bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Effects of General Anesthetics on G Protein–coupled Inwardly Rectifying and Other Potassium Channels
Authors: Yamakura Tomohiro , Lewohl Joanne M. , Harris R. Adron
Published: November 2003

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusion

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusion

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusions

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

Background

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

Methods

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

Results

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

Conclusion

These results suggest that nonspecific blood purification with high-volume CWH improves arterial oxygenation and lung function in endotoxin-induced acute lung injury in pigs, independent of improved hemodynamics, fluid removal, or body temperature.
Possible Involvement of Cyclic Adenosine Monophosphate–independent Mechanism in the Positive Chronotropic Effect of Norepinephrine in the Isolated Guinea Pig Right Atrium
Authors: Asada Mieko , Endou Masayuki
Published: November 2003

Background

Although both positive chronotropic and inotropic effects of beta-adrenergic stimulation are thought to be mediated by cyclic adenosine 3'5'-monophosphate, phosphodiesterase III inhibitors such as amrinone and milrinone potentiate the positive inotropic effect of catecholamines with minimum influence on the heart rate in clinical setting. The aim of the current study was to compare the positive chronotropic effect of norepinephrine with that of forskolin to elucidate whether cyclic adenosine monophosphate is relevant to the chronotropic effect of norepinephrine.

Methods

Concentration-response curves for the positive chronotropic effects of norepinephrine and forskolin on the spontaneously beating right atria of guinea pigs were determined in the absence and presence of phosphodiesterase inhibitors or ion channel inhibitors. In some experiments, the left atria driven electrically were used to determine the positive inotropic effect of norepinephrine.

Results

Norepinephrine and forskolin increased the beating rate in a concentration-dependent manner. The positive chronotropic effect of forskolin was potentiated by amrinone and 3-isobutyl-1-methylxanthine, whereas the positive chronotropic effect of norepinephrine was not potentiated by the phosphodiesterase inhibitors. In contrast, the positive inotropic effect of norepinephrine was potentiated by amrinone. The hyperpolarization-activated inward current inhibitor cesium chloride and L-type voltage-dependent Ca2+ current inhibitor verapamil suppressed the chronotropic effect of norepinephrine, whereas these inhibitors did not affect the chronotropic effect of forskolin.

Conclusion

Norepinephrine increases the spontaneously beating rate by a different mechanism from that of forskolin, suggesting that cyclic adenosine monophosphate is causally unrelated to the positive chronotropic effect of norepinephrine in the guinea pig heart.
Nitrous Oxide Activates GABAergic Neurons in the Spinal Cord in Fischer Rats
Authors: Hashimoto Toshikazu , Maze Mervyn , Ohashi Yoko , Fujinaga Masahiko
Published: November 2003

Background

Findings to date indicate that nitrous oxide exerts its antinociceptive effect by activating descending noradrenergic neurons. The mechanism whereby descending inhibitory neurons, including noradrenergic neurons, produce antinociceptive effect remains unclear. Using c-Fos protein as a marker for neuronal activation, we examined whether spinal cord neurons activated by nitrous oxide are y-aminobutyric acid-mediated (GABAergic) neurons.

Methods

Adult male Fischer (a strain in which nitrous oxide shows strong antinociceptive properties) and Lewis (a strain in which nitrous oxide lacks antinociceptive properties) rats were exposed to either air (control) or nitrous oxide. Frozen sections of the spinal cord were either stained for c-Fos or double-stained for c-Fos and glutamic acid decarboxylase (a rate-limiting enzyme for GABA synthesis) and analyzed by standard or confocal microscopy.

Results

In Fischer rats, 90 min of 75% N2O administration increased the number of c-Fos-positive cells in the spinal cord approximately threefold as compared with the control group. The c-Fos-positive cells induced by nitrous oxide were almost entirely colocalized with glutamic acid decarboxylase-positive cells. In contrast, exposure did not change the number of c-Fos-positive cells in the spinal cord in Lewis rats.

Conclusions

Exposure to nitrous oxide activates GABAergic neurons in the spinal cord. The dose-dependence of GABAergic neuronal activation in the Fischer rats and its absence in the Lewis rat correlate with antinociceptive responses previously reported in these same circumstances. Together, we interpret these data to indicate that activation of GABAergic neurons in the spinal cord are involved in the antinociceptive action of nitrous oxide.
Differential Modulation of the Cardiac L- and T-type Calcium Channel Currents by Isoflurane
Authors: Camara Amadou K. S. , Begic Zeljana , Kwok Wai-Meng , Bosnjak Zeljko J.
Published: November 2003

Background

Volatile anesthetics exert their negative chronotropic and inotropic effects, in part by depressing the L- and T-type calcium channels. This study examines and compares the dose-dependent effects of isoflurane on atrial L- and T-type calcium currents (I(Ca,L) and I(Ca,T)) and ventricular I(Ca,L).

Methods

Whole cell I(Ca) was recorded from enzymatically isolated guinea pig cardiomyocytes. Current-voltage relations for atrial and ventricular I(Ca,L) was obtained from holding potentials of -90 and -50 mV to test a potential of +60 mV in 10-mV increments. Atrial I(Ca,T) was determined by subtraction of currents obtained from holding potentials of -50 and -90 mV. Steady state inactivation was determined using standard two-pulse protocols, and data were fitted with the Boltzmann equation.

Results

Isoflurane depressed I(Ca) in a dose-dependent manner, with Kd values of 0.23+/-0.03, 0.34+/-0.03, and 0.71+/-0.02 mM of anesthetic for atrial I(Ca,T) and I(Ca,L) and ventricular (ICa,L), respectively, and caused a significant (P < 0.05) hyperpolarizing shift in steady state inactivation. At 1.2 and 1.6 mm, isoflurane caused a significant (P < 0.05) depolarizing shift in the steady state activation in ventricular I(Ca,L) but not in atrial I(Ca,L) or I(Ca,T). In addition to the depression of I(Ca,L), isoflurane also induced a hyperpolarizing shift in the reversal potential of I(Ca) for both atrial and ventricular L-type calcium channels.

Conclusion

The results show that atrial I(Ca,T) is more sensitive to isoflurane than atrial I(Ca,L), and ventricular I(Ca,L) was the least responsive to the anesthetic. These differential sensitivities of the calcium channels in the atrial and ventricular chambers might reflect phenotypic differences in the calcium channels or differences in modulation by the anesthetic.
Predictability of Processed Electroencephalography Effects on the Basis of Pharmacokinetic–Pharmacodynamic Modeling during Repeated Propofol Infusions in Patients with Extradural Analgesia
Authors: Kuizenga Karel , Proost Johannes H. , Wierda J. Mark , Kalkman Cor J.
Published: November 2003

Background

Pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to characterize the concentration-effect relation of drugs. If the concentration-effect relation of a hypnotic drug is stable over time, an effect parameter derived from the processed electroencephalographic signal may be used to control the infusion for hypnosis. Therefore, the stability of the propofol concentration-electroencephalographic effect relation over time was investigated under non-steady state conditions.

Methods

Three propofol infusions (25 mg x kg(-1) x h(-1) for 10 min, 22 mg x kg(-1) x h(-1) for 10 min, and 12.5 mg x kg(-1) x h(-1) for 20 min) were administered to 10 patients during extradural analgesia. Each successive infusion was started immediately after the patient had regained responsiveness after termination of the preceding infusion. Electroencephalography was recorded from bilateral prefrontal to mastoid leads. Electroencephalographic amplitude in the 11- to 15-Hz band and the Bispectral Index were used as electroencephalographic effect variables. PKPD parameters were calculated with use of parametric and nonparametric models based on electroencephalographic data and arterial propofol concentrations derived during the initial infusion, and these were used to predict electroencephalographic effect during the subsequent infusions. The predictability of the electroencephalographic effects was determined by the coefficient of determination (R2) and of the -2 log likelihood of the sequential infusions.

Results

The direction of electroencephalographic changes in response to the infusions was reproducible. Although PKPD parameters could be estimated well during the initial infusion (median [range] parametric R2 = 0.74 [0.56-0.95] for electroencephalographic amplitude and 0.90 [0.27-0.99] for Bispectral Index), none of the modeling techniques could predict accurately the electroencephalographic effect during subsequent infusions (R2 = 0.00 [-0.31-0.46] for electroencephalographic amplitude and 0.15 [-.46-0.57] for Bispectral Index; P < 0.01).

Conclusions

The relation between blood propofol concentrations and the electroencephalographic effect under non-steady state conditions is not stable over time and is too complex to be modeled by any of the applied PKPD models.
Effects of Lithotomy Position and External Compression on Lower Leg Muscle Compartment Pressure
Authors: Pfeffer Susanne D. , Halliwill John R. , Warner Mark A.
Published: November 2003

Background

Case reports have suggested that externally applied pressure from antithrombosis devices may contribute to the development of compartment syndromes during extended surgery in the lithotomy position. The purpose of this study was to assess the effects of a pneumatic compression device on directly measured intracompartment pressure in the lower leg with the leg positioned in the lithotomy position.

Methods

In 25 conscious, healthy men and women, the authors measured pressure within the tibialis anterior muscle compartment with the leg supine and in the lithotomy position with and without intermittent compression. Three different devices were used to keep the leg in the lithotomy position, supporting the leg either behind the knee, under the calf, or at the ankle.

Results

The lithotomy position with support behind the calf or knee increased intracompartment pressure to 16.5+/-3.4 versus 10.7+/-5.8 mmHg supine (mean +/- SD; P < 0.05). The addition of intermittent compression decreased pressure to 13.4+/-5.1 mmHg during lithotomy (P < 0.05) and to 9.1+/-7.0 mmHg in the supine position (P < 0.05). In contrast, the lithotomy position with support near the ankle decreased intracompartment pressure to 8.7+/-5.6 versus 13.3+/-5.1 mmHg supine (P < 0.05). The addition of intermittent compression decreased pressure to 6.5+/-5.4 mmHg during lithotomy (P < 0.05) and to 10.3+/-4.7 mmHg in the supine position (P < 0.05).

Conclusions

These results show that the lithotomy position is associated with changes in intracompartment pressure that are dependent on the method of leg support used. Furthermore, they indicate that intermittent external compression can reduce intracompartment pressure in the lower leg. Therefore, increases in intracompartment pressure during surgery in the lithotomy position with the calf or knee supported may be one of the factors that contribute to the development of compartment syndrome. Further, use of intermittent external compression may significantly reduce this pressure increase.
Phenylephrine Added to Prophylactic Ephedrine Infusion during Spinal Anesthesia for Elective Cesarean Section
Authors: Mercier Frédéric J. , Riley Edward T. , Frederickson Willard L. , Roger-Christoph Sandrine , Benhamou Dan , Cohen Sheila E.
Published: November 2003

Background

Because ephedrine infusion (2 mg/min) does not adequately prevent spinal hypotension during cesarean delivery, the authors investigated whether adding phenylephrine would improve its efficacy.

Methods

Thirty-nine parturients with American Society of Anesthesiologists physical status I-II who were scheduled for cesarean delivery received a crystalloid preload of 15 ml/kg. Spinal anesthesia was performed using 11 mg hyperbaric bupivacaine, 2.5 microg sufentanil, and 0.1 mg morphine. Maternal heart rate and systolic blood pressure were measured at frequent intervals. A vasopressor infusion was started immediately after spinal injection of either 2 mg/min ephedrine plus 10 microg/min phenylephrine or 2 mg/min ephedrine alone. Treatments were assigned randomly in a double-blind fashion. The infusion rate was adjusted according to systolic blood pressure using a predefined algorithm. Hypotension, defined as systolic blood pressure less than 100 mmHg and less than 80% of baseline, was treated with 6 mg ephedrine bolus doses.

Results

Hypotension occurred less frequently in the ephedrine-phenylephrine group than in the ephedrine-alone group: 37% versus 75% (P = 0.02). Ephedrine (36+/-16 mg, mean +/- SD) plus 178+/-81 microg phenylephrine was infused in former group, whereas 54+/-18 mg ephedrine was infused in the latter. Median supplemental ephedrine requirements and nausea scores (0-3) were less in the ephedrine-phenylephrine group (0 vs. 12 mg, P = 0.02; and 0 vs. 1.5, P = 0.01, respectively). Umbilical artery pH values were significantly higher in the ephedrine-phenylephrine group than in the group that received ephedrine alone (7.24 vs. 7.19). Apgar scores were similarly good in both groups.

Conclusion

Phenylephrine added to an infusion of ephedrine halved the incidence of hypotension and increased umbilical cord pH.
Propofol Attenuates Capacitative Calcium Entry in Pulmonary Artery Smooth Muscle Cells
Authors: Horibe Mayumi , Kondo Izumi , Damron Derek S. , Murray Paul A.
Published: November 2003

Background

Depletion of intracellular Ca2+ stores results in capacitative Ca2+ entry (CCE) in pulmonary artery smooth muscle cells (PASMCs). The authors aimed to investigate the effects of propofol on CCE and to assess the extent to which protein kinase C (PKC) and tyrosine kinases mediate propofol-induced changes in CCE.

Methods

Pulmonary artery smooth muscle cells were cultured from explants of canine intrapulmonary artery. Fura 2-loaded PASMCs were placed in a dish (37 degrees C) on an inverted fluorescence microscope. Intracellular Ca2+ concentration was measured using fura 2 in PASMCs using a dual-wavelength spectrofluorometer. Thapsigargin (1 microM), a sarcoplasmic reticulum Ca2+-adenosine triphosphatase inhibitor, was used to deplete intracellular Ca2+ stores after removing extracellular Ca2+. CCE was activated when extracellular Ca2+ (2.2 mM) was restored.

Results

Thapsigargin caused a transient increase in intracellular Ca2+ concentration (182+/-11%). Restoring extracellular calcium (to induce CCE) resulted in a peak (246+/-12% of baseline) and a sustained (187+/-7% of baseline) increase in intracellular Ca2+ concentration. Propofol (1, 10, 100 microM) attenuated CCE in a dose-dependent manner (peak: 85+/-3, 70+/-4, 62+/-4%; sustained: 94+/-5, 80+/-5, 72+/-5% of control respectively). Tyrosine kinase inhibition (tyrphostin 23) attenuated CCE (peak: 67+/-4%; sustained: 74+/-5% of control), but the propofol-induced decrease in CCE was still apparent after tyrosine kinases inhibition. PKC activation (phorbol 12-myristate 13-acetate) attenuated CCE (peak: 48+/-1%; sustained: 53+/-3% of control), whereas PKC inhibition (bisindolylmaleimide) potentiated CCE (peak: 132+/-11%; sustained: 120+/-4% of control). Moreover, PKC inhibition abolished the propofol-induced attenuation of CCE.

Conclusion

Tyrosine kinases activate and PKC inhibits CCE in PASMCs. Propofol attenuates CCE primarily via a PKC-dependent pathway. CCE should be considered a possible cellular target for anesthetic agents that alter vascular smooth muscle tone.
Lesions of the Basolateral Amygdala Complex Block Propofol-induced Amnesia for Inhibitory Avoidance Learning in Rats
Authors: Alkire Michael T. , Vazdarjanova Almira , Dickinson-Anson Heather , White Nathan S. , Cahill Larry
Published: November 2003

Background

As the unitary theory of anesthesia gives way to the "multiple sites, multiple mechanisms" concept, the sites involved in mediating the components of anesthesia must be identified. In the current study, we test the hypothesis that the basolateral amygdala complex (BLAC) is a brain site involved with mediating propofol-induced amnesia.

Methods

Male Sprague-Dawley rats were divided into two groups, sham-operated control animals and rats given bilateral excitotoxic N-methyl-D-aspartate lesions of the BLAC. For each group, animals were given intraperitoneal saline or propofol (25 mg/kg) 5 min before inhibitory avoidance learning. Rats were given a foot shock (0.4 mA) upon entering the dark side of a two-sided apparatus. Rats could escape additional shock by returning to and staying in the light side. Training ended after shock avoidance for greater than 60 s. Memory was tested at 24 h. Longer latencies to enter the dark side 24 h after training imply better memory.

Results

Sham-saline-treated animals had a robust memory latency (median latency [interquartile range] = 300 [163-567] s). Sham-propofo-treated animals exhibited a significant anterograde amnesia (latency = 63 [14-111] s) (P < 0.05 vs. sham-saline-treated animal). Both the saline-injected and propofol-injected animals with BLAC lesions showed robust memory (latency = 300 [264-485] and 323 [143480] s, respectively). These latencies did not differ from performance in the sham-saline-treated group and were significantly higher than the latency of the sham-propofol-treated group (both P < 0.05).

Conclusions

Discrete BLAC lesions blocked the amnestic effect of propofol. BLAC activity appears to be a requirement for propofol-induced amnesia. This finding suggests that the BLAC is a key brain site mediating anesthetic-induced amnesia.
Autosomal Dominant Canine Malignant Hyperthermia Is Caused by a Mutation in the Gene Encoding the Skeletal Muscle Calcium Release Channel (RYR1 )
Authors: Roberts Monica C. , Mickelson James R. , Patterson Edward E. , Nelson Thomas E. , Jane Armstrong P. , Brunson David B. , Hogan Kirk
Published: November 2003

Background

Malignant hyperthermia (MH) is an inherited disorder of skeletal muscle characterized by hypercarbia, rhabdomyolysis, generalized skeletal muscle contracture, cardiac dysrhythmia, and renal failure, that develops on exposure to succinylcholine or volatile anesthetic agents. All swine and up to 50% of human MH events are thought to be associated with mutations in the calcium release channel of the sarcoplasmic reticulum, also known as the ryanodine receptor (RYR1). Events resembling MH have been reported in other species, but none have undergone genetic investigation to date.

Methods

To determine the molecular basis of canine MH, a breeding colony was established with a male, mixed-breed, MH-susceptible (MHS) dog that survived an in vivo halothane-succinylcholine challenge. He was mated to three unaffected females to produce four litters and back-crossed to an affected daughter to produce one litter. One of his MHS sons was mated to an unaffected female to produce an additional litter. Forty-seven dogs were phenotyped with an in vitro contracture test and diagnosed as MHS or MH normal based on the North American in vitro contracture test protocol. Nine microsatellite markers in the vicinity of RYR1 on canine chromosome 1 (CFA01) were tested for linkage to the MHS phenotype. Mutational analysis in two MHS and two MH-normal dogs was performed with direct sequencing of polymerase chain reaction products and of cloned fragments that represent frequently mutated human RYR1 regions. A restriction fragment length polymorphism was chosen to detect the candidate mutation in the pedigree at large.

Results

Pedigree inspection revealed that MHS in this colony is transmitted as an autosomal dominant trait. FH2294, the marker closest to RYR1, is linked to MHS at a theta = 0.03 with a LOD score of 9.24. A T1640C mutation gives rise to an alanine for valine substitution of amino acid 547 in the RYR1 protein, generating a maximum LOD score of 12.29 at theta = 0.00. All dogs diagnosed as MHS by in vitro contracture test were heterozygous for the mutation, and all MH-normal dogs were homozygous for the T1640 allele.

Conclusions

These results indicate that autosomal dominant canine MH is caused by a mutation in the gene encoding the skeletal muscle calcium release channel and that the MHS trait in this pedigree of mixed-breed dogs is in perfect cosegregation with the RYR1 V547A mutation.
Opioid Action on Respiratory Neuron Activity of the Isolated Respiratory Network in Newborn Rats
Authors: Takeda Shinhiro , Eriksson Lars I. , Yamamoto Yuji , Joensen Henning , Onimaru Hiroshi , E. Lindahl Sten G.
Published: November 2003

Background

Underlying mechanisms behind opioid-induced respiratory depression are not fully understood. The authors investigated changes in burst rate, intraburst firing frequency, membrane properties, as well as presynaptic and postsynaptic events of respiratory neurons in the isolated brainstem after administration of opioid receptor agonists.

Methods

Newborn rat brainstem-spinal cord preparations were used and superfused with mu-, kappa-, and delta-opioid receptor agonists. Whole cell recordings were performed from three major classes of respiratory neurons (inspiratory, preinspiratory, and expiratory).

Results

Mu- and kappa-opioid receptor agonists reduced the spontaneous burst activity of inspiratory neurons and the C4 nerve activity. Forty-two percent of the inspiratory neurons were hyperpolarized and decreased in membrane resistance during opioid-induced respiratory depression. Furthermore, under synaptic block by tetrodotoxin perfusion, similar changes of inspiratory neuronal membrane properties occurred after application of mu- and kappa-opioid receptor agonists. In contrast, resting membrane potential and membrane resistance of preinspiratory and majority of expiratory neurons were unchanged by opioid receptor agonists, even during tetrodotoxin perfusion. Simultaneous recordings of inspiratory and preinspiratory neuronal activities confirmed the selective inhibition of inspiratory neurons caused by mu- and kappa-opioid receptor agonists. Application of opioids reduced the slope of rising of excitatory postsynaptic potentials evoked by contralateral medulla stimulation, resulting in a prolongation of the latency of successive first action potential responses.

Conclusions

Mu- and kappa-opioid receptor agonists caused reduction of final motor outputs by mainly inhibiting medullary inspiratory neuron network. This inhibition of inspiratory neurons seems to be a result of both a presynaptic and postsynaptic inhibition. The central respiratory rhythm as reflected by the preinspiratory neuron burst rate was essentially unaltered by the agonists.
Effects of Volatile Anesthetics on N -methyl-d-aspartate Excitotoxicity in Primary Rat Neuronal–Glial Cultures
Authors: Kudo Masaya , Aono Mitsuo , Lee Yoonki , Massey Gary , Pearlstein Robert D. , Warner David S.
Published: November 2003

Background

Volatile anesthetics are known to ameliorate experimental ischemic brain injury. A possible mechanism is inhibition of excitotoxic cascades induced by excessive glutamatergic stimulation. This study examined interactions between volatile anesthetics and excitotoxic stress.

Methods

Primary cortical neuronal-glial cultures were exposed to N-methyl-D-aspartate (NMDA) or glutamate and isoflurane (0.1-3.3 mM), sevoflurane (0.1-2.9 mM), halothane (0.1-2.9 mM), or 10 microM (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801). Lactate dehydrogenase release was measured 24 h later. In other cultures, effects of volatile anesthetics on Ca++ uptake and mitochondrial membrane potential were determined in the presence or absence of NMDA (0-200 microM).

Results

Volatile anesthetics reduced excitotoxin induced lactate dehydrogenase release by up to 52% in a dose-dependent manner. At higher concentrations, this protection was reversed. When corrected for olive oil solubility, the three anesthetics offered equivalent protection. MK-801 provided near-complete protection. Ca++ uptake was proportionally reduced with increasing concentrations of anesthetic but did not account for reversal of protection at higher anesthetic concentrations. Given equivalent NMDA-induced Ca++ loads, cells treated with volatile anesthetic had greater lactate dehydrogenase release than those left untreated. At protective concentrations, volatile anesthetics partially inhibited NMDA-induced mitochondrial membrane depolarization. At higher concentrations, volatile anesthetics alone were sufficient to induce mitochondrial depolarization.

Conclusions

Volatile anesthetics offer similar protection against excitotoxicity, but this protection is substantially less than that provided by selective NMDA receptor antagonism. Peak effects of NMDA receptor antagonism were observed at volatile anesthetic concentrations substantially greater than those used clinically.
Attenuation of Lung Inflammation by Adrenergic Agonists in Murine Acute Lung Injury
Authors: Dhingra Vinay K. , Uusaro Ari , Holmes Cheryl L. , Walley Keith R.
Published: November 2003

Background

Acute lung injury leading to a systemic inflammatory response greatly increases mortality in critically ill patients. Cardiovascular management of these patients frequently involves beta-adrenergic agonists. These agents may alter the inflammatory response. Therefore, the authors tested the hypothesis that beta-adrenergic agonists alter the pulmonary inflammatory response during acute lung injury in mice.

Methods

Five-week-old CD-1 mice received continuous infusions of 10 microg x kg(-1) x min(-1) dobutamine, 6 microg x kg(-1) x min(-1) dopexamine, or vehicle via intraperitoneal mini osmotic pumps, followed immediately by intratracheal instillation of approximately 2 microg/kg endotoxin (or phosphate-buffered saline control). Six hours later the mice were killed, and lung lavage was performed. Interleukin-6 and -10 concentrations in lung homogenates were measured using enzyme-linked immunosorbent assay. Interleukin-6 and macrophage inflammatory protein-2 mRNA was measured using reverse-transcription polymerase chain reaction.

Results

Interleukin-6 protein and mRNA significantly increased after intratracheal endotoxin (P < 0.001), and the fraction of neutrophils in lung lavage fluid increased in endotoxin-treated (41 +/- 25%) versus control mice (2 +/- 4%, P < 0.05). Treatment of endotoxic mice with dobutamine significantly decreased interleukin-6 protein (P < 0.05) and mRNA (P < 0.05) expression. Dopexamine had similar but less pronounced effects. Dobutamine decreased interleukin-10 expression, whereas dopexamine did not. In endotoxemic mice, both dobutamine and dopexamine decreased induction of macrophage inflammatory protein-2 mRNA (P < 0.05) and reduced the fraction of neutrophils in lung lavage fluid (P < 0.05).

Conclusions

In endotoxin-induced acute lung injury, beta-adrenergic agonists can significantly decrease proinflammatory cytokine expression, decrease induction of chemokine mRNA, and decrease the resultant neutrophil infiltrate in the lung.
Interaction of Volatile Anesthetics with Human Kv Channels in Relation to Clinical Concentrations
Authors: Friederich Patrick , Benzenberg Dietmar , Trellakis Sokratis , Urban Bernd W.
Published: November 2003

Background

Recent evidence shows that inhibition of human Kv3 channels by intravenous anesthetics occurs at clinical concentrations. The effects of volatile anesthetics on these human ion channels are unknown. This study was designed to establish whether minimum alveolar concentrations (MAC) of halothane, enflurane, isoflurane, and desflurane exhibit effects on Kv3 channeLs. To obtain an indication whether these findings may be specific to Kv3 channels, the effects of enflurane and isoflurane on human Kv1.1 channels were also investigated.

Methods

Kv3 channels natively expressed in SH-SY5Y cells and Kv1.1 channels expressed in HEK293 cells were measured with the whole cell patch clamp technique by standard protocols. Concentrations of volatile anesthetics were determined by gas chromatography.

Results

Halothane, enflurane, isoflurane, and desflurane reversibly inhibited Kv3 channels in a concentration-dependent manner. Concentrations at half-maximal effect (IC50 values) ranged between 1,800 and 4,600 microM. Hill coefficients were between 1.7 and 2.5. IC50 values for inhibition of Kv1.1 channels were 2,800 and 5,200 microM, and Hill coefficients were 3.9 and 5.6 for enflurane and isoflurane, respectively.

Conclusion

Volatile anesthetics inhibit human Kv3 channels at clinical concentrations. At 1-3 MAC, inhibition would account on average for 2-12%. Inhibition would be highest with enflurane (between 3% and 22%) and lowest with isoflurane (between 0.2% and 3%). Kv1.1 channels would only be inhibited by enflurane at clinical concentrations (2% at 2 MAC and 8% at 3 MAC). Whether the degree of K channel inhibition by volatile anesthetics may contribute to their clinical action needs further study.