bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of CNS Site-directed Carotid Arterial Infusions of Bupivacaine, Levobupivacaine, and Ropivacaine in Sheep
Authors: Ladd Leigh A. , Chang Dennis H-T. , Wilson Kylie A. , Copeland Susan E. , Plummer John L. , Mather Laurence E. 
Published: November 2003

Background
Previous preclinical safety studies in ewes have found intravenous levobupivacaine and ropivacaine to be less potent toward causing central nervous system (CNS) and cardiac toxicity than bupivacaine. Analogous cardiotoxicity has been demonstrated directly in various cardiac preparations ex vivo. Moreover, drug-related arrhythmogenicity has been demonstrated from direct CNS injection of local anesthetic agents in vivo, suggesting CNS-related cardiotoxicity. This study investigated whether CNS site-directed blood-borne drug administration (with minimal systemic recirculation) would demonstrate drug-related cardiotoxicity.

Methods
Direct CNS effects and indirect cardiotoxic sequelae were determined after bilateral carotid arterial infusions of levobupivacaine, bupivacaine, or ropivacaine in ewes. After pilot studies to validate the procedures, equimolar doses (24-96 micromol, approximately 7.5-30 mg) were infused over 3 min using a crossover design. Behavioral CNS signs, quantitative electroencephalographic (EEG), cardiovascular, and electrocardiographic effects were recorded. Drug blood concentrations in superior sagittal sinus and aorta were measured serially.

Results
Blood drug concentrations in the superior sagittal sinus were 5-10 times those concurrently in the aorta, confirming highly selective CNS delivery with minimal systemic recirculation. Dose-dependent CNS excitatory behavior and EEG changes, with increased mean arterial blood pressure, heart rate, cardiac output, and myocardial contractility, were found, consistent with sympathetic nervous system stimulation. The overall rank order of potency for these effects was ropivacaine < levobupivacaine < bupivacaine. Nonfatal cardiac arrhythmias were observed, but the type or frequency did not differ between drugs.

Conclusions
Although CNS site-selective drug delivery produced quantitative differences between bupivacaine, levobupivacaine, and ropivacaine in some CNS effects and cardiac sequelae, no differences were found in their arrhythmogenic potential.
Intrathecal Ropivacaine in Rabbits: Pharmacodynamic and Neurotoxicologic Study
Authors: Malinovsky Jean-Marc , Charles Florence , Baudrimont Marielle , Péréon Yann , Le Corre Pascal , Pinaud Michel , Benhamou Dan 
Published: November 2003

Background
Ropivacaine is available for spinal or intrathecal use in humans, although data on neurotoxicity after spinal injection are not yet available. The authors experimentally determined the relationship between doses of intrathecal ropivacaine and spinal effects and local neurotoxic effects.

Methods
Eighty rabbits equipped with an intrathecal lumbar catheter were studied. Sixty were randomly assigned to receive 0.2 ml of intrathecal solutions as a sole injection of: 0.2%, 0.75%, 1.0%, and 2.0% ropivacaine (doses from 0.4-4.0 mg; groups R0.2 to R2.0), 5.0% lidocaine (10 mg; group L), or 0.9% NaCl as control (group C). Twenty other rabbits received either repeated injections of 0.2 ml of 0.2% ropivacaine every 2 days during 2 weeks (total dose of 2.8 mg; group RINT); or a continuous intrathecal infusion of 0.2% ropivacaine at the rate of 1.8 ml/h over 45 min (2.7 mg; group RCONT). Injection rate was 30 s in all groups except Rcont. Time to onset, duration and extent of motor block, and variations of mean arterial blood pressure were recorded in all groups. Somatosensory evoked potentials were also recorded in group RCONT and RINT. Seven days after the last intrathecal injection spinal cord and nerves were sampled for histopathologic study.

Results
In groups R0.2 and RINT, the lowest dose of ropivacaine induced a clinically visible spinal block in only 50% of rabbits, but SEPs recorded in group RINT were decreased by 70% in the lumbar dermatome. Complete motor block was observed with doses greater than 1.5 mg of ropivacaine (group RCONT and R0.75 to R2.0). Onset time was shorter and duration of block increased as doses of ropivacaine increased. Significant hypotension was observed only with 4.0 mg of ropivacaine (concentration of 2.0%). Complete paralysis and hypotension were observed with 5.0% lidocaine. No neurologic clinical lesion was observed in rabbits receiving saline or ropivacaine within the 7 days after the last intrathecal injection, and histopathologic study revealed no sign of neurotoxicity in these groups. In contrast, intrathecal lidocaine induced clinical and histopathologic changes.

Conclusion
Ropivacaine induced dose-dependent spinal anesthesia, and did not induce any neurotoxicologic lesion in this experimental animal model.
Effects of Halothane and Enflurane Anesthesia on Sympathetic β-adrenoreceptor–mediated Pulmonary Vasodilation in Chronically Instrumented Dogs
Authors: Sato Kosei , Seki Sumihiko , Murray Paul A. 
Published: November 2003

Background
The authors previously reported that the pulmonary vasodilator response to the sympathetic beta-adrenoreceptor agonist isoproterenol is potentiated during isoflurane anesthesia compared with the conscious state. In the present in vivo study, the authors tested the hypothesis that halothane and enflurane anesthesia also enhance sympathetic beta adrenoreceptor-mediated pulmonary vasodilation. The authors also used the membrane-permeable analog of cyclic adenosine monophosphate (cAMP), dibutyryl cAMP, to help delineate the site in the signaling pathway for an anesthesia-induced effect on beta adrenoreceptor-mediated pulmonary vasodilation.

Methods
Mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relationship. LPQ plots were measured on separate days in the conscious, halothane-, and enflurane-anesthetized states at baseline, after preconstriction with the thromboxane analog U46619, and during the cumulative intravenous administration of isoproterenol. LPQ plots were also measured in conscious, halothane-, and isoflurane-anesthetized dogs after U46619 preconstriction and during the cumulative intravenous administration of dibutyryl cAMP.

Results
Compared with the conscious state, neither halothane nor enflurane had an effect on the baseline LPQ relationship. The magnitude of the pulmonary vasodilator response to isoproterenol was potentiated during halothane anesthesia but unchanged during enflurane anesthesia. The pulmonary vasodilator response to dibutyryl cAMP was not altered during either halothane or isoflurane anesthesia compared with the conscious state.

Conclusions
These results indicate that inhalational anesthetic agents can exert differential effects on the pulmonary vasodilator response to sympathetic beta-adrenoreceptor activation. The potentiated vasodilator response observed during halothane and isoflurane anesthesia is the result of effects proximal to cAMP accumulation in the beta-adrenoreceptor signaling pathway.
Epidural Analgesia Enhances Functional Exercise Capacity and Health-related Quality of Life after Colonic Surgery
Authors: Carli Franco , Mayo Nancy , Klubien Kristine , Schricker Thomas , Trudel Judith , Belliveau Paul 
Published: November 2003

Background
Multimodal analgesia programs have been shown to decrease hospital stay, but it not clear which functions are restored after surgery. The objective of this study is to evaluate the impact of epidural anesthesia and analgesia on functional exercise capacity and health-related quality of life.

Methods
Sixty-four patients undergoing elective colonic resection were randomized to either patient-controlled analgesia with morphine or thoracic epidural analgesia with bupivacaine and fentanyl (epidural group). All patients in both groups received similar perioperative care and were offered the same amount of postoperative oral nutrition and assistance with mobilization. Primary outcome was functional exercise capacity as measured by the 6-min walking test, and secondary outcome was health-related quality of life, as measured by the SF-36 health survey. These were assessed before surgery and at 3 and 6 weeks after hospital discharge. Other variables measured in hospital included pain and fatigue visual analogue scale, bowel function, time out of bed, nutritional intake, complication rate, readiness for discharge, and length of hospital stay.

Results
Although the 6-min walking test and the SF-36 physical health component decreased in both groups at 3 and 6 weeks after surgery, the patient-controlled analgesia group experienced a significantly greater decrease at both times (P < 0.01). Patients in the epidural group had lower postoperative pain and fatigue scores, which allowed them to mobilize to a greater extent (P < 0.05) and eat more (P < 0.05). Length of hospital stay and incidence of complications were similar in both groups, although patients in the epidural group were ready to be discharged earlier.

Conclusions
The superior quality of pain relief provided by epidural analgesia had a positive impact on out-of-bed mobilization, bowel function, and intake of food, with long-lasting effects on exercise capacity and health-related quality of life.
A Randomized Study of the Effects of Single-dose Gabapentin versus Placebo on Postoperative Pain and Morphine Consumption after Mastectomy
Authors: Dirks Jesper , Fredensborg Birgitte B. , Christensen Dennis , Fomsgaard Jonna S. , Flyger Henrik , Dahl Jørgen B. 
Published: November 2003

Background
The anticonvulsant gabapentin has proven effective for neuropathic pain in three large placebo-controlled clinical trials. Experimental and clinical studies have demonstrated antihyperalgesic effects in models involving central neuronal sensitization. It has been suggested that central neuronal sensitization may play an important role in postoperative pain. The aim of the study was to investigate the effect of gabapentin on morphine consumption and postoperative pain in patients undergoing radical mastectomy.

Methods
In a randomized, double-blind, placebo-controlled study, 70 patients received a single dose of oral gabapentin (1,200 mg) or placebo 1 h before surgery. Patients received patient-controlled analgesia with morphine at doses of 2.5 mg with a lock-out time of 10 min for 4 h postoperatively. Pain was assessed on a visual analog scale at rest and during movement, and side effects were assessed on a four-point verbal scale 2 and 4 h postoperatively.

Results
Thirty-one patients in the gabapentin group and 34 patients in the placebo group completed the study. Gabapentin reduced total morphine consumption from a median of 29 (interquartile range, 21-33) to 15 (10-19) mg (P< 0.0001). Pain during movement was reduced from 41 (31-59) to 22 (10-38) mm at 2 h postoperatively (P < 0.0001) and from 31 (12-40) to 9 (3-34) mm at 4 h postoperatively (P = 0.018). No significant differences between groups were observed with regard to pain at rest or side effects.

Conclusion
A single dose of 1,200 mg oral gabapentin resulted in a substantial reduction in postoperative morphine consumption and movement-related pain after radical mastectomy, without significant side effects. These promising results should be validated in other acute pain models involving central neuronal sensitization.
A Single Preoperative Oral Dose of Valdecoxib, a New Cyclooxygenase-2 Specific Inhibitor, Relieves Post-Oral Surgery or Bunionectomy Pain
Authors: Desjardins Paul J. , Shu Vincent S. , Recker David P. , Verburg Kenneth M. , Woolf Clifford J. 
Published: November 2003

Background
The trend toward day-case surgery, with discharge on oral medication, has highlighted the need for effective and safe analgesics that facilitate a rapid recovery and discharge time. This study evaluated the analgesic efficacy, dose dependency, duration of action, and safety of the cyclooxygenase-2 specific inhibitor, valdecoxib, administered before oral or orthopedic surgery.

Methods
Eligible healthy adult patients were scheduled to undergo either extraction of two impacted third molar teeth (n = 284) or bunionectomy surgery (n = 223) with local anesthesia in two randomized, double-blind, placebo-controlled studies conducted at three centers in the United States. Patients received a single, preoperatively administered oral dose of placebo or 10 (oral surgery only), 20, 40, or 80 mg valdecoxib. Analgesic efficacy was assessed postoperatively, over a 24-h treatment period, or until the patient required rescue medication. Efficacy measures included time to rescue medication, proportion of patients requiring such rescue, pain intensity, and the Patient's Global Evaluation of Study Medication.

Results
In both studies, all doses of valdecoxib produced analgesia with a duration (time to rescue analgesia) and magnitude (Pain Intensity, Patient's Global Evaluation) significantly greater than placebo. A dose-dependent effect was observed up to 40 mg valdecoxib, with an 80-mg dose providing no additional analgesic benefit. In both models, all doses of valdecoxib were well tolerated, with no clinically significant treatment-related gastrointestinal, renal, or platelet-derived adverse events, and no evidence of a dose-related increase in adverse events.

Conclusions
Preoperative orally administered valdecoxib provides well-tolerated and effective analgesia for mild to moderate postoperative pain.
Autonomic Nervous System Responses during Sedative Infusions of Dexmedetomidine
Authors: Hogue Charles W. , Talke Pekka , Stein Phyllis K. , Richardson Charles , Domitrovich Peter P. , Sessler Daniel I. 
Published: November 2003

Background
The purpose of this study was to determine the effects of dexmedetomidine on systemic and cardiac autonomic reflex responses during rest and during thermal stress.

Methods
Volunteers received either placebo or low- or high-dose dexmedetomidine (target plasma concentrations 0.3 or 0.6 ng/ml, respectively) infusions in a prospectively randomized, double-blinded crossover study design. After 1 h, baroreflex sensitivity was assessed, and then core body temperature was raised to the sweating threshold and then lowered to the shivering threshold. Plasma catecholamines and blood pressure were measured, and cardiac autonomic responses were assessed by analysis of heart rate variability.

Results
Compared with placebo, plasma norepinephrine concentrations, blood pressure, heart rate, and some heart rate variability measures were lower after 1-h infusion of dexmedetomidine, but baroreflex responses did not differ significantly. Dexmedetomidine blunted the systemic and cardiac sympathetic effects of sweating observed during placebo infusion but had no effect on parasympathetic measures. Increases in blood pressure, and systemic catecholamines due to shivering were observed during placebo and dexmedetomidine, but these responses were less with dexmedetomidine. During shivering, dexmedetomidine infusion was associated with higher low-frequency and high-frequency heart rate variability power but lower heart rate compared with the sweating threshold and with the control period, suggesting nonreciprocal cardiac autonomic responses.

Conclusions
Infusion of dexmedetomidine results in compensated reductions in systemic sympathetic tone without changes in baroreflex sensitivity. Dexmedetomidine blunts heart rate and the systemic sympathetic activation due to sweating, but it is less effective in blunting cardiac sympathetic responses to shivering. During dexmedetomidine infusion, cardiac sympathetic and parasympathetic tone may have nonreciprocal changes during shivering.
Can the Tomographic Aspect Characteristics of Patients Presenting with Acute Respiratory Distress Syndrome Predict Improvement in Oxygenation-related Response to the Prone Position?
Authors: Papazian Laurent , Paladini Marie-Héléne , Bregeon Fabienne , Thirion Xavier , Durieux Olivier , Gainnier Marc , Huiart Laetitia , Agostini Serge , Auffray Jean-Pierre 
Published: November 2003

Background
In some patients with acute respiratory distress syndrome, the prone position is able to improve oxygenation, whereas in others it is not. It could be hypothesized that the more opacities that are present in dependent regions of the lung when the patient is in the supine position, the better the improvement in oxygenation is observed when the patients are turned prone. Therefore, we conducted a prospective study to identify computed tomographic scan aspects that could accurately predict who will respond to the prone position.

Methods
We included 46 patients with acute respiratory distress syndrome (31 responders and 15 nonresponders). Computed tomographic scan was performed in the 6-h period preceding prone position. Blood gas analyses were performed before and at the end of the first 6-h period of prone position.

Results
Arterial oxygen partial pressure/fraction of inspired oxygen increased from 117 +/- 42 (mean +/- SD) in the supine position to 200 +/- 76 mmHg in the prone position (P < 0.001). There were 31 responders and 15 nonresponders. There was a vertebral predominance of the opacities (P < 0.0001). However, there was no difference between responders and nonresponders. When only the amount of consolidated lung located under the heart was evaluated, there was more consolidated tissue under the heart relative to total lung area in nonresponders than in responders (P = 0.01).

Conclusions
There are no distinctive morphologic features in the pattern of lung disease measured by computed tomographic scanning performed with the patient in the supine position that can predict response to the prone position.
Duration of Anesthesia before Muscle Relaxant Injection Influences Level of Paralysis
Authors: Plaud Benoît , Debaene Bertrand , Donati François 
Published: November 2003

Background
Dosage guidelines for muscle relaxants are based on dose-response studies, normally performed after several minutes of stable nitrous oxide (N O)-opioid anesthesia. However, relaxants are used immediately after induction of anesthesia. The study was designed to determine the influence of the duration of anesthesia and N O on the onset time at the adductor pollicis (AP) and the corrugator supercilii (CS) muscles of maximum neuromuscular blockade after mivacurium.

Methods
After institutional approval and informed consent, patients were randomly allocated into three groups. Anesthesia was induced with alfentanil and propofol. Group A (n = 10) received mivacurium (0.1 mg/kg) immediately after loss of consciousness. Groups B (n = 10) and C (n = 10) received mivacurium after 15 min of anesthesia with propofol alone (B) or propofol with N O (C). The evoked response to train-of-four stimulation was measured by acceleromyography at the AP and the CS.

Results
Maximum neuromuscular blockade (%T1, median [range]) was significantly less in group A than in groups B and C ( < 0.001) at both the AP (81 [47-90]; 90 [35-100]; 100 [93-100], respectively) and the CS (19 [5-63]; 68 [61-100]; 89 [72-100], respectively). Maximum neuromuscular blockade was less in group B than in group C ( < 0.001) at the AP. Onset time of maximum neuromuscular blockade was not different between groups but was shorter at the CS than at the AP.

Conclusions
Duration of anesthesia and N O before mivacurium injection affect intensity of neuromuscular blockade but not onset time. Neuromuscular blockade obtained at the AP after several minutes of stable anesthesia with N O is greater than immediately after induction. This explains in part the discrepancy between the measured ED and the intubating dose.
Growth Cone Collapsing Effect of Lidocaine on DRG Neurons Is Partially Reversed by Several Neurotrophic Factors
Authors: Radwan Inas A. M. , Saito Shigeru , Goto Fumio 
Published: November 2003

Background
Local anesthetics were suggested to have a potential for neurotoxicity in both clinical reports and laboratory experiments. Growing neurons have been shown to be susceptible to the toxic effects of local anesthetics in culture. These findings have generated the interest in factors that would rescue the neurons affected by the neurotoxicity of local anesthetics.

Methods
Primary cultured dorsal root ganglia were isolated from age-matched chick embryos and exposed to lidocaine. After 60 min of exposure, the culture media were replaced to wash out the lidocaine. Neurotrophic factors (NTFs)-brain-derived neurotrophic factor, glial-derived neurotrophic factor, or neurotrophin 3-were added to the replacement media to examine the capacity of these NTFs to support the reversibility of the lidocaine-induced growth cone collapse. The growth cone collapse assay was applied a quantitative method of assessment.

Results
When any of the three NTFs was added to the replacement media at a minimum concentration of 10 ng/ml, significantly high reversibility of the lidocaine-induced growth cone collapse was observed, especially at 48 h after washout (P < 0.05). At that time point, there was no significant difference between the values of growth cone collapse percentage in the cells that were exposed to lidocaine and supported by the NTFs after the washout, and the control cells (not exposed to lidocaine) (P > 0.05).

Conclusion
The NTFs-brain-derived neurotrophic factor, glial-derived neurotrophic factor, and neurotrophin 3-were demonstrated to support the reversibility of lidocaine-induced growth cone collapse in primary cultured sensory neurons, an effect that was concentration- and time-dependent. Because similar effects were observed after tetracaine washout, the supporting effects of NTFs may not be specific to lidocaine.
Pentobarbital Enhances GABAergic Neurotransmission to Cardiac Parasympathetic Neurons, Which Is Prevented by Expression of GABAAε Subunit
Authors: Irnaten Mustapha , Walwyn Wendy M. , Wang Jijiang , Venkatesan Priya , Evans Cory , Chang Kyoung S. K. , Andresen Michael C. , Hales Tim G. , Mendelowitz David 
Published: November 2003

Background
Pentobarbital decreases the gain of the baroreceptor reflex on the order of 50%, and this blunting is caused nearly entirely by decreasing cardioinhibitory parasympathetic activity. The most likely site of action of pentobarbital is the gamma-aminobutyric acid type A (GABA(A)) receptor. The authors tested whether pentobarbital augments the inhibitory GABAergic neurotransmission to cardiac parasympathetic neurons, and whether expression of the GABA(A) epsilon subunit prevents this facilitation.

Methods
The authors used a novel approach to study the effect of pentobarbital on identified cardiac parasympathetic preganglionic neurons in rat brainstem slices. The cardiac parasympathetic neurons in the nucleus ambiguus were retrogradely prelabeled with a fluorescent tracer and were visually identified for patch clamp recording. The effects of pentobarbital on spontaneous GABAergic synaptic events were tested. An adenovirus was used to express the epsilon subunit of the GABA(A) receptor in cardiac parasympathetic neurons to examine whether this transfection alters pentobarbital-mediated changes in GABAergic neurotransmission.

Results
Pentobarbital increased the duration but not the frequency or amplitude of spontaneous GABAergic currents in cardiac parasympathetic neurons. Transfection of cardiac parasympathetic neurons with the epsilon subunit of the GABA(A) receptor prevented the pentobarbital-evoked facilitation of GABAergic currents.

Conclusions
Pentobarbital, at clinically relevant concentrations, prolongs the duration of spontaneous inhibitory postsynaptic currents that impinge on cardiac parasympathetic neurons. This action would augment the inhibition of cardiac parasympathetic neurons, reduce parasympathetic cardioinhibitory activity, and increase heart rate. Expression of the GABA(A) receptor epsilon subunit in cardiac parasympathetic neurons renders the GABA receptors insensitive to pentobarbital.