two occasions during anesthesia with propofol. Mechanical responses to train-of-four stimulation were measured at the adductor pollicis and at the laryngeal adductors. Vecuronium (15-60 micrograms/kg) was given and arterial plasma samples were obtained from 0.5-60 min. Vecuronium doses differed by twofold on the two occasions. A pharmacokinetic model accounting for the presence and potency of vecuronium's 3-desacetyl metabolite and a sigmoid e-max pharmacodynamic model were fit to the resulting plasma concentration and effect (adductor pollicis and laryngeal adductors) data to determine relative sensitivities and rates of equilibration between plasma and effect site concentrations.

Results

The steady-state plasma concentration depressing laryngeal adductor twitch tension by 50% was approximately 1.5 times larger than that for the adductor pollicis. The equilibration rate constant between plasma and laryngeal adductor concentrations was about 1.5 faster than that between plasma and adductor pollicis concentrations. The Hill factor (gamma) that describes the steepness of the laryngeal adductor concentration-effect relation was approximately 0.6 times that of the adductor pollicis.

Conclusions

More rapid equilibration between plasma and laryngeal adductor vecuronium concentrations explains why onset is more rapid at the laryngeal adductors than at the adductor pollicis. During recovery, both rapid equilibration and lesser sensitivity of the laryngeal adductors contribute to earlier recovery.
Are Plasma Concentration Values Necessary for Pharmacodynamic Modeling of Muscle Relaxants?
Authors: Fisher Dennis M. , Wright Peter M. C.
Published: November 2003

Background

The traditional approach to pharmacokinetic/ pharmacodynamic modeling of muscle relaxants requires sampling of plasma to determine drug concentrations. The authors recently proposed that certain pharmacodynamic characteristics (IR50, the steady-state infusion rate to maintain 50% twitch depression; keo, the rate constant for equilibration between plasma concentration and effect; and gamma, the Hill factor describing sigmoidicity of the concentration-effect relation) could be estimated without plasma concentration data. Here estimates for IR50, keo, and gamma determined with and without plasma concentration data are compared.

Methods

Six volunteers were given 15-60 micrograms/kg vecuronium on each of two occasions during anesthesia with propofol. Mechanical responses to train-of-four stimulation were measured at the adductor pollicis and at the laryngeal adductors. Various pharmacokinetic models accounting for the presence and potency of vecuronium's 3-desacetyl metabolite and a sigmoid e-max pharmacodynamic model were fit to the resulting plasma concentration and effect (adductor pollicis and laryngeal adductors) data to determine IR50 keo, and gamma for each effect. One model related dose to effect without plasma concentration data.

Results

Values for IR50(adductor pollicis), IR50(laryngeal adductors), gamma (adductor pollicis), and gamma (laryngeal adductors) were similar when determined with and without plasma concentration values. Values for keo (adductor pollicis) and keo (laryngeal adductors) were larger when determined without plasma concentration values compared with those determined with these values; however, the ratio of keo (adductor pollicis) to keo(laryngeal adductors) was similar when determined with and without plasma concentration values.

Conclusions

Certain pharmacodynamic parameters were estimated accurately in the absence of plasma concentration values. This suggests limited utility for plasma concentration data under conditions similar to those of the present study.
Association between Latex Sensitization and Repeated Latex Exposure in Children
Authors: Porri F. , Pradal M. , Lemiere C. , Birnbaum J. , Mege J. L. , Lanteaume A. , Charpin D. , Vervloet D. , Camboulives J.
Published: November 2003

Background

Children with spina bifida are at greater risk for latex and ethylene oxide sensitization. The authors' aim in this study was to evaluate the role of previous surgical procedures in the development of sensitization to latex and ethylene oxide.

Methods

The authors investigated 80 children 1-16 yr old, separated into 3 groups. Two groups had a history of 3 or more general anesthetics: 29 children had spina bifida (spina bifida group) and 31 had undergone multiple surgeries for another disease (multiple surgeries group). A control group of 20 children had undergone less than 1 anesthetic. Clinical manifestations with latex, perioperative anaphylactic reactions, and number of previous anesthetics were recorded. Skin prick tests with a commercial extract of latex, four common inhalant allergens, and radioallergosorbent test to latex and ethylene oxide were performed.

Results

The three groups did not differ significantly with respect to age, sex, and atopic status. Mean number of anesthetics was comparable in the spina bifida and the multiple surgeries group. Latex sensitization was common in the spina bifida group (59%) and in the multiple surgeries group (55%) but not in the control group (0%, P < 0.05). Ethylene oxide sensitization was significantly more frequent in the spina bifida group than in the multiple surgeries group (44% vs. 19%; P = 0.052) and strongly associated with latex sensitization. Mean number of previous anesthetics was greater in children sensitized to latex (8.4 vs. 3.9; P < 0.05).

Conclusion

Results suggest that it is the number of surgical procedures rather than spina bifida per se that is related to sensitization to latex.
Comparison of Cuffed and Uncuffed Endotracheal Tubes in Young Children during General Anesthesia
Authors: Khine Henry H. , Corddry David H. , Kettrick Robert G. , Martin Thalia M. , McCloskey John J. , Rose John B. , Theroux Mary C. , Zagnoev Michael
Published: November 2003

Background

Uncuffed endotracheal tubes are routinely used in young children. This study tests a formula for selecting appropriately sized cuffed endotracheal tubes and compares the use of cuffed versus uncuffed endotracheal tubes for patients whose lungs are mechanically ventilated during anesthesia.

Methods

Full-term newborns and children (n = 488) through 8 yr of age who required general anesthesia and tracheal intubation were assigned randomly to receive either a cuffed tube sized by a new formula [size(mm internal diameter) = (age/4) + 3], or an uncuffed tube sized by the modified Cole's formula [size(mm internal diameter) = (age/4) + 4]. The number of intubations required to achieve an appropriately sized tube, the need to use more than 21.min-1 fresh gas flow, the concentration of nitrous oxide in the operating room, and the incidence of croup were compared.

Results

Cuffed tubes selected by our formula were appropriate for 99% of patients. Uncuffed tubes selected by Cole's formula were appropriate for 77% of patients (P < 0.001). The lungs of patients with cuffed tubes were adequately ventilated with 2 1.min-1 fresh gas flow, whereas 11% of those with uncuffed tubes needed greater fresh gas flow (P < 0.001). Ambient nitrous oxide concentration exceeded 25 parts per million in 37% of cases with uncuffed tubes and in 0% of cases with cuffed tubes (P < 0.001). Three patients in each group were treated for croup symptoms (1.2% cuffed; 1.3% uncuffed).

Conclusions

Our formula for cuffed tube selection is appropriate for young children. Advantages of cuffed endotracheal tubes include avoidance of repeated laryngoscopy, use of low fresh gas flow, and reduction of the concentration of anesthetics detectable in the operating room. We conclude that cuffed endotracheal tubes may be used routinely during controlled ventilation in full-term newborns and children during anesthesia.
Halothane and Isoflurane Differentially Affect the Regulation of Dopamine and Gamma-aminobutyric Acid Release Mediated by Presynaptic Acetylcholine Receptors in the Rat Striatum
Authors: Salord Francois , Keita Hawa , Lecharny Jean-Baptiste , Henzel Danielle , Desmonts Jean-Marie , Mantz Jean
Published: November 2003

Background

General anesthetics are thought to produce their hypnotic effects mainly by acting at ligand-gated ionic channels in the central nervous system (CNS). Although it is well established that volatile anesthetics significantly modify the activity of the acetylcholine nicotinic receptors of the neuromuscular junction, little is known about their actions on the acetylcholine receptors in the CNS. In this study, the effects of halothane and isoflurane on the regulation of dopamine (DA) (gamma-aminobutyric acid [GABA]) depolarization-evoked release mediated by nicotinic (muscarinic) presynaptic receptors were studied in the rat striatum.

Methods

Assay for GABA (dopamine) release consisted of 3H-GABA (3H-DA)-preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml/min, 37 degrees C) and measuring the radioactivity obtained from 1-min fractions for 18 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of depolarizing agents combined with vaporized halothane and isoflurane (0.5-5%, 5 min), and finally with no pharmacologic stimulation (5 min). The depolarizing agents were potassium chloride (KCl; 9 mM) alone or with acetylcholine (10(-6)-10(-4) M) and/or atropine (10(-5) M) for experiments with 3H-GABA, and KC1 (15 mM) and nicotine (10(-7) - 5 x 10(-4) M) alone or with mecamylamine (10(-5) M) for experiments with 3H-DA.

Results

Potassium chloride induced a significant, Ca(2+)-dependent release of both 3H-GABA and 3H-DA. Nicotine produced a concentration-related, mecamylamine-sensitive 3H-DA release that was significantly attenuated by nicotine (10(-7) M) preincubation. Acetylcholine elicited a dose-dependent, atropine-sensitive reduction of the KC1-evoked 3H-GABA release. Halothane and isoflurane significantly decreased the nicotine-evoked 3H-DA release but had only limited depressant effects on the KC1-stimulated 3H-DA and no action on the KC1-induced 3H-GABA release. The effects of acetylcholine on 3H-GABA release were reversed by halothane but not by isoflurane.

Conclusions

Clinically relevant concentrations of halothane and isoflurane significantly, but differentially, alter the presynaptic cholinergic regulation of the release of inhibitory neurotransmitters in the striatum. These results suggest that the cholinergic transmission may represent an important and specific presynaptic target for volatile anesthetics in the CNS.
Differential Inhibition of Lysophosphatidate Signaling by Volatile Anesthetics
Authors: Chan Carrie K. , Durieux Marcel E.
Published: November 2003

Background

Volatile anesthetics have been found to interfere with the functioning of several G protein-coupled receptors, effects that may be relevant to the mechanism of anesthetic action. Lysophosphatidate (1-acyl-2-sn-glycero-3-phosphate; LP) is the simplest natural phospholipid. It has pronounced biological effects and signals through a specific G protein-coupled receptor. Because of its lipophilicity, the LP receptor is a feasible site of anesthetic interaction. Therefore, the authors investigated the effects of halothane and isoflurane on LP signaling using Xenopus oocytes.

Methods

Mature oocytes were harvested from Xenopus frogs, isolated, and defolliculated manually. Lysophosphatidate receptors are endogenously present in these cells. Angiotensin receptors were expressed recombinantly to study anesthetic effects on intracellular signaling. Oocytes were studied individually with a two-electrode voltage clamp at room temperature. Integrated Ca(2+)-activated Cl- currents (ICl(Ca)) were used to evaluate the effects of anesthetics on changes in intracellular Ca2+ concentration in response to receptor agonists (10(-7) M LP or 10(-7) M angiotensin II) or intracellular inositoltrisphosphate (IP3) injection.

Results

Halothane depressed LP signaling in a concentration-dependent manner, with half-maximal inhibition at 0.23 mM and virtually complete inhibition at 0.34 mM. Responses could be recovered after an anesthetic-free wash. Oocyte injection with heparin, an IP3 receptor antagonist, completely blocked LP and angiotensin signaling, indicating similar IP3- dependent pathways. However, ICl(Ca) induced by angiotensin receptor activation or intracellular IP3 injection were not inhibited by halothane. Isoflurane, at comparable concentrations, did not depress LP responses in oocytes significantly.

Conclusions

Lipid-mediator signaling can be affected profoundly by volatile anesthetics. At clinically relevant concentrations, halothane and isoflurane have different effects on LP signaling. The inhibitory effects of halothane on the LP signaling pathway occur before the IP3 receptor.
Modulation of Cardiac Calcium Channels by Propofol
Authors: Zhou Weiguo , Fontenot Jerrel H. , Liu Shi , Kennedy Richard H.
Published: November 2003

Background

Propofol elicits a rapid depression of transsarcolemmal Ca2+ influx and myocardial contractility. However, the mechanism underlying this action has not been well described. The present study was designed to test the hypothesis that propofol acts as an antagonist of L-type calcium channels.

Methods

Experiments monitored effects of propofol on (1) the binding of [3H]nitrendipine (a 1,4-dihydropyridine calcium channel antagonist) to rat myocardial membranes; (2) L-type calcium current (ICa,L) as determined using whole-cell patch-clamp techniques in intact rat cardiomyocytes; and (3) myocardial contractility as examined in isolated rat papillary muscle.

Results

Propofol, in concentrations as low as 6 microM, increased the apparent dissociation constant (Kd) for [3H]nitrendipine without affecting binding-site density (Bmax). This decrease in dihydropyridine-binding affinity was associated with a depressed ICa,L in cardiomyocytes and diminished myocardial contractility. Other experiments showed that etomidate has no effect on [3H]nitrendipine binding, whereas ketamine enhances dihydropyridine binding.

Conclusion

Results suggest that propofol may inhibit cardiac L-type calcium current by interacting with the dihydropyridine-binding site.
Inhalational Anesthetic Effects on Rat Cerebellar Nitric Oxide and Cyclic Guanosine Monophosphate Production
Authors: Rengasamy Appavoo , Pajewski Thomas N. , Johns Roger A.
Published: November 2003

Background

Inhalational anesthetics interact with the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway in the central nervous system (CNS) and attenuate excitatory neurotransmitter-induced cGMP concentration. The site of anesthetic action on the NO-cGMP pathway in the CNS remains controversial. This study investigated the effect of inhalational anesthetics on N-methyl-D-aspartate (NMDA)-stimulated NO synthase activity and cyclic cGMP production in rat cerebellum slices.

Methods

The interaction of inhalational anesthetics with NO synthase activation and cGMP concentration was determined in cerebellum slices of 10-day-old rats. Nitric oxide synthase activity in cerebellum slices was assessed by measuring the conversion of L-[3H]arginine to L-[3H]citrulline. The cGMP content of cerebellum slices was measured by radioimmunoassay.

Results

Isoflurane at 1.5% and 3% enhanced the NMDA-stimulated NO synthase activity by two times while halothane at 1.5% and 3% produced no significant effect. However, the NMDA-stimulated cGMP production was inhibited by both anesthetic agents. The anesthetic inhibition of cGMP accumulation was not significantly altered by a mixture of superoxide dismutase and catalase or by glycine, a coagonist of the NMDA receptor.

Conclusions

The enhancement of NMDA-induced NO synthase activity by isoflurane and the inhibition of NMDA-stimulated cGMP production by halothane and isoflurane suggests that inhalational anesthetics interfere with the neuronal NO-cGMP pathway. This inhibitory effect of anesthetics on cGMP accumulation is not due to either their interaction with the glycine binding site of the NMDA receptor or to the action of superoxide anions.
Effect of Body Repositioning after Venous Air Embolism
Authors: Geissler Hans J. , Allen Steven J. , Mehlhorn Uwe , Davis Karen L. , Morris William P. , Butler Bruce D.
Published: November 2003

Background

Current therapy for massive venous air embolism (VAE) may include the use of the left lateral recumbent (LLR) position, although its effectiveness has been questioned. This study used transesophageal echocardiography to evaluate the effect of body repositioning on intracardiac air and acute cardiac dimension changes.

Methods

Eighteen anesthetized dogs in the supine position received a venous air injection of 2.5 ml/kg at a rate of 5 ml/ s. After 1 min the dogs were repositioned into either the LLR, LLR 10 degrees head down (LLR-10 degrees), right lateral recumbence, or remained in the supine position.

Results

Repositioning after VAE resulted in relocation of intracardiac air to nondependent areas of the right heart. Peak right ventricular (RV) diameter increase and mean arterial pressure decrease were greater in the repositioned animals compared with those in the supine position (P < 0.05). Right ventricular diameter and mean arterial pressure showed an inverse correlation (r = 0.81). Peak left atrial diameter decrease was greater in the LLR and LLR-10 degrees positions compared with the supine position (P < 0.05). Repositioning did not influence peak pulmonary artery pressure increase, and no correlation was found between RV diameter and pulmonary artery pressure. All animals showed electrocardiogram and echocardiographic changes reconcilable with myocardial ischemia.

Conclusions

In dogs, body repositioning after VAE provided no benefit in hemodynamic performance or cardiac dimension changes, although relocation of intracardiac air was demonstrated. Right ventricular air did not appear to result in significant RV outflow obstruction, as pulmonary artery pressure increased uniformly in all groups and was not influenced by the relocation of intracardiac air. The combination of increased RV afterload and arterial hypotension, possibly with subsequent RV ischemia rather than RV outflow obstruction by an airlock appeared to be the primary mechanism for cardiac dysfunction after VAE.
The Rate of Blood Withdrawal Affects the Accuracy of Jugular Venous Bulb
Authors: Matta Basil F. , Lam Arthur M.
Published: November 2003

Background

Accuracy of jugular venous oxygen saturation (SjvO2) measurement depends on sampling of cerebral venous outflow blood not contaminated by systemic venous blood. The influence of the rate of blood withdrawal has not been determined.

Methods

The authors examined the effect of withdrawing blood at different rates from jugular venous bulb catheters (JVBC) on SjvO2 in 10 mechanically ventilated patients undergoing neurosurgical procedures. All patients received a standardized anesthetic consisting of propofol, fentanyl, vecuronium, and isoflurane. Routine monitors included electrocardiograph (ECG), invasive blood pressure, pulse oximetry, and a JVBC. During a period of stable anesthetic and surgical conditions, JVBC blood samples were drawn at 2, 4, and 10 ml/min using a calibrated pump (Harvard Pump model 900, Harvard Apparatus, South Natick, MA) during mild and moderate hypocapnia (arterial carbon dioxide tension [PaCO2], 26.0 +/- 0.5 and 33.0 +/- 0.5 mmHg).

Results

Faster rates of withdrawal (10 and 4 ml/min vs. 2 ml/min) resulted in significantly higher SjvO2 values at both levels of PaCO2 (66.0 +/- 3% and 61.2 +/- 3% vs. 56.9 +/- 3% at PaCO2 = 26.0 +/- 0.5 mmHg, and 75.0 +/- 3% and 71.3 +/- 3% vs. 68.0 +/- 3% at PaCO2 = 33.0 +/- 0.5 mmHg, respectively; P < 0.01).

Conclusions

The authors conclude that the SjvO2 values measured with intermittent sampling are affected by the rate of withdrawing blood from JVBC, probably as a result of extracranial contamination. They recommend blood samples should be drawn slowly.
A Technique for Population Pharmacodynamic Analysis of Concentration-Binary Response Data
Authors: Bailey James M. , Gregg Keith M.
Published: November 2003

Background

Pharmacodynamic data frequently consist of the binary assessment (a "yes" or "no" answer) of the response to a defined stimulus (verbal stimulus, intubation, skin incision, and so on) for multiple patients. The concentration-effect relation is usually reported in terms of C50, the drug concentration associated with a 50% probability of drug effect, and a parameter the authors denote gamma, which determines the shape of the concentration-probability of effect curve. Accurate estimation of gamma, a parameter describing the entire curve, is as important as the estimation of C50, a single point on this curve. Pharmacodynamic data usually are analyzed without accounting for interpatient variability. The authors postulated that accounting for interpatient variability would improve the accuracy of estimation of gamma and allow the estimation of C50 variability.

Methods

A probit-based model for the individual concentration-response relation was assumed, characterized by two parameters, C50 and gamma. This assumption was validated by comparing probit regression with the more commonly used logistic regression of data from individual patients found in the anesthesiology literature. The model was then extended to analysis of population data by assuming that C50 has a log-normal distribution. Population data were analyzed in terms of three parameters, (C50), the mean value of C50 in the population; omega, the standard deviation of the distribution of the logarithm of C50; and gamma. The statistical characteristics of the technique were assessed using simulated data. The data were generated for a range of gamma and omega values, assuming that C50 and gamma had a log-normal distribution.

Results

The probit-based model describes data from individual patients and logistic regression does. Population analysis using the extended probit model accurately estimated (C50), gamma, and omega for a range of values, despite the fact that the technique accounts for C50 variability but not gamma variability.

Conclusions

A probit-based method of pharmacodynamic analysis of pooled population data facilitates accurate estimation of the concentration-response curve.
Recombinant Human Hemoglobin Does Not Affect Renal Function in Humans
Authors: Viele Maurene K. , Weiskopf Richard B. , Fisher Dennis MD
Published: November 2003

Background

Recombinant human hemoglobin (OptroD; rHb1.1) is a genetically engineered protein produced in Escherichia coli. The two alpha-globin polypeptides are genetically joined, resulting in a stable tetramer that does not dissociate into dimers or monomers. Historically, infusion in humans of acellular hemoglobin preparations has resulted in renal toxicity. This study was performed to evaluate the safety and pharmacokinetics of rHb1.1 when infused in humans.

Methods

After giving informed consent, 48 healthy male volunteers were randomly assigned to receive either 0.015-0.32 g/kg 5% rHb1.1 (n = 34) or an equivalent amount of 5% human serum albumin (HSA; n = 14) infused intravenously over 0.8-1.9 h. Serum creatinine, creatinine clearance, urine N-acetyl-beta-glucosaminidase, and serum rHb1.1 concentrations were measured before and at timed intervals after infusion.

Results

Postinfusion urine N-acetyl-beta-glucosaminidase activity did not exceed preinfusion values at any interval in either group. Serum creatinine did not differ from preinfusion values at 1 day, 2-3 days, or 7 days after infusion for either group. Creatinine clearance increased significantly for the HSA group 12 h after infusion (138 +/- 16 ml/min, means +/- SE) and in the rHb1.1 group 1 day after infusion (112 +/- 5 ml/min; P < 0.05). Values for creatinine clearance did not differ from preinfusion values for either group at any other postinfusion interval; serum creatinine and creatinine clearance did not differ between groups at any time. The amount of hemoglobin excreted in the urine did not exceed approximately 0.04% of the administered rHb1.1 dose in any volunteer. Plasma clearance of rHb1.1 decreased and half-life increased as a function of increasing plasma concentration (e.g., the half-life was 2.8 h at a plasma concentration of 0.5 mg/ml and 12 h at 5 mg/ml). The incidence of gastrointestinal symptoms, fever, and chills was greater after infusion of rHb1.1 than after HSA (P < 0.05).

Conclusions

No evidence for rHb1.1-mediated nephrotoxicity was observed in volunteers given doses of rHb1.1 as large as 0.32 g/kg. Because the clearance of rHb1.1 varies inversely with its concentration, additional studies with larger doses are necessary to determine the half-life expected in clinical use. Administration of rHb1.1 to conscious humans is associated with some side effects, such as gastrointestinal upset, fever, chills, headache, and backache.
Halothane-induced Dilatation of Intraparenchymal Arterioles in Rat Brain Slices
Authors: Harkin Christopher P. , Hudetz Antal G. , Schmeling William T. , Kampine John P. , Farber Neil E.
Published: November 2003

Background

Halothane is a potent dilator of cerebral arteries. The predominant site of cerebrovascular resistance is thought to be intracerebral arterioles, and the effects of halothane on these vessels were not previously examined. This study compared the effects of halothane with those of the vasodilator and nitric oxide donor, sodium nitroprusside, on intraparenchymal microvessel responsiveness in a brain slice preparation.

Methods

Anesthetized Sprague-Dawley rats underwent thoracotomy and intracardiac perfusion and then were decapitated. Hippocampal brain slices were prepared and placed in a perfusion/recording chamber and superfused with artificial cerebrospinal fluid. An arteriole was located within the brain parenchyma and its diameter was monitored with videomicroscopy before, during, and after various concentrations of halothane or sodium nitroprusside were equilibrated in the perfusate. All vessels were preconstricted with prostaglandin F2 alpha before halothane or sodium nitroprusside treatment. An observer blinded to treatment analyzed vessel diameter changes with a computerized videomicrometer.

Results

Baseline microvessel diameter was 18 +/- 2 microns in the halothane group (n = 14) and 15 +/- 1 microns in the sodium nitroprusside group (n = 15). Prostaglandin F2 alpha (0.5 micron) preconstricted vessels by approximately 15% from resting diameter in both groups. Halothane significantly and dose dependently dilated intracerebral microvessels by 54% +/- 6%, 74% +/- 8%, 108% +/- 13%, and 132% +/- 7% (normalized to the preconstricted diameter) at 0.5%, 1.0%, and 2.5% halothane, respectively. This dilatation corresponds to a decrease in a calculated index of cerebrovascular resistance index of up to 117% +/- 2% at 2.5% halothane. Sodium nitroprusside, in concentrations ranging from 10(-8) to 10(-3)M, also dose dependently dilated these intraparenchymal vessels by 129% +/- 7% at the highest concentration. These alterations in microvessel diameter corresponded to a decrease in the cerebrovascular resistance index of up to 116 +/- 4% for the largest dose.

Conclusions

Halothane produces dose-dependent vasodilatation of intraparenchymal cerebral microvessels, thus predicting marked decreases in cerebrovascular resistance in this in vitro brain slice preparation. The effects of halothane on these cerebral microvessels are similar to those of the potent vasodilator sodium nitroprusside. These findings suggest that direct effects of halathane on cerebral microvessels diameter contribute substantially to alterations in cerebrovascular resistance and flow produced by this agent.
Inhaled Nitric Oxide Pretreatment But Not Post-treatment Attenuates Ischemia-Reperfusion-induced Pulmonary Microvascular Leak
Authors: Chetham Paul M. , Sefton William D. , Bridges James P. , Stevens Troy , McMurtry Ivan F.
Published: November 2003

Background

Ischemia-reperfusion (I/R) pulmonary edema probably reflects a leukocyte-dependent, oxidant-mediated mechanism. Nitric oxide (NO) attenuates leukocyte-endothelial cell interactions and I/R-induced microvascular leak. Cyclic adenosine monophosphate (cAMP) agonists reverse and prevent I/R-induced microvascular leak, but reversal by inhaled NO (INO) has not been tested. In addition, the role of soluble guanylyl cyclase (sGC) activation in the NO protection effect is unknown.

Methods

Rat lungs perfused with salt solution were grouped as either I/R, I/R with INO (10 or 50 ppm) on reperfusion, or time control. Capillary filtration coefficients (Kfc) were estimated 25 min before ischemia (baseline) and after 30 and 75 min of reperfusion. Perfusate cell counts and lung homogenate myeloperoxidase activity were determined in selected groups. Additional groups were treated with either INO (50 ppm) or isoproterenol (ISO-10 microM) after 30 min of reperfusion. Guanylyl cyclase was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ-15 microM), and Kfc was estimated at baseline and after 30 min of reperfusion.

Results

(1) Inhaled NO attenuated I/R-induced increases in Kfc. (2) Cell counts were similar at baseline. After 75 min of reperfusion, lung neutrophil retention (myeloperoxidase activity) and decreased perfusate neutrophil counts were similar in all groups. (3) In contrast to ISO, INO did not reverse microvascular leak. (4) 8-bromoguanosine 3',5'-cyclic monophosphate (8-br-cGMP) prevented I/R-induced microvascular leak in ODQ-treated lungs, but INO was no longer effective.

Conclusions

Inhaled NO attenuates I/R-induced pulmonary microvascular leak, which requires sGC activation and may involve a mechanism independent of inhibition of leukocyte-endothelial cell interactions. In addition, INO is ineffective in reversing I/R-induced microvascular leak.
Multiple Mechanisms of Ketamine Blockade of N-methyl-D-aspartate Receptors
Authors: Orser Beverley A. , Pennefather Peter S. , MacDonald John F.
Published: November 2003

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusions

The attenuation of EFS-induced contractions by DAMGO in isolated bovine bronchi was mediated by prejunctional opioid receptors. In contrast, the inhibitory effect of U-50488 H was probably not mediated by opioid receptors in the bronchi.