bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Combining Propofol and Alfentanil on Ventilation, Analgesia, Sedation, and Emesis in Human Volunteers
Authors: Pavlin D. J. , Coda B. , Shen D. D. , Tschanz J. , Nguyen Q. , Schaffer R. , Donaldson G. , Jacobson R. C. , Chapman C. R.
Published: November 2003

Background

Propofol and alfentanil frequently are administered together for intravenous sedation. This study investigated pharmacokinetic and pharmacodynamic interactions between propofol and alfentanil, at sedative concentrations, with specific regard to effects on ventilation, analgesia, sedation, and nausea.

Methods

Ten male volunteers underwent steady-state infusions on 3 separate days consisting of propofol alone, alfentanil alone, or a combination of the two. Target plasma concentrations for propofol were 150, 300, and 600 ng/ml for 1 h at each concentration; for alfentanil it was 40 ng/ml for 3 h. Assessment included serial measurements of (1) ventilatory function (minute ventilation, carbon dioxide production, end-tidal carbon dioxide, ventilatory response to rebreathing 7% CO2); (2) analgesia (subjective pain report in response to graded finger shock and evoked potential amplitude); (3) sedation (subjective rating, observer scores, and digit symbol substitution test); (4) nausea (visual analog scale, 0-100 mm).

Results

During combination treatment, propofol plasma concentration was 22% greater than during propofol alone using replicate infusion schemes (P < 0.009). End-tidal carbon dioxide was unchanged by propofol, and increased equally by alfentanil and alfentanil/propofol combined (delta end-tidal carbon dioxide 7.5 and 6.2 mmHg, respectively). Analgesia with propofol/alfentanil combined was greater than with alfentanil alone. (Pain report decreased 50% by PA vs. 28% for alfentanil, P < 0.05). Sedation was greater with propofol/alfentanil combined than with alfentanil or propofol alone (digit symbol substitution test 30 for propofol/alfentanil combined vs. 57 for alfentanil, and 46 for propofol, P < 0.05). Nausea occurred in 50% of subjects during alfentanil, but in none during propofol/alfentanil combination treatment.

Conclusions

The combination of propofol and alfentanil produced greater sedation and analgesia than that with either drug alone. Propofol offset the emetic effects of alfentanil. Equivalent depression of the carbon dioxide response curve, and elevation of end-tidal carbon dioxide occurred with propofol/alfentanil combined and alfentanil.
Measuring the Performance of Anesthetic Depth Indicators
Authors: Smith Warren D. , Dutton Robert C. , Smith Ty N.
Published: November 2003

Background

An appropriate measure of performance is needed to identify anesthetic depth indicators that are promising for use in clinical monitoring. To avoid misleading results, the measure must take into account both desired indicator performance and the nature of available performance data. Ideally, anesthetic depth indicator value should correlate perfectly with anesthetic depth along a lighter-deeper anesthesia continuum. Experimentally, however, a candidate anesthetic depth indicator is judged against a "gold standard" indicator that provides only quantal observations of anesthetic depth. The standard anesthetic depth indicator is the patient's response to a specified stimulus. The resulting observed anesthetic depth scale may consist only of patient "response" versus "no response," or it may have multiple levels. The measurement scales for both the candidate anesthetic depth indicator and observed anesthetic depth are no more than ordinal; that is, only the relative rankings of values on these scales are meaningful.

Methods

Criteria were established for a measure of anesthetic depth indicator performance and the performance measure that best met these criteria was found.

Results

The performance measure recommended by the authors is prediction probability PK, a rescaled variant of Kim's dy.x measure of association. This performance measure shows the correlation between anesthetic depth indicator value and observed anesthetic depth, taking into account both desired performance and the limitations of the data. Prediction probability has a value of 1 when the indicator predicts observed anesthetic depth perfectly, and a value of 0.5 when the indicator predicts no better than a 50:50 chance. Prediction probability avoids the shortcomings of other measures. For example, as a nonparametric measure, PK is independent of scale units and does not require knowledge of underlying distributions or efforts to linearize or to otherwise transform scales. Furthermore, PK can be computed for any degree of coarseness or fineness of the scales for anesthetic depth indicator value and observed anesthetic depth; thus, PK fully uses the available data without imposing additional arbitrary constraints, such as the dichotomization of either scale. And finally, PK can be used to perform both grouped- and paired-data statistical comparisons of anesthetic depth indicator performance. Data for comparing depth indicators, however, must be gathered via the same response-to-stimulus test procedure and over the same distribution of anesthetic depths.

Conclusions

Prediction probability PK is an appropriate measure for evaluating and comparing the performance of anesthetic depth indicators.
Prospective Examination of Epidural Catheter Insertion
Authors: D'Angelo Robert , Berkebile Brenda L. , Gerancher J. C.
Published: November 2003

Background

Although it is generally accepted that inserting epidural catheters 3-4 cm into the epidural space minimizes complications, no prospective randomized examination of epidural catheter insertion length has been published.

Methods

Eight hundred healthy parturients requesting epidural analgesia were randomized to have open-tip epidural catheters inserted 2, 4, 6, or 8 cm within the epidural space. The incidences of intravenous cannulation, unilateral sensory analgesia, and subsequent catheter dislodgment were recorded. Catheter insertions that resulted in intravenous cannulation or unilateral analgesia were incrementally withdrawn and retested with additional local anesthetic to determine the effectiveness of epidural catheter manipulation.

Results

Epidural catheters inserted 8 cm within the epidural space were more likely to result in intravenous cannulation. Epidural catheters inserted 2 cm within the epidural space were less likely to result in unilateral sensory analgesia but were more likely to become dislodged. Twenty-three percent of epidural catheters inserted > 2 cm within the epidural space required manipulation. Epidural catheters inserted 2 or 4 cm required replacement more often than epidural catheters inserted 6 or 8 cm. Ninety-one percent and 50% of epidural catheters that resulted in unilateral sensory analgesia and intravenous cannulation, respectively, provided analgesia for labor and delivery after incremental withdrawal.

Conclusions

Epidural catheters should be inserted either 2 cm when rapid labor is anticipated or 6 cm when prolonged labor or cesarean delivery is likely. Additionally, epidural catheters that result in intravenous cannulation or unilateral sensory analgesia can be manipulated effectively to provide analgesia for labor and delivery.
Effect of Volatile Anesthetics on Hydrogen Peroxide-induced Injury in Aortic and Pulmonary Arterial Endothelial Cells
Authors: Johnson Michael E. , Sill Christopher J. , Uhl Cindy B. , Halsey Teresa J. , Gores Gregory J.
Published: November 2003

Background

Oxidant damage to endothelial cells occurs during inflammation and reperfusion after ischemia, mediated in part by endogenously produced hydrogen peroxide (H2O2). Previous studies have established a role for increased cytosolic calcium in the mechanism of endothelial oxidant injury, and have suggested that volatile anesthetics may exacerbate oxidant injury in pulmonary endothelium. However, the effect of volatile anesthetics on oxidant injury to systemic arterial endothelial cells, and their effect on oxidant-related changes in cytosolic calcium homeostasis, have not been reported previously.

Methods

Primary cultures of human aortic and pulmonary arterial endothelial cells were studied. The rate of cell death after H2O2 exposure was determined in cell suspension by propidium iodide fluorimetry and lactate dehydrogenase release. The final extent of cell death 24 h after H2O2 exposure was determined in monolayer cultures by methyl thiazolyl tetrazolium reduction. Cytosolic calcium and cell death were determined in single cells using fura-2 and propidium iodide imaging with digitized, multiparameter, fluorescent video microscopy.

Results

In aortic endothelial cells, clinical concentrations of halothane (1.0%) and isoflurane (1.5%) decreased both the rate of cell death and the final extent of cell death after H2O2 exposure, with halothane being more protective. Supraclinical concentrations of halothane (2.7%) and isoflurane (4.0%) were less protective. In pulmonary arterial endothelial cells, halothane and isoflurane had essentially no effect on H2O2-mediated cell death. The protective effect of anesthetic in aortic endothelial cells was not due to an enhanced removal of H2O2 by endogenous enzymes. Hydrogen peroxide exposure caused a large increase in cytosolic calcium well before cell death, and this was moderated by anesthetic treatment.

Conclusions

The effect of volatile anesthetics on oxidant injury to endothelial cells may differ between cells derived from systemic and pulmonary vascular beds. Halothane, and to a lesser extent, isoflurane, protects against oxidant injury in aortic endothelial cells. The mechanism of protection may involve modulation of the interaction of H2O2 with vital cellular constituents, and/or amelioration of the toxic increase in cytosolic calcium that follows such interaction.
Propofol Attenuates Hydrogen Peroxide-induced Mechanical and Metabolic Derangements in the Isolated Rat Heart
Authors: Kokita Naohiro , Hara Akiyoshi
Published: November 2003

Background

Oxygen-derived free radicals are involved in tissue damage during myocardial ischemia and reperfusion. Recent in vitro studies have demonstrated that a beneficial effect of propofol lies on its free radical scavenging properties. The current study, therefore, examined whether propofol is effective against the mechanical and metabolic damage induced by exogenously administered hydrogen peroxide in the isolated rat heart.

Methods

Rat hearts were perfused aerobically with Krebs-Henseleit bicarbonate buffer at a constant flow rate according to Langendorff's technique, while being paced electrically. Hearts were studied in control Krebs-Henseleit bicarbonate buffer, with Intralipid vehicle, with 25 microM or 50 microM propofol for 40 min, and with 50 microM propofol for 30 min followed by Intralipid for 10 min. A similar set of hearts was treated with hydrogen peroxide for 4 min, either in the absence of or beginning 10 min after Intralipid or propofol infusion. Left ventricular pressure was recorded as an index of mechanical function. The tissue concentrations of adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, and creatine phosphate were measured as indices of energy metabolism. The tissue concentration of malondialdehyde was measured to evaluate lipid peroxidation.

Results

Hydrogen peroxide (600 microM) significantly increased the left ventricular end-diastolic pressure, decreased the left ventricular developed pressure (i.e., it produced mechanical dysfunction), and decreased tissue concentrations of adenosine triphosphate and creatine phosphate (i.e., metabolic damage). Hydrogen peroxide also increased the tissue concentration of malondialdehyde. These mechanical and metabolic alterations induced by hydrogen peroxide were significantly attenuated by propofol (25 microM or 50 microM), while the increase in malondialdehyde was completely suppressed by propofol.

Conclusions

The current study demonstrates that in the isolated heart, propofol attenuates both mechanical and metabolic changes induced by exogenously applied hydrogen peroxide. The beneficial action of propofol is probably correlated with reduction of the hydrogen peroxide-induced lipid peroxidation.
Effect of Blood Pressure Changes on Air Flow Dynamics in the Upper Airway of the Decerebrate Cat
Authors: Mayor Alexander H. , Schwartz Alan R. , Rowley James A. , Willey Shannon J. , Gillespie Boyd M. , Smith Philip L. , Robotham James L.
Published: November 2003

Background

Previous studies suggest that upper airway neuromuscular activity can be affected by changes in blood pressure via a baroreceptor-mediated mechanism. It was hypothesized that increases in blood pressure would increase upper airway collapsibility predisposing to airway obstruction at a flow-limiting site in the hypopharynx.

Methods

To examine the effect of blood pressure on upper airway function, maximal inspiratory air flow was determined through the isolated feline upper airway before, during, and after intravenous infusion of phenylephrine (10-20 micrograms.kg-1.min) in six decerebrate, tracheotomized cats. Inspiratory flow, hypopharyngeal pressure, and pressure at the site of pharyngeal collapse were recorded as hypopharyngeal pressure was rapidly decreased to achieve inspiratory flow limitation in the isolated upper airway. Pressure-flow relationships were used to determine maximal inspiratory air flow and its mechanical determinants, the upper airway critical pressure (a measure of pharyngeal collapsibility), and the nasal resistance upstream to the site of flow limitation.

Results

An increased mean arterial blood pressure of 71 +/- 16 mmHg (mean +/- SD) was associated with significant decrease in maximal inspiratory air flow from 147 +/- 38 ml/s to 115 +/- 27 ml.sec-1 (P < 0.01). The decrease in maximal inspiratory air flow was associated with an increase in upper airway critical pressure from -8.1 +/- 3.8 to -5.7 +/- 3.7 cm H2O (p < 0.02), with no significant change in nasal resistance. When blood pressure was decreased to baseline by discontinuing the phenylephrine infusion, maximal inspiratory air flow and upper airway critical pressure returned to their baseline values.

Conclusions

Increased blood pressure increased the severity of upper airway air flow obstruction by increasing pharyngeal collapsibility. Previous studies relating baroreceptor activity to neuromuscular regulation of upper airway tone, are consistent with this effect being mediated by afferent activity from baroreceptors. These findings warrant further study because they suggest the possibility that upper airway obstruction in postoperative patients could either be caused or exacerbated by an increase in blood pressure.
Effects of Ventilation on Hemodynamics and Myocardial Blood Flow during Active Compression-Decompression Resuscitation in Pigs
Authors: Prengel Andreas W. , Lindner Karl H. , Pfenninger Ernst G. , Georgieff Michael
Published: November 2003

Background

Active compression-decompression (ACD) improves hemodynamics and vital organ blood flow during cardiopulmonary resuscitation. The effects of intermittent positive pressure ventilation (IPPV) on ACD have not been studied. This study was designed to compare the effects of ACD with and without IPPV on gas exchange, hemodynamics, and myocardial blood flow.

Methods

After 30 s ventricular fibrillation, 14 tracheally intubated pigs were allocated to receive either ACD combined with IPPV (ACD-IPPV) or ACD alone. In animals treated with ACD-IPPV, the lungs were ventilated using a servo ventilator. Animals treated with ACD received 100% oxygen by a reservoir but ventilation was not assisted.

Results

Minute ventilation (median) was 6.5 and 6.1 l/min after 1 and 7 min of ACD-IPPV, and was 4.2 and 1.6 l/min after 1 and 7 min of ACD. In contrast to ACD-IPPV, PaO2 was less and PaCO2 was greater with ACD. Mean arterial (53 and 40 mmHg; P < 0.05) and mean central venous pressure (25 and 14 mmHg; P < 0.01) were greater during ACD-IPPV as compared with ACD. After administration of epinephrine 0.2 mg/kg, myocardial blood flow increased only in ACD-IPPV treated animals, and 5 min after epinephrine administration, myocardial blood flow was greater during ACD-IPPV (33 ml.min-1.100 g-1) as compared with ACD (15 ml.min-1.100 g-1; P < 0.05). Restoration of spontaneous circulation could be achieved only in animals subjected to ACD-IPPV.

Conclusions

Gas exchange was critically impaired during the late phase of ACD. Compared with ACD-IPPV, myocardial blood flow was less preserved with ACD and was too low to achieve restoration of spontaneous circulation.
Intravenous Opioids Stimulate Norepinephrine and Acetylcholine Release in Spinal Cord Dorsal Horn
Authors: Bouaziz Herve , Tong Chuanyao , Yoon Young , Hood David D. , Eisenach James C.
Published: November 2003

Background

Opioids produce analgesia by direct effects as well as by activating neural pathways that release nonopioid transmitters. This study tested whether systematically administered opioids activate descending spinal noradrenergic and cholinergic pathways.

Methods

The effect of intravenous morphine on cerebrospinal fluid and dorsal horn microdialysate concentrations of norepinephrine and acetylcholine was examined in 20 sheep. Animals received either intravenous morphine or fentanyl alone, or morphine plus intravenous naloxone or intrathecal idazoxan.

Results

Intravenous morphine (0, 0.5, 1 mg/kg, intravenous) produced dose-dependent increases in cerebrospinal fluid norepinephrine and acetylcholine, but not epinephrine or dopamine. Morphine's effect was blocked by intravenous naloxone and by intrathecal idazoxan. In microdialysis experiments, intravenous morphine increased the concentration of norepinephrine and acetylcholine, but not epinephrine or dopamine, in the dorsal horn. In contrast, intravenous morphine exerted no effect on any of these monoamines in the ventral horn. Intravenous naloxone and cervical cord transection each blocked morphine's effect on dorsal horn norepinephrine.

Conclusions

These results support functional studies that indicate that systematically administered opioids cause spinal norepinephrine and acetylcholine release by a naloxone-sensitive mechanism. Idazoxan blockade of morphine's effects on cerebrospinal fluid norepinephrine was unexpected, and suggests that both norepinephrine and acetylcholine release in the spinal cord may be regulated by alpha 2-adrenoceptors. Microdialysis experiments suggest increased norepinephrine and acetylcholine levels in cerebrospinal fluid resulted from intravenous morphine-induced activation of bulbospinal pathways.
Continuous Intracisternal and High Cervical Intrathecal Bupivacaine Analgesia in Refractory Head and Neck Pain
Authors: Appelgren Lennart , Janson Magnus , Nitescu Petre , Curelaru Ioan
Published: November 2003

Background

The upper cervical component of the spinomesencephalic tract and cranial nerves V, VII (nervus intermedius), IX, and X are involved in mechanisms of acute and chronic pain from head and neck structures. To date there is no reliable method for relief of refractory pain (i.e., pain that cannot be relieved by conventional pharmacologic therapies) from these structures. Therefore, we explored continuous intracisternal infusion of bupivacaine for the treatment of refractory pain of the head and neck.

Methods

Intracisternal catheters were inserted in 13 adults with refractory nonmalignant (n = 4) and malignant (n = 9) pain from the head, face, mouth, neck, and upper extremities; 0.5% plain bupivacaine was infused continuously at rates of 1-7 (median 1.5) mg/h with optional bolus doses of 0.5-2.0 mg 4-2 times/h. The efficacy was assessed from pain relief (daily VAS(max), VAS(min), and VAS(mean) scores 0-10), daily doses of intracisternal bupivacaine and total opioid (expressed as mg parenteral morphine-eq), amount of nocturnal sleep, and rates of adverse effects.

Results

The 13 patients were treated for 3-182 days (median 37, total 712 days), 3 patients being treated at home for 10-112 days (median 88, total 210 days). In one patient, the efficacy of the treatment could not be estimated because of advanced senility. Eleven of the remaining 12 patients obtained acceptable pain relief with daily doses of intracisternal bupivacaine ranging from 20 to 118 mg (median 37 mg): VAS(mean) scores decreased from 7 to 2, mean pain relief increased for 30% to 80%, total opioid daily dose decreased from 53 to 36 mg parenteral morphine-eq, and nocturnal sleep increased from 2 to >6h (all figures are median values). Speech, eating, walking, and natural functions were generally not affected. Side effects such as tiredness and malaise, somnolence and sleep, feeling of coldness in the neck and skull base, transient post-spinal puncture headache, paresthesias, hoarseness, dysphagia, transient paresis of the upper/lower extremities, episodic miosis and conjunctival hyperemia, and transient orthostatic arterial hypotension were each observed in one or two patients. No patient presented clinical evidence of phrenic nerve paralysis. There was no nausea or vomiting. No persistent neurologic deficit or death could be attributed to the intracisternal pain treatment.

Conclusions

Continuous intracisternal infusion of bupivacaine may be a useful method in exceptional, well selected patients with refractory pain from the head and neck structures. Further studies are necessary to establish the indications and the safety of the method.
Magnetic Resonance Imaging of the Upper Airway
Authors: Mathru Mali , Esch Oliver , Lang John , Herbert Michael E. , Chaljub Gregory , Goodacre Brian , vanSonnenberg Eric
Published: November 2003

Background

Anesthetic agents inhibit the respiratory activity of upper airway muscles more than the diaphragm, creating a potential for narrowing or complete closure of the pharyngeal airway during anesthesia. Because the underlying mechanisms leading to airway obstruction in sleep apnea and during anesthesia are similar, it was hypothesized that anesthesia-induced pharyngeal narrowing could be counteracted by applying nasal continuous positive airway pressure (CPAP).

Methods

Anesthesia was induced in ten healthy volunteers (aged 25-34 yr) by intravenous administration of propofol in 50-mg increments every 30-s to a maximum of 300 mg. Magnetic resonance images of the upper airway (slice thickness of 5 mm or less) were obtained in the awake state, during propofol anesthesia, and during administration of propofol plus 10 cm nasal CPAP.

Results

Minimum anteroposterior diameter of the pharynx at the level of the soft palate decreased from 6.6 +/- 2.2 mm (SD) in the awake state to 2.7 +/- 1.5 mm (P < 0.05) during propofol anesthesia and increased to 8.43 +/- 2.5 mm (P < 0.05) after nasal CPAP application. Anteroposterior diameter of the pharynx at the level of the dorsum of the tongue increased from 7.9 +/- 3.5 mm during propofol anesthesia to 12.9 +/- 3.6 mm (P < 0.05) after nasal CPAP. Pharyngeal volume (from the tip of the epiglottis to the tip of the soft palate, assuming this space to be a truncated cone) significantly increased from 2,437 +/- 1,008 mm3 during propofol anesthesia to 5,847 +/- 2,827 mm3 (P < 0.05) after nasal CPAP application.

Conclusions

In contrast to the traditional view that relaxation of the tongue causes airway obstruction, this study suggests that airway closure occurs at the level of the soft palate. Application of nasal CPAP can counteract an anesthesia-induced pharyngeal narrowing by functioning as a pneumatic splint. This is supported by the observed reduction in anteroposterior diameter at the level of the soft palate during propofol anesthesia and the subsequent increase in this measurement during nasal CPAP application.
Inotropic Effects of Propofol, Thiopental, Midazolam, Etomidate, and Ketamine on Isolated Human Atrial Muscle
Authors: Gelissen Harry P. M. M. , Epema Anne H. , Henning Robert H. , Krijnen H. John , Hennis Pim J. , den Hertog Adriaan
Published: November 2003

Background

Cardiovascular instability after intravenous induction of anesthesia may be explained partly by direct negative inotropic effects. The direct inotropic influence of etomidate, ketamine, midazolam, propofol, and thiopental on the contractility of isolated human atrial tissue was determined. Effective concentrations were compared with those reported clinically.

Methods

Atrial tissue was obtained from 16 patients undergoing coronary bypass surgery. Each fragment was divided into three strips, and one anesthetic was tested per strip in increasing concentrations (10(-6) to 10(-2) M). Strips were stimulated at 0.5 Hz, and maximum isometric force was measured. Induction agents were studied in two groups, group 1 (n = 7) containing thiopental, midazolam, and propofol, and group 2 (n = 9) consisting of etomidate, ketamine, and propofol.

Results

The tested anesthetics caused a concentration-dependent depression of contractility resulting in complete cessation of contractions at the highest concentrations. The IC50s (mean +/- SEM; microM) for inhibition of the contractility were: thiopental 43 +/- 7.6, propofol 235 +/- 48 (group 1), and 246 +/- 42 (group 2), midazolam 145 +/- 54, etomidate 133 +/- 13, and ketamine 303 +/- 54.

Conclusions

This is the first study demonstrating a concentration-dependent negative inotropic effect of intravenous anesthetics in isolated human atrial muscle. No inhibition of myocardial contractility was found in the clinical concentration ranges of propofol, midazolam, and etomidate. In contrast, thiopental showed strong and ketamine showed slight negative inotropic properties. Thus, negative inotropic effects may explain in part the cardiovascular depression on induction of anesthesia with thiopental but not with propofol, midazolam, and etomidate. Improvement of hemodynamics after induction of anesthesia with ketamine cannot be explained by intrinsic cardiac stimulation.
Pharmacokinetics of Propofol after a Single Dose in Children Aged 1–3 Years with Minor Burns
Authors: Murat I. , Billard V. , Vernois J. , Zaouter M. , Marsol P. , Souron R. , Farinotti R.
Published: November 2003

Background

No complete pharmacokinetic profile of propofol is yet available in children younger than 3 yr, whereas clinical studies have demonstrated that both induction and maintenance doses of propofol are increased with respect to body weight in this age group compared to older children and adults. This study was therefore undertaken to determine the pharmacokinetics of propofol after administration of a single dose in aged children 1-3 yr requiring anesthesia for dressing change.

Methods

This study was performed in 12 children admitted to the burn unit and in whom burn surface area was less than or equal to 12% of total body surface area. Exclusion criteria were: unstable hemodynamic condition, inappropriate fluid loading, associated pulmonary injury, or burn injury older than 2 days. Propofol (4 mg.kg(-1))plus fentanyl (2.5 microg.kg(-1)) was administered while the children were bathed and the burn area cleaned during which the children breathed spontaneously a mixture of oxygen and nitrous oxide (50:50). Venous blood samples of 300 microl were obtained at 5, 15, 30, 60, 90, and 120 min, and 3, 4, 8, and 12 thereafter injection; an earlier sample was obtained from 8 of 12 children. The blood concentration curves obtained for individual children were analyzed by three different methods: noncompartmental analysis, mixed effects population model, and standard two-stage analysis.

Results

Using noncompartmental analysis, total clearance of propofol (+/-SD) was 0.053+/-0.013l.kg(-1).min(-1), volume of distribution at steady state9.5 +/- 3.7l.kg(-1),and residence time 188 +/- 85 min. Propofol pharmacokinetics were best described by a weight-proportional three-compartmental model in both population and two-stage analysis. Estimated and derived pharmacokinetic parameters were similar using these two pharmacokinetic approaches. Results of population versus two-stage analysis are as follow: systemic clearance 0.049 versus 0.048 l.kg(-).min(-1), volume of central compartment 1.03 versus 0.95 l.kg(-1), volume of steady state 8.09 versus 8.17 l.kg(-1).

Conclusions

The volume of the central compartment and the systemic clearance were both greater than all values reported in older children and adults. This is consistent with the increased propofol requirements for both induction and maintenance of anesthesia in children 1-3 yr. (Key words: Anesthesia: pediatric. Pharmacokinetics: propofol.)
Spinal Antinociceptive Action of an N-Type Voltage-dependent Calcium Channel Blocker and the Synergistic Interaction with Morphine
Authors: Omote Keiichi , Kawamata Mikito , Satoh Osamu , Iwasaki Hiroshi , Namiki Akiyoshi
Published: November 2003

Background

Four different voltage-dependent calcium channels (L-, N-, T-, and P-types) are distinguished in the central nervous system. Both L- and N-type calcium channels have been implicated in the release of neurotransmitters from sensory neurons in the spinal cord. It has been demonstrated that intrathecal L-type calcium channel blockers, which alone do not exhibit any antinociceptive effects, potentiate the antinociceptive effect of intrathecal morphine. The current study was designed to investigate the antinociceptive effects of the intrathecally administered N-type calcium channel blocker, omega-conotoxin GVIA (omega-CgTx). The interaction between morphine and omega-CgTx at the level of the spinal cord also was examined.

Methods

In male Sprague-Dawley rats, lumbar intrathecal catheters were chronically implanted. Tail flick and mechanical paw pressure tests were used to assess thermal and mechanical nociceptive thresholds, respectively. Morphine, omega-CgTx, or a combination of morphine and omega-CgTx was administered intrathecally, and the nociceptive thresholds were determined. Isobolographic analyses were used to define the nature of the functional interactions between morphine and omega-CgTx.

Results

Intrathecal omega-CgTx produced antinociception in a dose- and time-dependent manner. Isobolographic analyses revealed that intrathecal omega-CgTx and morphine interacted synergistically in both nociceptive tests.

Conclusions

This study indicates the importance of the N-type calcium channel in the spinal cord on nociception and suggests the functional interaction between the N-type calcium channel blocker and opioid at the level of the spinal cord.
Cardiovascular Events in the Postanesthesia Care Unit
Authors: Rose D. Keith , Cohen Marsha M. , DeBoer Donald P.
Published: November 2003

Background

The purpose of this study was to determine the relationship of four postanesthesia care unit (PACU) cardiovascular events to long-term outcomes (unplanned critical care admission or mortality) and to evaluate the contribution of anesthetic management compared with other perioperative factors in predicting these events.

Methods

For patients admitted to the PACU after receiving general anesthesia (n = 18,380), the risk of long-term outcomes was examined for patients in the PACU with hypertension, tachycardia, bradycardia, or hypotension. Using logistic regression (P < 0.05), risk factors (grouped as patients, surgical, anesthetic, operating room observations, and other PACU observations) for each cardiovascular event were determined. For each factor grouping, the relative contributions to each cardiovascular event were compared using maximum likelihood chi-square analysis.

Results

Patients in the PACU with hypertension or tachycardia had more unplanned critical care admissions (2.6% and 4.0% vs. 0.2% for patients with no events) and greater mortality (1.9% and 2.3% vs. 0.3% and 0.4%) (P < 0.01). For PACU hypertension (rate 2.0%), age, smoking, renal disease, female gender, and angina were significant risk factors. For PACU tachycardia (0.9%), intraoperative tachycardia and dysrhythmia were the major contributors. Patient factors also increased the risk of bradycardia (2.5%); namely age, ASA physical status 1 or 2, and preoperative beta blocker therapy. For hypotension (2.2%), duration of surgery > 2 h, completion after 6 PM, and gynecologic intraabdominal procedures were significant risk factors. Compared to patient, surgical, intraoperative, or PACU observations, anesthetic factors studied (premedication, induction agent, ventilation, use of opioids) provided only a small contribution in predicting these events.

Conclusions

Hypertension and tachycardia in the PACU, although infrequent, are associated with increased risk of unplanned critical care admission and mortality. Patient, surgical, intraoperative, or PACU observations contribute more to cardiovascular events in the PACU than do differences in anesthetic management identified in this study.
Randomized, Single-blinded Trial of Laparoscopic Versus Open Appendectomy in Children
Authors: Lejus C. , Delile L. , Plattner V. , Baron M. , Guillou S. , Heloury Y. , Souron R.
Published: November 2003

Background

The benefit of laparoscopy to patients has been clearly established in adults undergoing cholecystectomy. Results are less clear for appendectomy. The current study was undertaken to compare the respective 3-day postoperative periods after laparoscopic and open appendectomy in children.

Methods

Sixty-three children (aged 8-15 yr) scheduled for appendectomy were randomly assigned to two groups: open and laparoscopic. Postoperative evaluation included delay of postoperative recovery (walking and feeding), pain assessment by visual analog scale during the 3 subsequent days, amount of nalbuphine administered via a patient-controlled analgesia system during the first 48 h and responses by children, parents, and nurses on the overall quality of analgesia.

Results

There was no difference between groups for demographic data (particularly macroscopic aspect of appendix) analgesia, sedation, delay before eating and walking, incidence of urinary retention, nausea, vomiting. Operative time was long (P < or = to 0.05) in the laparoscopic group (54 +/- 17 min) than in the open group (39 +/- 18 min). Thirty five percent of the children had pain at the shoulder in the LAP group versus ten percent in the open group (P < or = 0.05).

Conclusions

Laparoscopy did not improve analgesia and postoperative recovery after appendectomy in children.
Pharmacokinetics and Pharmacodynamics of Remifentanil in Volunteer Subjects with Severe Liver Disease
Authors: Dershwitz Mark , Hoke J. Frank , Rosow Carl E. , Michalowski Piotr , Connors Patricia M. , Muir Keith T. , Dienstag Jules L.
Published: November 2003

Background

Remifentanil, a new mu-opioid agonist with an extremely short duration of action, is metabolized by circulating and tissue esterases; therefore, its clearance should be relatively unaffected by changes in hepatic or renal function. This study was designed to determine whether severe hepatic disease affects the pharmacokinetics or pharmacodynamics of remifentanil.

Methods

Ten volunteers with chronic, stable, severe hepatic disease and awaiting liver transplantation and ten matched controls were enrolled. Each subject was given a 4-h infusion of remifentanil. The first five pairs received 0.0125 microgram x kg(-1) x min(-1) for 1 h followed by 0.025 microgram x kg(-1) x min(-1) for 3 h; the second five pairs received double these infusion rates. During and after the infusion, arterial blood was obtained for pharmacokinetic analyses, and the ventilatory response to a hypercarbic challenge was assessed. Simultaneous pharmacokinetic and pharmacodynamic analyses were performed. The pharmacokinetics were described using a one-compartment intravenous infusion model, and ventilatory depression was modelled using the inhibitory E(max) model. The pharmacokinetics of the metabolite GR90291 were determined using noncompartmental methods.

Results

There were no differences in any of the pharmacokinetic parameters for remifentanil or GR90291 between the two groups. The subjects with liver disease were more sensitive to the ventilatory depressant effects of remifentanil. The EC(50) values (the remifentanil concentrations determined from simultaneous pharmacokinetic/pharmacodynamic analyses to depress carbon dioxide-stimulated minute ventilation by 50%) in the control and hepatic disease groups were 2.52 ng/ml (95% confidence interval 2.07-2.97 ng/ml) and 1.56 ng/ml (95% confidence interval 1.37-1.76 ng/ml), respectively.

Conclusions

The pharmacokinetics of remifentanil and GR90291 are unchanged in persons with severe, chronic liver disease. Such patients may be more sensitive to the ventilatory depressant effects of remifentanil, a finding of uncertain clinical significance, considering the extremely short duration of action of the drug.
Pharmacokinetics and Analgesic Effect of Ropivacaine during Continuous Epidural Infusion for Postoperative Pain Relief
Authors: Erichsen Carl-Johan , Sjovall Jan , Kehlet Henrik , Hedlund Cecilia , Arvidsson Torbjorn
Published: November 2003

Background

The pharmacokinetics and clinical efficacy of ropivacaine (2.5 mg/ml) during a 24-h continuous epidural infusion for postoperative pain relief in 20 patients scheduled for abdominal hysterectomy were characterized using an open-label, increasing-dose design.

Methods

Through an epidural catheter inserted at T10-T12, a test dose of 7.5 mg ropivacaine was given 3 min before a bolus dose of 42.5 mg and immediately followed by a 24-h continuous epidural infusion with either 10 or 20 mg/h. Peripheral venous plasma samples were collected up to 48 h after infusion, and urinary excretion was followed up to the end of infusion. Postoperative pain at rest, on coughing, and at mobilization was assessed by means of a visual analog scale 2,4,6,8,12, and 24 h after the end of surgery. Sensory (pinprick) and motor block (modified Bromage scale) were assessed at the same intervals.

Results

The total plasma concentrations of ropivacaine increased markedly and consistently during the 24-h epidural infusion, in contrast to stable unbound concentrations. Both total and unbound plasma concentrations at the end of infusion were proportional to the total dose, although only the latter was proportional to the infusion rate. The total and unbound plasma clearance was independent of dose. Total mean clearance decreased on average by 21% (P < 0.001) during the last 12 h of epidural infusion, i.e., from 539 +/- 191 ml/min to 418 +/- 138 ml/min, indicating time-dependent kinetics. The unbound clearance also varied between estimates after 8 h of infusion and the end of treatment, i.e., a 5.3% decrease from 10.4 +/- 5.3 l/min to 9.5 +/- 3.9 l/min (P < 0.05). The unbound fraction of ropivacaine in plasma decreased during treatment, and this was related to the increase in alpha1-acid glycoprotein concentration. Pain was generally well controlled, and median visual analog scale scores during mobilization were less than 30 mm in patients receiving ropivacaine at 20 mg/h.

Conclusions

The pharmacokinetics of ropivacaine were independent of dose, but total clearance decreased with time over 24 h. The consistent increase in total plasma concentration during the postoperative epidural infusion contrasted to much less variation in the unbound plasma concentrations of ropivacaine.
Location and Characteristics of Nitric Oxide Synthase in Sheep Spinal Cord and Its Interaction with α2-Adrenergic and Cholinergic Antinociception
Authors: Xu Zemin , Li Ping , Tong Chuanyao , Figueroa Jorge , Tobin Joseph R. , Eisenach James C.
Published: November 2003

Background

Nitric oxide synthase is located in the spinal cord dorsal horn and intermediolateral cell column, where it may modulate sensory and sympathetic neuronal activity. However, the biochemical characteristics of this enzyme have not been examined in these different areas in the spinal cord. Although alpha(2)-adrenergic agonists, muscarinic agonists, and nitric oxide may interact in the spinal cord to produce antinociception, these interactions have not been characterized.

Methods

Sheep spinal cord tissue was homogenized ad centrifuged at high sped to separate soluble and membrane-bound fractions. Nitric oxide synthase activity was determined by conversion of [(14)C]-L-arginine to [(14)C]-L-citrulline and its kinetic characteristics, dependency on cofactors, and sensitivity to inhibitors determined. Sheep spinal cord was stained for nicotinamide adenine dinucleotide phosphate diaphorase as a marker for nitric oxide synthase. Antinociception to a mechanical stimulus from intrathecal clonidine alone and with neostigmine was determined and the effects of L-arginine and n-methyl-L-arginine were determined.

Results

More than 85% of nitric oxide synthase activity was present in the soluble form and its kinetic, cofactor, and antagonist properties were similar to those of the neuronal isoform of nitric oxide synthase. Biochemical and histochemical studies localized nitric oxide synthase to the superficial dorsal horn and the intermediolateral cell column. Clonidine antinociception was enhanced by L-arginine and neostigmine, but not by D-arginine. Neostigmine's enhancement of clonidine antinociception was blocked by n-methyl-L-arginine.

Conclusions

These results confirm those of previous studies demonstrating localization of nitric oxide synthase to superficial dorsal horn and intermediolateral cell column of mammalian spinal cord, and suggesting its identity as the neuronal isoform. Spinal alpha(2)-adrenergic agonist antinociception may be partly dependent on cholinergic and nitric oxide mechanisms.
Continuous Intrathecal Administration of Short-lasting micro Opioids Remifentanil and Alfentanil in the Rat
Authors: Buerkle Hartmut , Yaksh Tony L.
Published: November 2003

Background

Lipid soluble mu opioids given intrathecally produce a potent, dose-dependent analgesic response, which because of rapid clearance, is of short duration. Such agents delivered by continuous infusion can result in systemic accumulation and significant extraspinally mediated side effects. The effects of intrathecal infusions of two lipid-soluble mu opioids were investigated: remifentanil, an esterase metabolized agent with an inactive metabolite, and alfentanil.

Methods

Rats with chronic lumbar intrathecal catheters received intrathecal infusions (in flow rates of 1.0 microliters/min and 0.1 microliters/min) of remifentanil or alfentanil and were tested for hind paw thermal withdrawal latency, supraspinal side effects (sedation, block of pinna, and corneal responses) and motor impairment. Remifentanil was delivered either in a glycine formulation (R(g)) or in a saline vehicle (R(s)). Separate studies with the glycine vehicle also were undertaken.

Results

At an infusion rate of 0.1 microliters/min, remifentanil and alfentanil produced naloxone-reversible, dose-dependent analgesia and supraspinal side effects with the intrathecal ED(50) (micrograms/min; 95% confidence interval) for analgesia: R(s) = 1.5 (1.2-1.8), R(g) = 1.2 (0.7-2.3); alfentanil = 1.5 (1.4-1.6) and for supraspinal side effects: R(s) = 1.7 (1.4-1.9); R(g) = 1.9 (1.6-2.4); alfentanil = 1.5 (1.4-1.7). There was no difference in potency or time until onset for analgesia at either delivery rate (12-20 min), whereas for supraspinal side effects, 1.0 microliters/min resulted in a faster onset for R(g). Recovery of normal thresholds after equianalgesic doses was faster in R(s) than alfentanil and for the supraspinal index faster in R(s) and R(g) groups. R(g), but not R(s), or alfentanil, produced a dose-dependent motor impairment after 90 min of intrathecal infusion at a flow rate of 0.1 microliters/min. Both glycine in R(g) and glycine (matching glycine dose) alone showed parallel time courses for motor impairment and similar intrathecal ED(50) (6.6 vs. 6.4 micrograms/min over 90 min) for this nonnaloxone reversible effect. Intrathecal bolus administration of the same total dose of glycine showed no significant motor effects.

Conclusions

Remifentanil has a rapid onset like alfentanil but shows a faster recovery of action after intrathecal infusion. Despite its rapid clearance, remifentanil induces supraspinal side effects at analgesic effective doses. Moreover, in the current formulation, with glycine, a reversible motor impairment can occur after intrathecal delivery.
Isoform-dependent Effects of Halothane in Human Skinned Striated Fibers
Authors: Tavernier Benoit M. , Haddad Elie , Adnet Pascal J. , Etchrivi Toussaint S. , Lacroix Dominique , Reyford Hugo
Published: November 2003

Background

Reports of the effects of halothane on isoform contractile proteins of striated muscles are conflicting. To determine whether halothane affects cardiac and skeletal contractile proteins differently, the authors examined the effects of two doses of halothane (0.44 and 1.26 mM, equivalent to 0.75 and 2.25 vol%, respectively) on the Ca++ sensitivity and maximal force in human skinned cardiac, type I (slow twitch), and type II (fast twitch) skeletal muscle fibers.

Methods

Left ventricular muscle strips and skeletal muscle biopsy specimens were obtained from eight and ten patients undergoing cardiac and orthopedic surgery, respectively. Sarcolemma and sarcoplasmic reticulum were destroyed with ethylene glycol bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid plus Brij 58. Ca++ sensitivity was studied by observing the isometric tension developed by skinned fibers challenged with increasing concentrations of Ca++. Muscle fiber type was determined in each skeletal fiber by the difference in strontium-induced tension measurements.

Results

Halothane shifted the Ca++ tension curves toward higher Ca++ concentrations and increased the Ca++ concentrations for half-maximal activation in both cardiac and type I skeletal muscle fibers (from 1.96 microM and 1.06 microM under control conditions to 2.92 microM and 1.71 microM in presence of 0.75 vol% halothane, respectively) without changing the slope of this relationship (Hill coefficient). In contrast, no significant effect was observed in type II fibers. Halothane also decreased the maximal activated tension in the three groups of fibers with a lesser effect in type II fibers.

Conclusions

Halothane decreases Ca++ sensitivity and maximal force in human skinned cardiac and type I fibers at 20 degrees C. It is concluded that the negative inotropic effects of halothane depend on contractile proteins isoforms.