bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response Surface Modeling of Alfentanil-Sevoflurane Interaction on Cardiorespiratory Control and Bispectral Index
Authors: Dahan Albert , Nieuwenhuijs Diederik , Olofsen Erik , Sarton Elise , Romberg Raymonda , Teppema Luc 
Published: November 2003

Background
Respiratory depression is a serious side effect of anesthetics and opioids. The authors examined the influence of the combined administration of sevoflurane and alfentanil on ventilatory control, heart rate (HR), and Bispectral Index (BIS) in healthy volunteers.

Methods
Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) at constant end-tidal partial pressure of carbon dioxide (approximately 48 mmHg) were performed in nine male volunteers at various concentrations of alfentanil and sevoflurane, ranging from 0 to 50 ng/ml for alfentanil and from 0 to 0.4 end-tidal concentration (ET%) for sevoflurane, and with various combinations of alfentanil and sevoflurane. The alfentanil-sevoflurane interactions on normoxic resting (hypercapnic) ventilation (Vi), HR, hypoxic Vi, and HR responses and BIS were assessed by construction of response surfaces that related alfentanil and sevoflurane to effect using a population analysis.

Results
Concentration-effect relations were linear for alfentanil and sevoflurane. Synergistic interactions were observed for resting Vi and resting HR. Depression of Vi by 25% occurred at 38 +/- 11 ng/ml alfentanil (population mean +/- SE) and at 0.7 +/- 0.4 ET% sevoflurane. One possibility for 25% reduction when alfentanil and sevoflurane are combined is 13.4 ng/ml alfentanil plus 0.12 ET% sevoflurane. Additive interactions were observed for hypoxic Vi and HR responses and BIS. Depression of the hypoxic Vi response by 25% occurred at 16 +/- 1 ng/ml alfentanil and 0.14 +/- 0.05 ET% sevoflurane. The effect of sevoflurane on the BIS (25% reduction of BIS occurred at 0.45 +/- 0.08 ET%) was independent of the alfentanil concentration.

Conclusions
Response surface modeling was used successfully to analyze the effect of interactions between two drugs on respiration. The combination of alfentanil and sevoflurane causes more depression of Vi and HR than does the summed effect of each drug administered separately. The effects of combining alfentanil and sevoflurane on hypoxic Vi and HR responses and BIS could be predicted from the separate dose-response curves. Over the dose range tested, the hypoxic response is more sensitive to the effects of anesthetics and opioids relative to resting ventilation.
Decreased Endotoxin Immunity Is Associated with Greater Mortality and/or Prolonged Hospitalization after Surgery
Authors: Bennett-Guerrero Elliott , Panah Michael H. , Robin Barclay G. , Bodian Carol A. , Winfree Wanda J. , Andres Lewis A. , Reich David L. , Mythen Michael G. 
Published: November 2003

Background
Patients undergoing noncardiac surgery often develop postoperative morbidity, potentially attributable to endotoxemia and the systemic inflammatory response syndrome. Endogenous antibodies to endotoxin may confer protection from endotoxin-mediated toxicity. The authors sought to determine the association of preoperative antiendotoxin immunity and death or prolonged hospitalization in a broad population of general surgical patients undergoing major surgery.

Methods
To test the hypothesis that low preoperative serum antiendotoxin core antibody (EndoCAb) concentration is an independent predictor of adverse outcome after general surgery, 1,056 patients undergoing routine noncardiac surgery were enrolled into a prospective, blinded, cohort study. Immunoglobulin M EndoCAb, immunoglobulin G EndoCAb, total inmunoglobulin M, and immunoglobulin G concentrations were measured in serum obtained preoperatively. A physiologic risk score using the established POSSUM criteria was assigned preoperatively to each patient. The primary predefined composite end point (postoperative complication) was either in-hospital death or postoperative length of stay greater than 10 days. Multivariate logistic regression was used to test the study hypothesis.

Results
Overall, postoperative complication occurred in 234 of the 1,056 patients (22.1%). Lower immunoglobulin M EndoCAb concentration (P = 0.006) predicted increased risk of postoperative complication independent of POSSUM physiologic risk score (P < 0.001). In contrast, total immunoglobulin M and total immunoglobulin G concentrations did not predict adverse outcome. Complications involved multiple organ systems and were generally unrelated to the type or site of surgery, consistent with the systemic inflammatory response syndrome.

Conclusions
Adverse outcome after routine noncardiac surgery is common and is predicted in part by low concentrations of EndoCAb. The authors' findings suggest that endotoxemia may be a cause of postoperative morbidity after routine noncardiac surgery.
Recovery of Intraoperative Microbicidal and Inflammatory Functions of Alveolar Immune Cells after a Tobacco Smoke-free Period
Authors: Kotani Naoki , Kushikata Tetsuya , Hashimoto Hiroshi , Sessler Daniel I. , Muraoka Masatoshi , Matsuki Akitomo 
Published: November 2003

Background
Tobacco smoking inhibits alveolar macrophage function, but cessation of smoking markedly reduces the risk of postoperative pulmonary complications. The authors therefore evaluated the effect of nonsmoking duration on both antimicrobial and inflammatory functions of alveolar macrophages during anesthesia and surgery.

Methods
The authors studied 15 patients who had never smoked, 15 current smokers, and 41 former smokers, all of whom underwent general anesthesia. Former smokers were further allocated to one of three groups depending on their smoke-free periods: 2 months (n = 13), 3-5 months (n = 13), and 6-12 months (n = 15). Alveolar immune cells were collected by bronchoalveolar lavage immediately after induction of anesthesia, at 2 and 4 h after induction of anesthesia, and at the end of surgery. Opsonized and nonopsonized phagocytosis were measured. Microbicidal activity was determined as the ability of the macrophages to kill Listeria monocytogenes directly. Finally, we determined the expression of proinflammatory cytokines, including interleukin 1beta, interleukin 8, interferon gamma, and tumor necrosis factor alpha, and of antiinflammatory cytokines (interleukin 4 and 10) by semiquantitative polymerase chain reaction.

Results
Nonopsonized and opsonized phagocytosis and microbicidal activity of alveolar macrophages (antimicrobial functions) decreased 20-50%, and the expression of genes for all proinflammatory and antiinflammatory cytokines increased 3-30-fold over time in all groups. Starting 4 h after induction of anesthesia, the decreases in antimicrobial functions were 1.5-3 times greater in current and former smokers (2 months' abstinence) than in patients who had never smoked. Starting 4 h after anesthesia, the increase in expression of all cytokines, except interleukin 8, was twofold to fivefold less in current and former smokers (2-6 months' abstinence) than in patients who had never smoked.

Conclusion
Our data suggest that former smokers may have a limited ability to mount effective pulmonary immune defenses for long as 6 months after stopping cigarette use.
Effect of the Deficiency of Spinal PSD-95/SAP90 on the Minimum Alveolar Anesthetic Concentration of Isoflurane in Rats
Authors: Tao Yuan-Xiang , Johns Roger A. 
Published: November 2003

Background
Spinal N-methyl-D-aspartate (NMDA) receptor activation has been demonstrated to play an important role in the processing of spinal nociceptive information and in the determination of the minimum alveolar anesthetic concentration (MAC) of inhalational anesthetics. Postsynaptic density-95 (PSD-95)/synapse-associated protein-90 (SAP90), a molecular scaffolding protein that binds and clusters the NMDA receptor perferentially at synapses, was implicated in NMDA-induced thermal hyperalgesia. The current study investigated the possible involvement of PSD-95/SAP9O in determining MAC for isoflurane anesthesia.

Methods
Sprague-Dawley rats were pretreated intrathecally with PSD-95/SAP90 antisense oligodeoxyribonucleotide (ODN), sense ODN, missense ODN, or saline every 24 h for 4 days. After initial baseline determination of the MAC, NMDA or saline was injected intrathecally. Ten minutes later, MAC measurement was repeated. The rats also were evaluated for the presence of locomotor dysfunction by intrathecal administration of NMDA or saline in the saline- and ODN-treated rats.

Results
In the groups treated with antisense ODNs, but not in those treated with sense or missense ODNs, there was a significant decrease in isoflurane MAC that was not accompanied by marked changes in either blood pressure or heart rate. In the saline-treated group, intrathecal NMDA caused an increase in isoflurane MAC. In contrast, in the antisense ODN-treated group, intrathecal NMDA did not produce a significant change in isoflurane MAC. An NMDA-induced increase in blood pressure but not heart rate was found in both saline- and antisense ODN-treated groups. Locomotor activity was not changed in any of the treated animals.

Conclusion
The results indicate not only a significant decrease in MAC for isoflurane but also an attenuation in the NMDA-induced increase in isoflurane MAC in the PSD-95/SAP90 antisense-treated animals, which suggests that PSD-95/SAP90 may mediate the role of the NMDA receptor in determining the MAC of inhalational anesthetics.
Analgesic and Antiinflammatory Effects of Two Novel κ-Opioid Peptides
Authors: Binder Waltraud , Machelska Halina , Mousa Shaaban , Schmitt Thomas , Rivière Pierre J. M. , Junien Jean-Louis , Stein Christoph , Schäfer Michael 
Published: November 2003

Background
This study investigates two new kappa-agonist tetrapeptides, FE 200665 and FE 200666, with high peripheral selectivity as a result of poor central nervous system penetration.

Methods
Four days after administration of Freund adjuvant into the hind paw of male Wistar rats, antinociceptive effects of intraplantar and subcutaneous injection of FE 200665 and FE 200666 were measured by paw pressure algesiometry and compared with the kappa-agonist U-69,593. Peripheral and kappa-receptor selectivity was assessed by the antagonists naloxone methiodide (NLXM) and nor-binaltorphimine, respectively. Antiinflammatory effects were evaluated by paw volume plethysmometry and histologic score.

Results
Similar to intraplantar U-69,593, intraplantar FE 200665 (3-100 microg) and FE 200666 (1-30 microg) resulted in significant and dose-related increases of paw pressure thresholds. Higher doses of FE 200665 (0.2-20 mg) and FE 200666 (0.06-6 mg) were required by subcutaneous route to produce similar antinociceptive responses, supporting a peripheral site of action. nor-Binaltorphimine dose-dependently antagonized this effect, implying kappa-opioid selectivity. Analgesic effects of subcutaneous FE 200665 and FE 200666 were abolished by intraplantar nor-binaltorphimine, and both subcutaneous and intraplantar effects were dose-dependently antagonized by subcutaneous NLXM, further demonstrating a peripheral site of action. One to 6 days after Freund adjuvant inoculation, single and repeated intraplantar injections of FE 200665, FE 200666, and U-69,593 significantly reduced paw volume and histologic scores. Both changes were reversed by intraplantar nor-binaltorphimine and subcutaneous NLXM.

Conclusion
FE 200665 is a peripherally selective kappa-agonist with potent analgesic and antiinflammatory properties that may lead to improved analgesic-antiinflammatory therapy compared with centrally acting opioids or standard nonsteroidal antiinflammatory drugs.
Partial Liquid Ventilation Reduces Fluid Filtration of Isolated Rabbit Lungs with Acute Hydrochloric Acid-induced Edema
Authors: Loer Stephan A. , Tarnow Jörg 
Published: November 2003

Background
Hydrochloric acid aspiration increases pulmonary microvascular permeability. The authors tested the hypothesis that partial liquid ventilation has a beneficial effect on filtration coefficients in acute acid-induced lung injury.

Methods
Isolated blood-perfused rabbit lungs were assigned randomly to one of four groups. Group 1 (n = 6) served as a control group without edema. In group 2 (n = 6), group 3 (n = 6), and group 4 (n = 6), pulmonary edema was induced by intratracheal instillation of hydrochloric acid (0.1 N, 2 ml/kg body weight). Filtration coefficients were determined 30 min after this injury (by measuring loss of perfusate after increase of left atrial pressure). Group 2 lungs were gas ventilated, and group 3 lungs received partial liquid ventilation (15 ml perfluorocarbon/kg body weight). In group 4 lungs, the authors studied the immediate effects of bronchial perfluorocarbon instillation on ongoing filtration.

Results
Intratracheal instillation of hydrochloric acid markedly increased filtration coefficients when compared with non-injured control lungs (2.3 +/- 0.7 vs. 0.31 +/- 0.08 ml.min(-1). mmHg(-1).100 g(-1) wet lung weight, P < 0.01). Partial liquid ventilation reduced filtration coefficients of the injured lungs (to 0.9 +/- 0.3 ml.min(-1).mmHg(-1).100 g(-1) wet lung weight, P = 0.022). Neither pulmonary artery nor capillary pressures (determined by simultaneous occlusion of inflow and outflow of the pulmonary circulation) were changed by hydrochloric acid instillation or by partial liquid ventilation. During ongoing filtration, bronchial perfluorocarbon instillation (5 ml/kg body weight) immediately reduced the amount of filtered fluid by approximately 50% (P = 0.027).

Conclusions
In the acute phase after acid injury, partial liquid ventilation reduced pathologic fluid filtration. This effect started immediately after bronchial perfluorocarbon instillation and was not associated with changes in mean pulmonary artery, capillary, or airway pressures. The authors suggest that in the early phase of acid injury, reduction of fluid filtration contributes to the beneficial effects of partial liquid ventilation on gas exchange and lung mechanics.
Anesthetic Properties of 4-Iodopropofol
Authors: Lingamaneni Ratnakumari , Krasowski Matthew D. , Jenkins Andrew , Truong Tuyen , Giunta Austin L. , Blackbeer Julie , MacIver M. Bruce , Harrison Neil L. , Hemmings Hugh C. 
Published: November 2003

Background
Positive modulation of gamma-aminobutyric acid type A (GABAA) receptor function is recognized as an important component of the central nervous system depressant effects of many general anesthetics, including propofol. The role for GABAA receptors as an essential site in the anesthetic actions of propofol was recently challenged by a report that the propofol analog 4-iodopropofol (4-iodo-2,6-diisopropylphenol) potentiated and directly activated GABAA receptors, yet was devoid of sedative-anesthetic effects in rats after intraperitoneal injection. Given the important implications of these findings for theories of anesthesia, the authors compared the effects of 4-iodopropofol with those of propofol using established in vivo and in vitro assays of both GABAA receptor-dependent and -independent anesthetic actions.

Methods
The effects of propofol and 4-iodopropofol were analyzed on heterologously expressed recombinant human GABAA alpha1beta2gamma2 receptors, evoked population spike amplitudes in rat hippocampal slices, and glutamate release from rat cerebrocortical synaptosomes in vitro. Anesthetic potency was determined by loss of righting reflex in Xenopus laevis tadpoles, in mice after intraperitoneal injection, and in rats after intravenous injection.

Results
Like propofol, 4-iodopropofol enhanced GABA-induced currents in recombinant GABAA receptors, inhibited synaptic transmission in rat hippocampal slices, and inhibited sodium channel-mediated glutamate release from synaptosomes, but with reduced potency. After intraperitoneal injection, 4-iodopropofol did not produce anesthesia in mice, but it was not detected in serum or brain. However, 4-iodopropofol did produce anesthesia in tadpoles (EC50 = 2.5 +/- 0.5 microM) and in rats after intravenous injection (ED50 = 49 +/- 6.2 mg/kg).

Conclusions
Propofol and 4-iodopropofol produced similar actions on several previously identified cellular and molecular targets of general anesthetic action, and both compounds induced anesthesia in tadpoles and rats. The failure of 4-iodopropofol to induce anesthesia in rodents after intraperitoneal injection is attributed to a pharmacokinetic difference from propofol rather than to major pharmacodynamic differences.
Isoflurane Blocks Synaptic Plasticity in the Mouse Hippocampus
Authors: Simon Wanda , Hapfelmeier Gerhard , Kochs Eberhard , Zieglgänsberger Walter , Rammes Gerhard 
Published: November 2003

Background
The volatile anesthetic isoflurane depresses glutamatergic transmission. In this study, the authors investigated the effects of isoflurane on the induction of long-term potentiation (LTP) and long-term depression (LTD) in slices from the juvenile and adult mouse hippocampus. Both forms of synaptic plasticity involve the activation of glutamate receptors.

Methods
Field excitatory postsynaptic potentials and excitatory postsynaptic currents from neurons in the CA1 area were evoked by stimulation of the Schaffer collateral-commissural pathway. Two independent synaptic inputs were stimulated. Clinically relevant concentrations (0.2-0.3 mM) of isoflurane were added to the perfusion solution.

Results
Field excitatory postsynaptic potentials from slices of juvenile and adult mice were depressed to 37.3 +/- 6.1% and 58.3 +/- 7.4%, respectively, and excitatory postsynaptic currents were reduced to 36.7 +/- 5.4% by isoflurane. A brief tetanic stimulation (100 Hz, 1 s) induced stable LTP of field excitatory postsynaptic potentials. In the presence of isoflurane, tetanization failed to induce LTP. The effect of isoflurane on LTP induction was reversible and could be prevented by antagonizing gamma-aminobutyric acid type A receptors (GABAA). Low-frequency stimulation (1 Hz/900 pulses) induced LTD. In the presence of isoflurane, low-frequency stimulation failed to induce LTD.

Conclusions
The prevention of the isoflurane-induced depression of LTP by the GABAA antagonist picrotoxin suggests an involvement of GABAA receptors. An enhancement of the efficacy of GABA-mediated inhibitory synaptic transmission prevents the depolarization of the postsynaptic membrane during tetanus, necessary for the induction of use-dependent alteration of synaptic strength. An impairment of these processes may be a cause for the transient loss of recall and cognitive impairment after anesthesia in juvenile and adult brains.
Attenuation of the Tumor-promoting Effect of Surgery by Spinal Blockade in Rats
Authors: Bar-Yosef Shahar , Melamed Rivka , Page Gayle G. , Shakhar Guy , Shakhar Keren , Ben-Eliyahu Shamgar 
Published: November 2003

Background
The perioperative period is characterized by a state of immunosuppression, which was shown in animal studies to underlie the promotion of tumor metastasis by surgery. As this immunosuppression is partly ascribed to the neuroendocrine stress response, the authors hypothesized that spinal blockade, known to attenuate this response, may reduce the tumor-promoting effect of surgery.

Methods
Fischer-344 rats were subjected to a laparotomy during general halothane anesthesia alone or combined with either systemic morphine (10 mg/kg) or spinal block using bupivacaine (50 microg) with morphine (10 microg). Control groups were either anesthetized or undisturbed. Blood was drawn 5 h after surgery to assess number and activity of natural killer cells, or rats were inoculated intravenously with MADB106 adenocarcinoma cells, which metastasize only to the lungs. Metastatic development was assessed by quantifying lung retention of tumor cells 24 h after inoculation or by counting pulmonary metastases 3 weeks later.

Results
Laparotomy conducted during general anesthesia alone increased lung tumor retention up to 17-fold. The addition of spinal block reduced this effect by 70%. The number of metastases increased from 16.7 +/- 10.5 (mean +/- SD) in the control group to 37.2 +/- 24.4 after surgery and was reduced to 10.5 +/- 4.7 during spinal block. Systemic morphine also reduced the effects of surgery, but to a lesser degree. Natural killer cell activity was suppressed to a similar extent by surgery and by anesthesia alone.

Conclusions
The addition of spinal blockade to general halothane anesthesia markedly attenuates the promotion of metastasis by surgery.
Local Anesthetic Inhibition of Voltage-activated Potassium Currents in Rat Dorsal Root Ganglion Neurons
Authors: Komai Hirochika , McDowell Thomas S. 
Published: November 2003

Background
Local anesthetic actions on the K+ channels of dorsal root ganglion (DRG) and dorsal horn neurons may modulate sensory blockade during neuraxial anesthesia. In dorsal horn neurons, local anesthetics are known to inhibit transient but not sustained K+ currents. The authors characterized the effects of local anesthetics on K+ currents of isolated DRG neurons.

Methods
The effects of lidocaine, bupivacaine, and tetracaine on K+ currents in isolated rat DRG neurons were measured with use of a whole cell patch clamp method. The currents measured were fast-inactivating transient current (I(Af)), slow-inactivating transient current (I(As)), and noninactivating sustained current (I(Kn)).

Results
One group of cells (type 1) expressed I(Af) and I(Kn). The other group (type 2) expressed I(As) and I(Kn). The diameter of type 2 cells was smaller than that of type 1 cells. Lidocaine and bupivacaine inhibited all three K+ currents. Tetracaine inhibited I(As) and I(Kn) but not I(Af) For bupivacaine, the concentration for half-maximal inhibition (IC50) of I(Kn) in type 2 cells was lower than that for I(Kn) in type 1 cells (57 vs. 121 microM). Similar results were obtained for tetracaine (0.6 vs. 1.9 mM) and for lidocaine (2.2 vs. 5.1 mM).

Conclusions
Local anesthetics inhibited both transient and sustained K+ currents in DRG neurons. Because K+ current inhibition is known to potentiate local anesthetic-induced impulse inhibition, the lower IC50 for I(Kn) of small type 2 cells may reflect preferential inhibition of impulses in nociceptive neurons. The overall modulatory actions of local anesthetics probably are determined by their differential effects on presynaptic (DRG) and postsynaptic (dorsal horn neurons) K+ currents.