bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in Cardiotoxicity of Bupivacaine and Ropivacaine Are the Result of Physicochemical and Stereoselective Properties
Authors: Graf Bernhard M. , Abraham Ingo , Eberbach Nicole , Kunst Gudrun , Stowe David F. , Martin Eike
Published: November 2003

Background

Ropivacaine is believed to have a lower incidence of clinical cardiac side effects than bupivacaine. The aim of this study was to compare the direct cardiac effects of the optically pure S(-)-ropivacaine isomer and its nonclinically used R(+)-isomer with both optically pure bupivacaine isomers in isolated hearts. The hypothesis was that differences in direct cardiac effects are distinguished not only by stereoselective actions of local anesthetic molecules to specific receptors, but also by physicochemical differences triggered by replacing the butyl- by a propyl-residual on pipecoloxylide.

Methods

Guinea pig hearts (n = 31) were excised and perfused by the Langendorff method. Atrial and ventricular bipolar electrodes were placed to measure heart rate and atrioventricular conduction time. Left ventricular pressure, coronary flow, and oxygen tensions were measured. Twelve hearts were perfused with increasing concentrations (0.5, 1.0, 5.0, and 10 microm) of both isomers of bupivacaine, and 13 hearts were perfused with the same concentrations of ropivacaine isomers. Six hearts were perfused with higher concentrations (20, 30, 40, and 50 microm) of both isomers of ropivacaine. The order of isomers and anesthetic chosen were randomized.

Results

Both anesthetics had negative inotropic and chronotropic effects without evidence of stereoselectivity. Equal concentrations of both isomers of bupivacaine had negative inotropic effects greater than that of ropivacaine isomers. Atrioventricular conduction time was prolonged by both anesthetics in a concentration-dependent manner, but bupivacaine isomers increased atrioventricular conduction time more than ropivacaine isomers. In contrast to other variables, atrioventricular conduction time showed evident stereoselectivity for bupivacaine at the lowest concentration (0.5 microm) but only at higher concentrations for ropivacaine (> 30 microm). The R(+)-isomer was more potent than the S(-)-isomer on increasing atrioventricular conduction time for both bupivacaine and ropivacaine.

Conclusions

The results confirm that stereoselectivity can be demonstrated by a lengthening of atrioventricular conduction time for the more fat-soluble bupivacaine. However, for the less fat-soluble ropivacaine, the S(-)-isomer has no advantage over the R(+)-isomer for preventing slowing of atrioventricular conduction in clinical concentrations. Neither anesthetic showed stereoselective inotropic effects, but ropicavaine isomers had lesser cardiodepressant effects than bupivacaine isomers because of the replacement of the butyl- by a propyl-terminal group.
Role of Adenosine Receptors in Spinal G-Protein Activation after Peripheral Nerve Injury
Authors: Bantel Carsten , Childers Steven R. , Eisenach James C.
Published: November 2003

Background

Spinally injected adenosine induces antinociception in animal models of neuropathic but not acute pain. The reasons for this discrepancy remain unclear. Adenosine receptors are coupled to G proteins, and increased efficiency of adenosine-induced G-protein activity in neuropathic pain could contribute to the antinociceptive effect of adenosine. In this study the authors used [(35)S]guanosine-5'-O-(3-thiotriphosphate) ([(35)S]GTP gamma S) autoradiography in rat spinal cord sections to test this possibility.

Methods

The spinal cords of normal animals and those that underwent left L5 and L6 spinal nerve ligation (SNL) were removed and immediately frozen. Horizontal spinal cord sections were cut and mounted on chrom-alum gelatin-subbed slides. Sections were incubated with guanosine diphosphate, [(35)S]GTP gamma S, the adenosine A1 agonist R-N6-phenylisopropyladenosine, and various other drugs, apposed to films, and analyzed.

Results

Baseline and R-N6-phenylisopropyladenosine-stimulated [(35)S]GTP gamma S binding was predominantly localized to the superficial dorsal horns of both normal and SNL animals. This binding was significantly increased in SNL compared with normal animals. In contrast, no difference in R-N6-phenylisopropyladenosine-stimulated [(35)S]GTP gamma S binding was observed between SNL and normal animals. Blockade of adenosine A1 receptors by 1,3-dipropyl-8-cyclopentylxanthine, or adenosine destruction by added adenosine deaminase, reduced the increased basal activity in SNL to baseline levels of normal dorsal horns, whereas atropine and naloxone had no effect.

Conclusion

This study shows an increased basal G-protein activity in lumbar spinal cords during conditions of SNL. The data suggest that increased adenosine release during conditions of SNL results in an increased basal activity of G proteins in the spinal cord during neuropathic pain.
Nicotinic Acetylcholine Receptor Regulation of Spinal Norepinephrine Release
Authors: Li Xinhui , Eisenach James C.
Published: November 2003

Background

Neuronal nicotinic acetylcholine receptor (nAChR) agonists produce antinociception in animals. nAChRs exist almost exclusively on presynaptic terminals in the central nervous system and stimulate neurotransmitter release. This study tested whether nAChR agonists stimulate spinal release of the neurotransmitter norepinephrine either by direct actions on noradrenergic terminals or indirectly by stimulating release of other neurotransmitters to induce norepinephrine release.

Methods

Adult male rats were anesthetized and microdialysis probes inserted in the L2-L4 dermatomes of the spinal cord. Probes were perfused with artificial cerebrospinal fluid containing nicotine, the specific alpha(4)beta(2*) nAChR agonist metanicotine, or nicotine plus nAChR antagonists and norepinephrine measured in the microdialysates. The effects of specific glutamate receptor antagonists and nitric oxide synthase inhibitors were also examined. To determine direct effects on noradrenergic terminals, synaptosomes were prepared from spinal cord and incubated with nAChR agonists and antagonists.

Results

Both nicotine and metanicotine induced norepinephrine release in spinal microdialsyates, an effect reduced by nicotinic antagonists but not glutamate antagonists or nitric oxide synthase inhibitors. Both of the nicotinic agonists stimulated norepinephrine release in synaptosomes, and the effect of metanicotine was blocked at lower concentrations of alpha(4)beta(2*)- than alpha(7*)-preferring nAChR antagonists.

Conclusion

These results suggest that one mechanism by which nAChR agonists act for analgesia is to stimulate spinal norepinephrine release. They do so by actions on alpha(4)beta(2*) nAChRs, and perhaps other subtypes, most likely located on noradrenergic terminals, rather than by indirectly stimulating norepinephrine release through glutamate release or nitric oxide synthesis.
Isoflurane-induced Dilation of Porcine Coronary Microvessels Is Endothelium Dependent and Inhibited by Glibenclamide
Authors: Gamperl A. Kurt , Hein Travis W. , Kuo Lih , Cason Brian A.
Published: November 2003

Background

Isoflurane has been reported to cause dose-dependent constriction in isolated coronary microvessels. However, these results are inconsistent with data from in situ and in vivo heart preparations which show that isoflurane dilates the coronary vasculature. To clarify the direct effects of isoflurane on coronary tone, we measured the response of isolated porcine resistance arterioles (ID, 75 +/- 4.0 microm; range, 41-108 microm) to isoflurane in the presence and absence of adenosine triphosphate-sensitive and Ca2+-activated potassium channel blockers and also after endothelial removal.

Methods

Subepicardial arterioles were isolated, cannulated, and pressurized to 45 mmHg without flow in a 37 degrees C vessel chamber filled with MOPS buffer (pH = 7.4). After all vessels developed spontaneous (intrinsic) tone, dose-dependent (0.17-0.84 mm; approximately 0.5-2.5 minimum alveolar concentration) isoflurane-mediated effects on vessel ID were studied in the presence and absence of extraluminal glibenclamide (1 microm; an adenosine triphosphate-sensitive channel blocker) or iberiotoxin (100 nm; a Ca2+-activated potassium channel blocker) or before and after endothelial denudation using the nonionic detergent CHAPS (0.4%). Vessel ID was measured using an inverted microscope and videomicrometer, and vasomotor responses were analyzed by normalizing changes in arteriole ID to the dilation observed after exposure to 10-4 m sodium nitroprusside, which causes maximal dilation.

Results

Isoflurane caused dose-dependent dilation of all coronary arterioles. This vasodilation was 6.0 +/- 0.7 microm at an isoflurane concentration of 0.16 mm (approximately 0.5 minimum alveolar concentration) and 25.3 +/- 2.1 microm at 0.75 mm (approximately 2.5 minimum alveolar concentration). These values represent 18.1 +/- 1.7% and 74.1 +/- 3.3%, respectively, of that observed with 10-4 sodium nitroprusside (34 +/- 3 microm). Glibenclamide, but not iberiotoxin, exposure affected arteriolar dilation in response to isoflurane. Glibenclamide caused a downward displacement of the isoflurane dose-response curve, reducing isoflurane-mediated dilation by an average of 36%. Denuded arterioles showed a marked (approximately 70%) reduction in their ability to dilate in response to isoflurane.

Conclusions

The authors conclude that isoflurane dilates coronary resistance arterioles in a dose-dependent manner, and that this dilation is partially mediated by adenosine triphosphate-sensitive channels and is highly dependent on the presence of a functioning endothelium.
Effects of Xenon on In Vitro and In Vivo Models of Neuronal Injury
Authors: Wilhelm Stefan , Ma Daqing , Maze Mervyn , Franks Nicholas P.
Published: November 2003

Background

Xenon, the "inert" gaseous anesthetic, is an antagonist at the N-methyl-D-aspartate (NMDA)-type glutamate receptor. Because of the pivotal role that NMDA receptors play in neuronal injury, the authors investigated the efficacy of xenon as a neuroprotectant in both in vitro and in vivo paradigms.

Methods

In a mouse neuronal-glial cell coculture, injury was provoked either by NMDA, glutamate, or oxygen deprivation and assessed by the release of lactate dehydrogenase into the culture medium. Increasing concentrations of either xenon or nitrogen (10-75% of an atmosphere) were coadministered and maintained until injury was assessed. In separate in vivo experiments, rats were administered N-methyl-dl-aspartate and killed 3 h later. Injury was quantified by histologic assessment of neuronal degeneration in the arcuate nucleus of the hypothalamus.

Results

Xenon exerted a concentration-dependent protection against neuronal injury provoked by NMDA (IC(50) = 19 +/- 6% atm), glutamate (IC(50) = 28 +/- 8% atm), and oxygen deprivation (IC(50) = 10 +/- 4% atm). Xenon (60% atm) reduced lactate dehydrogenase release to baseline concentrations with oxygen deprivation, whereas xenon (75% atm) reduced lactate dehydrogenase release by 80% with either NMDA- or glutamate-induced injury. In an in vivo brain injury model in rats, xenon exerted a concentration-dependent protective effect (IC(50) = 78 +/- 8% atm) and reduced the injury by 45% at the highest xenon concentration tested (75% atm).

Conclusions

Xenon, when coadministered with the injurious agent, exerts a concentration-dependent neuroprotective effect at concentrations below which anesthesia is produced in rodents. Unlike either nitrous oxide or ketamine (other anesthetics with NMDA antagonist properties), xenon is devoid of both neurotoxicity and clinically significant adverse hemodynamic properties. Studies are proposed to determine whether xenon can be used as a neuroprotectant in certain clinical settings.
Effects of Volatile Anesthetics on Glutamate Transporter, Excitatory Amino Acid Transporter Type 3
Authors: Do Sang-Hwan , Kamatchi Ganesan L. , Washington Jacqueline M. , Zuo Zhiyi
Published: November 2003

Background

Glutamate transporters play an important role in maintaining extracellular glutamate homeostasis. The authors studied the effects of volatile anesthetics on one type of glutamate transporters, excitatory amino acid transporter type 3 (EAAT3), and the role of protein kinase C in mediating these effects.

Methods

Excitatory amino acid transporter type 3 was expressed in Xenopus oocytes by injection of EAAT3 mRNA. Using two-electrode voltage clamp, membrane currents were recorded before, during, and after application of L-glutamate. Responses were quantified by integrating the current trace and are reported as microcoulombs. Data are mean +/- SEM.

Results

L-Glutamate-induced responses were increased gradually with the increased concentrations of isoflurane, a volatile anesthetic. At 0.52 and 0.70 mm isoflurane, the inward current was significantly increased compared with control. Isoflurane (0.70 mm) significantly increased Vmax (maximum velocity) (3.6 +/- 0.4 to 5.1 +/- 0.4 microC; P < 0.05) but not Km (Michoelis-Menten Constant) (55.4 +/- 17.0 vs. 61.7 +/- 13.6 microm; P > 0.05) of EAAT3 for glutamate compared with control. Treatment of the oocytes with phorbol-12-myrisate-13-acetate, a protein kinase C activator, caused a significant increase in transporter current (1.7 +/- 0.2 to 2.5 +/- 0.2 microC; P < 0.05). Responses in the presence of the combination of phorbol-12-myrisate-13-acetate and volatile anesthetics (isoflurane, halothane, or sevoflurane) were not greater than those when volatile anesthetic was present alone. Oocytes pretreated with any of the three protein kinase C inhibitors alone (chelerythrine, staurosporine, or calphostin C) did not affect basal transporter current. Although chelerythrine did not change the anesthetic effects on the activity of EAAT3, staurosporine or calphostin C abolished the anesthetic-induced increase of EAAT3 activity.

Conclusions

These data suggest that volatile anesthetics enhance EAAT3 activity and that protein kinase C is involved in mediating these anesthetic effects.
Mechanisms of Desflurane-induced Preconditioning in Isolated Human Right Atria In Vitro
Authors: Hanouz Jean-Luc , Yvon Alexandra , Massetti Massimo , Lepage Olivier , Babatasi Gérard , Khayat André , Bricard Henri , Gérard Jean-Louis
Published: November 2003

Background

The authors examined the role of adenosine triphosphate-sensitive potassium (K(ATP)) channels, adenosine A1 receptor, and alpha and beta adrenoceptors in desflurane-induced preconditioning in human myocardium, in vitro.

Methods

The authors recorded isometric contraction of human right atrial trabeculae suspended in oxygenated Tyrode's solution (34 degrees C; stimulation frequency, 1 Hz). Before a 30-min anoxic period, 3, 6, and 9% desflurane was administered during 15 min. Desflurane, 6%, was also administered in the presence of 10 microm glibenclamide, a K(ATP) channels antagonist; 10 microm HMR 1098, a sarcolemmal K(ATP) channel antagonist; 800 microm 5-hydroxy-decanoate (5-HD), a mitochondrial K(ATP) channel antagonist; 1 microm phentolamine, an alpha-adrenoceptor antagonist; 1 microm propranolol, a beta-adrenoceptor antagonist; and 100 nm 8-cyclopentyl-1,3-dipropylxanthine (DPX), the adenosine A1 receptor antagonist. Developed force at the end of a 60-min reoxygenation period was compared (mean +/- SD).

Results

Desflurane at 3% (95 +/- 13% of baseline), 6% (86 +/- 6% of baseline), and 9% (82 +/- 6% of baseline) enhanced the recovery of force after 60 min of reoxygenation as compared with the control group (50 +/- 11% of baseline). Glibenclamide (60 +/- 12% of baseline), 5-HD (57 +/- 21% of baseline), DPX (63 +/- 19% of baseline), phentolamine (56 +/- 20% of baseline), and propranolol (63 +/- 13% of baseline) abolished desflurane-induced preconditioning. In contrast, HMR 1098 (85 +/- 12% of baseline) did not modify desflurane-induced preconditioning.

Conclusions

In vitro, desflurane preconditions human myocardium against simulated ischemia through activation of mitochondrial K(ATP) channels, adenosine A1 receptor, and alpha and beta adrenoceptors.
Positioning in Anesthesiology
Authors: Coppieters Michel W. , Van De Velde Marc , Stappaerts Karel H.
Published: November 2003

Background

Stretch-induced neuropathy of the brachial plexus and median nerve in conventional perioperative care remains a relatively frequent and poorly understood complication. Guidelines for positioning have been formulated, although the protective effect of most recommendations remains unexamined. The similarity between the stipulated potentially dangerous positions and the components of the brachial plexus tension test (BPTT) justified the analysis of the BPTT to quantify the impact of various arm and neck positions on the peripheral nervous system.

Methods

Four variations of the BPTT in three different shoulder positions were performed in 25 asymptomatic male participants. The impact of arm and neck positions on the peripheral nervous system was evaluated by analyzing the maximal available range of motion, pain intensity, and type of elicited symptoms during the BPTT.

Results

Cervical contralateral lateral flexion, lateral rotation of the shoulder and fixation of the shoulder girdle in a neutral position in combination with shoulder abduction, and wrist extension all significantly reduced the available range of motion. Elbow extension also challenged the nervous system substantially. A cumulative impact could be observed when different components were simultaneously added, and a neutralizing effect was noted when an adjacent region allowed for unloading of the nervous system.

Conclusions

The experimental findings support the experientially based guidelines for positioning. Especially when simultaneously applied, submaximal joint positions easily load the nervous system, which may substantially compromise vital physiologic processes in and around the nerve. Therefore, even when the positioning of all upper limb joints is carefully considered, complete prevention of perioperative neuropathy seems almost inconceivable.
Effects of Subhypnotic Doses of Propofol on Gastric Emptying in Volunteers
Authors: Chassard Dominique , Lansiaux Sabine , Duflo Frédéric , Mion François , Bleyzac Nathalie , Debon Richard , Allaouchiche Bernard
Published: November 2003

Background

Drugs which accelerate gastric emptying (GE) decrease nausea and vomiting. This could contribute to the antiemetic potential of subhypnotic doses of propofol. On the contrary, subhypnotic doses of propofol used for sedation could decrease GE and thus favor regurgitation and pulmonary inhalation. Therefore, the aim of this study was to assess the effect of low-dose propofol infusion on GE.

Methods

On three separate occasions, 10 volunteers received either a propofol infusion at a rate set to achieve a target plasma concentration of 0.5 microg/ml or equivalent volumes of 10% Intralipid(R) or 0.9% saline. GE for solids was measured by using the octanoic acid breath test. An acetaminophen absorption technique measured the GE rate for liquids. Blood samples were assayed for acetaminophen and propofol. Breath samples were analyzed for (13)CO(2) concentration by isotope-ratio mass spectrometry. Carbon dioxide production (VCO(2)) was measured instead of calculated by indirect calorimetry. Sedation was evaluated by the Bispectral Index of the electroencephalogram.

Results

Propofol blood concentrations were 0.32 +/- 0.20 and 0.45 +/- 0.18 microg/ml at 60 and 165 min, respectively. These concentrations were not sedative. Propofol or its solvent did not modify GE for solids or liquids. In all groups, differences in GE were obtained if measured VCO(2) was integrated in the formula instead of calculated VCO(2) (P < 0.002).

Conclusions

Subhypnotic doses of propofol known to be antiemetic do not inhibit GE. These results suggest that the antiemetic properties of propofol are not peripheral and that propofol cannot be considered as a prokinetic agent. V(13)CO(2) must be measured instead of calculated to accurately determine GE.
Gabapentin Suppresses Cutaneous Hyperalgesia following Heat-Capsaicin Sensitization
Authors: Dirks Jesper , Petersen Karin L. , Rowbotham Michael C. , Dahl Jørgen B.
Published: November 2003

Background

The anticonvulsant gabapentin, proven effective for neuropathic pain in two large, placebo-controlled clinical trials, is widely used for treatment of chronic pain. Preclinical studies have demonstrated analgesic and antiallodynic effects in models involving neuronal sensitization and nerve injury, without affecting acute pain transmission. The aim of the present study was to link data from animal models and clinical trials for chronic pain by investigating the effect of gabapentin on acute nociception and experimentally induced cutaneous hyperalgesia in healthy volunteers.

Methods

The human experimental hyperalgesia model, the heat-capsaicin sensitization model, was induced in 25 healthy male volunteers. Subjects received oral gabapentin (1,200 mg) or placebo after heat-capsaicin sensitization was established on the forearm. The primary outcome measures were the sizes of the areas of secondary hyperalgesia to von Frey hair and brush stimulation on the forearm. Secondary outcome measures were as follows: (1) size of secondary hyperalgesia area in response to brief thermal sensitization procedure on the thigh; (2) heat pain detection thresholds in normal and sensitized skin; and (3) painfulness of 1 min of 45 degrees C stimulation in normal skin.

Results

Oral gabapentin profoundly suppressed established cutaneous sensitization on the forearm and prevented development of cutaneous sensitization on the thigh. Thermal nociception in normal skin was unchanged. Side effects were modest.

Conclusion

The results link preclinical findings with results from clinical trials of neuropathic pain. The results further suggest that gabapentin may prove effective in acute pain disorders involving neuronal sensitization, such as postoperative pain and acute herpetic pain, and could prove effective in prevention of chronic pain.
Differences in Systemic Opioid Use Do Not Explain Increased Fever Incidence in Parturients Receiving Epidural Analgesia
Authors: Gross Jeffrey B. , Cohen Amy P. , Lang Janet M. , Frigoletto Fredric D. , Lieberman Ellice S.
Published: November 2003

Background

It has been hypothesized that an increased incidence of fever in patients receiving epidural analgesia might result not from epidural per se, but rather from the antipyretic effect of opioids preferentially administered to women in the no-epidural group. If this were the case, then one would expect the incidence of fever in parturients who did not receive systemic opioids to be independent of whether they received epidural analgesia.

Methods

Using a cohort study design, the authors evaluated the records of 1,233 nulliparous patients whose labor analgesia was managed with (1) no medication (N = 170); (2) 10 mg intravenous systemic nalbuphine plus 10 mg intramuscular every 3 to 4 h as required (N = 327); (3) epidural analgesia with continuous infusion of 0.125% bupivacaine with 2 microg/ml fentanyl (N = 278); or (4) patients who received both systemic nalbuphine and epidural analgesia (N = 458). Fever was diagnosed if the maximum temperature during labor exceeded 100.4 degrees F (38 degrees C).

Results

The incidence of fever did not differ according to nalbuphine administration for women not receiving epidural analgesia (1% no nalbuphine, 0.3% with nalbuphine, P = 0.27) or for women receiving epidural analgesia (17% no nalbuphine, 17% with nalbuphine, P = 1.0). However, the incidence of fever differed significantly between patients who received no analgesia as compared to those who received epidural analgesia alone (1% vs. 17%, P = 10(-6)). Controlling for confounding did not alter these associations.

Conclusions

Our findings suggest that an antipyretic effect of nalbuphine in patients who do not receive an epidural does not explain the greater incidence of fever observed in women who receive epidural analgesia for labor.
The Invention and Development of Blood Gas Analysis Apparatus
Authors: Severinghaus John W.
Published: November 2003

In 1953, the doctor draft interrupted Dr. Severinghaus' anesthesia and physiology training and sent him to the National Institutes of Health as director of anesthesia research at the newly opened Clinical Center. He developed precise laboratory partial pressure of carbon dioxide (PCO(2)) and pH analysis to investigate lung blood gas exchange during hypothermia. Constants for carbon dioxide solubility and pK' were more accurately determined. In August 1954, he heard Richard Stow describe invention of a carbon dioxide electrode and immediately built one, improved its stability, and tested its response characteristics. In April 1956, he also heard Leland Clark reveal his invention of an oxygen electrode. Dr. Severinghaus obtained one and constructed a stirred cuvette in which blood partial pressure of oxygen (PO(2)) could be accurately measured. Technician Bradley and Dr. Severinghaus combined these, making the first blood gas analysis system in 1957 and 1958, and shortly thereafter, they added a pH electrode. Blood gas analyzers rapidly developed commercially. Dr. Severinghaus collaborated with Astrup and other Danes on the Haldane and Bohr effects and their concepts of base excess during two sabbaticals in Copenhagen. Work with both Astrup and Roughton on the oxygen dissociation curve led Dr. Severinghaus to devise a modified Hill equation that closely fit their new, better human oxygen dissociation curve and a blood gas slide rule that solved oxygen dissociation curve, PCO(2), pH, and acid-base questions. Blood gas analysis revolutionized both clinical medicine and cardiorespiratory and metabolic physiology.
Efficacy and Safety of Intravenous Parecoxib Sodium in Relieving Acute Postoperative Pain following Gynecologic Laparotomy Surgery
Authors: Barton Scott F. , Langeland Fred F. , Snabes Michael C. , LeComte Diane , Kuss Michael E. , Dhadda Shobha S. , Hubbard Richard C.
Published: November 2003

Background

This study tested the hypothesis that an injectable cyclooxygenase (COX)-2-specific inhibitor will be at least as effective and well tolerated as a COX-nonspecific conventional nonsteroidal antiinflammatory drug (NSAID) by comparing the analgesic efficacy and tolerability of one intravenous dose of parecoxib sodium, an injectable prodrug of the novel COX-2-specific inhibitor, valdecoxib, with ketorolac and placebo in postoperative laparotomy surgery patients. Intravenous morphine, 4 mg, was studied as a positive analgesic control.

Methods

In this multicenter, double-blinded, placebo-controlled study, women experiencing moderate-to-severe pain on the first day after abdominal hysterectomy or myomectomy received one intravenous dose of parecoxib sodium, 20 or 40 mg, ketorolac, 30 mg, morphine, 4 mg, or placebo. Analgesic efficacy and tolerability were evaluated for 24 h postdose or until patients, whose pain was not adequately controlled, opted to receive rescue analgesia.

Results

Two hundred two patients were enrolled. All treatment groups had comparable demographics and baseline pain status. All active treatments had an equally rapid time to onset of analgesia (10-23 min). Overall, each parecoxib sodium dose and ketorolac were significantly superior to morphine and placebo for most measures of analgesic efficacy at most time points, including a significantly longer (two- to threefold) time to rescue analgesia (P </= 0.05). All treatments were well tolerated.

Conclusions

Single intravenous doses of parecoxib sodium, 20 mg and 40 mg, have comparable analgesic effects and are well tolerated after laparotomy surgery. Parecoxib sodium appears to be as effective as intravenous ketorolac, 30 mg, and superior to intravenous morphine, 4 mg.
Low Complication Rate Associated with Cesarean Section under Spinal Anesthesia for HIV-1–Infected Women on Antiretroviral Therapy
Authors: Avidan Michael S. , Groves Philippa , Blott Margaret , Welch Jan , Leung Theresa , Pozniak Anton , Davies Edward , Ball Colin , Zuckerman Mark
Published: November 2003

Background

Elective cesarean section decreases the likelihood of vertical human immunodeficiency virus (HIV) transmission from mother to infant. This study aimed to determine whether cesarean section done with spinal anesthesia on HIV-1-infected pregnant women taking antiretroviral therapy is associated with intraoperative hemodynamic instability, postoperative complications, or changes in immune function or HIV-1 viral load.

Methods

A case-controlled study was conducted over a 3-year period in a London academic hospital. Forty-four women infected with HIV-1 and a control group of 45 HIV-negative women undergoing cesarean sections were included. The main outcome measures included intraoperative blood pressure, heart rate, blood loss, and ephedrine requirements, and postoperative infective complications, blood transfusion, changes in blood HIV-1 viral load and lymphocyte subsets, and time to hospital discharge.

Results

There were no differences in hemodynamic stability and postoperative complications between the HIV-infected group and the controls. There was an acute postoperative increase in the CD4T lymphocyte count (P = 0.01), but the CD4T:CD8T ratio and viral load did not change.

Conclusions

Elective cesarean section under spinal anesthesia for women infected with HIV-1 taking antiretroviral therapy was not associated with intraoperative or postoperative complications.
Comparison of Conventional Averaged and Rapid Averaged, Autoregressive-based Extracted Auditory Evoked Potentials for Monitoring the Hypnotic Level during Propofol Induction
Authors: Litvan Héctor , Jensen Erik W. , Galan Josefina , Lund Jeppe , Rodriguez Bernardo E. , Henneberg Steen W. , Caminal Pere , Villar Landeira Juan M.
Published: November 2003

Background

The extraction of the middle latency auditory evoked potentials (MLAEP) is usually done by moving time averaging (MTA) over many sweeps (often 250-1,000), which could produce a delay of more than 1 min. This problem was addressed by applying an autoregressive model with exogenous input (ARX) that enables extraction of the auditory evoked potentials (AEP) within 15 sweeps. The objective of this study was to show that an AEP could be extracted faster by ARX than by MTA and with the same reliability.

Methods

The MTA and ARX methods were compared with the Modified Observer's Assessment of Alertness and Sedation Scale (MOAAS) in 15 patients scheduled for cardiac surgery and anesthetized with propofol. The peak amplitudes and latencies were recorded continuously for the MTA- and ARX-extracted AEP. An index, AAI, was derived from the ARX-extracted AEP as well.

Results

The best predictors of the awake and anesthetized states, in terms of the prediction probability, Pk, were the AAI (Pk [SE] = 0.93 [0.01]) and Na-Pa amplitude (MTA, Pk [SE] = 0.89 [0.02]; ARX, Pk [SE] = 0.87[0.02]). When comparing the AAI at the MOAAS levels 5-3 versus 2-0, significant differences were achieved. During the transitions from awake to asleep, the ARX-extracted AEP were obtained with significantly less delay than the MTA-extracted AEP (28.4 s vs. 6 s).

Conclusion

The authors conclude that the MLAEP peaks and the AAI correlate well to the MOAAS, whether extracted by MTA or ARX, but the ARX method produced a significantly shorter delay than the MTA.
Intraoperative Low-volume Acute Normovolemic Hemodilution in Adult Open-heart Surgery
Authors: Casati Valter , Speziali Giovanni , D'Alessandro Cesare , Cianchi Clara , Antonietta Grasso Maria , Spagnolo Salvatore , Sandrelli Luca
Published: November 2003

Background

Recently, various studies have questioned the efficacy of intraoperative acute normovolemic hemodilution (ANH) in reducing bleeding and the need for allogeneic transfusions in cardiac surgery. The aim of the present study was to reevaluate the effects of a low-volume ANH in elective, adult open-heart surgery.

Methods

Two hundred four consecutive adult patients undergoing cardiac surgery were prospectively randomized in a nonblinded manner into two groups: ANH group (103 patients), where 5-8 ml/kg of blood was withdrawn before systemic heparinization and replaced with colloid solutions, and a control group, where no hemodilution was performed (101 patients). Procedures included single and multiple valve surgery, aortic root surgery, coronary surgery combined with valve surgery, or partial left ventriculectomy. The purpose of the study was to evaluate the efficacy of ANH in reducing the need for allogeneic blood components. Routine hematochemical evaluations, perioperative blood loss, major complications, and outcomes were also recorded.

Results

No differences were found between the groups regarding demographics, baseline hematochemical data, and operative characteristics. There was no difference in the amount of transfusions of packed red cells, fresh frozen plasma, platelet concentrates, total number of patients transfused (control group, 36% vs. ANH group, 34.3%; P = 0.88), and amount of postoperative bleeding (control group, 412 ml [313-552 ml] vs. ANH group, 374 ml [255-704 ml]) (median [25th-75th percentiles]); P = 0.94. Further, perioperative complications, postoperative hematochemical data, and outcomes were not different.

Conclusions

In patients undergoing elective open-heart surgery, low-volume ANH showed lack of efficacy in reducing the need for allogeneic transfusions and postoperative bleeding.
Epidural Blockade Modifies Perioperative Glucose Production without Affecting Protein Catabolism
Authors: Lattermann Ralph , Carli Franco , Wykes Linda , Schricker Thomas
Published: November 2003

Background

Epidural blockade with local anesthetic has been shown to blunt the increase in plasma glucose concentration during and after abdominal surgery. The aim of the study was to test the hypothesis that epidural blockade inhibits this hyperglycemic response by attenuating endogenous glucose production. The authors further examined if the modification of glucose production by epidural blockade has an impact on perioperative protein catabolism.

Methods

Sixteen patients undergoing colorectal surgery received either general anesthesia and epidural blockade with local anesthetic (n = 8) or general anesthesia alone (control, n = 8). Glucose and protein kinetics were assessed by stable isotope tracer technique ([6,6-2H2]glucose, L-[1-13C]leucine) during and 2 h after surgery. Plasma concentrations of glucose, lactate, free fatty acids (FFA), cortisol, glucagon, and insulin were also determined.

Results

Epidural blockade blunted the perioperative increase in the plasma concentration of glucose, cortisol, and glucagon when compared with the control group (P < 0.05). Plasma concentrations of lactate, FFA, and insulin did not change. Intra- and postoperative glucose production was lower in patients with epidural blockade than in control subjects (intraoperative, epidural blockade 8.2 +/- 1.9 vs. control 10.7 +/- 1.4 micromol x kg(-1) x min(-1), P < 0.05; postoperative, epidural blockade 8.5 +/- 1.8 vs. control 10.5 +/- 1.2 micromol x kg(-1) x min(-1), P < 0.05), whereas glucose clearance decreased to a comparable extent in both groups (P < 0.05). Protein breakdown (P < 0.05), protein synthesis (P < 0.05), and amino acid oxidation (P > 0.05) decreased with both anesthetic techniques.

Conclusions

Epidural blockade attenuates the hyperglycemic response to surgery through modification of glucose production. The perioperative suppression of protein metabolism was not influenced by epidural blockade.
Effect of a Nonsedative Dose of Propofol on Memory for Aversively Loaded Information in Rats
Authors: Pain Laure , Angst Marie-Josée , LeGourrier Laurence , Oberling Philippe
Published: November 2003

Background

The effects of propofol on memory for aversive information are not well determined. The authors evaluated the effects of a minimal nonsedative dose of propofol or midazolam on memory in rats, using an apparatus composed of two compartments: a large bright anxiogenic one and a small dark neutral one.

Methods

Groups of rat received propofol (9 mg/kg, intraperitoneally) or midazolam (3 mg/kg). Anxiety was assessed in rats placed in the anxiogenic compartment as the time before the animals entered the neutral compartment. Memory for an aversive event was assessed in rats placed in the anxiogenic compartment as the time to enter the neutral one where they previously experienced foot shocks (fear conditioning). To assess the memory for a nonaversive event, rats were placed in the neutral compartment with no shocks (preexposure). The following day, rats were placed in it and they experienced foot shocks. As a result of the preexposure, rats exhibit less fear to enter it.

Results

Propofol and midazolam increased the time to enter the neutral compartment. Propofol or midazolam was given to rats before experiencing foot shocks in the neutral compartment. When later tested, the time to enter it was decreased. Propofol or midazolam was given to rats before the preexposure to the neutral compartment. When later tested, the latency to enter it was not modified by the preexposure.

Conclusions

Propofol and midazolam impaired memory for aversive and for nonaversive experiences at equianxiolytic doses that do not produce locomotor impairment in rats.
Modulation of Rat Pial Arteriolar Responses to Flow by Glucose
Authors: Ward Michael E. , Yan Lu , Angle Mark R.
Published: November 2003

Background

Pial arteriolar responses to flow contribute to regulation of cerebral perfusion and vary according to the transmural pressure to which the vessel is exposed. This study determined the effect of increased glucose concentration on the flow responses of pial arterioles at low and high levels of transmural pressure.

Methods

Pial arterioles from Sprague-Dawley rats were mounted in a perfusion myograph. In some arterioles, the endothelium was removed by perfusion with air. Diameters were recorded at transmural pressures of 60 and 120 mmHg during superfusion with physiologic saline containing 5 mm D-glucose, 20 mm D-glucose, or 5 mm D-glucose and 15 mm L-glucose. Diameters during superfusion with saline containing 44 mm D-glucose were measured at an intraluminal pressure of 60 mmHg. Flow-diameter relationships (5-30 microl/min) were recorded during perfusion with the same solutions.

Results

Increasing D-glucose concentration caused constriction (P < 0.05) in endothelium-denuded but not in endothelium-intact arterioles. Addition of L-glucose caused constriction in endothelium-intact and -denuded vessels (P < 0.05 for both). At a D-glucose concentration of 5 mm and at low intraluminal pressure, flow elicits endothelium-dependent dilation such that shear stress remains constant. At a D-glucose concentration of 20 or 44 mm, after addition of L-glucose (15 mm), and at high intraluminal pressures, flow elicits constriction and shear stress is unregulated.

Conclusions

High glucose concentrations elicit increased basal arteriolar smooth muscle tone that is counteracted by release of endothelium-derived relaxing factors. Endothelium-dependent relaxation to flow (shear stress) is inhibited at high glucose concentrations.
Different Mechanisms of Development and Maintenance of Experimental Incision-induced Hyperalgesia in Human Skin
Authors: Kawamata Mikito , Watanabe Hiroaki , Nishikawa Kohki , Takahashi Toshiyuki , Kozuka Yuji , Kawamata Tomoyuki , Omote Keiichi , Namiki Akiyoshi
Published: November 2003

Background

To determine the mechanisms of postoperative pain, the effects of local anesthesia on development and maintenance of surgical incision-induced hyperalgesia were evaluated in a crossover, double-blinded, placebo-controlled human study using 17 subjects.

Methods

An experimental 4-mm-long incision through skin, fascia, and muscle was made in the volar forearm of each subject. In experiment 1, 1% lidocaine or saline in a volume of 0.2 ml was subcutaneously injected into the incision site pretraumatically and posttraumatically. In experiment 2, a 5-cm-long strip of skin was subcutaneously injected with 0.2 ml of 1% lidocaine near the incision site pretraumatically and posttraumatically. Flare, spontaneous pain, and primary and secondary hyperalgesia to punctate mechanical stimuli were assessed after the incision had been made.

Results

Pretraumatic lidocaine injection prevented the occurrence of spontaneous pain and development of flare formation that was found surrounding the incision site immediately (1 min) after the incision had been made. The lidocaine suppressed primary hyperalgesia more effectively than did posttraumatic block, but only for the first 4 h after the incision. The preincision block prevented development of secondary hyperalgesia, whereas posttraumatic block did not significantly affect the fully developed secondary hyperalgesia. The area of flare formation and the area of secondary hyperalgesia did not extend over the strip of the skin that had been pretraumatically anesthetized, whereas the posttraumatic block did not significantly reduce the area of fully developed secondary hyperalgesia.

Conclusions

Pretraumatic injection of lidocaine reduces primary hyperalgesia more effectively than does posttraumatic injection, but only for a short period after incision. The spread of secondary hyperalgesia is mediated peripheral nerve fibers, but when secondary hyperalgesia has fully developed, it becomes less dependent on or even independent of peripheral neural activity originating from the injured site.
Low-flow Sevoflurane Compared with Low-flow Isoflurane Anesthesia in Patients with Stable Renal Insufficiency
Authors: Conzen Peter F. , Kharasch Evan D. , Czerner Stephan F. A. , Artru Alan A. , Reichle Florian M. , Michalowski Piotr , Rooke G. Alec , Weiss Branko M. , Ebert Thomas J.
Published: November 2003

Background

Sevoflurane is degraded to compound A (CpA) by carbon dioxide absorbents containing strong base. CpA is nephrotoxic in rats. Patient exposure to CpA is increased with low fresh gas flow rates, use of Baralyme, and high sevoflurane concentrations. CpA formation during low-flow and closed circuit sevoflurane anesthesia had no significant renal effects in surgical patients with normal renal function. Preexisting renal insufficiency is a risk factor for postoperative renal dysfunction. Although preexisting renal insufficiency is not affected by high-flow sevoflurane, the effect of low-flow sevoflurane in patients with renal insufficiency is unknown.

Methods

After obtaining institutional review board approval, 116 patients with a stable preoperative serum creatinine concentration 1.5 mg/dl or greater were assessable. Patients were randomized to receive either sevoflurane (n = 59, 0.8-2.5 vol%) or isoflurane (n = 57, 0.5-1.4 vol%) at a fresh gas flow rate of 1 l/min or less. Use of opioids was restricted to a minimum, and Baralyme was used to increase CpA exposure. Inspiratory and expiratory CpA concentrations were measured during anesthesia. Renal function (serum creatinine and blood urea nitrogen, urine protein and glucose, creatinine clearance) was measured preoperatively and 24 and 72 h after induction.

Results

Demographic patient data did not differ between groups. Patients received 3.1 +/- 2.4 minimum alveolar concentration-hours sevoflurane or 3.8 +/- 2.6 minimum alveolar concentration-hours isoflurane (mean +/- SD). Durations of low flow were 201.3 +/- 98.0 and 213.6 +/- 83.4 min, respectively. Maximum inspiratory CpA with sevoflurane was 18.9 +/- 7.6 ppm (mean +/- SD), resulting in an average total CpA exposure of 44.0 +/- 30.6 ppm/h. There were no statistically significant changes from baseline to 24- and 72-h values for serum creatinine or blood urea nitrogen, creatinine clearance, urine protein, and glucose, nor were there significant differences between both anesthetics.

Conclusion

There were no statistically significant differences in measured parameters of renal function after low-flow sevoflurane anesthesia compared with isoflurane. These results suggest that low-flow sevoflurane anesthesia is as safe as low-flow isoflurane and does not alter kidney function in patients with preexisting renal disease.
Clinical Trial of the Neuroprotectant Clomethiazole in Coronary Artery Bypass Graft Surgery
Authors: Kong Robert S. , Butterworth John , Aveling Wynne , Stump David A. , Harrison Michael J. G. , Hammon John , Stygall Jan , Rorie Kashemi D. , Newman Stanton P.
Published: November 2003

Background

The neuroprotective property of clomethiazole has been demonstrated in several animal models of global and focal brain ischemia. In this study the authors investigated the effect of clomethiazole on cerebral outcome in patients undergoing coronary artery bypass surgery.

Methods

Two hundred forty-five patients scheduled for coronary artery bypass surgery were recruited at two centers and prospectively randomized to clomethiazole edisilate (0.8%), 225 ml (1.8 mg) loading dose followed by a maintenance dose of 100 ml/h (0.8 mg/h) during surgery, or 0.9% NaCl (placebo) in a double-blind trial. Coronary artery grafting was completed during moderate hypothermic (28-32 degrees C) cardiopulmonary bypass. Plasma clomethiazole was measured at several intervals during and up to 24 h after the end of infusion. A battery of eight neuropsychological tests was administered preoperatively and repeated 4-7 weeks after surgery. Analysis of the change in neuropsychological test scores from baseline was used to determine the effect of treatment.

Results

Neuropsychological assessments were completed in 219 patients (110 clomethiazole; 109 placebo). The mean plasma concentration of clomethiazole during surgery was 66.2 microm. There was no difference between the clomethiazole and placebo group in the postoperative change in neuropsychological test scores.

Conclusion

Clomethiazole did not improve cerebral outcome following coronary artery bypass surgery.
Effect of Low Isoflurane Concentrations on the Ventilation–Perfusion Distribution in Injured Canine Lungs
Authors: Putensen Christian , Räsänen Jukka , Putensen-Himmer Gabriele , Downs John B.
Published: November 2003

Background

Rapid recovery and weaning from ventilatory support and cardiovascular stability are suggested advantages of isoflurane inhalation, in concentrations ranging from 0.1 to 0.6 vol%, for long-term sedation in mechanical ventilated patients. This study was designed to determine whether isoflurane in low concentrations impairs pulmonary gas exchange by increasing ventilation and perfusion (V(A)/Q) mismatch during lung injury.

Methods

Fourteen anesthetized dogs received in random order 0, 0.25, or 0.5 vol% end-tidal isoflurane before and after induction of lung injury with oleic acid. Gas exchange was assessed by blood gas analysis and by estimating the V(A)/Q distributions using the multiple inert gas elimination technique.

Results

Administration of oleic acid produced a lung injury with severe V(A)/Q mismatch and 38 +/- 4% intrapulmonary shunting of blood. During lung injury, isoflurane accounted for a dose-related increase in blood flow to shunt units from 38 +/- 4 to 42 +/- 3 (0.25 vol%) and 48 +/- 4% (0.5 vol%) (P < 0.05), dispersion pulmonary blood flow distribution from 0.94 +/- 0.07 to 1.01 +/- 0.09 (0.25 vol%) and 1.11 +/- 0.11% (0.5 vol%) (P < 0.05), and a decrease in perfusion of normal V(A)/Q units from 58 +/- 5 to 55 +/- 4 (0.25 vol%) and 50 +/- 4% (0.5 vol%) (P < 0.05) (mean +/- SE). Isoflurane decreased arterial oxygen partial pressure from 72 +/- 4 to 62 +/- 4 mmHg (0.25 vol%) and 56 +/- 4 mmHg (0.5 vol%) (P < 0.05) and oxygen delivery from 573 +/- 21 to 529 +/- 19 ml. kg. min (0.25 vol%) and 505 +/- 22 ml. kg. min (0.5 vol%) (P < 0.05). Gas exchange, perfusion of shunt and normal V(A)/Q units, and pulmonary blood flow distribution was similar in absence of lung injury with and without isoflurane. Isoflurane 0.5 vol% lowered cardiac output during all conditions (P < 0.05). CONCLUSIONS Inhalation of low concentrations of isoflurane contributed to increased V(A)/Q mismatch and decreased systemic blood flow and oxygen delivery in mechanically ventilated animals with injured lungs.