bluuebunny/crossref_metadata_2025 huggingface dataset:
Sevoflurane-induced Reduction of Hypoxic Drive Is Sex-independent
Authors: Sarton Elise , van der Wal Minke , Nieuwenhuijs Diederik , Teppema Luc , Robotham James L. , Dahan Albert
Published: November 2003

Background

Although the mu-opioid agonist morphine affects ventilatory control in men and women in different ways, no data exist regarding the influence of sex on the ventilatory effects of inhalational anesthetics. The authors compared the effect of sevoflurane on the ventilatory response to isocapnic hypoxia in healthy young men and women.

Methods

Breath-to-breath ventilatory responses to hypoxic steps (number of hypoxic steps, four-six; duration, 3 min; end-tidal oxygen tension, approximately 50 mmHg; end-tidal carbon dioxide tension clamped at approximately 4 mmHg above resting values) were assessed in nine men and nine women without and with low-dose sevoflurane (end-tidal concentration, 0.25%). The bispectral index of the electroencephalogram was measured concomitantly.

Results

Sevoflurane reduced the hypoxic ventilatory sensitivity significantly in both sexes (men: control, 0.62 +/- 0.17 vs. sevoflurane, 0.38 +/- 0.19 l x min(-1) x %(-1); women: control, 0.52 +/- 0.30 vs. sevoflurane, 0.34 +/- 0.15 l x min(-1) x %(-1)). Sevoflurane-induced reductions of the hypoxic responses were not different in the men and women. During sevoflurane inhalation, the bispectral index values decreased equally in men and women.

Conclusion

In contrast to morphine, the influence of a low dose of the inhalational anesthetic sevoflurane on the ventilatory response to hypoxia is independent of sex.
Acupressure-Acupuncture Antiemetic Prophylaxis in Children Undergoing Tonsillectomy
Authors: Shenkman Ze'ev , Holzman Robert S. , Kim Cheonil , Ferrari Lynne R. , DiCanzio James , Highfield Ellen S. , Van Keuren Korinne , Kaptchuk Ted , Kenna Margaret A. , Berde Charles B. , Rockoff Mark A.
Published: November 2003

Background

Acupuncture or acupressure at the Nei-Guan (P.6) point on the wrist produces antiemetic effects in awake but not anesthetized patients. The authors studied whether a combined approach using preoperative acupressure and intra- and postoperative acupuncture can prevent emesis following tonsillectomy in children.

Methods

Patients 2-12 yr of age were randomly assigned to study or placebo groups. Two Acubands with (study) and two without (placebo) spherical beads were applied bilaterally on the P.6 points; non-bead- and bead-containing Acubands, respectively, were applied on the sham points. All Acubands were applied before any drug administration. After anesthetic induction, acupuncture needles were substituted for the beads and remained in situ until the next day. All points were covered with opaque tape to prevent study group identification. A uniform anesthetic technique was used; postoperative pain was managed initially with morphine and later with acetaminophen and codeine. Emesis, defined as retching or vomiting, was assessed postoperatively. Ondansetron was administered only after two emetic episodes at least 2 min apart. Droperidol was added if emesis persisted.

Results

One hundred patients were enrolled in the study. There were no differences in age, weight, follow-up duration, or perioperative opioid administration between groups. Retching occurred in 26% of the study patients and in 28% of the placebo patients; 51 and 55%, respectively, vomited; and 60 and 59%, respectively, did either. There were no significant differences between the groups. Redness occurred in 8.5% of acupuncture sites.

Conclusion

Perioperative acupressure and acupuncture did not diminish emesis in children following tonsillectomy.
The Dynamic Relationship between End-tidal Sevoflurane and Isoflurane Concentrations and Bispectral Index and Spectral Edge Frequency of the Electroencephalogram
Authors: Olofsen Erik , Dahan Albert
Published: November 2003

Background

Inhalational anesthetics produce dose-dependent effects on electroencephalogram-derived parameters, such as 95% spectral edge frequency (SEF) and bispectral index (BIS). The authors analyzed the relationship between end-tidal sevoflurane and isoflurane concentrations (FET) and BIS and SEF and determined the speed of onset and offset of effect (t1/2k(e0)).

Methods

Twenty-four patients with American Society of Anesthesiologists physical status I or II were randomly assigned to receive anesthesia with sevoflurane or isoflurane. Several transitions between 0.5 and 1.5 minimum alveolar concentration were performed. BIS and SEF data were analyzed with a combination of an effect compartment and an inhibitory sigmoid Emax model, characterized by t1/2k(e0), the concentration at which 50% depression of the electroencephalogram parameters occurred (IC50), and shape parameters. Parameter values estimated are mean +/- SD.

Results

The model adequately described the FET-BIS relationship. Values for t1/2k(e0), derived from the BIS data, were 3.5 +/- 2.0 and 3.2 +/- 0.7 min for sevoflurane and isoflurane, respectively (NS). Equivalent values derived from SEF were 3.1 +/- 2.4 min (sevoflurane) and 2.3 +/- 1.2 min (isoflurane; NS). Values of t1/2k(e0) derived from the SEF were smaller than those from BIS (P < 0.05). IC50 values derived from the BIS were 1.14 +/- 0.31% (sevoflurane) and 0.60 +/- 0.11% (isoflurane; P < 0.05).

Conclusions

The speed of onset and offset of anesthetic effect did not differ between isoflurane and sevoflurane; isoflurane was approximately twice as potent as sevoflurane. The greater values of t1/2k(e0) derived from the BIS data compared with those derived from the SEF data may be related to computational and physiologic delays.
Actions of Ketamine and Its Isomers on Contractility and Calcium Transients in Human Myocardium
Authors: Kunst Gudrun , Martin Eike , Graf Bernhard M. , Hagl Siegfried , Vahl Christian F.
Published: November 2003

Background

Ketamine has a species-dependent inotropic effect on myocardium. The authors' aim was to investigate the direct inotropic effect and the corresponding intracellular Ca2+ transients of ketamine and its isomers on human myocardium.

Methods

Right auricular myocardial strips obtained during open heart surgery were exposed to increasing concentrations (73 microM, 360 microM, and 730 microM) of racemic ketamine (n = 12), S(+)-ketamine (n = 12), or R(-)-ketamine (n = 11). Isometric force, isotonic shortening, contractility, relaxation, and time to maximal isotonic and isometric force were assessed. Ten muscle strips in each group were loaded with the calcium-sensitive fluorescent dye FURA-2/AM for simultaneous measurements of calcium transients.

Results

Compared with the initial control maximal isometric developed force, maximal isotonic shortening amplitude, contractility, and relaxation increased by 12.5-22.4% after perfusion with S(+)-ketamine at the concentration of 73 microM (P < 0.05). In contrast, no changes were seen after addition of 73 microM R(-)-ketamine. The effect of racemic ketamine (73 microM) was between that of the two isomers. At the highest concentration (730 microM) ketamine and its isomers decreased maximal isometric developed force, maximal shortening amplitude, contractility, and relaxation by 26.8-57.4% (P < 0.05), accompanied by a significant decrease of the intracellular calcium transient (by 21.0-32.2%, P < 0.05).

Conclusions

In contrast to R(-)-ketamine, S(+)-ketamine increased isometric force, isotonic shortening, contractility, and relaxation at low concentrations (73 microM) compared with the initial control. At higher concentrations (730 microM) a direct negative inotropic action was observed after perfusion with ketamine and its isomers, which was accompanied by a decreased intracellular Ca2+ transient.
Pharmacokinetics and Efficacy of Epidurally Delivered Sustained-release Encapsulated Morphine in Dogs
Authors: Yaksh Tony L. , Provencher Jean C. , Rathbun Michael L. , Kohn Fred R.
Published: November 2003

Background

We evaluated the epidural effects of a multivesicular liposome-based sustained-release preparation of morphine (C0401) on behavior and lumbar cerebrospinal fluid and serum kinetics of morphine.

Methods

Beagle dogs were prepared with lumbar epidural catheters with subcutaneous injection ports and lumbar intrathecal catheters. Each dog (n = 6) received the following by the epidural route: 5 mg/3 ml morphine sulfate in saline (MS-5), 10 mg/3 ml C0401 (C0401-10), and 30 mg/3 ml C0401 (C0401-30). Behavioral and physiologic parameters and nociceptive responses (skin twitch latency) were evaluated, and morphine concentrations were determined in lumbar cerebrospinal fluid and serum.

Results

All morphine treatments blocked the skin twitch response. Time to onset was 1.3 +/- 0.3 h for C0401-30; 2.6 +/- 0.6 h for C0401-10; and 0.4 +/- 0.2 h for MS-5. Duration of action was 62 +/- 0.3 h for C0401-30; 27 +/- 2 h for MS-5. All treatments produced a modest reduction in arousal, muscle tone, and coordination, with the duration of the C0401-30 preparation being longer lasting. Respiratory rate was mildly depressed by all treatments, and moderate hypotension was noted. Time to peak cerebrospinal fluid morphine concentration was 11 h for C0401-30; 3 h for C0401-10; and 5 min for MS-5. Peak lumbar cerebrospinal fluid level was 34,992 +/- 5,578 ng/ml for MS-5; 14,483 +/- 3,438 ng/ml for C0401-30; and 10,730 +/- 2,888 ng/ml for C0401-10. Morphine mean residence time in lumbar cerebrospinal fluid was 0.8 +/- 0.1 h for MS-5; 8.9 +/- 1.0 h for C0401-30.

Discussion

Kinetics studies showed that multivesicular liposome sequestration results in a restrained and persistent release of morphine from the epidural space. This extended release corresponded with an extended duration of analgesia without an attendant increase in the incidence of side effects.
Intrathecal Adenosine
Authors: Chiari Astrid I. , Eisenach James C.
Published: November 2003

Background

Spinal adenosine receptor agonists exert antinociception in animal models of acute and chronic pain, but adenosine itself has not been examined. The authors tested the antinociceptive and antihypersensitivity interactions of intrathecal adenosine and its interactions with intrathecal clonidine and neostigmine in rat models of acute thermal nociception and postoperative hypersensitivity.

Methods

Rats were prepared with lumbar intrathecal catheters. Responses to acute noxious stimulation were evaluated by latency to paw withdrawal from a radiant heat source focused on the hind paw. Postoperative hypersensitivity was measured after an incision in the rat hind paw by application of von Frey filaments to the heel adjacent to the wound. An isobolographic design was used to distinguish between additive and synergistic drug interactions.

Results

Spinal administration of clonidine and neostigmine, but not adenosine, produced dose-dependent antinociception to noxious thermal stimulation. Addition of adenosine enhanced the antinociceptive effect of clonidine but not neostigmine. In contrast, each of these three agents alone reversed postoperative hypersensitivity. Pretreatment with the alpha-adrenergic antagonist phentolamine completely reversed adenosine's antihypersensitivity action. Adenosine interacted synergistically with neostigmine and additively with clonidine in reducing postoperative hypersensitivity.

Conclusions

These data indicate that intrathecal adenosine by itself has no antinociceptive properties to acute noxious thermal stimulation in rats, but enhances clonidine's antinociception. In contrast, intrathecal adenosine is active against postoperative hypersensitivity by an adrenergic mechanism. Different interactions between adenosine, clonidine, and neostigmine in acute nociception and postoperative hypersensitivity models are consistent with altered central processing of sensory information after peripheral injury.
Role of the Hematocrit in a Rabbit Model of Arterial Thrombosis and Bleeding
Authors: Ouaknine-Orlando Barbara , Samama Charles-Marc , Riou Bruno , Bonnin Philippe , Guillosson Jean-Jacques , Beaumont Jean-Louis , Coriat Pierre
Published: November 2003

Background

A decrease in hematocrit lengthens bleeding time. The authors studied the role of hematocrit variations in an experimental model of arterial thrombosis and bleeding.

Methods

The Folts model was used in 24 rabbits. After anesthesia was induced and common monitors were positioned, the right common carotid artery was exposed and a 60% stenosis was induced. A compression injury of the artery was then produced, which triggered a series of cyclic episodes of thrombosis and clot lysis (cyclic flow reductions [CFRs]). After counting the number of CFRs that occurred in 20 min (CFR1), the animals were assigned randomly to one of three groups (n = 8 in each group): control, hemodilution with rabbit homologous platelet-rich plasma, and hemodilution with gelatin solution and then reinfusion of the shed blood. The effect of hemodilution with replacement by platelet-rich plasma or by colloid was observed by recording the number of CFRs during another 20-min period (CFR2). A third period of observation (CFR3) followed shed blood reinfusion in the gelatin solution group. Ear immersion bleeding time was recorded after each CFR period.

Results

In the two experimental groups, the decrease in hematocrit (from 36 +/- 3% to 23 +/- 2% and from 38 +/- 3% to 23 +/- 2%, respectively; mean +/- SD) abolished CFRs (from a median of 4 to 0 and 7 to 0, respectively) and significantly lengthened bleeding time (from 76 +/- 24 s to 114 +/- 36 s and from 84 +/- 37 s to 127 +/- 29 s, respectively). Blood reinfusion in the group that received the gelatin solution caused CFR to reappear (CFR3 = 4).

Conclusions

Decreases in hematocrit reduced the cyclic arterial thrombosis rate and increased the bleeding time in the rabbits in this study. Hematocrit normalization caused thrombosis to reappear.
Study of Three Different Doses of Epidural Neostigmine Coadministered with Lidocaine for Postoperative Analgesia
Authors: Lauretti Gabriela R. , de Oliveira Raquel , Reis Marlene P. , Juliao Maria-do-Carmo C. , Pereira Newton L.
Published: November 2003

Background

Intrathecal neostigmine produces analgesia in volunteers and patients. However, the use of epidural neostigmine has not been investigated. The purpose of the current study was to define the analgesic effectiveness of epidural neostigmine coadministered with lidocaine and side effects in patients after minor orthopedic procedures.

Methods

After Institutional Review Board approval and informed consent, 48 patients (n = 12) undergoing knee surgery were randomly allocated to one of four groups and studied in a prospective way. After 0.05-0.1 mg/kg intravenous midazolam premedication, patients were randomized to receive 20 mg intrathecal bupivacaine plus epidural lidocaine (85 mg) with saline (control group); 1 microg/kg epidural neostigmine (1 microg group); 2 microg/kg epidural neostigmine (2 microg group); or 4 microg/kg epidural neostigmine (4 microg group). The concept of the visual analog scale, which consisted of a 10-cm line with 0 equaling "no pain at all" and 10 equaling "the worst possible pain" was introduced. Postoperatively, pain was assessed using the visual analog scale, and intramuscular 75 mg diclofenac was available at patient request.

Results

Groups were demographically the same and did not differ in intraoperative characteristics (blood pressure, heart rate, ephedrine consumption, oxyhemoglobin saturation, sensory loss before start of surgery, or duration of sensory motor block). The visual analog scale score at first rescue analgesic and the incidence of adverse effects were similar among groups (P > 0.05). The time (min +/- SD) to first rescue analgesic was as follows: control group: 205+/-48; 1-microg group: 529+/-314; 2-microg group: 504+/-284; 4-microg group: 547+/-263 (P < 0.05). The analgesic consumption (number of intramuscular diclofenac injections [mean, 25th-75th percentile]) in 24 h was as follows: control group: 3 [3 or 4]; 1-microg group: 1 [1 or 2]; 2-microg group: 2 [1 or 2]; 4-microg group: 2 [1-3] (P < 0.05). The 24-h-pain visual analog scale score (cm +/- SD) that represents the overall impression for the last 24 h was as follows: control group: 5+/-1.6; 1-microg group: 1.6+/-1.8; 2-microg group: 1.4+/-1.6; 4-microg group: 2.2+/-1.9 (P < 0.005). The incidence of adverse effects was similar among groups (P > 0.05).

Conclusion

Epidural neostigmine (1, 2, or 4 microg/kg) in lidocaine produced a dose-independent analgesic effect (approximately 8 h) compared to the control group (approximately 3.5 h), and a reduction in postoperative rescue analgesic consumption without increasing the incidence of adverse effects.
The Effect of Naloxone on Ketamine-induced Effects on Hyperalgesia and Ketamine-induced Side Effects in Humans
Authors: Mikkelsen Soren , Ilkjaer Susanne , Brennum Jannick , Borgbjerg Finn M. , Dahl Jorgen B.
Published: November 2003

Background

The (NMDA) receptor plays a significant role in wind-up and spinal hypersensitivity and is involved in the occurrence of secondary hyperalgesia. Ketamine is an NMDA-receptor antagonist and has proven effective in alleviating secondary hyperalgesia in humans. Although it is disputed, the actions of ketamine have been ascribed not only to NMDA receptor antagonism, but also to opioid receptor agonism. A study therefore was designed in which the abolishment of a previously demonstrated effect of ketamine on secondary hyperalgesia was sought by pretreatment with naloxone.

Methods

Twenty-five volunteers were subjected to three treatment regimens. A standardized first-degree burn injury was induced. On appearance of primary and secondary hyperalgesia, one of the following infusion schemes was applied in a randomized, double-blind, cross-over fashion: (1) infusion of naloxone (0.8 mg/15 min followed by 0.4 mg/h), succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); (2) infusion of placebo, succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); and (3) infusion of placebo, succeeded by infusion of placebo. Heat-pain detection thresholds, magnitude of secondary hyperalgesia around the burn injury, and side effects were determined.

Results

Ketamine reduced secondary hyperalgesia. Naloxone did not affect the action of ketamine. The magnitudes of side effects were equal if the subjects received ketamine, regardless of preceding infusion of naloxone.

Conclusions

In this experimental setting, opioid receptor blockade does not inhibit ketamine-induced reductions of secondary hyperalgesia.
Phase-contrast MRI Measurement of Systolic Cerebrospinal Fluid Peak Velocity (CSFVPeak) in the Aqueduct of Sylvius
Authors: Kolbitsch Christian , Schocke Michael , Lorenz Ingo H. , Kremser Christian , Zschiegner Fritz , Pfeiffer Karl P. , Felber Stephan , Aichner Franz , Hormann Christoph , Benzer Arnulf
Published: November 2003

Background

Cerebrospinal fluid (CSF) outflow to intra- and extracranial subarachnoid spaces caused by arterial inflow to the brain predominantly compensates systolic increases in cerebral blood volume. Phase-contrast magnetic resonance imaging is a new tool for noninvasive assessment of CSF displacement by measuring CSF peak velocity (CSFV(Peak)). The authors tested this new tool in an experimental human model of increased intracranial pressure and reduced cerebral capacity by means of continuous positive airway pressure (CPAP) breathing.

Methods

The authors investigated systolic CSFV(Peak) in the aqueduct of Sylvius in 11 awake, normocapnic (end-tidal carbon dioxide [ET(CO2)] = 40 mmHg) volunteers without CPAP and at two different CPAP levels (6 and 12 cm H2O) by means of electroencephalography-gated phase-contrast magnetic resonance imaging.

Results

Administration of 6 cm H2O CPAP did not change systolic CSFV(Peak) (-4.9+/-2.8 cm/s vs. control: -5.1+/-2.7 cm/s), whereas 12 cm H2O CPAP significantly reduced systolic CSFV(Peak) (-4.0+/-1.8 cm/s vs. control: -5.1+/-2.7 cm/s; P < 0.05).

Conclusions

These findings in awake volunteers show that monitoring CSFV(Peak) in the aqueduct of Sylvius is a sensitive method for detecting even minor impairment of cerebral capacity caused by experimentally induced increases in intracranial pressure.
Clinical Effects and Maternal and Fetal Plasma Concentrations of 0.5% Epidural Levobupivacaine versus Bupivacaine for Cesarean Delivery
Authors: Bader Angela M. , Tsen Lawrence C. , Camann William R. , Nephew Elizabeth , Datta Sanjay
Published: November 2003

Background

Bupivacaine exists as a mixture of two enantiomers, levobupivacaine and dexbupivacaine. Data suggest that levobupivacaine has equal local anesthetic potency, with reduced potential for central nervous system and cardiovascular toxicity. The present study compares the efficacy of 0.5% levobupivacaine with 0.5% bupivacaine for epidural anesthesia in parturients undergoing elective cesarean delivery.

Methods

Sixty healthy obstetric patients undergoing elective cesarean delivery with epidural anesthesia completed the study. Patients were randomized to receive 30 ml of either 0.5% levobupivacaine or 0.5% bupivacaine in a double-blind fashion. The efficacy endpoint measures included onset, offset, and quality of anesthesia. Neonatal blood gas analyses, Apgar score determinations, and neurobehavioral examinations were performed. Venous samples for pharmacokinetic studies and serial electrocardiograms were obtained in 10 patients in each group.

Results

Levels of sensory block, motor block, muscle relaxation, and overall quality of anesthesia did not differ between groups. The frequency of hypotension was 84.4% in the levobupivacaine group and 100% for the bupivacaine group (P < or = 0.053). No significant difference in observed maximum concentration of drug after dosing or area under the plasma drug concentration versus time curve were seen. The maximum concentrations were 1.017 and 1.053 microg/ml, and the areas were 4.082 and 3.765 h(microg/ml) for the levobupivacaine and bupivacaine groups, respectively. Umbilical vein-to-maternal vein ratios were 0.303 for the levobupivacaine group and 0.254 for the bupivacaine group.

Conclusions

The use of epidural 0.5% levobupivacaine for cesarean delivery results in equally efficacious anesthesia compared with 0.5% bupivacaine. Pharmacokinetic parameters were similar in the two groups.
The Effects of Two Antiinflammatory Pretreatments on Bacterial-induced Lung Injury
Authors: Miyazaki Hiroshi , Broaddus V. Courtney , Wiener-Kronish Jeanine P. , Sawa Teiji , Pittet Jean-Francois , Kravchenko Vladimir , Mathison John C. , Nishizawa Hideo , Hattori Satoshi , Yamakawa Tadashi , Yamada Hiroshi , Kudoh Ichidai
Published: November 2003

Background

Two antiinflammatory therapies that have been effective in preventing acid-induced lung injury were evaluated. Specifically, their effects on a subsequent bacterial-airspace challenge were compared. Bacteria were instilled 24 h after acid-induced lung injury. Pseudomonas aeruginosa PAO-1 was used as the bacteria, because its effects in healthy lungs was documented previously.

Methods

New Zealand white rabbits were anesthetized and three pretreatments were administered: (1) pentoxifylline pretreatment (a 20-mg/kg bolus dose and then 6 mg x kg(-1) x h(-1) given intravenously), (2) 1 ml anti-tumor necrosis factor alpha antiserum given intravenously, or (3) normal saline given intravenously. The pretreatment doses were shown previously to prevent acid-induced lung injury. Then 1.2 ml/kg hydrochloric acid (HCl), pH 1.25, was instilled into the rabbits' right lungs. All the animals underwent mechanical ventilation for 8 h. Twenty-four hours after the acid instillation, the rabbits were anesthetized again and 2 ml/kg (10(9) colony forming units/ml) PAO-1 was instilled into their left lungs. The rabbits' breathing was aided by mechanical ventilation for another 8 h, and then they were killed and exsanguinated.

Results

Both pretreatments attenuated the acid-induced lung injury of the noninstilled left lungs. Arterial oxygen tension and the lung edema of pretreated, acid-exposed animals were significantly and almost equally improved (compared with no pretreatments) by either of the pretreatments. However, when the bacteria were instilled into the left lungs 24 h after the acid injury, the pentoxifylline pretreatment but not the anti-tumor necrosis factor alpha pretreatment prevented much of the bacteria-induced lung injury. Pentoxifylline pretreatment significantly improved the measurements of left lung edema and epithelial and endothelial permeability. There was also a trend for improved oxygenation in the pentoxifylline-pretreated and infected animals. In contrast, the anti-tumor necrosis factor alpha pretreatment did not prevent the bacteria-induced lung injury and increased some of the measurements of lung injury.

Conclusions

Two antiinflammatory therapies that prevented acid-induced lung injury to the noninstilled left lungs had significantly different effects on a subsequent bacteria-induced lung injury to the left lungs. The therapies differed in their mechanism of tumor necrosis factor alpha blockade, and this may have affected the bacteria-induced injury to the lungs.
The Comparative Toxicity of Cocaine and Its Metabolites in Conscious Rats
Authors: Morishima Hisayo O. , Whittington Robert A. , Iso Ayako , Cooper Thomas B.
Published: November 2003

Background

The metabolites of cocaine, benzoylecgonine and ecgonine methyl ester, have been considered pharmacologically inactive when administered systemically. However, recent in vitro studies suggest that this may not be true. The current study was designed to evaluate the systemic toxicity of cocaine and its metabolites when administered systemically to awake rats fitted with catheters for long-term monitoring.

Methods

Cocaine, norcocaine, cocaethylene, benzoylecgonine, and ecgonine methyl ester were infused intravenously to produce sequential behavioral alterations and central nervous system and cardiovascular toxic effects. Arterial blood pressure and heart rate were monitored continuously. Plasma and tissue samples were analyzed for all compounds by capillary gas chromatography-mass spectrometry.

Results

The dose of norcocaine necessary to produce toxic effects was smaller than that of cocaine and cocaethylene. Benzoylecgonine and ecgonine methyl ester did not produce toxic manifestations at infusion rates that produced toxicity in the cocaine, norcocaine, and cocaethylene groups. Furthermore, 30- and 60-fold higher doses of benzoylecgonine and ecgonine methyl ester, respectively, were necessary to produce only mild neurobehavioral changes. Benzoylecgonine was not lethal even at doses 100 times greater than cocaine.

Conclusions

These results indicate that benzoylecgonine and ecgonine methyl ester are not as toxic as cocaine, norcocaine, or cocaethylene when administered intravenously to pharmacologically naive rats.
Preparation of Barbiturate Optical Isomers and Their Effects on GABA (A) Receptors
Authors: Tomlin Sarah L. , Jenkins Andrew , Lieb William R. , Franks Nicholas P.
Published: November 2003

Background

Barbiturate anesthetics are optically active and usually exist in two mirror-image enantiomeric forms. Their stereoselective effects in mammals are well known, but remarkably few data are available concerning their effects on anesthetic targets in vitro. This is in part because of the lack of availability of pure barbiturate enantiomers. Such in vitro data could be used to test the relevance of putative molecular targets.

Methods

A high-performance liquid chromatography technique using a permethylated beta-cyclodextrin column was used to separate the optical isomers of three barbiturates in preparative quantities. The effects of the isomers on GABA-induced currents in stably transfected mouse fibroblast cells were investigated using the whole-cell patch-clamp technique.

Results

Highly purified optical isomers of hexobarbital, pentobarbital, and thiopental were prepared, and their effects were studied on a gamma-aminobutyric acid type A receptor of defined subunit composition. For each of the three barbiturates, both enantiomers potentiated gamma-aminobutyric acid-induced currents at pharmacologically relevant concentrations, with the S-enantiomer being more potent than the R-enantiomer by a factor of between 1.7 and 3.5. The degree of stereoselectivity did not vary greatly with anesthetic concentration.

Conclusions

The rank order and degree of stereoselectivity that we have observed for the enantiomers of hexobarbital, pentobarbital, and thiopental acting on the gamma-aminobutyric acid type A receptor are entirely consistent with this receptor playing a central role in the anesthetic actions of barbiturates.
4-Chloro-m-cresol Triggers Malignant Hyperthermia in Susceptible Swine at Doses Greatly Exceeding Those Found in Drug Preparations
Authors: Iaizzo Paul A. , Johnson Brooks A. , Nagao Kaoru , Gallagher William J.
Published: November 2003

Background

Chlorocresols are used as preservatives in numerous commercial drugs that have been shown to induce myoplasmic Ca2+ release; the most potent isoform is 4-chloro-m-cresol. The aims of this study were to (1) examine the in vivo effects of 4-chloro-m-cresol on swine susceptible to malignant hyperthermia and (2) contrast in vivo versus in vitro dose-response curves.

Methods

Susceptible swine (weight: 38.5 kg+/-3.55 kg) were anesthetized and monitored for variations in physiological responses, including end-tidal CO2, heart rate, blood pressure, blood chemistry, and temperatures. In the first animals studied, 4-chloro-m-cresol, at equivalent cumulative doses of 0.14, 0.28, 0.57, 1.14, 2.27, 4.54, and 9.08 mg/kg (n = 3; 12.5, 25, 50, 100, 200, 400, and 800 micromol) were administered, and in a second group, larger doses were used: 1.14, 3.41, 7.95, 17.04 (n = 4), and/or 35.22 (n = 1) mg/kg (100, 300, 700, 1,500, and/or 3,100 micromol). For comparison, in vitro rectus abdominis muscle preparations obtained from normal and susceptible swine were exposed to 4-chloro-m-cresol, at cumulative concentrations of 6.25, 12.5, 25, 50, 100, 200, 400, 800, and 1,600 micromol; standard caffeine and halothane contracture testing was also performed.

Results

Episodes of malignant hyperthermia were not triggered in response to administration of low doses of 4-chloro-m-cresol, but transient cardiovascular reactions (e.g., tachycardia, arrhythmias, and hypotension) were observed. Subsequently, episodes in these animals were triggered when halothane (0.87; 1 MAC) and succinylcholine (2 mg/kg) were given. Animals administered the higher doses of 4-chloro-m-cresol all had fulminant episodes of malignant hyperthermia that were fatal, when equivalent cumulative concentrations were greater than 1,500 micromol. The levels of 4-chloro-m-cresol in the plasma rapidly decreased: e.g., 5 min postadministration of the 1,500-micromol dose, the mean plasma level was only 52+/-18 micromol (n = 4). Hemolysis was detected following 4-chloro-m-cresol administration at concentrations > 200 micromol. In vitro, muscle from susceptible animals elicited contractures > 200 mg at 50-micromol bath concentrations of 4-chloro-m-cresol (n = 29), whereas normal muscle did not elicit such contractures until bath concentrations were > 800 micromol (n = 10).

Conclusions

4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine, but only when serum concentrations are far above those likely to be encountered in humans. A relatively low concentration of 4-chloro-m-cresol, 50 micromol, is sufficient to activate sarcoplasmic [Ca+2] release in vitro (e.g., contractures); this same bolus dose administered in vivo (0.57 mg/kg) has minimal effects due to the rapid decrease in its plasma levels.
Deep Sedation and Mechanical Ventilation without Paralysis for 3 Weeks in Normal Beagles
Authors: Gronert Gerald A. , Fung Dennis L. , Haskins Steve C. , Steffey Eugene P.
Published: November 2003

Background

Patients in the intensive care unit may have muscle weakness in the recovery phase, and disuse atrophy may play a role in this weakness. To assess this problem, the authors measured changes in the potency of the nondepolarizing neuromuscular blocking agent metocurine in a canine model that involved 3 weeks of intensive care, nonparalyzing anesthesia with pentobarbital, and positive-pressure ventilation.

Methods

Six dogs were anesthetized with pentobarbital to a sufficient depth that spontaneous and reflex muscle movements were absent. Their tracheas were intubated, their lungs were mechanically ventilated, and they received round-the-clock intensive medical and nursing care for 3 weeks. Transduced gastrocnemius muscle responses to metocurine were determined weekly. A 4- to 15-min infusion of 148-4,300 microg/min (longer durations and greater concentrations on progressive weeks) yielded more than 80% paralysis. Serial metocurine plasma concentrations during the onset of the block and recovery provided data to determine pharmacokinetics using NONMEM. Metocurine plasma concentrations and the degree of paralysis were used to model the effect compartment equilibration constant, and the Hill equation was used to yield the slope factor and potency within the effect compartment.

Results

The metocurine effect compartment concentration associated with a 50% diminution of twitch height after 3 weeks was 1,716+/-1,208 ng/ml (mean +/- SD), which was significantly different from 257+/-34 ng/ml, the value on day 0. There were no pharmacokinetic differences.

Conclusion

The absence of muscle tone and reflex responsiveness for 3 weeks was associated with exaggerated resistance to the neuromuscular blocker metocurine.
The Relationship between the Visual Analog Pain Intensity and Pain Relief Scale Changes during Analgesic Drug Studies in Chronic Pain Patients
Authors: Angst Martin S. , Brose William G. , Dyck John B.
Published: November 2003

Background

Most analgesic drug studies in humans quantify drug action based on verbal reports of pain intensity and pain relief. Although measures of pain intensity and pain relief show a good overall correlation, it is not known if they relate to each other consistently over time Such consistency is necessary if both measures are used to depict analgesic drug action versus time. This study examined in chronic pain patients if the relationship between visual analog pain intensity and pain relief scores was consistent during two analgesic drug studies.

Methods

Data from two independently performed analgesic drug studies were analyzed using linear regression. Data were split into pain intensity and pain relief scores recorded before and after patients' experience of maximum analgesia (>90% of maximum pain relief). The slopes of the linear regression line depicting pain intensity versus pain relief scores before and after maximum analgesia were statistically compared.

Results

The slope of the linear regression line before and after maximum analgesia was significantly different in both drug studies (nonoverlapping 95% confidence intervals), -2.16+/-0.57 versus -1.05+/-0.10 and -1.47+/-0.26 versus -1.09+/-0.07, respectively. These results are compatible with the observation that patients indicating the same pain intensity before and after maximum analgesia reported a different magnitude of pain relief.

Conclusions

The relationship between visual analog pain intensity and pain relief scores changed systematically during both analgesic drug studies. The authors hypothesize that patients' interpretation of the pain relief scale had changed during the studies and therefore suggest using the pain intensity scale to quantify analgesic drug action over time.
Pharmacodynamics and the Plasma Concentration of Mivacurium during Spontaneous Recovery and Neostigmine-facilitated Recovery
Authors: Lien Cynthia A. , Belmont Matthew R. , Roth Doreen L. Wray , Okamoto Michiko , Abalos Amy , Savarese John J.
Published: November 2003

Background

The authors examined the plasma concentrations of the isomers of mivacurium and its pharmacodynamics during spontaeous and neostigmine-facilitated recovery after a mivacurium infusion.

Methods

Sixteen patients receiving nitrous oxide-opioid anesthesia received 0.25 mg/kg mivacurium. Patient response to neuromuscular stimulation was determined using a mechanomyograph Once T1 had recovered to 25% of its baseline height, a mivacurium infusion was begun and adjusted to maintain 95-99% neuromuscular block. The infusion was discontinued after 90 min and muscle strength allowed to recover either spontaneously or after neostigmine/glycopyrrolate (0.05/0.01 mg/kg). Plasma concentrations of the isomers of mivacurium after discontinuation of the infusion were determined using an HPLC assay. Differences between the groups were determined using a one-way analysis of variance with a Bonferroni-corrected t test or Student t test as appropriate. P < or = 0.05 was considered significant.

Results

Differences in the times for recovery to a train-of-four ratio of 70% did not achieve statistical significance (mean+/-SD, 13.3+/-6.0 vs. 16.3+/-2.5 min for the neostigmine and spontaneous groups, respectively). Plasma cholinesterase activity decreased significantly from baseline values after administration of neostigmine (5.88+/-0.21 vs. 0.43+/-0.04 U/ml plasma). Plasma concentrations of the trans-trans isomer were significantly greater in the neostigmine group than in the spontaneous recovery group 5, 6, 8, and 10 min after discontinuation of the infusion. Differences in the plasma concentration of the cis-trans isomer did not achieve statistical significance.

Conclusions

Although administration of neostigmine decreased plasma cholinesterase activity and caused the trans-trans isomer to remain in the plasma at higher concentration, it did not delay recovery from mivacurium-induced block.
The Alkyl Chain Dependence of the Effect of Normal Alcohols on Agonist-induced Nicotinic Acetylcholine Receptor Desensitization Kinetics
Authors: Raines Douglas E. , Zachariah Vinu T.
Published: November 2003

Background

The nAcChoR is the prototypical member of a superfamily of ligand-gated ion channels that are all relevant targets of anesthetics and undergo desensitization upon prolonged exposure to agonist. This study was designed to investigate the effects of representative normal alcohols on the apparent rate of acetylcholine-induced nAcChoR desensitization.

Methods

Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana. The apparent rate of acetylcholine-induced desensitization in the presence and absence of normal alcohols was measured using stopped-flow fluorescence.

Results

Normal alcohols as long as octanol (the longest studied) increased the apparent rate of desensitization induced by low concentrations of acetylcholine, shifting the agonist concentration-response curve for desensitization to the left Ethanol butanol, and, to a lesser extent, hexanol increased the maximal rate of desensitization induced by high, saturating concentrations of agonist. Beyond hexanol, heptanol and octanol had no effect on this maximal apparent rate of desensitization, even at concentrations that approach those that directly induce desensitization in the absence of agonist.

Conclusion

Normal alcohols ranging from ethanol to octanol increase the apparent affinity of nAcChoR for agonist with potencies that are proportional to their hydrophobicities. However, normal alcohol effects on the rate constant for desensitization show a cutoff beyond hexanoL This suggests that the effects of normal alcohols on the apparent agonist affinity and rate constant for desensitization of nAcChoR may be modulated by distinct sites that have different steric constraints; the site(s) responsible for increasing the maximal rate of desensitization are predicted to be smaller than those that increase the apparent agonist affinity.
The Effect of Prophylactic ε-Aminocaproic Acid on Bleeding, Transfusions, Platelet Function, and Fibrinolysis during Coronary Artery Bypass Grafting
Authors: Troianos Christopher A. , Sypula Richard W. , Lucas Donna M. , D'Amico Frank , Mathie Thomas B. , Desai Manish , Pasqual Roberta T. , Pellegrini Ronald V. , Newfeld Mark L.
Published: November 2003

Background

Antifibrinolytic medications administered before skin incision decrease bleeding after cardiac surgery. Numerous case reports indicate thrombus formation with administration of epsilon-aminocaproic acid (epsilon-ACA). The purpose of this study was to examine the efficacy of epsilon-ACA administered after heparinization but before cardiopulmonary bypass in reducing bleeding and transfusion requirements after primary coronary artery bypass surgery.

Methods

Seventy-four adult patients undergoing primary coronary artery bypass surgery were randomized to receive 125 mg/kg epsilon-ACA followed by an infusion of 12.5 mg x kg(-1) x h(-1) or an equivalent volume of saline. Coagulation studies, thromboelastography, and platelet aggregation tests were performed preoperatively, after bypass, and on the first postoperative day. Mediastinal drainage was recorded during the 24 h after surgery. Homologous blood transfusion triggers were predefined and transfusion amounts were recorded.

Results

One patient was excluded for surgical bleeding and five patients were excluded for transfusion against predefined criteria One patient died from a dysrhythmia 2 h postoperatively. Among the remaining 67, the epsilon-ACA group had less mediastinal blood loss during the 24 h after surgery, 529+/-241 ml versus 691+/-286 ml (mean +/- SD), P < 0.05, despite longer cardiopulmonary bypass times and lower platelet counts, P < 0.05. Platelet aggregation was reduced in both groups following cardiopulmonary bypass but did not differ between groups. Homologous blood transfusion was similar between both groups.

Conclusions

Prophylactic administration of epsilon-ACA after heparinization but before cardiopulmonary bypass is of minimal benefit for reducing blood loss postoperatively in patients undergoing primary coronary artery bypass grafting.
Effect of Combined Spinal-Epidural Ambulatory Labor Analgesia on Balance
Authors: Pickering Anthony E. , Parry Martin G. , Ousta Basil , Fernando Roshan
Published: November 2003

Background

Low-dose combined spinal-epidural analgesia in labor has proved popular with women because lower-limb motor power is preserved, allowing ambulation. However, there has been debate about the safety of allowing women to walk following low-dose regional analgesia because of somatosensory impairment. The authors undertook a prospective controlled observational study using computerized dynamic posturography to examine balance function in pregnant women after combined spinal-epidural analgesia.

Methods

The authors performed posturographic testing on 44 women in labor after institution of regional analgesia and compared them with a control group of 44 pregnant women. A separate group of six women were tested both before and after combined spinal-epidural analgesia.

Results

Neurologic examination after regional analgesia showed two parturients (4%) to have motor weakness (excluded from posturography). Four women (9%) had clinical dorsal column sensory loss; these women all completed posturography. The spinal-epidural analgesia group showed a small, statistically significant reduction in one of six posturographic sensory-organization tests; however, this difference was functionally minor. There were no other differences in posturography between the control and spinal-epidural groups. Similar results were found in the paired study, in which there was minimal change in balance function after spinal-epidural analgesia.

Conclusions

This is the first study to objectively examine the effect of spinal-epidural analgesia on balance function. Using computerized dynamic posturography, the authors were unable to find any functional impairment of balance function after spinal-epidural ambulatory analgesia in women in labor who had no clinical evidence of motor block.
Suppression of Central Nervous System Sodium Channels by Propofol
Authors: Rehberg Benno , Duch Daniel S.
Published: November 2003

Background

Previous studies have provided evidence that clinical levels of propofol alter the functions of voltage-dependent sodium channels, thereby inhibiting synaptic release of glutamate. However, most of these experiments were conducted in the presence of sodium-channel activators, which alter channel inactivation. This study electrophysiologically characterized the interactions of propofol with unmodified sodium channels.

Methods

Sodium currents were measured using whole-cell patch-clamp recordings of rat brain IIa sodium channels expressed in a stably transfected Chinese hamster ovary cell line. Standard electrophysiologic protocols were used to record sodium currents in the presence or absence of externally applied propofol.

Results

Propofol, at concentrations achieved clinically in the brain, significantly altered sodium channel currents by two mechanisms: a voltage-independent block of peak currents and a concentration-dependent shift in steady-state inactivation to hyperpolarized potentials, leading to a voltage dependence of current suppression. The two effects combined to give an apparent concentration yielding a half-maximal inhibitory effect of 10 microM near the threshold potential of action potential firing (about -60 mV). Propofol inhibition was also use-dependent, causing a further block of sodium currents at these anesthetic concentrations.

Conclusions

In these experiments with pharmacologically unaltered sodium channels, propofol inhibition of currents occurred at concentrations about eight-fold above clinical plasma levels and thus at brain concentrations reached during clinical anesthesia. Therefore, the results indicate a possible role for sodium-channel suppression in propofol anesthesia.
Sevoflurane and Isoflurane Protect the Reperfused Guinea Pig Heart by Reducing Postischemic Adhesion of Polymorphonuclear Neutrophils
Authors: Heindl Bernhard , Reichle Florian M. , Zahler Stefan , Conzen Peter F. , Becker Bernhard F.
Published: November 2003

Background

Polymorphonuclear neutrophils (PMNs) contribute to reperfusion injury. Because volatile anesthetics can reduce PMN adhesion in the reperfused, nonworking heart, the authors analyzed whether this action of volatile anesthetics affects cardiac performance after ischemia and reperfusion and further clarified the underlying mechanism.

Methods

Isolated guinea pig hearts perfused with crystalloid buffer and performing pressure-volume work were used. Hearts were subjected to 15 min global ischemia and 20 min reperfusion. In the intervention groups an intracoronary bolus of 3 x 10(6) PMNs was applied in the second min of reperfusion, either in the absence or presence of 0.5 or 1 minimum alveolar concentration sevoflurane or isoflurane. The number of sequestered PMNs was calculated from the difference between coronary input and output (coronary effluent) of PMNs. Performance of external heart work, determined pre- and postischemically, served as criterion for recovery of myocardial function. Additionally, the expression of the integrin CD11b on the cell surface of PMN was measured before and after coronary passage.

Results

Injection of PMN in the reperfusion phase, but not under nonischemic conditions, reduced recovery of external heart work significantly (from 55+/-7% to 19+/-11%). Addition of sevoflurane or isoflurane in concentrations of 0.5 and 1 minimum alveolar concentration to the perfusate reduced postischemic PMN adhesion from 36+/-8% to basal values (20+/-7%) and prevented decline of cardiac function. CD11b expression on PMNs increased significantly during postischemic coronary passage under control conditions. Again, both anesthetics in both concentrations inhibited that activation.

Conclusions

Volatile anesthetics reduce PMN adhesion in the reperfused coronary system and thereby preserve cardiac function. Reduced expression of the adhesion molecule CD11b on PMNs in the presence of sevoflurane or isoflurane is, at least in part, responsible for the cardioprotective effect.