bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple Agents Potentiate α1-Adrenoceptor–induced Conduction Depression in Canine Cardiac Purkinje Fibers
Authors: Kulier Alexander H. , Turner Lawrence A. , Vodanovic Sanja , Contney Stephen , Lathrop David A. , Bosnjak Zeljko J
Published: November 2003

Background

Halothane more so than isoflurane potentiates an alpha1-adrenoceptor (alpha1-AR)-mediated action of epinephrine that abnormally slows conduction in Purkinje fibers and may facilitate reentrant arrhythmias. This adverse drug interaction was further evaluated by examining conduction responses to epinephrine in combination with thiopental and propofol, which "sensitize" or reduce the dose of epinephrine required to induce arrhythmias in the heart, and with etomidate, which does not, and responses to epinephrine with verapamil, lidocaine, and l-palmitoyl carnitine, a potential ischemic metabolite.

Methods

Action potentials and conduction times were measured in vitro using two microelectrodes in groups of canine Purkinje fibers stimulated at 150 pulses/min. Conduction was evaluated each minute after exposure to 5 microm epinephrine (or phenylephrine) alone or with the test drugs. Changes in the rate of phase 0 depolarization (Vmax) and the electrotonic spread of intracellular current were measured during exposure to epinephrine with octanol to evaluate the role of inhibition of active and passive (intercellular coupling) membrane properties in the transient depression of conduction velocity.

Results

Lidocaine (20 microm) and octanol (0.2 mm) potentiated alpha1-AR-induced conduction depression like halothane (0.4 mm), with maximum depression at 3-5 min of agonist exposure, no decrease of Vmax, and little accentuation at a rapid (250 vs. 150 pulses/min) stimulation rate. Thiopental (95 microm), propofol (50 microm), and verapamil (2 microm) similarly potentiated epinephrine responses, whereas etomidate (10 microm) did not. Between groups, the decrease of velocity induced by epinephrine in the presence of (10 microm) l-palmitoyl carnitine (-18%) was significantly greater than that resulting from epinephrine alone (-6%; 0.05 </= P </= 0.10). Current injection experiments were consistent with marked transient inhibition of cell-to-cell coupling correlating with alpha1-AR conduction depression in fibers exposed to octanol.

Conclusions

Anesthetic "sensitization" to the arrhythmogenic effects of catecholamines may be a special case of a more general phenomenon by which not only some anesthetics and antiarrhythmic drugs but also possible ischemic fatty acid metabolites potentiate conduction depression due to acute alpha1-AR-mediated cell-to-cell uncoupling.
Volatile Anesthetics Activate the Human Tandem Pore Domain Baseline K+Channel KCNK5
Authors: Gray Andrew T. , Zhao Byron B. , Kindler Christoph H. , Winegar Bruce D. , Mazurek Matthew J. , Xu Jie , Chavez Raymond A. , Forsayeth John R. , Yost C. Spencer
Published: November 2003

Background

Previous studies have identified a volatile anesthetic-induced increase in baseline potassium permeability and concomitant neuronal inhibition. The emerging family of tandem pore domain potassium channels seems to function as baseline potassium channels in vivo. Therefore, we studied the effects of clinically used volatile anesthetics on a recently described member of this family.

Methods

A cDNA clone containing the coding sequence of KCNK5 was isolated from a human brain library. Expression of KCNK5 in the central nervous system was determined by Northern blot analysis and reverse-transcription polymerase chain reaction. Functional expression of the channel was achieved by injection of cRNA into Xenopus laevis oocytes.

Results

Expression of KCNK5 was detected in cerebral cortex, medulla, and spinal cord. When heterologously expressed in Xenopus oocytes, KCNK5 currents exhibited delayed activation, outward rectification, proton sensitivity, and modulation by protein kinase C. Clinical concentrations of volatile general anesthetics potentiated KCNK5 currents by 8-30%.

Conclusion

Human KCNK5 is a tandem pore domain potassium channel exhibiting delayed activation and sensitivity to volatile anesthetics and may therefore have a role in suppressing cellular excitability during general anesthesia.
Sarcolemmal and Mitochondrial Adenosine Triphosphate– dependent Potassium Channels
Authors: Toller Wolfgang G. , Gross Eric R. , Kersten Judy R. , Pagel Paul S. , Gross Garrett J. , Warltier David C.
Published: November 2003

Background

Volatile anesthetic-induced preconditioning is mediated by adenosine triphosphate-dependent potassium (KATP) channels; however, the subcellular location of these channels is unknown. The authors tested the hypothesis that desflurane reduces experimental myocardial infarct size by activation of specific sarcolemmal and mitochondrial KATP channels.

Methods

Barbiturate-anesthetized dogs (n = 88) were acutely instrumented for measurement of aortic and left ventricular pressures. All dogs were subjected to a 60-min left anterior descending coronary artery occlusion followed by 3-h reperfusion. In four separate groups, dogs received vehicle (0.9% saline) or the nonselective KATP channel antagonist glyburide (0.1 mg/kg intravenously) in the presence or absence of 1 minimum alveolar concentration desflurane. In four additional groups, dogs received 45-min intracoronary infusions of the selective sarcolemmal (HMR 1098; 1 microg. kg-1. min-1) or mitochondrial (5-hydroxydecanoate [5-HD]; 150 microg. kg-1. min-1) KATP channel antagonists in the presence or absence of desflurane. Myocardial perfusion and infarct size were measured with radioactive microspheres and triphenyltetrazolium staining, respectively.

Results

Desflurane significantly (P < 0.05) decreased infarct size to 10 +/- 2% (mean +/- SEM) of the area at risk as compared with control experiments (25 +/- 3% of area at risk). This beneficial effect of desflurane was abolished by glyburide (25 +/- 2% of area at risk). Glyburide (24 +/- 2%), HMR 1098 (21 +/- 4%), and 5-HD (24 +/- 2% of area at risk) alone had no effects on myocardial infarct size. HMR 1098 and 5-HD abolished the protective effects of desflurane (19 +/- 3% and 22 +/- 2% of area at risk, respectively).

Conclusion

Desflurane reduces myocardial infarct size in vivo, and the results further suggest that both sarcolemmal and mitochondrial KATP channels could be involved.
Single-beat Estimation of Ventricular End-systolic Elastance–Effective Arterial Elastance as an Index of Ventricular Mechanoenergetic Performance
Authors: Hayashi Kazuko , Shigemi Kenji , Shishido Toshiaki , Sugimachi Masaru , Sunagawa Kenji
Published: November 2003

Background

The ratio of ventricular end-systolic elastance (Ees) to effective arterial elastance (Ea) is known to reflect not only ventricular mechanical performance but also energetic performance. Despite these useful features, technical difficulties associated with estimating Ees make the clinical application of Ees/Ea impractical. We developed a framework to estimate Ees/Ea without measuring ventricular volume or altering the loading condition.

Methods

To achieve this goal, we approximated the ventricular time-varying elastance curve with two straight lines, one for the isovolumic phase and the other for the ejection phase, and characterized the curve with the slope ratio, k, of these two straight lines. Using the concept of the pressure-volume relationship, Ees/Ea is algebraically expressed as Ees/Ea = Pad/Pes (1 + k. ET/PEP) - 1, where Pes is end-systolic pressure, Pad is aortic diastolic pressure, ET is ejection time, and PEP is pre-ejection period. In 11 anesthetized dogs, we recorded arterial and ventricular pressures and ventricular volume and estimated Ees and Ea under various contractile states and loading conditions.

Results

An empirical relation between k and Ees/Ea was found as k = 0.53 (Ees/Ea)0.51. Simultaneous solution of these two equations yielded Ees/Ea as a function of Pad/Pes and ET/PEP. The estimated Ees/Ea values correlated well with the measured Ees/Ea values ([Measured Ees/Ea] = 0.96 [Estimated Ees/Ea] + 0.098, r = 0.925, SEE = 0.051).

Conclusions

The proposed framework is capable of estimating Ees/Ea from ventricular and aortic pressure.
Hypersensitivity of Malignant Hyperthermia–susceptible Swine Skeletal Muscle to Caffeine Is Mediated by High Resting Myoplasmic [Ca2+]
Authors: López Jose R. , Contreras Jaime , Linares Nancy , Allen Paul D.
Published: November 2003

Background

Malignant hyperthermia (MH) is an inherited pharmacogenetic syndrome that is triggered by halogenated anesthetics and/or depolarizing muscle relaxants. MH-susceptible (MHS) skeletal muscle has been shown to be more sensitive to caffeine-induced contracture than muscle from nonsusceptible (MHN) subjects and is the basis for the most commonly used clinical diagnostic test to determine MH susceptibility.

Methods

We studied the effects of caffeine on myoplasmic free calcium concentration ([Ca2+]i) in MHN and MHS swine muscle fibers by means of Ca2+-selective microelectrodes before and after K+-induced partial depolarization.

Results

[Ca2+]i in untreated MHN fibers was 123 +/- 8 nm versus 342 +/- 33 nm in MHS fibers. Caffeine (2 mm) caused an increase in [Ca2+]i in both groups (296 +/- 41 nm MHN vs. 1,159 +/- 235 nm MHS) with no change in resting membrane potential. When either MHN or MHS, muscle fibers were incubated in 10 mm K+ [Ca2+]i transiently increased to 272 +/- 22 nm in MHN and 967 +/- 38 nm in MHS for 6-8 min. Exposure of MHN fibers to 2 mm caffeine while resting [Ca2+]i was elevated induced an increment in [Ca2+]i to 940 +/- 37 nm. After 6-8 min of exposure to 10 mm K+, [Ca2+]i returned to control levels in all fibers, and the effect of 2 mm caffeine on resting [Ca2+]i returned to control, despite continued partial membrane depolarization.

Conclusions

These results suggest that the increased "sensitivity" to caffeine of MHS swine muscle fibers is a nonspecific response related, at least in part, to the high resting [Ca2+]i and not an increased caffeine sensitivity of the sarcoplasmic reticulum Ca2+ release channel per se.
Supplemental Intraoperative Oxygen Augments Antimicrobial and Proinflammatory Responses of Alveolar Macrophages
Authors: Kotani Naoki , Hashimoto Hiroshi , Sessler Daniel I. , Muraoka Masatoshi , Hashiba Eiji , Kubota Takeshi , Matsuki Akitomo
Published: November 2003

Background

The first goal was to test the hypothesis that 100% inspired oxygen maintained for approximately 8 h intraoperatively is not associated with impaired pulmonary oxygenation. The authors also tested the hypothesis that intraoperative inhalation of 100% oxygen augments proinflammatory and antimicrobial responses of alveolar macrophages during anesthesia and surgery.

Methods

The authors studied patients administered 100% oxygen (n = 30) and 30% oxygen (n = 30) during propofol-fentanyl general anesthesia. Alveolar macrophages were harvested by bronchoalveolar lavage immediately, 2, 4, and 6 h after induction of anesthesia, and at the end of surgery. The authors measured "opsonized" and "unopsonized" phagocytosis and microbicidal activity. RNA was extracted from harvested cells and cDNA was synthesized. The expression of interleukin(IL)-1beta, IL-6, IL-8, interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) was measured by semiquantitative polymerase chain reaction.

Results

Gene expression of all proinflammatory cytokines except IL-6 increased fourfold to 20-fold over time in both groups. However, expression of TNF-alpha and IL-8, IFN-gamma, and IL-6 and IL-1beta was 2-20 times greater in patients administered 100% than in those administered 30% oxygen. Unopsonized and opsonized phagocytosis and microbicidal activity decreased progressively, with the decreases being nearly twice as great during inhalation of 30% oxygen versus 100% oxygen.

Conclusion

Inhalation of 100% oxygen improved intraoperative decreases in phagocytic and microbicidal activity possibly because expression of proinflammatory cytokines was augmented. These data therefore suggest that intraoperative inhalation of 100% oxygen augments antimicrobial and proinflammatory responses in alveolar macrophages during anesthesia and surgery.
Comparison of Isoflurane Effects on Motor Evoked Potential and F Wave
Authors: Zhou Henry H. , Zhu Ching
Published: November 2003

Background

Volatile anesthetics produce surgical immobility by suppressing the motor system. The anesthetic action site in the motor pathway is unclear. Anesthetic effects on the whole and the lower portion of motor pathway can be studied by measuring the motor evoked potentials (MEP) and the F wave. This study measured the effect of isoflurane on the MEP and the F wave.

Methods

With institutional review board approval, we studied 12 adult patients with American Society of Anesthesiologists physical status I or II. After intubation, anesthesia was maintained with nitrous oxide/oxygen and propofol infusion. MEPs were elicited by transcranial electrical stimuli (train-of-five pulse; stimuli intensity 40-160 mA) through electrodes placed in the scalp at C3/C4 positions and recorded at the anterior tibialis muscle with an Axon Sentinel-4EP monitor. F waves were elicited by an electrode fixed over the posterior tibial nerve at the medial malleolus and recorded at the abductor hallucis muscle. After end-tidal concentration of isoflurane was maintained at 0.5% for 20 min, the MEP and F wave were measured again. MEP and F-wave changes before and after isoflurane were analyzed using paired Wilcoxon test with Bonferroni correction. The difference between the changes in MEP and F wave was analyzed using Friedman's test.

Results

Motor evoked potential amplitudes (median, 205 microV; 25th-75th percentiles, 120-338 microV), F-wave amplitude (median, 100 microV; 25th-75th percentiles, 64.2-137.5 microV), and F-wave persistence (59 +/- 29%) were decreased to 0 microV (0-15 microV), 49 microV (12.4-99.6 microV), and 30 +/- 31%, respectively, by 0.5% isoflurane. MEP amplitude suppression was different from the changes in F-wave amplitude and persistence (P < 0.02).

Conclusions

Isoflurane 0.5% suppresses the motor pathway by decreasing both MEP and F wave. The MEP is suppressed more than the F wave.
Relation between Perioperative Hypertension and Intracranial Hemorrhage after Craniotomy
Authors: Basali Ayman , Mascha Edward J. , Kalfas Iain , Schubert Armin
Published: November 2003

Background

Previous data suggest that systemic hypertension (HTN) is a risk factor for postcraniotomy intracranial hemorrhage (ICH). The authors examined the relation between perioperative blood pressure elevation and postoperative ICH using a retrospective case control design.

Methods

The hospital's database of all patients undergoing craniotomy from 1976 to 1992 was screened. Coagulopathic and unmatchable patients were excluded. There were 69 evaluable patients who developed ICH postoperatively (n = 69). A 2-to-1 matched (by age, date of surgery, pathologic diagnosis, surgical procedure, and surgeon) control group without postoperative ICH was assembled (n = 138). Preoperative, intraoperative, and postoperative blood pressure records (up to 12 h) were examined. Incidence of perioperative HTN (blood pressure > or = 160/90 mmHg) and odds ratios for ICH were determined.

Results

Of the 11,214 craniotomy patients, 86 (0.77%) suffered ICH, and 69 fulfilled inclusion criteria. The incidence of preoperative HTN was similar in the ICH (34%) and the control (24%) groups. ICH occurred 21 h (median) postoperatively, with an interquartile range of 4-52 h. Sixty-two percent of ICH patients had intraoperative HTN, compared with only 34% of controls (P < 0.001). Sixty-two percent of the ICH patients had prehemorrhage HTN in the initial 12 postoperative hours versus 25% of controls (P < 0.001), with an odds ratio of 4.6 (P < 0.001) for postoperative ICH. Hospital stay (median, 24.5 vs. 11.0 days), and mortality (18.2 vs. 1.6%) were significantly greater in the ICH than in the control groups.

Conclusions

ICH after craniotomy is associated with severely prolonged hospital stay and mortality. Acute blood pressure elevations occur frequently prior to postcraniotomy ICH. Patients who develop postcraniotomy ICH are more likely to be hypertensive in the intraoperative and early postoperative periods.
Regulation of Proprioceptive Memory by Subarachnoid Regional Anesthesia
Authors: Isaacson Sheldon A. , Funderburk Matthew , Yang Jay
Published: November 2003

Background

Patient perception of limb position during regional anesthesia is frequently incorrect. The existing model ascribes this misperception, or phantom sensation, as a reversion to a fixed, slightly flexed, body schema. A model was developed to evaluate the influence of limb position changes on the incidence of incorrect or phantom sensations during regional anesthesia.

Methods

Forty American Society of Anesthesiologists physical status I-III adult patients undergoing genitourinary procedures under subarachnoid anesthesia were assigned to a lidocaine or bupivacaine treatment group and randomly assigned to one of four time groups (1, 4, 7, and 10 min). After blockade, patients were placed supine and blinded to limb positioning manipulations. One leg was flexed and the contralateral leg extended, with leg positions subsequently reversed at the assigned time point. At 10 min, patients were asked to identify the position of each leg. Percentage of incorrect response was analyzed using a logistic regression model with two independent variables: treatment and time. A supplemental study was undertaken to evaluate the observed difference in incorrect perceptions relative to flexed first versus extended limb first sequencing.

Results

The inability to perceive a change in limb position under regional anesthesia is dependent on the time after the block that the position change is initiated in relation to the onset characteristics of the local anesthetic. A phantom sensation of an extended leg position clearly exists. The flexed-first limb has a significantly higher incidence of incorrect or phantom perceptions.

Conclusion

Proprioceptive memory involves a dynamic neuroplastic imprinting process that is influenced by limb or joint position prior to onset of regional anesthesia. This contrasts with previously held beliefs of a purely fixed body schema.
Usefulness of Continuous Oxygen Insufflation into Trachea for Management of Upper Airway Obstruction during Anesthesia
Authors: Okazaki Junko , Isono Shiroh , Tanaka Atsuko , Tagaito Yugo , Schwartz Alan R. , Nishino Takashi
Published: November 2003

Background

Severe complications associated with upper airway obstruction often occur during the perioperative period. Development of a simple and reliable technique for reversing the impaired airway patency may improve airway management. The purpose of the current study is to evaluate the usefulness of transtracheal oxygen insufflation (TTI) for management of upper airway obstruction during anesthesia and to explore the mechanisms of TTI in detail.

Methods

During propofol anesthesia in eight spontaneously breathing patients, the upper airway cross-sectional area and pressure-flow measurements during neck flexion with TTI were compared with those during triple airway maneuvers (TAM) without TTI. Blood gas analyses assessed efficacy of CO2 elimination during TTI in an additional nine patients.

Results

TTI achieved adequate PaCO2 and PaO2 levels equivalent to those during TAM. In addition to a significantly smaller cross-sectional area during TTI, the location and slope of the pressure-flow relation during TTI completely differed from those during TAM, indicating that upper airway resistance was much higher during TTI. Notably, minute ventilation during TTI was significantly smaller than that during TAM, suggesting reduced dead space or other mechanisms for CO2 elimination.

Conclusions

TTI is capable of maintaining adequate blood gases through mechanisms different from those of conventional airway support in anesthetized subjects with upper airway obstruction.
Lumbar Plexus Block Reduces Pain and Blood Loss Associated with Total Hip Arthroplasty
Authors: Stevens Robert D. , Van Gessel Elisabeth , Flory Nicolas , Fournier Roxane , Gamulin Zdravko
Published: November 2003

Background

The usefulness of peripheral nerve blockade in the anesthetic management of hip surgery has not been clearly established. Because sensory afferents from the hip include several branches of the lumbar plexus, the authors hypothesized that a lumbar plexus block could reduce pain from a major hip procedure.

Methods

In a double-blind prospective trial, 60 patients undergoing total hip arthroplasty were randomized to receive general anesthesia with (plexus group, n = 30) or without (control group, n = 30) a posterior lumbar plexus block. The block was performed after induction using a nerve stimulator, and 0.4 ml/kg bupivacaine, 0.5%, with epinephrine was injected. General anesthesia was standardized, and supplemental fentanyl was administered per hemodynamic guidelines. Postoperative pain and patient-controlled intravenous morphine use were serially assessed for 48 h.

Results

The proportion of patients receiving supplemental fentanyl intraoperatively was more than 3 times greater in the control group (20 of 30 vs. 6 of 29, P = 0.001). In the postanesthesia care unit, a greater than fourfold reduction in pain scores was observed in the plexus group (visual analogue scale [VAS] pain score at arrival 1.3 +/- 2 vs. 5.6 +/- 3, P < 0.001), and "rescue" morphine boluses (administered if VAS > 3) were administered 10 times less frequently (in 2 of 28 vs. in 22 of 29 patients, P < 0.0001). Pain scores and morphine consumption remained significantly lower in the plexus group until 6 h after randomization (VAS at 6 h, 1.4 +/- 1.3 vs. 2.4 +/- 1.4, P = 0.007; cumulative morphine at 6 h, 5.6 +/- 4.7 vs. 12.6 +/- 7.5 mg, P < 0.0001). Operative and postoperative (48 h) blood loss was modestly decreased in the treated group. Epidural-like distribution of anesthesia occurred in 3 of 28 plexus group patients, but no other side-effects were noted.

Conclusions

Posterior lumbar plexus block provides effective analgesia for total hip arthroplasty, reducing intra- and postoperative opioid requirements. Moreover, blood loss during and after the procedure is diminished. Epidural anesthetic distribution should be anticipated in a minority of cases.
Effect of Intravenous versus Epidural Fentanyl on the Minimum Local Analgesic Concentration of Epidural Bupivacaine in Labor
Authors: Polley Linda S. , Columb Malachy O. , Naughton Norah N. , Wagner Deborah S. , Dorantes Deanna M. , van de Ven Cosmas J. M.
Published: November 2003

Background

The minimum local analgesic concentration (MLAC) has been defined as the median effective local analgesic concentration (EC50) in a 20-ml volume for epidural analgesia in the first stage of labor. The aim of this study was to determine the relative local anesthetic sparing efficacies of intravenous and epidural fentanyl by comparison of their effects on the MLAC of bupivacaine.

Methods

In this double-blind, randomized, prospective study, 84 parturients at < or = 7-cm cervical dilation who requested epidural analgesia were allocated to one of two groups. After lumbar epidural catheter placement, 20 ml bupivacaine (n = 44) or bupivacaine with 3 microg/ml (60 microg) fentanyl (n = 40) was administered. The plain bupivacaine group then received 60 microg intravenous fentanyl. The bupivacaine-fentanyl group received intravenous saline. The concentration of bupivacaine was determined by the response of the previous patient in that group to a higher or lower concentration using up-down sequential allocation. Analgesic efficacy was assessed using 100-mm visual analog pain scores, with < or = 10 mm within 30 min define as effective.

Results

The MLAC of bupivacaine-intravenous fentanyl was 0.064% wt/vol (95% confidence interval, 0.049-0.080), and the MLAC of bupivacaine-epidural fentanyl was 0.034% wt/vol (95% confidence interval, 0.017-0.050). Epidural fentanyl significantly increased the analgesic potency of bupivacaine by a factor of 1.88 (95% confidence interval, 1.09-3.67) compared with intravenous fentanyl. The epidural fentanyl group demonstrated significantly higher dermatomal spread (P = 0.0064) and increased pruritus (P = 0. 01).

Conclusions

Epidural fentanyl significantly reduced the MLAC of bupivacaine when compared with intravenous fentanyl for the parturients in this study. The significantly enhanced local anesthetic sparing, dermatomal level, and pruritus with epidural fentanyl suggest a primarily spinal site of action.
Norepinephrine-induced Apoptosis Is Inhibited in Adult Rat Ventricular Myocytes Exposed to Volatile Anesthetics
Authors: Zaugg Michael , Jamali Nasir Z. , Lucchinetti Eliana , Shafiq Saiyid A. , Siddiqui Mohamed A. Q.
Published: November 2003

Background

Volatile anesthetics are used to provide anesthesia to patients with heart disease under heightened adrenergic drive. The purpose of this study was to test whether volatile anesthetics can inhibit norepinephrine (NE)-induced apoptosis in cardiomyocytes.

Methods

Rat ventricular cardiomyocytes were exposed to NE (10 microm) alone or in the presence of increasing concentrations of isoflurane and halothane.

Results

Isoflurane at 1.6 minimum alveolar concentration (MAC) (4 +/- 2% [SD]) and halothane at 1.2 MAC (3 +/- 2%) abolished the percentage of cardiomyocytes undergoing NE-induced apoptosis (34 +/- 8%), as assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) (P < 0.0001). Lower concentrations of isoflurane and halothane markedly decreased the number of TUNEL-positive cells. Similarly, isoflurane at 1.6 MAC (5 +/- 3%) and halothane at 1.2 MAC (6 +/- 3%) prevented the increase in annexinV-staining cardiomyocytes (38 +/- 7%; P < 0. 0001). These findings were corroborated with a decreased quantity of NE-induced DNA laddering by volatile anesthetics. Halothane at 1.2 MAC abolished the increase in TUNEL-positive cardiomyocytes exposed to the dihydropyridine Ca2+-channel agonist BAY K-8644 (1 microm) (BAY K-8644 + halothane: 3 +/- 2% vsBAY K-8644: 34 +/- 6%; P < 0. 0001) and the Ca2+-ionophore 4-bromo-A23187 (1 microm) (4-bromo-A23187 + halothane: 2 +/- 2% vs4-bromo-A23187: 13 +/- 4%; P = 0.03). NE treatment increased caspase-9 activity to 197 +/- 62% over control myocytes (P < 0.0001), whereas no caspase-8 activation was detectable. This increase in caspase-9 activity was blocked by isoflurane at 1.6 MAC and halothane at 1.2 MAC.

Conclusions

Volatile anesthetics offer significant protection against beta-adrenergic apoptotic death signaling in ventricular cardiomyocytes. The authors present evidence that this protection is mainly mediated through modulation of cellular Ca2+ homeostasis and inhibition of the apoptosis initiator caspase-9.
Assessment of Length-dependent Regulation of Myocardial Function in Coronary Surgery Patients Using Transmitral Flow Velocity Patterns
Authors: De Hert Stefan G. , Vander Linden Philippe J. , Broecke Pieter W. ten , De Mulder Peter A. , Rodrigus Inez E. , Adriaensen Hugo F.
Published: November 2003

Background

In a subset of coronary surgery patients, a transient increase in cardiac load by leg elevation resulted in a decrease in maximal rate of pressure development (dP/dtmax) and a major increase in end-diastolic pressure (EDP). This impairment of left ventricular (LV) function appeared to be related to a deficient length-dependent regulation of myocardial function. The present study investigated whether analysis of transmitral flow patterns with transesophageal echocardiography constituted a noninvasive method to identify these patients.

Methods

High-fidelity LV pressure tracings and transmitral flow signals were obtained in 50 coronary surgery patients during an increase in cardiac load by leg elevation. Using linear regression analysis, changes in transmitral E-wave velocity and deceleration time (DT) were related to changes in dP/dtmax and EDP.

Results

Changes in dP/dtmax with leg elevation were closely related to corresponding changes in E-wave velocity (r = 0.81; P < 0. 001) and to changes in DT (r = 0.78; P < 0.001). Similarly, changes in EDP were related to changes in E-wave velocity (r = 0.83; P < 0. 001) and to changes in DT (r = 0.84; P < 0.001). The decrease in dP/dtmax and the major increase in EDP in some patients was associated with an increase in E-wave velocity and a decrease in DT, indicating development of a restrictive LV filling pattern.

Conclusions

Impairment of LV function with leg elevation was associated with the development of a restrictive transmitral filling pattern. Analysis of transmitral flow patterns by means of transesophageal echocardiography therefore allowed noninvasive identification of a subset of coronary surgery patients with impaired length-dependent regulation of LV function.
The Effects of Increasing Plasma Concentrations of Dexmedetomidine in Humans
Authors: Ebert Thomas J. , Hall Judith E. , Barney Jill A. , Uhrich Toni D. , Colinco Maelynn D.
Published: November 2003

Background

This study determined the responses to increasing plasma concentrations of dexmedetomidine in humans.

Methods

Ten healthy men (20-27 yr) provided informed consent and were monitored (underwent electrocardiography, measured arterial, central venous [CVP] and pulmonary artery [PAP] pressures, cardiac output, oxygen saturation, end-tidal carbon dioxide [ETCO2], respiration, blood gas, and catecholamines). Hemodynamic measurements, blood sampling, and psychometric, cold pressor, and baroreflex tests were performed at rest and during sequential 40-min intravenous target infusions of dexmedetomidine (0.5, 0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng/ml; baroreflex testing only at 0.5 and 0.8 ng/ml).

Results

The initial dose of dexmedetomidine decreased catecholamines 45-76% and eliminated the norepinephrine increase that was seen during the cold pressor test. Catecholamine suppression persisted in subsequent infusions. The first two doses of dexmedetomidine increased sedation 38 and 65%, and lowered mean arterial pressure by 13%, but did not change central venous pressure or pulmonary artery pressure. Subsequent higher doses increased sedation, all pressures, and calculated vascular resistance, and resulted in significant decreases in heart rate, cardiac output, and stroke volume. Recall and recognition decreased at a dose of more than 0.7 ng/ml. The pain rating and mean arterial pressure increase to cold pressor test progressively diminished as the dexmedetomidine dose increased. The baroreflex heart rate slowing as a result of phenylephrine challenge was potentiated at both doses of dexmedetomidine. Respiratory variables were minimally changed during infusions, whereas acid-base was unchanged.

Conclusions

Increasing concentrations of dexmedetomidine in humans resulted in progressive increases in sedation and analgesia, decreases in heart rate, cardiac output, and memory. A biphasic (low, then high) dose-response relation for mean arterial pressure, pulmonary arterial pressure, and vascular resistances, and an attenuation of the cold pressor response also were observed.
Propofol Attenuates Acetylcholine-induced Pulmonary Vasorelaxation
Authors: Horibe Mayumi , Ogawa Koji , Sohn Ju-Tae , Murray Paul A.
Published: November 2003

Background

The mechanism by which propofol selectively attenuates the pulmonary vasodilator response to acetylcholine is unknown. The goals of this study were to identify the contributions of endogenous endothelial mediators (nitric oxide [NO], prostacyclin, and endothelium-derived hyperpolarizing factors [EDHFs]) to acetylcholine-induced pulmonary vasorelaxation, and to delineate the extent to which propofol attenuates responses to these endothelium-derived relaxing factors.

Methods

Canine pulmonary arterial rings were suspended for isometric tension recording. The effects of propofol on the vasorelaxation responses to acetylcholine, bradykinin, and the guanylyl cyclase activator, SIN-1, were assessed in phenylephrine-precontracted rings. The contributions of NO, prostacyclin, and EDHFs to acetylcholine-induced vasorelaxation were assessed in control and propofol-treated rings by pretreating the rings with a NO synthase inhibitor (l-NAME), a cyclooxygenase inhibitor (indomethacin), and a cytochrome P450 inhibitor (clotrimazole or SKF 525A) alone and in combination.

Results

Propofol caused a dose-dependent rightward shift in the acetylcholine dose-response relation, whereas it had no effect on the pulmonary vasorelaxant responses to bradykinin or SIN-1. Cyclooxygenase inhibition only attenuated acetylcholine-induced relaxation at high concentrations of the agonist. NO synthase inhibition and cytochrome P450 inhibition each attenuated the response to acetylcholine, and combined inhibition abolished the response. Propofol further attenuated acetylcholine-induced relaxation after NO synthase inhibition and after cytochrome P450 inhibition.

Conclusion

These results suggest that acetylcholine-induced pulmonary vasorelaxation is mediated by two components: NO and a cytochrome P450 metabolite likely to be an EDHF. Propofol selectively attenuates acetylcholine-induced relaxation by inhibiting both of these endothelium-derived mediators.
Absence of Stereospecific Effects of Bupivacaine Isomers on Heart Mitochondrial Bioenergetics
Authors: Sztark François , Nouette-Gaulain Karine , Malgat Monique , Dabadie Philippe , Mazat Jean-Pierre
Published: November 2003

Background

Highly lipophilic local anesthetics interfere with mitochondrial energy metabolism. These metabolic effects could, in part, explain some toxic effects of local anesthetics, such as bupivacaine-induced myocardial depression. The purpose of this study was to compare the optically pure isomers of bupivacaine on heart mitochondrial bioenergetics.

Methods

Both bupivacaine enantiomers were tested on rat heart isolated mitochondria. Oxygen consumption, adenosine triphosphate synthesis, and enzymatic activities of the four complexes of the respiratory chain were measured.

Results

No significant differences were found between R(+)- and S(-)-bupivacaine on mitochondrial oxidative phosphorylation with a similar dose-dependent decrease in adenosine triphosphate synthesis. Complex I (nicotinamide adenine dinucleotide ubiquinone reductase) was the enzymatic complex of the respiratory chain most sensitive to the bupivacaine isomers. Half-inhibitory concentrations for R(+)- and S(-)-bupivacaine were not statistically different (3.3 +/- 0.4 mm and 2.8 +/- 0.6 mm, respectively).

Conclusions

No stereospecific effects of bupivacaine enantiomers were shown in the inhibition of complex I activity and uncoupling of oxidative phosphorylation. This can be correlated with the lack of stereospecific effects of bupivacaine on myocardial depression. The lipid solubility of local anesthetics appears to be the principal physicochemical factor affecting the potency of these tertiary amines on mitochondrial bioenergetics.
Propofol Stimulates Ciliary Motility via the Nitric Oxide–Cyclic GMP Pathway in Cultured Rat Tracheal Epithelial Cells
Authors: Shirakami Gotaro , Li Dechun , Zhan Xinhua , Johns Roger A.
Published: November 2003

Background

Airway ciliary motility is impaired by inhaled anesthetics. Recent reports show that nitric oxide (NO) induces upregulation in ciliary beat frequency (CBF), and others report that propofol, an intravenous anesthetic, stimulates NO release; this raises the possibility that propofol increases CBF by stimulating the NO-cyclic guanosine monophosphate (cGMP) signal pathway. In this study, the authors investigated the effects of propofol on CBF and its relation with the NO-cGMP pathway using the pharmacologic blockers NG-monomethyl-l-arginine (l-NMMA), an NO synthase inhibitor; 1H-[1,2,4]oxidazole[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor; and KT5823, a cGMP-dependent protein kinase inhibitor, in cultured rat tracheal epithelial cells.

Methods

Rat tracheal tissues were explanted and cultured for 3-5 days. Images of ciliated cells were videotaped using a phase-contrast microscope. Baseline CBF and CBF 25 min after exposure to propofol or blocker were measured using video analysis.

Results

Vehicle (0.1% dimethyl sulfoxide; n = 11) increased CBF by 0.2 +/- 1.7% (mean +/- SD) from baseline. Propofol stimulated CBF significantly (P < 0.01) and dose dependently (1 microM, 2.0 +/- 1. 9%, n = 6; 10 microM, 8.2 +/- 6.7%, n = 9; 100 microM, 14.0 +/- 4.7%, n = 10). Intralipid (0.05%), the clinical vehicle of propofol, did not affect CBF (-0.2 +/- 2.2%; n = 5). The enhancement of CBF with use of 100 microm propofol was abolished (P < 0.01) by coadministration of 10 mmicroM l-NMMA (2.4 +/- 3.6%; n = 5), 100 microM ODQ (-0.3 +/- 2.2%; n = 6) or 30 microM KT5823 (-0.1 +/- 4. 1%; n = 8). l-NMMA, ODQ, or KT5823 alone did not change CBF.

Conclusions

These results show that propofol stimulates CBF viathe NO-cGMP pathway in rat tracheal epithelial cells, suggesting a possible advantage of propofol in decreasing respiratory risk.
Midazolam
Authors: Kain Zeev N. , Hofstadter Maura B. , Mayes Linda C. , Krivutza Dawn M. , Alexander Gerianne , Wang Shu-Ming , Reznick J. Steven
Published: November 2003

Background

The minimum time interval between administration of oral midazolam and separation of children from their parents that ensures good anterograde amnesia has not been previously determined. This is of particular importance in a busy operating room setting where schedule delays secondary to midazolam administration may not be tolerated.

Methods

Children (n = 113) undergoing general anesthesia and surgery completed preoperative baseline memory testing using a validated series of picture cards and were randomly assigned to one of three midazolam groups or a control group. Exactly, 5, 10, or 20 min after receiving oral midazolam (0.5 mg/kg) or 15 min after receiving placebo, children were administered a second memory test that used pictures. Anxiety of children was assessed during induction of anesthesia with use of a validated anxiety measurement tool. Postoperatively, recall and recognition for picture cards seen during baseline testing and postintervention testing were assessed.

Results

Postoperatively, recall and recognition of pictures presented to patients after drug administration (anterograde amnesia) showed significant group differences (P = 0.0001), with recall impaired in the 10- (P = 0.004) and 20-min groups (P = 0.0001). Similarly, recognition memory was impaired in the 5- (P = 0.0008), 10- (P = 0.0001) and 20-min (P = 0.0001) groups. Significant anxiolytic effects of midazolam were observed as early as 15 +/- 4 min after midazolam administration (P = 0.02).

Conclusions

Midazolam administered orally produces significant anterograde amnesia when given as early as 10 min before a surgical procedure.
Sedation during Spinal Anesthesia
Authors: Pollock Julia E. , Neal Joseph M. , Liu Spencer S. , Burkhead Dan , Polissar Nayak
Published: November 2003

Background

Central neuraxial anesthesia has been reported to decrease the dose of both intravenous and inhalational anesthetics needed to reach a defined level of sedation. The mechanism behind this phenomenon is speculated to be decreased afferent stimulation of the reticular activating system. The authors performed a two-part study (nonrandomized pilot study and a subsequent randomized, double-blind, placebo-controlled study) using the Bispectral Index (BIS) monitor to quantify the degree of sedation in unmedicated volunteers undergoing spinal anesthesia.

Methods

Twelve volunteers underwent BIS monitoring and observer sedation scoring (Observer's Assessment of Alertness/Sedation Scale [OAA/S]) before and after spinal anesthesia with 50 mg hyperbaric lidocaine, 5%. Subsequently, 16 volunteers blinded to the study were randomized to receive spinal anesthesia with 50 mg hyperbaric lidocaine, 5% (n = 10) or placebo (n = 6) and underwent BIS and OAA/S monitoring.

Results

In part I, significant changes in BIS scores of the volunteers occurred progressively (P = 0.003). The greatest variations from baseline BIS measurement occurred at 30 and 70 min. In part II, there were significant decreases in OAA/S and self-sedation scores for patients receiving spinal anesthesia versuscontrol patients (P = 0.04 and 0. 01, respectively). The greatest decrease in OAA/S scores occurred at 60 min. BIS scores were similar between groups (P = 0.4).

Conclusions

Spinal anesthesia is accompanied by significant sedation progressively when compared with controls as measured by OAA/S and self-sedation scores. This effect was not related to block height. The late sedation observed by OAA/S at 60 min may indicate a second mechanism of sedation, such as delayed rostral spread of local anesthetics. BIS was not a sensitive measure of the sedation associated with spinal anesthesia in the randomized, blinded portion of this study.
Ceftriaxone Pharmacokinetics during Iatrogenic Hydroxyethyl Starch-induced Hypoalbuminemia
Authors: Mimoz Olivier , Soreda Stéphan , Padoin Christophe , Tod Michel , Petitjean Olivier , Benhamou Dan
Published: November 2003

Background

Although various drugs used by anesthesiologists highly bind to plasma proteins, the impact of iatrogenically induced hypoproteinemia on their pharmacologic effects has never been investigated. The authors determined the pharmacokinetics of ceftriaxone, a cephalosporin that binds strongly to albumin in postsurgical patients with hydroxyethyl starch-induced hypoalbuminemia.

Methods

Eleven hypoalbuminemic (serum albumin < 25 g/l) patients and age (+/- 5 yr)-, sex-, and body surface area (+/- 10%)-matched healthy volunteers received a 2-g ceftriaxone dose infused over a 15-min period. Fourteen venous blood samples were collected during the 24-h study period. Free ceftriaxone concentrations were determined by ultrafiltration. Antibiotic concentrations in plasma and ultrafiltrate were measured by ion-paired reversed-phase chromatography. The pharmacokinetic parameters derived from total and free antibiotic concentrations were determined using a noncompartmental method. Data are expressed as median and range.

Results

The pharmacokinetic parameters derived from total ceftriaxone concentrations were similar for the two groups, except for the median corrected volume of distribution at steady state, which was increased (P = 0.05) to 0.18 l/kg (range, 0. 11-0.29 l/kg) in patients, compared with 0.15 l/kg (range, 0.13-0.22 l/kg) in volunteers. The area under the free ceftriaxone concentration-time curve was twice as high in patients as in volunteers (median 192, range 114-301 vs. median 122, range 84-169 h. mg-1. l-1;P = 0.03). Moreover, the free ceftriaxone concentration remained more than 4 mg/l during more time in patients (median, 16. 7; range, 12.6-21.4 vs. median, 11.1; range, 6.0-19.0 h; P = 0.03).

Conclusions

Compared with healthy volunteers, patients with iatrogenic hypoalbuminemia have higher free ceftriaxone concentrations during the 24 h after antibiotic administration. This modification increases drug distribution into extravascular space and may enhance effectiveness.
Stereoselective Loss of Righting Reflex in Rats by Isoflurane
Authors: Dickinson Robert , White Ian , Lieb William R. , Franks Nicholas P.
Published: November 2003

Background

Although it is accepted widely that optically active intravenous general anesthetics produce stereoselective effects in animals, the situation regarding volatile agents is confused. Conventional studies with scarce isoflurane enantiomers have been limited to small numbers of animals and produced conflicting results. By injecting these volatile enantiomers intravenously, however, it is possible to study large numbers of animals and obtain reliable results that can help to identify the molecular targets for isoflurane.

Methods

Pure isoflurane enantiomers were administered intravenously to rats after solubilization in a lipid emulsion. The ability of each enantiomer to produce a loss of righting reflex was determined as a function of dose, and quantal dose-response curves were constructed. In addition, sleep times were recorded with each enantiomer. Chiral gas chromatography was used to measure relative enantiomer concentrations in the brains of rats injected with racemic isoflurane.

Results

The S(+)-enantiomer was 40 +/- 8% more potent than the R(-)-enantiomer at producing a loss of righting reflex. The S(+)-enantiomer induced longer sleep times (by about 50%) than did the R(-)-enantiomer. Rats anesthetized by a dose of racemic isoflurane sufficient to achieve a half-maximal effect had essentially identical brain concentrations of the two enantiomers.

Conclusions

The S(+)-enantiomer of the general anesthetic isoflurane is significantly (P < 0.001) more potent than the R(-)-enantiomer at causing a loss of righting reflex in rats. This confirms the view that isoflurane acts by binding to chiral sites. The observed degree of stereoselectivity provides a useful guide for ascertaining from in vitro experiments which molecular targets are most likely to play major roles in the loss of righting reflex caused by isoflurane.
Pulmonary Disposition of Propofol in Surgical Patients
Authors: He Yan-Ling , Ueyama Hiroshi , Tashiro Chikara , Mashimo Takashi , Yoshiya Ikuto
Published: November 2003

Background

The lungs have been mentioned as a possible site contributing to the extrahepatic clearance of propofol. The objective of the present study was to clarify the pulmonary disposition of propofol directly in human lungs by investigating both the first-pass uptake and pulmonary extraction at pseudo-steady state.

Methods

Nine patients were enrolled in the first-pass uptake study. Propofol (5 mg) and indocyanine green (ICG; 15 mg) were simultaneously administered via a central venous catheter within 1 s, and sequential arterial blood samples were obtained from the radial artery at 1-s intervals up to 45 s. Eleven patients were included in the infusion study, and propofol was infused via the jugular vein at a rate of 50 microgram. kg-1. min-1. Blood samples were simultaneously collected from pulmonary and radial arteries up to 60 min.

Results

A pronounced difference in the dilution curves between propofol and ICG was observed, and 28.4 +/- 11.6% (mean +/- SD) of propofol was taken up during the single passage through the human lung. The mean pulmonary transit time of propofol (31.3 +/- 6.0 s) was significantly longer than that of ICG (22.4 +/- 2.7 s; P < 0.01), indicating that some of the propofol trapped by lungs returned to the circulation by back diffusion. In the constant infusion study, no significant differences were observed with the plasma concentrations of propofol between pulmonary and radial arteries except for that at 2 min. The area under the curve of pulmonary and radial arterial concentration curves to 60 min were 59.1 +/- 14.8 and 56.8 +/- 12.5 microg. ml-1. min-1, respectively. No significant difference was observed with the area under the curve, suggesting that metabolism was not involved in the pulmonary uptake in human lungs.

Conclusions

Most of the propofol that undergoes pulmonary uptake during the first pass was released back to the circulation by back diffusion. Metabolism was not involved in the pulmonary uptake in human lungs.