bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Physiologic Assessment of Intrathecal Amitriptyline in Sheep
Authors: Cerda Sergio E. , Tong Chuanyao , Deal Dwight D. , Eisenach James C. 
Published: November 2003

Background
Intrathecal injection of amitriptyline enhances antinociception from intravenous morphine and reduces neuropathic pain behavior in animals. This study represents part of a preclinical assessment of intrathecal amitriptyline to determine its safety for use in humans.

Methods
Low thoracic intrathecal, femoral, and pulmonary arterial catheters were inserted in 18 adult ewes, followed 96 h later by intrathecal injection of saline or 5 mg amitriptyline and by determination of spinal cord blood flow, hemodynamic variables, behavioral changes, cerebrospinal fluid concentrations of catecholamines and amitriptyline, and spinal tissue concentrations of amitriptyline. In six other ewes, low thoracic intrathecal and femoral arterial catheters were inserted and blood pressure and heart rate were measured after intrathecal injection of saline or 0.25, 1, or 5 mg amitriptyline. Four other ewes received cervical intrathecal injection of 5 and 10 mg amitriptyline, and antinociception was determined.

Results
Thoracic intrathecal injection of amitriptyline produced dose-dependent sedation but did not significantly affect spinal cord blood flow or hemodynamic variables. Spinal cord tissue concentrations of amitriptyline were 100 times greater in tissue near the tip of the thoracic intrathecal catheter compared with cervical cord tissue. Cerebrospinal fluid concentrations of catecholamines did not significantly change after amitriptyline was administered. Cervical intrathecal injection of 5 mg amitriptyline produced mild antinociception, whereas 10 mg produced intense sedation and, in one sheep, seizures and death.

Conclusions
Although other preclinical toxicity studies are necessary before introducing intrathecal amitriptyline for use in humans, this study did not reveal dangerous changes in blood pressure or spinal cord blood flow from this agent.
Assessment of Low-flow Sevoflurane and Isoflurane Effects on Renal Function Using Sensitive Markers of Tubular Toxicity
Authors: Kharasch Evan D. , Frink Edward J. , Zager Richard , Bowdle T. Andrew , Artru Alan , Nogami Wallace M. 
Published: November 2003

Background
Carbon dioxide absorbents degrade sevoflurane, particularly at low gas flow rates, to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A). Compound A causes renal proximal tubular injury in rats but has had no effect on blood urea nitrogen (BUN) or creatinine concentrations in patients. This investigation compared the effects of low-flow sevoflurane and isoflurane on renal tubular function in surgical patients using conventional (BUN and creatinine) and finer indices of renal injury, specifically those biomarkers sensitive for compound A toxicity in rats (glucosuria, proteinuria, and enzymuria [N-acetyl-beta-D-glucosaminidase (NAG) and alpha-glutathione-S-transferase (alpha GST)]).

Methods
Consenting patients with normal preoperative renal function at two institutions were randomized to receive sevoflurane (n = 36) or isoflurane (n = 37) in oxygen and air. Total gas flow was 1 l/min, opioid doses were minimized, and barium hydroxide lime was used to maximize anesthetic degradation. Inspiratory and expiratory compound A concentrations were quantified every 30-60 min. Blood and urine were obtained before and 24-72 h after anesthesia for laboratory evaluation.

Results
Sevoflurane and isoflurane groups were similar with respect to age, weight, sex, American Society of Anesthesiologists status, anesthetic duration (3.7 or 3.9 h), and anesthetic exposure (3.6 or 3 minimum alveolar concentration [MAC]-hour). Maximum inspired compound A concentration (mean +/- standard deviation) was 27 +/- 13 ppm (range, 10-67 ppm). Areas under the inspired and expired compound A concentration versus time curves (AUC) were 79 +/- 54-ppm-h (range, 10-223 ppm-h) and 53 +/- 40 ppm-h (range, 6-159 ppm-h), respectively. There was no significant difference between anesthetic groups in postoperative serum creatinine or BUN, or urinary excretion of protein, glucose, NAG, proximal tubular alpha GST, or distal tubular pi GST. There was no significant correlation between compound A exposure (AUC) and protein, glucose, NAG, alpha GST, or pi GST excretion. Postoperative alanine and aspartate aminotransferase concentrations were not different between the anesthetic groups, and there were no significant correlations between compound A exposure and alanine or aspartate aminotransferase concentrations.

Conclusions
The renal tubular and hepatic effects of low-flow sevoflurane and isoflurane were similar as assessed using both conventional measures of hepatic and renal function and more sensitive biochemical markers of renal tubular cell necrosis. Moderate duration low-flow sevoflurane anesthesia, during which compound A formation occurs, appears to be as safe as low-flow isoflurane anesthesia.
Concentration-effect Relations for Intravenous Lidocaine Infusions in Human Volunteers
Authors: Wallace Mark S. , Laitin Steve , Licht Darren , Yaksh Tony L. 
Published: November 2003

Background
Preclinical studies have emphasized that persistent small afferent input will induce a state of central facilitation that can be regulated by systemically administered lidocaine. The authors extended these preclinical studies to human volunteers by examining the concentration-dependent effects of intravenous lidocaine on acute sensory thresholds and facilitated processing induced by intradermal capsaicin.

Methods
Fifteen healthy persons received a lidocaine or a placebo infusion. A computer-controlled infusion pump targeted sequential stepwise increases in plasma lidocaine concentration steps of 1, 2, and 3 microg/ml. At each plasma concentration, neurosensory testing (thermal and von Frey hair test stimulation) were performed. After completing the tests at the 3 microg/ml plasma lidocaine level, intradermal capsaicin was injected into the volar aspect of the left forearm, and the flare response and hyperalgesia to von Frey hair stimulation, stroking, and heat was assessed.

Results
The continuous infusion of lidocaine and placebo had no significant effect on any stimulus threshold. Although intravenous lidocaine resulted in a decrease in all secondary hyperalgesia responses, this was only significant for heat hyperalgesia. Intravenous lidocaine resulted in a significant decrease in the flare response induced by intradermal capsaicin.

Conclusions
These studies suggest that the facilitated state induced by persistent small afferent input human pain models may predict the activity of agents that affect components of nociceptive processing that are different from those associated with the pain state evoked by "acute" thermal or mechanical stimuli. Such insight may be valuable in the efficient development of novel analgesics for both neuropathic and post-tissue-injury pain states.
ORG 9487 Neuromuscular Block at the Adductor Pollicis and the Laryngeal Adductor Muscles in Humans
Authors: Debaene Bertrand , Lieutaud Thomas , Billard Valerie , Meistelman Claude 
Published: November 2003

Background
ORG 9487 is a new steroidal nondepolarizing muscle relaxant with a rapid onset of action. This study was designed to determine the neuromuscular blocking profile of ORG 9487 at the adductor muscles of the larynx and the adductor pollicis.

Methods
In 30 adults, anesthesia was induced with propofol (2-5 mg/kg) and fentanyl (2-3 microg/kg). After train-of-four stimulation, the block of the laryngeal adductor muscles was evaluated by measuring the pressure changes in the cuff of the tracheal tube placed between the vocal cords, and the force of the contraction of the adductor pollicis was measured with a force transducer. Patients were randomly allocated to receive ORG 9487 at intravenous bolus doses of 0.75, 1.5 or 2 mg/kg (n = 10 in each group).

Results
Time to peak effect was significantly shorter at the vocal cords than at the adductor pollicis muscle (P < 0.001). Onset time at the vocal cords was 62 +/- 16 s, 62 +/- 13 s, and 52 +/- 14 s (mean +/- SD) after doses of 0.75, 1.5, and 2 mg/kg, respectively (not significant). Onset time at the adductor pollicis muscle was 126 +/- 33 s, 96 +/- 20 s, and 82 +/- 21 s after 0.75, 1.5, and 2 mg/kg doses, respectively (P < 0.001). Maximum block was significantly less intense at the vocal cords than at the adductor pollicis muscle (69 +/- 15% vs. 94 +/- 4% after 0.75 mg/kg; 86 +/- 7% vs. 97 +/- 4% after 1.5 mg/kg; and 91 +/- 5% vs. 99 +/- 1% after 2 mg/kg). After 1.5 mg/kg duration to 25%, recovery was 3.7 +/- 2.2 min versus 10.2 +/- 2.5 min at the vocal cords and the adductor pollicis muscle, respectively, and 75% recovery occurred at 9.7 +/- 3.7 min at the vocal cords and at 18.3 +/- 5.2 min at the adductor pollicis muscle.

Conclusions
ORG 9487 has a rapid onset of action at the laryngeal adductor and the adductor pollicis muscles. Onset and duration of action are faster at the vocal cords than at the adductor pollicis muscle. However, the maximum block obtained at the laryngeal muscles was less than at the adductor pollicis, regardless of the dose of ORG 9487.
Effects of Intracoronary Fentanyl on Left Ventricular Mechanoenergetics in the Excised Cross-circulated Canine Heart
Authors: Kohno Kunihisa , Takaki Miyako , Ishioka Kazunari , Nakayama Yasunori , Suzuki Shunsuke , Araki Junichi , Namba Taketoshi , Suga Hiroyuki 
Published: November 2003

Background
It is still unclear whether fentanyl directly alters left ventricular (LV) contractility and oxygen consumption. This is because of the difficulty in defining and evaluating contractility and energy use independently of ventricular loading conditions and heart rate in beating whole hearts.

Methods
This study was conducted to clarify the mechanoenergetic effects of intracoronary fentanyl in six excised cross-circulated canine hearts. The authors used the framework of the E(max) (a contractility index)-PVA (systolic pressure-volume area, a measure of total mechanical energy)-VO2 (myocardial oxygen consumption per beat) relationship practically independent of ventricular loading conditions. The authors measured LV pressure, volume, coronary flow, and arteriovenous oxygen content difference to calculate E(max), PVA, and VO2. They first obtained the VO2-PVA relationship for varied LV volumes at control E(max). The authors then obtained the VO2-PVA relationship at a constant LV volume, whereas coronary blood fentanyl concentration was increased in steps up to 240 ng/ml. Finally, they obtained the VO2-PVA relationship for varied LV volumes at the final dose of fentanyl.

Results
Fentanyl at any concentrations did not significantly change E(max), PVA, and VO2 from the control. The linear end-systolic pressure-volume relations and their slopes were virtually the same between the control and fentanyl volume loading in each heart. Further, either the slope (oxygen cost of PVA) or the VO2 intercept (unloaded VO2) of the linear VO2-PVA relationship remained unchanged by fentanyl.

Conclusions
These results indicate that intracoronary fentanyl produces virtually no effects on LV mechanoenergetics for a wide range of its blood concentration.
Increase of Glutamate Uptake in Astrocytes
Authors: Miyazaki Hirofumi , Nakamura Yoichi , Arai Tatsuru , Kataoka Kiyoshi 
Published: November 2003

Background
Glutamate is the most ubiquitous excitatory neurotransmitter in the vertebrate central nervous system. Astrocytes play an important role in terminating glutamatergic neurotransmission by removing released glutamate from the synaptic cleft. The authors examined the effects of several anesthetics on the glutamate uptake activity of astrocytes.

Methods
Cultured astrocytes from hippocampi of rat embryos were incubated with solution containing [3H]glutamate, which was pre-equilibrated with 0-4% halothane at 37 degrees C. The uptake activity was evaluated as the amount of radioactivity per cell of protein.

Results
When the reaction solution was equilibrated with 4% halothane, glutamate uptake increased to about 165% of the control. The effect of halothane was dose-dependent, and a significant augmentation (30-50%) of glutamate uptake was observed at a range in clinical use concentrations (1-2%). On the other hand, the uptake of gamma-aminobutyric acid, an inhibitory transmitter, was hardly affected by 1-4% halothane. The effect of halothane on glutamate uptake was also examined in neuron-rich culture, and similar augmentation was observed, although the extent was less than that in astrocyte culture. Biochemical subcellular fractions (i.e., glial plasmalemmal vesicles and synaptosomes) were also examined, however, only slight (not significant) increase was detected in the glutamate uptake activity. Other volatile anesthetics, such as enflurane, isoflurane, and sevoflurane, also enhanced glutamate uptake, whereas the intravenous anesthetics ketamine and pentobarbital showed no effect on glutamate uptake.

Conclusions
The increase of glutamate uptake by astrocytes in the presence of volatile anesthetics potentially attenuates excitatory synaptic transmission in the entire central nervous system, a finding that may explain in part the action of volatile anesthetics.
Intrathecal α2-Adrenergic Agonists Stimulate Acetylcholine and Norepinephrine Release from the Spinal Cord Dorsal Horn in Sheep
Authors: Klimscha W. , Tong C. , Eisenach J. C. 
Published: November 2003

Background
Intrathecal injection of clonidine and dexmedetomidine produce behavioral analgesia by an alpha 2-adrenergic mechanism. Functional and anatomic studies suggest that this analgesia is mediated by cholinergic activation. This hypothesis was directly tested by measuring extracellular acetylcholine concentrations in spinal cord interstitial fluid by means of microdialysis after intrathecal injection of these alpha 2-adrenergic agonists in sheep.

Methods
Twelve sheep with chronically implanted thoracic intrathecal catheters were anesthetized with halothane. Multiple 200-micron-diameter dialysis fibers were inserted surgically at a mid-thoracic level through the dorsal horn and perfused with artificial cerebrospinal fluid. After baseline sampling, either clonidine (100 micrograms), dexmedetomidine (100 micrograms), or saline were injected intrathecally. Microdialysis samples were analyzed by high-pressure liquid chromatography for acetylcholine and norepinephrine.

Results
Both alpha 2-adrenergic agonists increased acetylcholine in microdialysate, whereas intrathecal saline had no effect. Analysis of the raw data showed that all groups differed significantly, with greater levels of acetylcholine following administration of dexmedetomidine than clonidine or saline. Unexpectedly, intrathecal clonidine also increased microdialysate norepinephrine levels.

Conclusions
These data are consistent with previous experiments measuring acetylcholine concentrations in cerebrospinal fluid and support analgesia from alpha 2-adrenergic agonists mediated in part by cholinergic activation. In addition, the increase in norepinephrine concentrations after intrathecal administration of clonidine suggest stimulation of norepinephrine release by this agent.
Actions of Phenylephrine, Isoproterenol, and Epinephrine Halothane on Endocardial Conduction and Activation in Canine Left Ventricular Papillary Muscles
Authors: Vodanovic Sanja , Turner Lawrence A. , Hoffmann Raymond G. , Kampine John P. , Bosnjak Zeljko J. 
Published: November 2003

Background
Myocardial sensitization by halothane to the arrhythmogenic effects of epinephrine involves synergistic actions mediated by alpha 1- and beta-adrenoceptors. Halothane potentiates a transient a1-adrenoceptor-mediated negative dromotropic effect of epinephrine on Purkinje fibers. This study examines how halothane alters the actions of alpha 1- and beta-agonists and epinephrine on endocardial conduction.

Methods
Superfused canine papillary muscles were mapped to locate a Purkinje-ventricular muscle junction (PVJ), and bipolar electrodes were placed to measure Purkinje and endocardial conduction velocity and PVJ conduction time during stimulation of the Purkinje layer. The effects of exposure to 5 microM phenylephrine, 1 microM isoproterenol, or 5 microM epinephrine on conduction were determined in the absence and presence of 0.4 mM halothane in three groups of 10 preparations.

Results
Isoproterenol slightly increased Purkinje conduction velocity and markedly improved conduction at the PVJ and in the endocardium similarly in the presence or absence of halothane. Phenylephrine depressed Purkinje velocity (-12%) only in the presence of halothane and did not slow conduction at the PVJ or in the myocardium. Epinephrine transiently depressed Purkinje velocity, more so with (-22%) than without (-12%) halothane (P < or = 0.01), and simultaneously facilitated conduction at the PVJ and in the myocardium.

Conclusions
The prodysrhythmic actions of epinephrine with halothane may involve disparate effects on conduction, including speeding on conduction at the PVJ and in the myocardium, similar to that produced by isoproterenol, accompanied by simultaneous but transient alpha 1-mediated depression of conduction in the Purkinje system.
Isoflurane Mimics Ischemic Preconditioning via Activation of KATPChannels
Authors: Kersten Judy R. , Schmeling Todd J. , Pagel Paul S. , Gross Garrett J. , Warltier David C. 
Published: November 2003

Background
The authors tested the hypothesis that isoflurane directly preconditions myocardium against infarction via activation of K(ATP) channels and that the protection afforded by isoflurane is associated with an acute memory phase similar to that of ischemic preconditioning.

Methods
Barbiturate-anesthetized dogs (n = 71) were instrumented for measurement of systemic hemodynamics. Myocardial infarct size was assessed by triphenyltetrazolium chloride staining. All dogs were subjected to a single prolonged (60 min) left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Ischemic preconditioning was produced by four 5-min LAD occlusions interspersed with 5-min periods of reperfusion before the prolonged LAD occlusion and reperfusion. The actions of isoflurane to decrease infarct size were examined in dogs receiving 1 minimum alveolar concentration (MAC) isoflurane that was discontinued 5 min before prolonged LAD occlusion. The interaction between isoflurane and ischemic preconditioning on infarct size was evaluated in dogs receiving isoflurane before and during preconditioning LAD occlusions and reperfusions. To test whether the cardioprotection produced by isoflurane can mimic the acute memory of ischemic preconditioning, isoflurane was discontinued 30 min before prolonged LAD occlusion and reperfusion. The mechanism of isoflurane-induced cardioprotection was evaluated in two final groups of dogs pretreated with glyburide in the presence or absence of isoflurane.

Results
Myocardial infarct size was 25.3 +/- 2.9% of the area at risk during control conditions. Isoflurane and ischemic preconditioning produced significant (P < 0.05) and equivalent reductions in infarct size (ischemic preconditioning alone, 9.6 +/- 2.0; isoflurane alone, 11.8 +/- 2.7; isoflurane and ischemic preconditioning, 5.1 +/- 1.9%). Isoflurane-induced reduction of infarct size also persisted 30 min after discontinuation of the anesthetic (13.9 +/- 1.5%), independent of hemodynamic effects during LAD occlusion. Glyburide alone had no effect on infarct size (28.3 +/- 3.9%), but it abolished the protective effects of isoflurane (27.1 +/- 4.6%).

Conclusions
Isoflurane directly preconditions myocardium against infarction via activation of K(ATP) channels in the absence of hemodynamic effects and exhibits acute memory of preconditioning in vivo.
Serious Complications Related to Regional Anesthesia
Authors: Auroy Yves , Narchi Patrick , Messiah Antoine , Litt Lawrence , Rouvier Bernard , Samii Kamran 
Published: November 2003

Background
Serious complications related to regional anesthesia have previously been described primarily in case reports and retrospective surveys. The authors prospectively evaluated a multicenter series of regional anesthetics, using preplanned criteria to measure the incidence and characteristics of associated serious complications.

Methods
Requests were sent to 4,927 French anesthesiologists in advance of a subsequent 5-month study period. Participating anesthesiologists were asked for detailed reports of serious complications occurring during or after regional anesthetics performed by them during the study interval. Details regarding each complication then were obtained via a second questionnaire.

Results
The number of responding anesthesiolgists was 736. The number of regional anesthetics performed was 103,730, corresponding to 40,640 spinal anesthetics, 30,413 epidural anesthetics, 21,278 peripheral nerve blocks, and 11,229 intravenous regional anesthetics. Reports of 98 severe complications were received, with follow-up information being obtained for 97. In 89 cases, complications were attributed fully or partially to regional anesthesia. Thirty-two cardiac arrests, seven of which were fatal, occurred during the study. Of these, 26 occurred during spinal anesthesia, with 6 being fatal, 3 occurred during epidural anesthesia, and 3 more occurred during peripheral blocks. The higher incidence of cardiac arrest during spinal anesthesia (6.4 +/- 1.2 per 10,000 patients) compared with all other regional anesthesia (1.0 +/- 0.4 per 10,000 patients) was statistically significant (P < 0.05). Of 34 neurologic complications (radiculopathy, cauda equina syndrome, paraplegia), 21 were associated either with paresthesia during puncture (n = 19) or with pain during injection (n = 2), suggesting nerve trauma or intraneural injection. Twelve patients who had neurologic complications after spinal anesthetics had no paresthesia during needle placement and no pain on injection. Of these 12 patients (7 with radiculopathy and 5 with cauda equina syndrome), 9 received intrathecal hyperbaric lidocaine, 5%. The incidence of neurologic injury was significantly greater after spinal anesthesia (6 +/- 1 per 10,000 cases; P < 0.05) than after each of the other types of regional procedures (1.6 +/- 0.5 per 10,000 cases for the weighted average). Seizures attributed to elevated serum levels of local anesthetics occurred in 23 patients, but none suffered a cardiac arrest.

Conclusions
(1) The incidence of cardiac arrest and neurologic injury related to regional anesthesia were very low, but both were more than three SDs greater after spinal anesthesia than after other regional procedures. (2) Two thirds of the patients with neurologic deficits had either a paresthesia during needle placement or pain on injection. (3) Seventy-five percent of the neurologic deficits after nontraumatic spinal anesthesia occurred in patients who had received hyperbaric lidocaine, 5%.