bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liposomal Bupivacaine
Authors: Mowat Jeffrey J. , Mok Miranda J. , MacLeod Bernard A. , Madden Thomas D. 
Published: November 2003

Background
There is a clinical requirement for longer-acting local anesthetics, particularly for the management of post-operative and chronic pain. In this regard, liposomes have been suggested to represent a potentially useful vehicle for sustained drug release after local administration. In the current study, the authors used a transmembrane pH gradient to efficiently encapsulate bupivacaine within large unilamellar vesicles. They report on the kinetics of drug uptake and release and the duration of nerve blockade.

Methods
The rate and extent of bupivacaine uptake into large unilamellar vesicles that exhibit a pH gradient (interior acidic) were determined and compared to drug association with control liposomes that did not exhibit a proton gradient. In subsequent studies, researchers examined the kinetics of bupivacaine release from these liposome systems in vitro. Using the guinea pig cutaneous wheal model, the rate of clearance of the liposome carrier was monitored after intradermal administration, using a radiolabelled lipid marker, and the duration of nerve blockade produced by free and liposomal bupivacaine was compared.

Results
Bupivacaine was rapidly and efficiently accumulated within liposomes that exhibited a pH gradient (interior acidic) with trapping efficiencies of 64-82% of total drug, depending on the initial bupivacaine:phospholipid ratio. Little uptake was seen, however, for control vesicles that did not exhibit a transmembrane proton gradient. Using an in vitro model of drug clearance, liposomally encapsulated bupivacaine was found to be slowly released for a longer period of time compared with either the free drug or bupivacaine associated with control (no pH gradient liposomes). In the guinea pig cutaneous wheal model, more than 85% of the liposomal carrier was found to remain at the site of administration for 2 days. The sustained drug release afforded by liposomes that exhibited a pH gradient resulted in an increase in the duration of nerve blockade of as much as threefold compared with either the free drug or bupivacaine in the presence of control (no pH gradient) liposomes. Recovery of half maximal response (R2.5) after administration of 0.75% free bupivacaine, for example, was approximately 2 h, whereas the same dose of bupivacaine in pH gradient liposomes exhibited a R2.5 of approximately 6.5 h.

Conclusions
Large unilamellar vesicles that exhibit a pH gradient can efficiently encapsulate bupivacaine and subsequently provide a sustained-release system that greatly increases the duration of neural blockade.
Small, Oral Dose of Clonidine Reduces the Incidence of Intraoperative Myocardial Ischemia in Patients Having Vascular Surgery
Authors: Stuhmeier Klaus-Dieter , Mainzer Bernd , Cierpka Jochen , Sandmann Wilhelm , Tarnow Jorg 
Published: November 2003

Background
Most new perioperative myocardial ischemic episodes occur in the absence of hypertension or tachycardia. The ability of alpha 2-adrenoceptor agonists to inhibit central sympathetic outflow may benefit patients with coronary artery disease by increasing the myocardial oxygen supply and -demand ratio.

Methods
A randomized double-blind study design was used in 297 patients scheduled to have elective vascular surgical procedures to evaluate the effects of 2 micrograms/kg-1 oral clonidine (n = 145) or placebo (n = 152) on the incidence of perioperative myocardial ischemic episodes, myocardial infarction, and cardiac death. Continuous real-time S-T segment trend analysis (lead II and V5) was performed during anesthesia and surgery and correlated with arterial blood pressure and heart rate before and during ischemic events. Dose requirements for vasoactive and antiischemic drugs to control blood pressure and heart rate as well as episodes of myocardial ischemia (i.e., catecholamines, beta-adrenoceptor antagonists, nitrates, and systemic vasodilators) and fluid volume load were recorded.

Results
Administration of clonidine reduced the incidence of perioperative myocardial ischemic episodes from 39% (59 of 152) to 24% (35 of 145) (P < 0.01). Hemodynamic patterns, percentage of ischemic time, and the number of ischemic episodes per patient did not differ. Nonfatal myocardial infarction developed after operation in four patients receiving placebo compared with none receiving clonidine (day 2 to 21; P = 0.07). The incidence of fatal cardiac events (1 vs. 2) was not different. Dose requirements for vasoactive and antiischemic drugs did not differ between the groups, but the amount of presurgical fluid volume was slightly greater in patients receiving clonidine (951 +/- 388 vs. 867 +/- 381 ml; P < 0.03).

Conclusion
A small oral dose of clonidine, given prophylactically, can reduce the incidence of perioperative myocardial ischemic episodes without affecting hemodynamic stability in patients with suspected or documented coronary artery disease.
Effect of Flumazenil on Ventilatory Drive during Sedation with Midazolam and Alfentanil
Authors: Gross Jeffrey B. , Blouin Robert T. , Zandsberg Shaul , Conard Pattilyn F. , Haussler Jurgen 
Published: November 2003

Background
Patients who receive a combination of a benzodiazepine and an opioid for conscious sedation are at risk for developing respiratory depression. While flumazenil effectively antagonizes the respiratory depression associated with a benzodiazepine alone, its efficacy in the presence of both a benzodiazepine and an opioid has not been established. This study was designed to determine whether flumazenil can reverse benzodiazepine-induced depression of ventilatory drive in the presence of an opioid.

Methods
Twelve healthy volunteers completed this randomized, double-blind, crossover study. Ventilatory responses to carbon dioxide and to isocapnic hypoxia were determined during four treatment phases: (1) baseline, (2) alfentanil infusion; (3) combined midazolam and alfentanil infusions, and (4) combined alfentanil, midazolam, and "study drug" (consisting of either flumazenil or flumazenil vehicle) infusions. Subjects returned 2-6 weeks later to receive the alternate study drug.

Results
Alfentanil decreased the slope of the carbon dioxide response curve from 2.14 +/- 0.40 to 1.43 +/- 0.19 l.min-1.mmHg-1 (x +/- SE, P < 0.05), and decreased the minute ventilation at P(ET)CO2 = 50 mmHg (VE50) from 19.7 +/- 1.2 to 14.8 +/- 0.9l.min-1 (P < 0.05). Midazolam further reduced these variables to 0.87 +/- 0.17 l.min-1.mmHg-1 (P < 0.05) and 11.7 +/- 0.8 l.min-1 (P < 0.05), respectively. With addition of flumazenil, slope and VE50 increased to 1.47 +/- 0.37 l.min-1.mmHg-1 (P < 0.05) and 16.4 +/- 2.0l.min-1 (P < 0.05); after placebo, the respective values of 1.02 +/- 0.19 l.min-1.mmHg-1 and 12.5 +/- 1.2 l.min-1 did not differe significantly from their values during combined alfentanil and midazolam administration. The effect of flumazenil differed significantly from that of placebo (P < 0.05). Both the slope and the displacement of the hypoxic ventilatory response, measured at P(ET)CO2 = 46 +/- 1 mmHG, were affected similarly, with flumazenil showing a significant improvement compared to placebo.

Conclusions
Flumazenil effectively reverses the benzodiazepine component of ventilatory depression during combined administration of a benzodiazepine and an opioid.
Human Chest Wall Function during Epidural Anesthesia
Authors: Warner David O. , Warner Mark A. , Ritman Erik L. 
Published: November 2003

Background
Although epidural anesthesia (EA) can significantly disrupt the function of the respiratory system, data concerning its effects on respiratory muscle activity and the resulting motion of the chest wall are scarce. This study aimed to determine the effects of lumbar EA on human chest wall function during quiet breathing.

Methods
Six persons were studied while awake and during mid-thoracic (approximately a T6 sensory level) and high (approximately a T1 sensory level) lumbar EA produced by either 2% lidocaine (two persons) or 1.5% etidocaine (four persons) with 1:200,000 epinephrine. Respiratory muscle activity was measured using fine-wire electromyography electrodes. Chest wall configuration during high EA was determined using images of the thorax obtained by three-dimensional, fast computed tomography. The functional residual capacity was measured using a nitrogen dilution technique.

Results
High EA abolished activity in the parasternal intercostal muscles of every participant but one, whereas the mean phasic activity of the scalene muscles was unchanged. High EA significantly decreased the inspiratory volume displacement of the rib cage compared with intact breathing but did not have a significant effect on diaphragm displacement. Therefore, high EA decreased the percentage contribution of rib cage expansion to inspiratory increases in thoracic volume (delta Vth) (from 27 +/- 2 [MSE] to 10 +/- 11% of delta Vth). Paradoxic rib cage motion during inspiration (i.e., a net inward motion during inspiration) developed in only one participant. High EA substantially increased the functional residual capacity (by 295 +/- 89 ml), with a significant net caudad motion of the end expiratory position of the diaphragm. In addition, high EA significantly decreased the volume of liquid in the thorax at end expiration in five of the six participants, a factor that also contributed to the increase in functional residual capacity in these persons.

Conclusions
Rib cage expansion continues to contribute to tidal volume during high EA in most subjects, even when most of the muscles of the rib cage are paralyzed; the mean phasic electrical activity of unblocked respiratory muscles such as scalenes does not increase in response to rib cage muscle paralysis produced by EA; and high EA increases the functional residual capacity, an increase produced in most participants by a caudad motion of the diaphragm and a decrease in intrathoracic blood volume.
Minimum Alveolar Concentration of Halothane and Enflurane Are Decreased in Early Pregnancy
Authors: Chan Matthew T.V. , Mainland Phoebe , Gin Tony 
Published: November 2003

Background
Minimum alveolar concentration (MAC) of isoflurane is decreased in early pregnancy but it is not known whether this occurs to the same extent with other inhalational anesthetics. The MAC of halothane and enflurane were compared in pregnant women undergoing elective termination of pregnancy and in nonpregnant women.

Methods
We studied 16 pregnant women scheduled for termination of pregnancy at 8 to 13 weeks gestation and 16 non-pregnant patients undergoing laparoscopic sterilization. Eight patients in each group received halothane and the others received enflurane. After inhalational induction of anesthesia and tracheal intubation, MAC was determined in each patient by observing the motor response to a 10-s, 50-Hz, 80-mA transcutaneous electric tetanic stimulus to the ulnar nerve at varying concentrations of either halothane or enflurane. The end-tidal concentration of inhalational anesthetic was kept constant for at least 15 min before each stimulus and the concentration was varied ultimately in steps of 0.05 vol% (halothane) or 0.10 vol% (enflurane) until a sequence of three alternate responses (move, not move, move) or (not move, move, not move) was obtained. Minimum alveolar concentration for each person was taken as the mean of the two concentrations just permitting and just preventing movement, and MAC for the group was the median of individual MAC values. Confidence intervals were calculated for the percentage decrease in MAC for pregnant women compared with nonpregnant women.

Results
The median (range) MAC of halothane, 0.58 vol% (0.53 to 0.58), and enflurane, 1.15 vol% (0.95-1.25), in the pregnant women were less than those in the nonpregnant women, 0.75 vol% (0.70 to 0.78), P = 0.0005 and 1.65 vol% (1.45 to 1.75), P = 0.0007, respectively. The percentage decrease (95% CI) in MAC for pregnant women was 27% (20 to 27%) for halothane and 30% (24 to 36%) for enflurane.

Conclusions
The MAC of halothane and enflurane were reduced by a similar degree in pregnant women at 8 to 13 weeks gestation compared with nonpregnant women.
Effects of General Anesthesia and Paralysis on Upper Airway Changes Due to Head Position in Humans
Authors: Sivarajan Murali , Joy James V. 
Published: November 2003

Background
In supine patients with their heads in flexion, general anesthesia causes posterior displacement of upper airway structures that is associated with airway obstruction, and extension of the head helps restore patency. However, the independent effects of head position, general anesthesia, and muscle paralysis on upper airway structures are not known.

Methods
Lateral radiographs of the neck were taken in supine patients with the head in flexion and extension, during consciousness, and after induction of general anesthesia and muscle paralysis. The following measurements were made distances from the horizontal plane to the epiglottis, the hyold, and the thyroid cartilage to detect anteroposterior displacements; distances from the transverse plane to the hyold and the thyroid cartilage to detect cephalocaudad displacements; and widths of the oropharynx, the laryngeal vestibule, and the laryngeal sinus.

Results
With the head in flexion, anesthesia and paralysis compared with the conscious state caused posterior displacement of the epiglottis, narrowing of the oropharynx, and widening of the laryngeal vestibule. With the head in extension, anesthesia and paralysis compared with the conscious state caused anterior displacements of the epiglottis, the hyold, and the thyroid cartilage, narrowing of the oropharynx, and widening of the laryngeal vestibule and the laryngeal sinus.

Conclusion
Loss of tonic muscular activity due to anesthesia and paralysis results in anteroposterior displacements of the upper airway structures with flexion and extension of the head that are in the same direction as that of the mandible. Anesthesia and paralysis also widen the dimensions of the larynx. These changes might have implications for instrumentation and protection of the airway during general anesthesia or unconsciousness.
Peripheral and Spinal Actions of Opioids in the Blockade of the Autonomic Response Evoked by Compression of the Inflamed Knee Joint
Authors: Nagasaka Hiroshi , Awad Hamdy , Yaksh Tony L. 
Published: November 2003

Background
Three types of opioid receptors, mu, delta, and kappa, are present in the periphery and in the central nervous system. In contrast to the effects in the central nervous system, the antinociceptive action of opioids in the periphery is not as well characterized. The effects of intraarticular, spinal, and intramuscular injections of mu, delta, and kappa opioid agonists on the autonomic response evoked by compression of an inflamed knee joint were evaluated.

Methods
In halothane-anesthetized rats, arthritis was induced by injecting kaolin and carrageenan into the right knee joint. Standardized compression of the knee joint by inflation of a pediatric blood pressure cuff to 200 mmHg for 2 min produced a reliable stimulus-dependent hypertension (delta = 13 mmHg). Drugs were delivered intramuscularly, intrathecally through a chronic catheter, or intraarticularly into the right knee joint. The drug injection was performed 4 hr after induction of the inflammation.

Results
The intrathecal administration of mu, delta, and kappa agonists resulted in a dose-dependent blockade of the cuff-evoked increase in blood pressure. The order of intrathecal drug activity on the compression-evoked blood pressure responses with median effective dose (ED50) was sufentanil (0.02 nmol; mu) > PD117302 (0.5 nmol; kappa); spiradoline (1.5 nmol; kappa) morphine (2.4 nmol; mu) > DADL (15 nmol; delta); DPDPE (18 nmol; delta) > U-50,488H (620 nmol; kappa) > naloxone = 0. The intraarticular administration of mu and kappa, but not delta agonists, produced a dose-dependent blockade of a compression-evoked increase in blood pressure, with the order of drug activity (ED40) as follows: sufentanil (0.04 mumol) > PD117302 (0.3 mumol); spiradoline (0.8 mumol), morphine (0.9 mumol) > U-50,488H (0.9 mumol) > DPDPE (> 5 mumol); DADL (> 18 mumol) > naloxone = 0. Intramuscular injection of these agonists caused suppression, with the order of drug activity (ED50) as follows: sufentanil (0.2 mumol) > PD117302 (2 mumol); spiradoline (11 mumol) morphine (9 mumol) > DPDPE (> 5 mumol); DADL (18 mumol) > U-50,488H (22 mumol) > naloxone = 0. All intraarticular effects were reversible by injecting naloxone intramuscularly, with the ordering of naloxone potency against equiactive doses of morphine > U50,488H.

Conclusions
The activity of the respective agonists and the intraarticular > intramuscular ordering of systemic potency in this model indicate that opioids, by an action at mu and kappa, can exert a direct antihyperalgesic action at the terminals of primary afferents projecting to a region of inflammation. These observations offer strong support for a peripheral action of opioids in certain states in inflammation-induced hyperalgesia.
Volatile Anesthetics Depress Glutamate Transmission Via Presynaptic Actions
Authors: MacIver Bruce M. , Mikulec Anthony A. , Amagasu Shanti M. , Monroe Frances A. 
Published: November 2003

Background
Recent evidence for a presynaptic depression of glutamate release produced by volatile anesthetics prompted the current study of isoflurane and halothane effects on glutamate-mediated transmission in the mammalian central nervous system.

Methods
Electrophysiologic recordings from CA1 neurons in rat hippocampal brain slices were used to measure anesthetic effects on glutamate-mediated excitatory postsynaptic potential (EPSP) amplitudes and paired pulse facilitation. Paired pulse facilitation is known to be altered when the calcium-dependent release of glutamate is depressed, but not when EPSP amplitudes are depressed by postsynaptic mechanisms.

Results
Isoflurane depressed EPSP amplitudes over a concentration range of 0.35-2.8 vol %, with a 50% depression (EC50) occurring at 1.0 vol % (0.71 rat minimum alveolar concentration). This depression was accompanied by an increase in paired-pulse facilitation of approximately 30% at 1.7 vol %, using interpulse intervals of 120 ms. Halothane depressed EPSP amplitudes in a concentration-dependent manner (0.3-2.4 vol %, EC50 = 1.1 minimum alveolar concentration; 1.3 vol %) and also increased facilitation by approximately 20% at 1.2 vol %. These effects persisted in the presence of 10 microM bicuculline, indicating that enhanced gamma-aminobutyric acid-mediated inhibition was not involved. The anesthetic-induced increase in facilitation and EPSP depression was mimicked by lowering extracellular calcium, which is known to depress glutamate release at these synapses. The postsynaptic glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione depressed EPSP amplitudes with no change in facilitation.

Conclusions
Our results confirm earlier findings that clinically relevant concentrations of volatile anesthetics depress glutamate-mediated synaptic transmission. The observed increases in synaptic facilitation support recent findings from biochemical and electrophysiologic studies indicating presynaptic sites of action contribute to anesthetic-induced depression of excitatory transmission. This anesthetic-induced reduction in glutamate release would contribute to the central nervous system depression associated with anesthesia by adding to postsynaptic depressant actions on glutamate receptors.
Antinociceptive Response to Nitrous Oxide Is Mediated by Supraspinal Opiate and Spinal α2Adrenergic Receptors in the Rat
Authors: Guo Tian-Zhi , Poree Lawrence , Golden Wendy , Stein Joshua , Fujinaga Masahiko , Maze Mervyn 
Published: November 2003

Background
Despite nearly 150 years of clinical use, the mechanism(s) of action of nitrous oxide (N2O) remains in doubt. In some but not all studies the analgesic properties of N2O can be attenuated by opiate receptor antagonists. The purported mechanism for the opiate antagonistic effect relates to the finding that N2O increases supraspinal levels of endogenous opiates, although this finding has been disputed. Based on the observations that (1) N2O promotes the release of catecholamines, including the endogenous alpha 2 adrenergic agonist norepinephrine, and (2) that descending noradrenergic inhibitory pathways are activated by opioid analgesics, this study sought to determine whether alpha 2 adrenergic receptors are involved in the antinociceptive action of nitrous oxide.

Methods
Institutional approval was obtained for the study. Rats breathed 70% N2O and 30% O2 in an enclosed chamber. After a 30-min exposure, significant antinociception was indicated by an increase in the latency response to a noxious stimulus (tail-flick latency). The tail-flick latency was tested in rats exposed to 70% N2O after either systemic or regional (intrathecal or intracerebroventricular) injections with either competitive (atipamezole; yohimbine) or noncompetitive (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) alpha 2 adrenoceptor antagonists, or the opiate receptor antagonist naloxone.

Results
When administered systemically, both the opiate (naloxone) and alpha 2 adrenoceptor antagonists (atipamezole, yohimbine, and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) blocked the enhanced tail-flick latency response to N2O-Naloxone administered intracerebroventricularly, but not intrathecally, blocked the enhanced tail-flick latency response to N2O. Conversely, atipamezole administered intrathecally, but not intracerebroventricularly, blocked the enhanced tail-flick latency response to N2O.

Conclusions
These data suggest that both supraspinal opiate and spinal alpha 2 adrenoceptors play a mediating role in the antinociceptive response to N2O in rats. A possible mechanism may involve a descending inhibitory noradrenergic pathway that may be activated by opiate receptors in the periaqueductal gray region of the brain stem in the rat after exposure to N2O.
Prevention of Lidocaine Aerosol-induced Bronchoconstriction with Intravenous Lidocaine
Authors: Bulut Yonca , Hirshman Carol A. , Brown Robert H. 
Published: November 2003

Background
Lidocaine applied topically provokes bronchoconstriction in persons with hyperreactive airway disease. The authors questioned whether intravenous lidocaine would prevent lidocaine-aerosol induced bronchoconstriction. They compared the effects of lidocaine administered intravenously and by the aerosol route on baseline airway tone, and on the prevention of histamine-induced bronchoconstriction in five Basenji-Greyhound dogs.

Methods
Dogs were pretreated with either intravenous or aerosol lidocaine followed by histamine aerosol challenge. On separate days, dogs were pretreated with intravenous lidocaine, followed by aerosol lidocaine administration at similar doses. Airway caliber was assessed using high-resolution computed tomography. Data were analyzed by two-way analysis of variance. Serum lidocaine concentrations were obtained.

Results
Histamine alone decreased the airway area by 32 +/- 3%. Lidocaine administered intravenously or by the aerosol route significantly inhibited histamine-induced bronchoconstriction. There was no significant difference between the two routes in preventing histamine-induced bronchoconstriction. At the dose that inhibited histamine-induced bronchoconstriction, lidocaine administered by the aerosol route decreased baseline airway area by 27 +/- 3% (P < 0.01), whereas intravenous lidocaine had no effect. Intravenous lidocaine prevented lidocaine aerosol-induced bronchoconstriction, and the combination of intravenous and aerosol lidocaine significantly dilated the airways by 20 +/- 5% (P < 0.01 compared with control).

Conclusions
An intravenous bolus of lidocaine prevents the initial bronchoconstriction induced by lidocaine when administered as an aerosol.