bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Bupivacaine after Continuous Epidural Infusion in Infants with and without Biliary Atresia
Authors: Meunier Jean-François , Goujard Etienne , Dubousset Anne-Marie , Samii Kamran , Xavier Mazoit Jean 
Published: November 2003

Background
Continuous epidural infusion of bupivacaine is widely practiced for postoperative pain relief in pediatric patients. However, bupivacaine may induce adverse effects in infants (convulsions or cardiac arrhythmias), likely because of decreased hepatic clearance and serum protein binding capacity. The authors wanted to examine the complex relations between age, alpha-1 acid glycoprotein (AAG) concentration, and unbound and total bupivacaine serum concentrations in infants receiving bupivacaine epidurally for 2 days.

Methods
Twenty-two infants aged 1-7 months (12 with biliary atresia and 10 with another disease) received a continuous epidural infusion of 0.375 mg x kg(-1) x h(-1) bupivacaine during 2 days (during and after surgery). Unbound and total bupivacaine concentration in serum was measured 0.5, 4, 24, and 48 h after infusion initiation. AAG concentration was measured in serum before and 2 days after surgery. In eight additional infants, the blood/plasma concentration ratio was measured in vitro at whole blood concentrations of 2 and 20 microg/ml. Bupivacaine concentration was fitted to a one-compartment model to calculate basic pharmacokinetic parameters.

Results
No adverse effects were observed. AAG increased markedly after surgery, and the increase was correlated to both age and preoperative AAG concentration. Two infants aged 1.8 months had unbound concentrations greater than 0.2 microg/ml. Clearance of unbound drug significantly increased with age. Because of increased drug binding, clearance of bound drug decreased both with time (from 0.5 to 48 h) and with age. Blood/plasma ratio was 0.77+/-0.08 and 0.85+/-0.24 at 2 and 20 microg/ml, respectively.

Conclusions
Because of a low AAG concentration and a low intrinsic clearance, unbound bupivacaine increased to concentrations greater than 0.2 microg/ml in two infants younger than 2 months, after 2 days of infusion at a rate of 0.375 mg x kg(-1) x h(-1). The increase in AAG observed after surgery did not fully buffer this unbound fraction. Similarly, the buffer capacity of erythrocytes did not sufficiently increase at high concentration to compensate the saturation of the AAG system. Thus, we propose the use of a maximum dose of 0.25 mg x kg(-1) x h(-1) in infants younger than 4 months and a maximum of 0.3 mg x kg(-1) x h(-1) in infants older than 4 months.
Effects of Thoracic Epidural Anesthesia with and without Autonomic Nervous System Blockade on Cardiac Monophasic Action Potentials and Effective Refractoriness in Awake Dogs
Authors: Meissner Andreas , Eckardt Lars , Kirchhof Paulus , Weber Thomas , Rolf Norbert , Breithardt Günter , Van Aken Hugo , Haverkamp Wilhelm 
Published: November 2003

Background
The effects of thoracic epidural anesthesia (TEA) on myocardial repolarization and arrhythmogenicity are only incompletely understood. This is primarily because of the lack of appropriate experimental models. In most of the studies performed thus far, TEA was used in anesthetized animals. Baseline anesthesia itself may have modified the effects of TEA. This study investigates right atrial and ventricular repolarization by recording monophasic action potentials after TEA in awake dogs. The authors hypothesized that an antiarrhythmic role of TEA exists, which may be related to a direct effect of TEA on myocardial repolarization.

Methods
The hypothesis was tested in an in vivo canine model, in which atrial and ventricular myocardial action potential duration and refractoriness are recorded by means of monophasic action potential catheters.

Results
Thoracic epidural anesthesia significantly increased ventricular monophasic action potential duration for cycle lengths shorter than 350 ms. Changes in monophasic action potential duration were paralleled by a concomitant prolongation of effective refractory period (ERP) at higher rates so that the ratio of ERP to action potential duration was unaffected.

Conclusions
This model helps to study the role of TEA on ventricular repolarization and arrhythmogenicity. Because lengthening of repolarization and prolongation of refractoriness may, in some circumstances, be antiarrhythmic, TEA may be protective against generation of ventricular arrhythmias mediated, e.g., by increased sympathetic tone. The results also imply that the beneficial role of TEA might be stronger at the ventricular site as compared with the atrium. At atrial sites there was only a trend toward prolongation of repolarization even at short cycle lengths.
Differential Effects of General Anesthetics on G Protein–coupled Inwardly Rectifying and Other Potassium Channels
Authors: Yamakura Tomohiro , Lewohl Joanne M. , Harris R. Adron 
Published: November 2003

Background
General anesthetics differentially affect various families of potassium channels, and some potassium channels are suggested to be potential targets for anesthetics and alcohols.

Methods
The voltage-gated (ERG1, ELK1, and KCNQ2/3) and inwardly rectifying (GIRK1/2, GIRK1/4, GIRK2, IRK1, and ROMK1) potassium channels were expressed in Xenopus oocytes. Effects of volatile agents [halothane, isoflurane, enflurane, F3 (1-chloro-1,2,2-trifluorocyclobutane), and the structurally related nonimmobilizer F6 (1,2-dichlorohexafluorocyclobutane)], as well as intravenous (pentobarbital, propofol, etomidate, alphaxalone, ketamine), and gaseous (nitrous oxide) anesthetics and alcohols (ethanol and hexanol) on channel function were studied using a two-electrode voltage clamp.

Results
ERG1, ELK1, and KCNQ2/3 channels were either inhibited slightly or unaffected by concentrations corresponding to twice the minimum alveolar concentrations or twice the anesthetic EC50 of volatile and intravenous anesthetics and alcohols. In contrast, G protein-coupled inwardly rectifying potassium (GIRK) channels were inhibited by volatile anesthetics but not by intravenous anesthetics. The neuronal-type GIRK1/2 channels were inhibited by 2 minimum alveolar concentrations of halothane or F3 by 45 and 81%, respectively, whereas the cardiac-type GIRK1/4 channels were inhibited only by F3. Conversely, IRK1 and ROMK1 channels were completely resistant to all anesthetics tested. Current responses of GIRK2 channels activated by mu-opioid receptors were also inhibited by halothane. Nitrous oxide (approximately 0.6 atmosphere) slightly but selectively potentiated GIRK channels. Results of chimeric and multiple amino acid mutations suggest that the region containing the transmembrane domains, but not the pore-forming domain, may be involved in determining differences in anesthetic sensitivity between GIRK and IRK channels.

Conclusions
G protein-coupled inwardly rectifying potassium channels, especially those composed of GIRK2 subunits, were inhibited by clinical concentrations of volatile anesthetics. This action may be related to some side effects of these agents.
Risk Factors for Perioperative Adverse Respiratory Events in Children with Upper Respiratory Tract Infections
Authors: Tait Alan R. , Malviya Shobha , Voepel-Lewis Terri , Munro Hamish M. , Siewert Monica , Pandit Uma A. 
Published: November 2003

Background
Anesthesia for the child who presents for surgery with an upper respiratory infection (URI) presents a challenge for the anesthesiologist. The Current prospective study was designed to determine the incidence of and risk factors for adverse respiratory events in children with URTs undergoing elective surgical procedures.

Methods
The study population included 1,078 children aged 1 month to 18 yr who presented for an elective surgical procedure. Parents were given a short questionnaire detailing their child's demographics, medical history, and presence of any symptoms of a URT. Data regarding the incidence and severity of perioperative respiratory events were collected prospectively. Adverse respiratory events (any episode of laryngospasm, bronchospasm, breath holding > 15 s, oxygen saturation < 90%, or severe cough) were recorded. In addition, parents were contacted 1 and 7 days after surgery to determine the child's postoperative course.

Results
There were no differences between children with active URIs, recent URIs (within 4 weeks), and asymptomatic children with respect to the incidences of laryngospasm and bronchospasm. However, children with active and recent URIs had significantly more episodes of breath holding, major desaturation (oxygen saturation < 90%) events, and a greater incidence of overall adverse respiratory events than children with no URIs. Independent risk factors for adverse respiratory events in children with active URIs included use of an endotracheal tube (< 5 yr of age), history of prematurity, history of reactive airway disease, paternal smoking, surgery involving the airway, the presence of copious secretions, and nasal congestion. Although children with URIs had a greater incidence of adverse respiratory events, none were associated with any long-term adverse sequelae.

Conclusions
The current study identified several risk factors for perioperative adverse respiratory events in children with lulls. Although children with acute and recent URIs are at greater risk for respiratory complications, these results suggest that most of these children can undergo elective procedures without significant increase in adverse anesthetic outcomes.
Concentration–Effect Relationship of Cisatracurium at Three Different Dose Levels in the Anesthetized Patient
Authors: Bergeron Luc , Bevan David R. , Berrill Andrew , Kahwaji Raymond , Varin France 
Published: November 2003

Background
The linearity of cisatracurium elimination and its concentration-effect relation were determined as part of a traditional rich data study with three dose levels in patients receiving balanced anesthesia.

Methods
Forty-eight adults with American Society of Anesthesiologists status I-II were randomized to receive an intravenous bolus dose of 0.075, 0.15, or 0.30 mg/kg cisatracurium. Anesthesia was induced and maintained with nitrous oxide-oxygen, propofol, and fentanyl. The mechanical response of the adductor pollicis muscle was recorded. Arterial blood samples were collected over 8 h. Cisatracurium, laudanosine, and the monoquaternary alcohol concentrations were measured by high-performance liquid chromatography. To assess the relative contribution of the input function, a parametric (assuming elimination from both the central and peripheral compartments) and a nonparametric pharmacokinetic-pharmacodynamic model were both applied to data.

Results
Dose proportionality of the body disposition of cisatracurium and its two major metabolites at doses up to 0.30 mg/kg was confirmed. With the parametric approach, the effect compartment concentration at 50% block (EC50) significantly increased with the dose (136 vs. 157 vs. 209 ng/ml), whereas the effect compartment equilibration rate constant decreased (0.0675 vs. 0.0568 vs. 0.0478 min(-1)). A similar dose-dependent effect of the pharmacokinetic-pharmacodynamic relation was observed with the nonparametric approach, but the trend was 50% less pronounced.

Conclusion
A dose-related change in pharmacokinetic-pharmacodynamic parameters was identified with both modeling approaches. A pharmacokinetic origin was ruled out, although no definite explanation of the underlying mechanism could be provided. These findings suggest that doses relevant to the anesthetic practice be used for estimation of EC50.
Effectiveness of Epidural Blood Patch in the Management of Post–Dural Puncture Headache
Authors: Safa-Tisseront Valérie , Thormann Françoise , Malassiné Patrick , Henry Michel , Riou Bruno , Coriat Pierre , Seebacher Jeanne 
Published: November 2003

Background
Lumbar epidural blood patch (EBP) is a common treatment of post-dural puncture headache, but its effectiveness and mode of action remain a matter of debate. The aim of this study was to assess both the effectiveness and the predictive factors of failure of EBP on severe post-dural puncture headache.

Methods
This prospective observational study includes all patients treated in the authors' hospital with EBP for incapacitating post-dural puncture headache, from 1988 to 2000. The EBP effect was classified into complete relief (disappearance of all symptoms), incomplete relief of symptoms (clinically improved patients who recovered sufficiently to perform normal daily activity), and failure (persistence of severe symptoms). The following data were analyzed using a logistic regression to identify predictive factors of failure of EBP: (1) patient characteristics; (2) circumstances of dural puncture; (3) delay between dural puncture and EBP; and (4) the volume of blood injected for EBP.

Results
A total of 504 patients were analyzed. The frequency rates of complete relief, incomplete relief of symptoms, and failure after EBP were 75% (n = 377), 18% (n = 93), and 7% (n = 34), respectively. In a multivariate analysis, only the diameter of the needle used to perform dura mater puncture (odds ratio = 5.96; 95% confidence interval, 2.63-13.47; P < 0.001) and a delay in EBP less than 4 days (odds ratio = 2.63; 95% confidence interval, 1.06-6.51; P = 0.037) were independent significant risk factors for a failure of EBP.

Conclusions
Epidural blood patch is an effective treatment of severe post-dural puncture headache. Its effectiveness is decreased if dura mater puncture is caused by a large bore needle.
Gel Lubrication of the Tracheal Tube Cuff Reduces Pulmonary Aspiration
Authors: Blunt Mark C. , Young Peter J. , Patil Anita , Haddock Alan 
Published: November 2003

Background
Leakage of fluid occurs along the longitudinal folds within the wall of an inflated high-volume, low-pressure cuff. Theoretically, lubrication of the cuff with a water-soluble gel might prevent aspiration by plugging the channels in the cuff wall. Pulmonary aspiration during anesthesia has been linked with postoperative pneumonia and during critical illness causes ventilator-associated pneumonia.

Methods
Lubricated cuffs were compared with nonlubricated cuffs for leakage of dye placed in the subglottic space to the tracheobronchial tree in a benchtop model (n = 5) and in a prospective double-blinded randomized controlled trial of anesthetized patients (n = 36). The duration of the efficacy of the lubricant was determined in a prospective open observational study of critically ill patients with tracheostomies (n = 9). Dye was detected clinically by dye coloration of secretions during tracheal suctioning.

Results
In the benchtop model the incidence of leakage was 0% in the lubrication group and 100% in the nonlubrication group (P < 0.01). Dye leakage in anesthetized patients was 11% in the lubrication group and 83% in the nonlubrication group (P < 0.0001). In the critically ill patients with lubricated cuffed tracheostomy tubes, leakage first occurred after a median period of 48 h (range, 24-120 h).

Conclusions
Cuff lubrication with a water-soluble gel reduces pulmonary aspiration in anesthetized patients. In the critically ill patient with a tracheostomy the protective effect is lost after 24-120 h.
Cardiorespiratory Effects of Automatic Tube Compensation during Airway Pressure Release Ventilation in Patients with Acute Lung Injury
Authors: Wrigge Hermann , Zinserling Jörg , Hering Rudolf , Schwalfenberg Nico , Stüber Frank , von Spiegel Tilman , Schroeder Stefan , Hedenstierna Göran , Putensen Christian 
Published: November 2003

Background
Spontaneous breaths during airway pressure release ventilation (APRV) have to overcome the resistance of the artificial airway. Automatic tube compensation provides ventilatory assistance by increasing airway pressure during inspiration and lowering airway pressure during expiration, thereby compensating for resistance of the artificial airway. The authors studied if APRV with automatic tube compensation reduces the inspiratory effort without compromising cardiovascular function, end-expiratory lung volume, and gas exchange in patients with acute lung injury.

Methods
Fourteen patients with acute lung injury were breathing spontaneously during APRV with or without automatic tube compensation in random order. Airway pressure, esophageal and abdominal pressure, and gas flow were continuously measured, and tracheal pressure was estimated. Transdiaphragmatic pressure time product was calculated. End-expiratory lung volume was determined by nitrogen washout. The validity of the tracheal pressure calculation was investigated in seven healthy ventilated pigs.

Results
Automatic tube compensation during APRV increased airway pressure amplitude from 7.7+/-1.9 to 11.3+/-3.1 cm H2O (mean +/- SD; P < 0.05) while decreasing trans-diaphragmatic pressure time product from 45+/-27 to 27+/-15 cm H2O x s(-1) x min(-1) (P < 0.05), whereas tracheal pressure amplitude remained essentially unchanged (10.3+/-3.5 vs. 10.1+/-3.5 cm H2O). Minute ventilation increased from 10.4+/-1.6 to 11.4+/-1.5 l/min (P < 0.001), decreasing arterial carbon dioxide tension from 52+/-9 to 47+/-6 mmHg (P < 0.05) without affecting arterial blood oxygenation or cardiovascular function. End-expiratory lung volume increased from 2,806+/-991 to 3,009+/-994 ml (P < 0.05). Analysis of tracheal pressure-time curves indicated nonideal regulation of the dynamic pressure support during automatic tube compensation as provided by a standard ventilator.

Conclusion
In the studied patients with acute lung injury, automatic tube compensation markedly unloaded the inspiratory muscles and increased alveolar ventilation without compromising cardiorespiratory function and end-expiratory lung volume.
The Staircase Phenomenon
Authors: Kopman Aaron F. , Kumar Sanjeev , Klewicka Monika M. , Neuman George G. 
Published: November 2003

Background
Repeated indirect stimulation enhances the evoked mechanical response of muscle (the staircase phenomenon). There are few data that document the magnitude of this effect in man. Inexpensive acceleromyographic monitors of neuromuscular function are now available. If these units are to be used as scientific tools or clinical monitors, additional information regarding how to achieve proper baseline stabilization and calibration is needed.

Methods
Anesthesia was induced and maintained with nitrous oxide, propofol, and an opioid. Tracheal intubation or laryngeal mask insertion was accomplished without muscle relaxants. Thirty adult patients classified as American Society of Anesthesiologists physical status I or II were divided into groups of 10. The mechanical response of the thumb to supramaximal ulnar nerve stimulation was recorded continuously with an acceleromyograph. Group 1 had train-of-four stimuli at 15-s intervals for 25 min. Group 2 had single stimuli at 1.0 Hz for 10 min. Group 3 had the same stimuli as group 1 except that a 50-Hz tetanus of 5 seconds' duration immediately preceded instrument calibration.

Results
In group 1, average twitch height (T1) increased rapidly to 148+/-19% (mean +/- SD) of control at 15 min and then more slowly to reach 158+/-26% of control at 25 min. The train-of-four fade ratio did not vary with the duration of stimulation. In group 2, T1 increased to 172+/-19% of control after 400 stimuli (6.7 min) and 180+/-22% of control at 10 min In group 3, average T1 did not decrease below 97+/-5% or increase above 105+/-15% of control at any time.

Conclusions
A 5-s, 50-Hz tetanus administered before initial twitch calibration considerably shortens the time required to achieve baseline stability.
Lack of Hypercapnic Increase in Cerebral Blood Flow at High Blood Viscosity in Conscious Blood-exchanged Rats
Authors: Lenz Christian , Rebel Annette , Bucci Enrico , van Ackern Klaus , Kuschinsky Wolfgang , Waschke Klaus F. 
Published: November 2003

Background
The hypothesis of a compensatory dilation of cerebral vessels to maintain cerebral blood flow at a high blood viscosity was tested during hypercapnia in the study after replacement of blood by hemoglobin solutions of defined viscosities. If compensatory vasodilation exists at normocapnia at a high blood viscosity, vasodilatory mechanisms may be exhausted when hypercapnia is added, resulting in a lack of increase in cerebral blood flow at hypercapnia.

Methods
In conscious rats, blood was replaced by ultrapurified cross-linked hemoglobin solutions that had defined and shear rate-independent low or high viscosities (low- and high-viscosity groups). Blood viscosity differed threefold between both groups (1.2 vs. 3.6 mP x s). Thereafter, rats inhaled either a normal or an increased concentration of carbon dioxide in air. Cerebral blood flow was determined by the iodo[14C]antipyrine method.

Results
During normocapnia, global and local cerebral blood flows did not differ between both groups. With increasing degrees of hypercapnia, global and local cerebral blood flows were gradually elevated in the low-viscosity group (2.8 ml x mmHg(-1) CO2 x 100 g(-1) x min(-1)), whereas they remained unchanged in the high-viscosity group.

Conclusions
Changes in blood viscosity do not result in changes of cerebral blood flow as long as cerebral vessels can compensate for these changes by vasodilation or vasoconstriction. However, such vascular compensatory adjustments may be exhausted in their response to further pathophysiologic conditions in blood vessels that have already been dilated or constricted as a result of changes in blood viscosity.
Continuous Venovenous Hemofiltration Improves Arterial Oxygenation in Endotoxin-induced Lung Injury in Pigs
Authors: Ullrich Roman , Roeder Georg , Lorber Christine , N. Quezado Zenaide M. , Kneifel Werner , Gasser Harald , Schlag Guenther , Redl Heinz , Germann Peter 
Published: November 2003

Background
Hypoxemia is common in septic acute lung failure. Therapy is mainly supportive, and most trials using specific inhibitors of key inflammatory mediators (ie., tumor necrosis factor alpha, interleukin 1) have failed to prove beneficial. The authors investigated if a nonspecific blood purification technique, using zero-balanced high-volume continuous venovenous hemofiltration (CWH), might improve arterial oxygenation in a fluid-resuscitated porcine model of endotoxin-induced acute lung injury.

Methods
Piglets of both sexes weighing 25-30 kg were anesthetized and mechanically ventilated. After baseline measurements, animals received an intravenous infusion of 0.5 mg/kg endotoxin (Escherichia coli lipopolysaccharide). One hour after endotoxin, animals were randomly assigned to either treatment with CWH (endotoxin + hemofiltration, n = 6) or spontaneous course (endotoxin, n = 6). At 4 h after randomization, animals were killed. Hemofiltration was performed from femoral vein to femoral vein using a standard circuit with an EF60 polysulphone hemofilter.

Results
Endotoxin challenge induced arterial hypoxemia, an increase in peak inspiratory pressure, pulmonary hypertension, and systemic hypotension. Treatment with CWH did not improve systemic or pulmonary hemodynamics. However, arterial oxygenation was increased in endotoxin-challenged animals at 5 h after completion of endotoxin infusion, as compared with animals not receiving CVVH (arterialoxygen tension, 268+/-33 vs. 176+/-67 mm/Hg, respectively, P < 0.01). In addition, treatment with CWH attenuated the endotoxin-induced increase in peak inspiratory pressure and increased lung compliance.

Conclusion
These results suggest that nonspecific blood purification with high-volume CWH improves arterial oxygenation and lung function in endotoxin-induced acute lung injury in pigs, independent of improved hemodynamics, fluid removal, or body temperature.