bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic Toxicity of Levobupivacaine, Bupivacaine, and Ropivacaine during Continuous Intravenous Infusion to Nonpregnant and Pregnant Ewes
Authors: Santos Alan C. , DeArmas Pedro I. 
Published: November 2003

Background
Levobupivacaine, the single levorotatory isomer of bupivacaine, is now available for clinical use. This study was undertaken to determine whether pregnancy affects the systemic toxicity of levobupivacaine and to compare the systemic toxicity of levobupivacaine with that of bupivacaine and ropivacaine.

Methods
Chronically prepared nonpregnant and pregnant sheep were randomized to receive an intravenous infusion of 0.52% levobupivacaine, 0.52% bupivacaine, or 0.50% ropivacaine at a constant rate of 0.1 ml x kg(-1) x min(-1) until circulatory collapse. The investigators were blinded to the identity of the local anesthetic. Physiologic parameters, including cardiac rhythm, were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations. These were analyzed for total and free serum drug concentrations as well as arterial blood pH and gas tensions.

Results
The doses of all three drugs required to produce convulsions were lower in pregnant than nonpregnant animals. However, as the infusion continued, there were no significant differences between pregnant and nonpregnant ewes in the dose of drug required to produce more advanced manifestations of toxicity: hypotension, apnea, and circulatory collapse. The mean cumulative dose and serum concentration at each toxic manifestation was lowest for bupivacaine, intermediate for levobupivacaine, and highest for ropivacaine in both pregnant and nonpregnant animals. For all three local anesthetics, there were no significant differences between pregnant and nonpregnant ewes in total and free serum drug concentrations, except that at circulatory collapse, these were higher in pregnant animals.

Conclusions
Pregnancy increases the risk of convulsions but not of more advanced manifestations of local anesthetic toxicity. The risk of toxicity is greatest with bupivacaine and least with ropivacaine. However, in actual clinical practice, the risk of systemic toxicity may also be affected by the relative potency and effectiveness of these drugs.
The Transfer Half-life of Morphine-6-glucuronide from Plasma to Effect Site Assessed by Pupil Size Measurement in Healthy Volunteers
Authors: Lötsch Jörn , Skarke Carsten , Schmidt Helmut , Grösch Sabine , Geisslinger Gerd 
Published: November 2003

Background
Clinical and experimental data suggested a long delay between the plasma concentration versus time course of morphine-6-glucuronide and the time course of its central opioid effects. This study was aimed at the quantification of the transfer half-life (t(1/2,ke0)) of this delay.

Methods
Pupil size was used as a measure of central opioid effect. Eight healthy volunteers (four men, four women) participated in that single-blind randomized crossover study. Median dosages administered intravenously were 0.5 mg morphine as loading dose followed by 10.7 mg given as infusion over a period of 4.7 h, and 10.2 mg M6G as loading dose followed by 39.1 mg M6G given over a period of 3.7 h. The duration of the infusion was tailored to achieve submaximum pupil constriction. The pupil diameter was assessed every 20 min for approximately 18 h. Values of t(1/2,ke0) were obtained by semiparametric pharmacokinetic-pharmacodynamic modeling.

Results
The estimated median t(1/2,ke0) of M6G was 6.4 h (range, 2.9-16.2 h), and that of morphine was 2.8 h (range, 1.8-4.4 h). The individual t(1/2,ke0) of M6G was always longer than that of morphine. Judged by the concentration at half-maximun effect (EC50) values of the sigmoid pupil size at maximum constriction (Emax) model describing concentration-response relation, M6G was apparently 22 times less potent than morphine (EC50 = 740.5 nm [range, 500-1,520 nm] for M6G and 36.2 nm [range, 19.7-43.3 nm] for morphine). The steepness of the sigmoid Emax model did not significantly differ between morphine and M6G (gamma = 1.9 and 2.6, respectively). To produce similar pupil effects, the M6G dose had to be 2.8 times greater than the morphine dose.

Conclusions
The reported numerical value of the t(1/2,ke0) of M6G in humans obtained after direct administration of M6G is a step toward a complete modeling approach to the prediction of the clinical effects of morphine. The study raises questions about the high interindividual variability of the transfer half-life between plasma and effect site (ke0) values and the apparent low potency of M6G.
Adaptive Support Ventilation for Fast Tracheal Extubation after Cardiac Surgery
Authors: Sulzer Christopher F. , Chioléro René , Chassot Pierre-Guy , Mueller Xavier M. , Revelly Jean-Pierre 
Published: November 2003

Background
Adaptive support ventilation (ASV) is a microprocessor-controlled mode of mechanical ventilation that maintains a predefined minute ventilation with an optimal breathing pattern (tidal volume and rate) by automatically adapting inspiratory pressure and ventilator rate to changes in the patient's condition. The aim of the current study was to test the hypothesis that a protocol of respiratory weaning based on ASV could reduce the duration of tracheal intubation after uncomplicated cardiac surgery ("fast-track" surgery).

Methods
A group of patients being given ASV (group ASV) was compared with a control group (group control) in a randomized controlled study. After coronary artery bypass grafting during general anesthesia with midazolam and fentanyl, patients were randomly assigned to group ASV or group control. Both protocols were divided into three predefined phases, and weaning progressed according to arterial blood gas and clinical criteria. In phase 1, ASV mode was set at 100% of the theoretical value of volume/minute in group ASV, and synchronized intermittent mandatory ventilation mode was used in group control. When spontaneous breathing occurred, ASV setting was reduced by 50% of minute ventilation (phase 2) and again by 50% (phase 3), and the trachea was extubated. In group control, the ventilator was switched to 10 cm H2O inspiratory pressure support (phase 2), then to 5 cm H2O (phase 3) until extubation.

Results
Forty-nine patients were enrolled. Sixteen patients completed the ASV protocol, and 20 the standard protocol; 7 patients were excluded in group ASV and 6 in group control according to explicit, predefined criteria. There were no differences between groups in perioperative characteristics or in the doses of sedation. The primary outcome of the study, that is, the duration of tracheal intubation, was shorter in group ASV than in group control (median [quartiles]: 3.2 [2.5-4.6] vs. 4.1 [3.1-8.6] h; P < 0.02). Fewer arterial blood analyses were performed in group ASV (median number [quartiles]: 3 [3-4] vs. 4 [3-6]), suggesting that fewer changes in the settings of the ventilator were required in this group.

Conclusions
A respiratory weaning protocol based on ASV is practicable; it may accelerate tracheal extubation and simplify ventilatory management in fast-track patients after cardiac surgery. The evaluation of potential advantages of the use of such technology on patient outcome and resource utilization deserves further studies.
Internal Jugular Vein Occlusion Test for Rapid Diagnosis of Misplaced Subclavian Vein Catheter into the Internal Jugular Vein
Authors: Ambesh Sushil P. , Pandey Jyotish C. , Dubey Prakash K. 
Published: November 2003

Background
During subclavian vein catheterization, the most common misplacement of the catheter is cephalad, into the ipsilateral internal jugular vein (IJV). This can be detected by chest radiography. However, after any repositioning of the catheter, subsequent chest radiography is required. In an effort to simplify the detection of a misplaced subclavian vein catheter, the authors assessed a previously published detection method.

Methods
One hundred adult patients scheduled for subclavian vein cannulation were included in this study. After placement of subclavian vein catheter, chest radiography was performed. While the x-ray film was being processed, the authors performed an IJV occlusion test by applying external pressure on the IJV for approximately 10 s in the supraclavicular area and observed the change in central venous pressure and its waveform pattern. The observations thus obtained were compared with the position of catheter in chest radiographs, and the sensitivity and specificity of this method were evaluated using a 2 x 2 table.

Results
In 96 patients, subclavian vein cannulation was successfully performed. In four patients, cannulation was unsuccessful; therefore, these patients were excluded from the study. There were six misplacements of venous catheters as detected by radiography. In five (5.2%) patients, the catheter tip was located in the ipsilateral IJV, and in one (1.02%), the catheter tip was located in the contralateral subclavian vein. In the patients who had a misplaced catheter into the IJV, IJV occlusion test results were positive, with an increase of 3-5 mmHg in central venous pressure, whereas the test results were negative in patients who had normally placed catheters or misplacement of a catheter other than in the IJV. There were no false-positive or false-negative test results.

Conclusion
The IJV occlusion test successfully detects the misplacement of subclavian vein catheter into the IJV. However, it does not detect any other misplacement. The test may allow avoidance of repeated exposure to x-rays after catheter insertion and repositioning.
Protamine-induced Cardiotoxicity Is Prevented by Anti-TNF-α Antibodies and Heparin
Authors: Pevni Dmitry , Frolkis Inna , Iaina Adrian , Wollman Yoram , Chernichovski Tamara , Shapira Izhak , Paz Josef , Kramer Amir , Loker Chaim , Mohr Rephael 
Published: November 2003

Background
We investigated the role of tumor necrosis factor alpha (TNF-alpha) in protamine-induced cardiotoxicity and the possibility of preventing or decreasing this effect by anti TNF-alpha antibodies and heparin.

Methods
Isolated rat hearts were perfused for 60 min with Krebs-Henseleit solution (KH). The control group was perfused with KH alone, the KH > protamine > KH group was treated from the 20th to the 40th minute with protamine, and the KH + anti-TNF > protamine + anti-TNF > KH + anti-TNF group was treated the same as the KH > protamine > KH group but with anti-TNF-alpha antibodies added throughout perfusion. The KH + heparin > protamine + heparin > KH + heparin group was treated the same as the KH > protamine > KH group but with heparin added to KH throughout perfusion. The KH > protamine > KH + heparin was perfused the same as the KH> protamine > KH group but with heparin added to KH for the last 20 min. Left ventricular (LV) function and coronary flow were measured every 10 min. TNF-alpha was measured in the coronary sinus effluent. Left ventricular TNF messenger RNA was determined in the control and KH > protamine > KH groups at baseline and after the 40-min perfusion.

Results
Protamine caused a significant decrease of peak systolic pressure and dP/dt (to 25% of baseline). Significant amounts of TNF-alpha in the effluent in the KH > protamine > KH group (102.3 +/- 15.5 pg/min) and TNF messenger RNA expression in left ventricular samples were detected. TNF-alpha was below detectable concentrations in the control, KH + anti-TNF > protamine + anti-TNF > KH + anti-TNF, and KH + heparin > protamine + heparin > KH + heparin groups. TNF-alpha concentrations correlated with depression of LV peak systolic pressure (r = 0.984; P = 0.01) and first derivate of the increase of LV pressure (r = 0.976; P = 0.001). Heparin improved LV recovery and decreased protamine-induced TNF-alpha release (KH > protamine > KH + heparin group).

Conclusions
Anti-TNF-alpha antibodies and heparin prevent protamine-induced TNF-alpha release and depression of LV function. Heparin improves protamine-induced depression of cardiac function.
Rapid Endotoxin-induced Alterations in Myocardial Calcium Handling
Authors: Stamm Christof , Cowan Douglas B. , Friehs Ingeborg , Noria Sabrena , del Nido Pedro J. , McGowan Francis X. 
Published: November 2003

Background
Bacterial endotoxin (lipopolysaccharide [LPS]) induces septic shock and depressed myocardial contractility. The mechanism of LPS-mediated cardiac dysfunction remains controversial. We hypothesized that LPS exerts significant effects on myocardial excitation-contraction coupling by rapid stimulation of tumor necrosis factor alpha (TNF-alpha) expression in the heart.

Methods
Isolated rat hearts were studied with and without recirculation of cell-free perfusate. The effects of LPS, exogenous TNF-alpha, anti-TNF-alpha antibody, and ceramidase inhibition were examined. Measurements included myocardial uptake of LPS, left ventricular contractility, myocardial oxygen consumption, intracellular calcium [Ca2+] cycling, and TNF-alpha concentrations in coronary perfusate and myocardium.

Results
Lipopolysaccharide was rapidly taken up by the perfused heart. With non-recirculating perfusion, LPS had no effect on contractility, oxygen consumption, coronary vascular resistance, or intracellular free calcium concentration ([Ca2+]i). However, with recirculating perfusion contractility was significantly impaired after 30 min of LPS, associated with lower [Ca2+]i levels and attenuated systolic rise in [Ca2+]i. Significant amounts of TNF-alpha accumulated in recirculating perfusate and myocardial tissue from LPS-perfused hearts. Ceramidase inhibition or neutralizing anti-TNF-alpha antibody inhibited the effects of LPS on contractility and [Ca2+]i. Recombinant rat TNF-alpha mimicked the LPS effects with faster onset.

Conclusions
Lipopolysaccharide exerts rapid, negative inotropic effects on the isolated whole rat heart. The reduction in contractility is associated with depressed intracellular calcium cycling. In response to LPS, TNF-alpha is rapidly released from the heart and mediates the effects of LPS via the sphingomyelinase pathway. The present study for the first time directly links LPS-stimulated TNF-alpha production, abnormal calcium cycling, and decreased contractility in intact hearts.
Effects of Vaporized Perfluorocarbon on Pulmonary Blood Flow and Ventilation/Perfusion Distribution in a Model of Acute Respiratory Distress Syndrome
Authors: Hübler Matthias , Souders Jennifer E. , Shade Erin D. , Polissar Nayak L. , Schimmel Carmel , Hlastala Michael P. 
Published: November 2003

Background
Perfluorocarbon (PFC) liquids are known to improve gas exchange and pulmonary function in various models of acute respiratory failure. Vaporization has been recently reported as a new method of delivering PFC to the lung. Our aim was to study the effect of PFC vapor on the ventilation/perfusion (VA/Q) matching and relative pulmonary blood flow (Qrel) distribution.

Methods
In nine sheep, lung injury was induced using oleic acid. Four sheep were treated with vaporized perfluorohexane (PFX) for 30 min, whereas the remaining sheep served as control animals. Vaporization was achieved using a modified isoflurane vaporizer. The animals were studied for 90 min after vaporization. VA/Q distributions were estimated using the multiple inert gas elimination technique. Change in Qrel distribution was assessed using fluorescent-labeled microspheres.

Results
Treatment with PFX vapor improved oxygenation significantly and led to significantly lower shunt values (P < 0.05, repeated-measures analysis of covariance). Analysis of the multiple inert gas elimination technique data showed that animals treated with PFX vapor demonstrated a higher VA/Q heterogeneity than the control animals (P < 0.05, repeated-measures analysis of covariance). Microsphere data showed a redistribution of Qrel attributable to oleic acid injury. Qrel shifted from areas that were initially high-flow to areas that were initially low-flow, with no difference in redistribution between the groups. After established injury, Qrel was redistributed to the nondependent lung areas in control animals, whereas Qrel distribution did not change in treatment animals.

Conclusion
In oleic acid lung injury, treatment with PFX vapor improves gas exchange by increasing VA/Q heterogeneity in the whole lung without a significant change in gravitational gradient.
Cervicomedullary Intrathecal Injection of Morphine Produces Antinociception in the Orofacial Formalin Test in the Rat
Authors: Grabow Theodore S. , Dougherty Patrick M. 
Published: November 2003

Background
High cervical and medullary drug delivery has been advocated for the treatment of refractory head and neck pain in humans. Currently, parallel models in animals have not been developed to support this methodology. We combined an accepted animal model of pain of cranial origin with a novel technique of neuraxial drug delivery to address this issue.

Methods
Male Wistar rats were implanted with intrathecal catheters that were advanced cephalad through a lumbar guide cannula to the high cervical spinal cord. The orofacial formalin test was used to assess antinociception. Vehicle or morphine (1, 3, 6, 10, 30 microg) was injected intrathecally followed 10 minutes later by injection of formalin solution, 2.5%, into the vibrissal pad. Motor assessment and hemodynamic and respiratory blood gas measurements were evaluated in a separate group of animals.

Results
Intrathecal morphine produced a dose-dependent decrease in the first and second phases of the behavioral response (P < 0.05). The ED50 (95% confidence limits) values for the first and second phases were 6.65 microg (3.52-14.9 microg) and 3.40 microg (2.37-4.61 microg), respectively. Ten micrograms intrathecal naloxone antagonized the morphine effect (P < 0.05). Significant cardiovascular and respiratory depression was observed. No significant motor dysfunction was observed.

Conclusions
Cervicomedullary injection of morphine produced antinociception in the orofacial formalin test in the rat. This animal model may be useful to assess analgesics designed for parallel clinical application in humans.
Preferential Block of Small Myelinated Sensory and Motor Fibers by Lidocaine
Authors: Gokin Alexander P. , Philip Benjamin , Strichartz Gary R. 
Published: November 2003

Background
Controversy still surrounds the differential susceptibility of nerve fibers to local anesthetics and its relation to selective functional deficits. In the current study we report features of conduction blockade in different classes of rat sciatic nerve fibers after injection of lidocaine by a percutaneous procedure that closely resembles clinical applications.

Methods
In 30 adult male Sprague-Dawley rats (weight, 300-400 g) during general anesthesia, impulses were recorded in different classes of sensory axons (large, Aalpha and beta fibers; small, Adelta myelinated fibers and unmyelinated C fibers) and motor axons (large, Aalpha fibers; small, Agamma myelinated fibers) classified by conduction velocity. The sciatic nerve was stimulated distally, and impulses were recorded from small filaments teased from L4-L5 dorsal (sensory) and ventral (motor) roots sectioned acutely from the spinal cord. Lidocaine at concentration of 0.05-1% was injected percutaneously in 0.1-ml solutions at the sciatic notch. Both tonic (stimulated at 0.5 Hz) and use-dependent (stimulated at 40 Hz for Adelta and Agamma fibers and at 5 Hz for C fibers) impulse inhibitions by lidocaine were assayed.

Results
Minimal effective (threshold) lidocaine concentrations (i.e., to block conduction in 10% of fibers) were, for sensory, 0.03% for Adelta, 0.07% for Aalphabeta, and 0.09-0.1% for C fibers, and for motor, 0.03% for Agamma and 0.05% for Aalpha fibers. The order of fiber susceptibility, ranked by concentrations that gave peak tonic fiber blockade of 50% (IC50s), was Agamma > Adelta = Aalpha > Aalphabeta > C. Faster-conducting C fibers (conduction velocity > 1 m/s) were more susceptible (IC50 = 0.13%) than slower ones (conduction velocity < 1 m/s; IC50 = 0.30%). At 1% lidocaine, all fibers were tonically blocked. Use-dependent effects accounted for only a modest potentiation of block (at a lidocaine concentration of 0.25%) in Adelta and Agamma fibers, and in C fibers phasic stimulation had even smaller effects and sometimes relieved tonic block.

Conclusions
Susceptibility to lidocaine does not strictly follow the "size principle" that smaller (slower) axons are always blocked first. This order of fiber blockade is qualitatively consistent with previous reports of the order of functional deficits in the rat after percutaneous lidocaine, that is, motor = proprioception > nociception, if we assume that motor deficits first arise from conduction failure in Agamma fibers and that nociception relies on C fiber conduction.
Stereospecific Effect of Pregabalin on Ectopic Afferent Discharges and Neuropathic Pain Induced by Sciatic Nerve Ligation in Rats
Authors: Chen Shao-Rui , Xu Zemin , Pan Hui-Lin 
Published: November 2003

Background
The new anticonvulsants, gabapentin and pregabalin, are effective in the treatment of neuropathic pain. The sites and mechanisms of their analgesic action are not fully known. The authors have previously demonstrated that systemic gabapentin suppresses ectopic afferent discharges recorded from injured sciatic nerves in rats. In the current study, they further examined the stereospecific effect of pregabalin on neuropathic pain and afferent ectopic discharges in a rodent model of neuropathic pain.

Methods
Tactile allodynia and thermal hyperalgesia were induced by partial ligation of the left sciatic nerve in rats. Single-unit activity of afferent ectopic discharges was recorded from the sciatic nerve proximal to the site of ligation.

Results
Intravenous injection of 10-30 mg/kg pregabalin dose-dependently attenuated tactile allodynia (n = 10) and thermal hyperalgesia (n = 8). The stereoisomer of pregabalin, R-3-isobutylgaba, had no analgesic effect in this dose range. Furthermore, intravenous injection of pregabalin, but not R-3-isobutylgaba, significantly inhibited the ectopic discharges from injured afferents in a dose-dependent manner (from 20.8 +/- 2.4 impulses/s during control to 2.3 +/- 0.7 impulses/s after treatment with 30 mg/kg pregabalin, n = 15). Pregabalin did not affect the conduction velocity of afferent fibers and the response of normal afferent nerves to mechanical stimulation.

Conclusions
These data strongly suggest that the analgesic effect of pregabalin on neuropathic pain is likely mediated, at least in part, by its peripheral inhibitory action on the impulse generation of ectopic discharges caused by nerve injury.