bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatic Ischemia Is Associated with an Increase in Liver Parenchyma Nitric Oxide That Is in Part Enzyme-Independent
Authors: Lhuillier Franck , Parmantier Pierre , Goudable Joelle , Crova Philippe , Delafosse Bertrand , Annat Guy , Cespuglio Raymond , Viale Jean Paul
Published: November 2003

Background

Nitric oxide (NO) might be involved in liver response to local ischemia-reperfusion injury.

Methods

A specific NO-sensitive electrode was inserted into liver parenchyma of anesthetized rabbits. After a 45-min period of stable NO signal, the vascular pedicle of the caudal lobe of the liver was clamped for 45 min, then the clamp was removed. Perfusion of the right upper lobe was left unchanged. The same procedure was applied in other animals after administration of a long-acting nonspecific NO synthase inhibitor NAPNA.

Results

Occlusion of the caudal pedicle was associated with a mean threefold increase in NO signal measured in the caudal lobe. After unclamping, this signal returned within 8 min to baseline value and remained stable for the next 6 h. In the right upper lobe, NO signal was unaffected by caudal lobe ischemia. By the end of the 6-h reperfusion period, administration of the NO inhibitor l-NAME led to a suppression of the NO signal, thus demonstrating the specificity of the measurement. Plasma nitrate and nitrite concentrations remained almost unchanged during the study period in all groups. In animals whose NO synthases had been previously inhibited by NAPNA, clamping the caudal pedicle for 45 min was still associated with a significant increase in caudal lobe NO signal.

Conclusion

Nitric oxide is present in liver parenchyma, and its generation is dramatically affected by an ischemia injury. The increased NO generation during local ischemia is, at least in part, independent of NO synthases.
Respiratory Depression by Tramadol in the Cat
Authors: Teppema Luc J. , Nieuwenhuijs Diederik , Olievier Cees N. , Dahan Albert
Published: November 2003

Background

Tramadol hydrochloride (tramadol) is a synthetic opioid analgesic with a relatively weak affinity at opioid receptors. At analgesic doses, tramadol seems to cause little or no respiratory depression in humans, although there are some conflicting data. The aim of this study was to examine whether tramadol causes dose-dependent inhibitory effects on the ventilatory carbon dioxide response curve and whether these are reversible or can be prevented by naloxone.

Methods

Experiments were performed in cats under alpha-chloralose-urethane anesthesia. The effects of tramadol and naloxone were studied by applying square-wave changes in end-tidal pressure of carbon dioxide (Petco2; 7.5-11 mmHg) and by analyzing the dynamic ventilatory responses using a two-compartment model with a fast peripheral and a slow central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and a single offset (apneic threshold).

Results

In five animals 1, 2, and 4 mg/kg tramadol (intravenous) increased the apneic threshold (control: 28.3 +/- 4.8 mmHg [mean +/- SD]; after 4 mg/kg: 36.7 +/- 7.1 mmHg; P < 0.05) and decreased the total carbon dioxide sensitivity (control: 109.3 +/- 41.3 ml x min(-1) x mmHg(-1) ) by 31, 59, and 68%, respectively, caused by proportional equal reductions in sensitivities of the peripheral and central chemoreflex loops. Naloxone (0.1 mg/kg, intravenous) completely reversed these effects. In five other cats, 4 mg/kg tramadol caused an approximately 70% ventilatory depression at a fixed Pet co2 of 45 mmHg that was already achieved after 15 min. A third group of five animals received the same dose of tramadol after pretreatment with naloxone. At a fixed Petco of 45 mmHg, naloxone prevented more than 50% of the expected ventilatory depression in these animals.

Conclusions

Because naloxone completely reversed the inhibiting effects of tramadol on ventilatory control and it prevented more than 50% of the respiratory depression after a single dose of tramadol, the authors conclude that this analgesic causes respiratory depression that is mainly mediated by opioid receptors.
Ketamine and Midazolam Differentially Inhibit Nonadrenergic Noncholinergic Lower Esophageal Sphincter Relaxation in Rabbits
Authors: Kohjitani Atsushi , Miyawaki Takuya , Funahashi Makoto , Higuchi Hitoshi , Matsuo Ryuji , Shimada Masahiko
Published: November 2003

Background

The authors previously reported that ketamine and midazolam inhibited nitric oxide-mediated nonadrenergic noncholinergic (NANC) lower esophageal sphincter (LES) relaxation nitric oxide-3',5'-cyclic guanosine monophosphate pathway modulation. The mechanisms inhibiting the NANC relaxation by ketamine and midazolam were investigated.

Methods

The isometric tension of circular distal esophageal muscle strips from Japanese White rabbits was examined. NANC relaxation was induced by KCl (30 mm) in the presence of atropine (3 x 10(-6) m) and guanethidine (3 x 10(-6) m). Nitric oxide synthase activity in the absence and presence of ketamine and midazolam was analyzed using the biochemical conversion of L-[3H]arginine to L-[3H]citrulline.

Results

The ketamine-induced inhibition of the NANC relaxation was partly reversed by superoxide dismutase (200, 400 U/ml) but not by catalase (100 U/ml). Ketamine concentration-dependently inhibited the relaxation induced by N-ethylethanamine:1,1-diethyl-2-hydroxy-2-nitrosohydrazine (diethylamine NONOate) and S-nitrosoglutathione. The NANC relaxation itself was not affected by superoxide dismutase. The midazolam-induced inhibition of the NANC relaxation was reversed neither by superoxide dismutase nor by catalase, and midazolam did not affect the relaxations induced by nitric oxide donors. The nitric oxide synthase activity was concentration-dependently suppressed by midazolam, but there was no marked effect of ketamine. Pyrogallol, a superoxide generator, inhibited the NANC and the diethylamine NONOate-induced relaxations. The pyrogallol-induced inhibition of the NANC relaxation was reversed by superoxide dismutase.

Conclusion

These findings suggest that ketamine inhibits NANC LES relaxation by the extracellular production of superoxide anion, and that midazolam inhibits it by the inhibition of nitric oxide synthase activity.
Nociception in Persistent Pancreatitis in Rats
Authors: Vera-Portocarrero Louis P. , Lu Ying , Westlund Karin N.
Published: November 2003

Background

Most animal models of pancreatitis are short-lived or very invasive. A noninvasive animal model of pancreatitis developed in highly inbred rats by Merkord with symptoms persisting for 3 weeks was adopted in the current study to test its validity as a model of visceral pain in commercially available rats.

Methods

The persistent pancreatitis model was established by tail vein injection of dibutyltin dichloride. Animals were given 10% alcohol in their drinking water to enhance the pancreatitis attack. Blood serum pancreatic enzymes and nociceptive state were monitored for 3 weeks after dibutyltin dichloride or vehicle. Behavioral testing included reflexive withdrawal to mechanical and thermal stimulation of the abdominal area. The effect of morphine on nociceptive behaviors was tested. Histologic analysis of the pancreas and immunohistochemical analysis of substance P and calcitonin gene-related peptide in the spinal cord are included in the study.

Results

Compared with naïve and vehicle-only injected control groups, rats receiving dibutyltin dichloride demonstrated an increase in withdrawal events after von Frey stimulation and decreased withdrawal latency after thermal stimulation, signaling a sensitized nociceptive state through 7 days. These pain-related measures were abrogated by morphine. Blood serum concentrations of amylase and lipase as well as tissue inflammatory changes and substance P were also significantly elevated during this same time period.

Conclusions

These results indicate that animals with the dibutyltin dichloride-induced experimental pancreatitis expressed serum, histologic, and behavioral characteristics similar in duration to those present during acute attacks experienced by patients with chronic pancreatitis. These findings and responsivity to morphine suggest the utility of this model developed in a commercially available strain of rats for study of persistent visceral pain.
Sustained Prolongation of the QTc Interval after Anesthesia with Sevoflurane in Infants during the First 6 Months of Life
Authors: Loeckinger Alex , Kleinsasser Axel , Maier Stephan , Furtner Bernhard , Keller Christian , Kuehbacher Gabriele , Lindner Karl H.
Published: November 2003

Background

Sevoflurane, an inhalational anesthetic frequently administered to infants, prolongs the QT interval of the electrocardiogram in adults. A long QT interval resulting in fatal arrhythmia may also be responsible for some cases of sudden death in infants. As the QT interval increases during the second month of life and returns to the values recorded at birth by the sixth month, we evaluated the effect of sevoflurane on the QT interval during and after anesthesia in this particular population.

Methods

In this prospective two-group trial we examined pre-, peri-, and postoperative electrocardiograms of 36 infants aged 1 to 6 months scheduled for elective inguinal or umbilical hernia repair. Anesthesia was induced and maintained with either sevoflurane, or the well-established pediatric anesthetic halothane. Heart rate corrected (c) QTc and JTc interval (indicator of intraventricular conduction delays) were recorded from electrocardiograms before and during anesthesia, and at 60 min after emergence from anesthesia.

Results

Prolonged QTc was observed during sevoflurane anesthesia (mean [+/-SD], 473 +/- 19 ms, P< 0.01). Sixty minutes after emergence from anesthesia, QTc was still prolonged (433 +/- 15 ms) in infants treated with sevoflurane compared with those treated with halothane (407 +/- 33 ms, P< 0.01). Analogous differences were found for the JTc interval.

Conclusions

Despite a shorter elimination time than better known inhalational anesthetics, sevoflurane induction and anesthesia results in sustained prolongations of QTc and JTc interval in infants in the first 6 months of life. Electrocardiogram monitoring until the QTc interval has returned to preanesthetic values may increase safety after sevoflurane anesthesia.
Randomized Assessment of Resource Use in Fast-track Cardiac Surgery 1-Year after Hospital Discharge
Authors: Cheng Davy C. H. , Wall Claus , Djaiani George , Peragallo Raul A. , Carroll Jo , Li Cindy , Naylor David
Published: November 2003

Background

The authors assessed the safety and resource use associated with fast-track cardiac anesthesia (FTCA) after coronary artery bypass graft surgery (CABG) over a 1-yr period.

Methods

One hundred twenty patients were initially randomized to FTCA (n = 60) or conventional anesthetic (n = 60) for primary elective CABG surgery. Patients were followed for 1-yr after index surgery through linkage to universal administrative databases. Acute care hospital readmission rates and length of stay (LOS) and the downstream use of health resources were compared. Resource use was analyzed as use of hospital and rehabilitation center bed-days, expenditures on physician services, and use of cardiac drugs.

Results

There were no deaths during the 1-yr follow-up after initial discharge; 15 (25%) patients from both groups were readmitted to acute care hospitals in the follow-up period. The mean LOS for acute care readmission was 0.3 (1.0) in the FTCA and 1.6 (6.3) days in the conventional group at 3 months; P= 0.01, 95% CI (0.1, 5.7) and 0.8 (1.8) and 2.9 (9.6) days at 12 months; P= 0.01, 95% CI (0.2, 7.5). Two (3.3%) patients in the FTCA group and 9 (15%) patients in the conventional group were transferred to rehabilitation facilities. The LOS was 0.3 (1.5) and 2.3 (5.7) days respectively; P= 0.001, 95% CI (0.6, 4.0). Specialist visits were more frequent in the FTCA group 6.2 (13.2) versus 1.9 (2.2) visits respectively; P= 0.002, 95% CI (-9.0, -1.3). Percentage reduction of FTCA cost was 68% at 3 months, P= 0.0002 and 49.5% at 1-yr, P= 0.004 after index hospital discharge.

Conclusions

Fast-track cardiac anesthesia is a safe practice that decreases resource use for a 1-yr period after index hospitalization.
Isoflurane but Not Mechanical Ventilation Promotes Extravascular Fluid Accumulation during Crystalloid Volume Loading
Authors: Connolly Cara M. , Kramer George C. , Hahn Robert G. , Chaisson Neil F. , Svensén Christer H. , Kirschner Robert A. , Hastings Dennis A. , Chinkes David L. , Prough Donald S.
Published: November 2003

Background

The combination of isoflurane anesthesia and mechanical ventilation reduces urinary output and promotes redistribution of a crystalloid bolus into the extravascular space. The authors hypothesized that mechanical ventilation rather than isoflurane causes this alteration.

Methods

The fate of a 25-ml/kg, 20-min, 0.9% saline fluid bolus was studied in four different experiments per sheep: while conscious and spontaneously ventilating (CSV), while conscious and mechanically ventilated (CMV), while anesthetized with isoflurane and mechanical ventilated (ISOMV), and while anesthetized with isoflurane and spontaneously ventilating (ISOSV).

Results

By calculations based on the indicator dilution and mass balance principles, plasma expansion was similar between protocols. Isoflurane but not mechanical ventilation reduced urinary output and increased interstitial fluid volume (P < 0.001): At 180 min, mean total urinary outputs were 15.6 +/- 2.1 and 15.9 +/- 2.9 ml/kg in the CSV and CMV protocols and 2.7 +/- 0.6 and 3.1 +/- 1.1 ml/kg in the ISOSV and ISOMV protocols, respectively. The net changes in extravascular volume, assumed to be interstitial fluid volume, were 8.6 +/- 3.3 and 8.1 +/- 3.1 ml/kg, and 22.5 +/- 1.5 and 22.1 +/- 1.6 ml/kg in the corresponding protocols. Volume kinetic analysis demonstrated extravascular fluid accumulation associated with isoflurane anesthesia similar to the calculated interstitial accumulation of 20.2 +/- 0.5 and 26.5 +/- 0.3 ml/kg in the ISOSV and ISOMV protocols, respectively.

Conclusion

Isoflurane, but not mechanical ventilation, decreased urinary excretion and increased interstitial fluid volume. Volume kinetic analysis indicated "third-space" losses due to isoflurane. Perioperative fluid retention may be associated not only with surgical tissue manipulation, but with anesthesia per se.
α2Adrenoceptor–mediated Presynaptic Inhibition of Primary Afferent Glutamatergic Transmission in Rat Substantia Gelatinosa Neurons
Authors: Kawasaki Yasuhiko , Kumamoto Eiichi , Furue Hidemasa , Yoshimura Megumu
Published: November 2003

Background

Although intrathecal administration of norepinephrine is known to produce analgesia, cellular mechanisms for this action have not yet been fully understood.

Methods

The actions of norepinephrine (50 microm) on glutamatergic transmission were examined by using the whole cell patch clamp technique in substantia gelatinosa neurons of an adult rat spinal cord slice with an attached dorsal root.

Results

Norepinephrine inhibited the amplitude of monosynaptically evoked A delta-fiber and C-fiber excitatory postsynaptic currents in a reversible manner. When compared in magnitude between the A delta-fiber and C-fiber excitatory postsynaptic currents, the former inhibition (50 +/- 4%, n = 20) was significantly larger than the latter one (28 +/- 4%, n = 8). Both actions of norepinephrine were mimicked by an alpha2 adrenoceptor agonist, clonidine (10 microm), and an alpha 2A agonist, oxymetazoline (10 microm), but not by an alpha1 agonist, phenylephrine (10 microm), and a beta agonist, isoproterenol (40 microm). The inhibitory actions were antagonized by an alpha 2 antagonist, yohimbine (1 microm), all of the results of which indicate an involvement of alpha 2 adrenoceptors. Norepinephrine did not affect the amplitude of miniature excitatory postsynaptic current and of a response of substantia gelatinosa neurons to AMPA, indicating that its action on evoked excitatory postsynaptic currents is presynaptic in origin.

Conclusions

Norepinephrine inhibits A delta-fiber- and C-fiber-mediated sensory transmission to substantia gelatinosa neurons through the activation of the alpha 2 adrenoceptor (possibly alpha2A type, based on the current, published behavioral and anatomical data) existing in primary afferent terminals; this action of norepinephrine is more effective in A delta-fiber than C-fiber transmission. This could contribute to at least a part of inhibitory modulation of pain sensation in the substantia gelatinosa by intrathecally administered norepinephrine.
Vasopressin, but Not Fluid Resuscitation, Enhances Survival in a Liver Trauma Model with Uncontrolled and Otherwise Lethal Hemorrhagic Shock in Pigs
Authors: Stadlbauer Karl H. , Wagner-Berger Horst G. , Raedler Claus , Voelckel Wolfgang G. , Wenzel Volker , Krismer Anette C. , Klima Guenter , Rheinberger Klaus , Nussbaumer Walter , Pressmar Daniel , Lindner Karl H. , Königsrainer Alfred
Published: November 2003

Background

The authors compared the effects of vasopressin fluid resuscitation on survival in a liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs.

Methods

A midline laparotomy was performed on 23 domestic pigs, followed by an incision, and subsequent finger fraction across the right medial liver lobe. During hemorrhagic shock, animals were randomly assigned to receive either 0.4 U/kg vasopressin (n = 9), or fluid resuscitation (n = 7), or saline placebo (n = 7), respectively. A continuous infusion of 0.08 U x kg(-1) x min(-1) vasopressin in the vasopressin group, or normal saline was subsequently administered in the fluid resuscitation and saline placebo group, respectively. After 30 min of experimental therapy, bleeding was controlled by surgical intervention, and blood transfusion and rapid fluid infusion were subsequently performed.

Results

Maximum mean arterial blood pressure during experimental therapy in the vasopressin-treated animals was significantly higher than in the fluid resuscitation and saline placebo groups (mean +/- SD, 72 +/- 26 vs 38 +/- 16 vs 11 +/- 7 mmHg, respectively; P< 0.05). Subsequently, mean arterial blood pressure remained at approximately 40 mmHg in all vasopressin-treated animals, whereas mean arterial blood pressure in all fluid resuscitation and saline placebo pigs was close to aortic hydrostatic pressure (approximately 15 mmHg) within approximately 20 min of experimental therapy initiation. Total blood loss was significantly higher in the fluid resuscitation pigs compared with vasopressin or saline placebo after 10 min of experimental therapy (65 +/- 6 vs 42 +/- 4 vs 43 +/- 6 ml/kg, respectively; P< 0.05). Seven of seven fluid resuscitation, and seven of seven saline placebo pigs died within approximately 20 min of experimental therapy, while 8 of 9 vasopressin animals survived more than 7 days (P < 0.05).

Conclusions

Vasopressin, but not fluid resuscitation or saline placebo, ensured survival with full recovery in this liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs.
Morphine Enhances Pharmacological Preconditioning by Isoflurane
Authors: Ludwig Lynda M. , Patel Hemal H. , Gross Garrett J. , Kersten Judy R. , Pagel Paul S. , Warltier David C.
Published: November 2003

Background

Adenosine triphosphate-regulated potassium channels mediate protection against myocardial infarction produced by volatile anesthetics and opioids. We tested the hypothesis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors.

Methods

Barbiturate-anesthetized rats (n = 131) were instrumented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size was determined using triphenyltetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats received 5-hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or absence of isoflurane, morphine, and morphine plus isoflurane.

Results

Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) reduced infarct size (41 +/- 3%; n = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further decreased infarct size to 26 +/- 3% (n = 11). 5-HD and naloxone alone did not affect infarct size, but abolished cardioprotection produced by isoflurane, morphine, and morphine plus isoflurane.

Conclusions

Combined administration of isoflurane and morphine enhances the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors in vivo.
Gabapentin Markedly Reduces Acetic Acid–induced Visceral Nociception
Authors: Feng Yi , Cui Minglei , Willis William D.
Published: November 2003

Background

Gabapentin has recently been used clinically as an antihyperalgesic agent to treat certain neuropathic pain states. The aim of this study is to test whether gabapentin is able to inhibit responses to peritoneal irritation-induced visceral pain and to examine the effect of gabapentin on spinal cord amino acid release.

Methods

The acetic acid-induced writhing assay was used in rats to determine the degree of antinociception. The rats received an intraperitoneal injection of acetic acid 40 min after intraperitoneal administration of vehicle or gabapentin (50, 100, or 200 mg/kg). Cerebrospinal fluid dialysate was collected by microdialysis from the spinal subarachnoid space in anesthetized rats. Acetic acid-induced release of amino acids into the dialysate, including glutamate, aspartate, serine, glutamine, and glycine, following intraperitoneal injection of acetic acid was evaluated by measurements of changes in the concentrations of these amino acids. The effects of pretreatment with saline or gabapentin (100 mg/kg intraperitoneal) on amino acid release were compared.

Results

Gabapentin reduced writhing responses in a dose-related fashion. Dialysate concentrations of glutamate, aspartate, and serine increased significantly following intraperitoneal injection of acetic acid, while glutamine and glycine concentrations were not increased significantly. When compared to saline-treated rats, animals pretreated with 100 mg/kg gabapentin showed suppression of the acetic acid-induced increases in glutamate, aspartate, and serine concentrations.

Conclusions

These data demonstrate that gabapentin effectively inhibits acetic acid-induced nociception, and the antinociceptive effect of gabapentin correlates with the suppression of noxious-evoked release of excitatory amino acids in the spinal cord.
Intrathecal Coadministration of D-APV and Morphine Is Maximally Effective in a Rat Experimental Pancreatitis Model
Authors: Lu Ying , Vera-Portocarrero Louis P. , Westlund Karin N.
Published: November 2003

Background

Many studies have demonstrated that either glutamate -methyl-d-aspartate (NMDA) receptor antagonists or opioid receptor agonists provide antinociception. Spinal coadministration of an NMDA receptor antagonist and morphine has an additive action for control of various pain states in animal models. The current study examined spinal coadministration of low doses of NMDA receptor antagonist, D-(-)-2-Amino-5-phosphonovalerate (D-APV), and mu-opioid receptor agonist, morphine sulfate (MS), in reducing visceral nociception using an acute bradykinin induced pancreatitis model in rats.

Methods

An intrathecal catheter was surgically inserted into the subarachnoid space for spinal drug administration in Sprague-Dawley rats. A laparotomy was performed for ligation and cannulation of the bile-pancreatic duct. Rats were pretreated intrathecally with artificial cerebrospinal fluid (aCSF), D-APV, MS, or combined administration of D-APV and MS. These treatments were given 30 min before noxious visceral stimulation with bradykinin injected through the bile-pancreatic catheter. Spontaneous behavioral activity tests, including cage crossing, rearing, and hind limb extension, were conducted before and after bradykinin injection into the bile-pancreatic duct to assess visceral nociception.

Results

Spinal pretreatment of D-APV or low doses of MS partially reduced visceral pain behaviors in this model. Pretreatments with combinations of low doses of MS (0.05-0.5 microg) and D-APV (1 microg) were maximally effective in returning all spontaneous behavioral activities to baseline.

Conclusions

Spinal administration of combined doses of NMDA receptor antagonist, D-APV, and MS reversed three behavioral responses to induction of an acute pancreatitis model. These results suggest that in the clinical management of visceral pain, such as pancreatitis, restricted usage of glutamate antagonists might be useful as adjuvant potentiation at the onset of morphine therapy.
The Importance of Prior Stroke for the Adjusted Risk of Neurologic Injury after Cardiac Surgery for Women and Men
Authors: Hogue Charles W. , De Wet Charl J. , Schechtman Kenneth B. , Dávila-Román Victor G.
Published: November 2003

Background

Women are at higher risk for stroke after cardiac surgery than men. Prior analysis of risk profiles for perioperative stroke that have mostly combined data from women and men may fail to identify gender-specific risks. The purpose of this study was to evaluate whether patient gender impacts adjusted risk for stroke after cardiac surgery.

Methods

Demographic and perioperative data were prospectively collected from 2,972 patients undergoing cardiac surgery. Carotid artery ultrasound examination was performed before surgery for patients aged 65 yr or older or when there was a history of transient ischemic attacks or prior stroke. Epiaortic ultrasound was performed at the time of surgery in all patients to assess for atherosclerosis of the ascending aorta.

Results

Strokes occurred after surgery in 30 women and 18 men (P < 0.0001). Based on multivariate logistic regression analysis, a history of a stroke was the strongest predictor of new stroke for both women and men. Low cardiac output syndrome, atherosclerosis of the ascending aorta, and diabetes mellitus were significantly associated with stroke for women but not for men. Analysis on the data from all patients using a gender-interaction term found that the risk for stroke associated with patient age, atherosclerosis of the aorta, diabetes, and duration of cardiopulmonary bypass was not affected by gender. The prior stroke-gender interaction, however, was significant (P = 0.017), suggesting that a prior cerebrovascular event was a more important predictor of stroke for men than women.

Conclusions

These data show that prior stroke before surgery is strongly and independently associated with susceptibility for stroke after cardiac surgery, particularly for men. Other risk factors for perioperative stroke, though, do not appear to be influenced by patient gender.
Simultaneous Assessment of Drug Interactions with Low- and High-Extraction Opioids
Authors: Ibrahim Andra E. , Feldman Jennifer , Karim Aziz , Kharasch Evan D.
Published: November 2003

Background

Parecoxib is a parenteral cyclooxygenase-2 (COX-2) inhibitor intended for perioperative analgesia. It is an inactive prodrug hydrolyzed in vivo to the active inhibitor valdecoxib, a substrate for hepatic cytochrome P450 3A4 (CYP3A4); hence, a potential exists for metabolic interactions with other CYP3A substrates. This study determined the effects of parecoxib on the pharmacokinetics and pharmacodynamics of the CYP3A substrates fentanyl and alfentanil compared with the CYP3A inhibitor troleandomycin. Alfentanil is a low-extraction drug with a clearance that is highly susceptible to drug interactions; fentanyl is a high-extraction drug and, thus, is theoretically less vulnerable. We therefore also tested the hypothesis that the extraction ratio influences the consequence of altered hepatic metabolism of these opioids.

Methods

After Institutional Review Board-approved, written, informed consent was obtained, 12 22- to 40-yr-old healthy volunteers were enrolled in the study. The protocol was a randomized, double-blinded, balanced, placebo-controlled, three-session (placebo, parecoxib, or troleandomycin pretreatment) crossover. Subjects received both alfentanil (15 microg/kg) and fentanyl (5 microg/kg; 15-min intravenous infusion) 1 h after placebo, parecoxib (40 mg intravenously every 12 h), or troleandomycin (every 6 h). Study sessions were separated by 7 or more days. Opioid concentrations in venous blood were determined by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Opioid effects were determined by pupillometry, respiratory rate, and Visual Analog Scale scores.

Results

There were no significant differences between the placebo and parecoxib treatments in alfentanil or fentanyl plasma concentration, maximum observed plasma concentration, area under the plasma time-concentration time curve, clearance, elimination half-life, or volume of distribution. However, disposition of alfentanil, and to a lesser extent fentanyl, was significantly altered by troleandomycin. Clearances were reduced to 12% (0.64 +/- 0.25 ml. kg-1. min-1) and 61% (9.35 +/- 3.07) of control (5.53 +/- 2.16 and 15.3 +/- 5.0) for alfentanil and fentanyl (P < 0.001). Pupil diameter versus time curves were similar between placebo and parecoxib treatments but were significantly different after troleandomycin.

Conclusions

Single-dose parecoxib does not alter fentanyl or alfentanil disposition or clinical effects and does not appear to cause significant CYP3A drug interactions. CYP3A inhibition decreases alfentanil clearance more than fentanyl clearance, confirming that the extraction ratio influences the consequence of altered hepatic drug metabolism. Modified cassette, or "cocktail," dosing is useful for assessing drug interactions in humans.
Optimal Adrenergic Support in Septic Shock Due to Peritonitis
Authors: Sun Qinghua , Tu Zizhi , Lobo Suzana , Dimopoulos George , Nagy Nathalie , Rogiers Peter , De Backer Daniel , Vincent Jean-Louis
Published: November 2003

Background

The authors evaluated optimal adrenergic support using norepinephrine, dopamine, and dobutamine in a clinically relevant model of septic shock.

Methods

Twenty-eight mature, female, anesthetized sheep (weight, 30.5 +/- 3.6 kg) underwent cecal ligation and perforation and were randomized into four groups of seven animals to be treated with norepinephrine, dopamine-norepinephrine, dobutamine-norepinephrine, or no adrenergic agent. In all groups, lactated Ringer's solution was administered to restore cardiac filling pressures to baseline. In the norepinephrine group, norepinephrine (0.5-5 microg. kg(-1). min(-1)) was titrated to maintain mean arterial pressure between 75-85 mmHg. In the dopamine-norepinephrine group, dopamine was given first, and norepinephrine was added only when mean arterial pressure remained below 75 mmHg despite the infusion of 20 microg. kg(-1). min(-1) dopamine. In the dobutamine-norepinephrine group, dobutamine was started at the same time as norepinephrine and titrated up to 20 microg. kg(-1). min(-1) to get a 15% increase in cardiac output.

Results

The dobutamine-norepinephrine group had greater cardiac output; superior mesenteric blood flow, oxygen delivery (Do(2)), and oxygen consumption ([OV0312]o(2)); and lower blood lactate concentration and partial pressure of carbon dioxide (Pco(2)) gap than the controls did. Cumulative urine output was significantly higher in the dobutamine-norepinephrine group than in the other groups. Survival time was significantly longer in the dobutamine-norepinephrine (24 +/- 4 h), dopamine- norepinephrine (24 +/- 6 h), and norepinephrine (20 +/- 1 h) groups than the control group (17 +/- 2 h; P < 0.05 vs. other groups), and significantly longer in the combined dopamine-norepinephrine and dobutamine-norepinephrine groups (24 +/- 5 h) than in the norepinephrine alone group (P < 0.05). Histologic examination of lung biopsies revealed less severe lesions in the dobutamine-norepinephrine group than in the control and norepinephrine alone groups. Anatomic alterations in the lung, liver, and small intestine were less severe in the dobutamine-norepinephrine group than in the other groups.

Conclusions

In this prolonged septic shock model, association of norepinephrine with either dopamine or dobutamine resulted in the longest survival and the least severe pulmonary lesions. The combination of dobutamine with norepinephrine was associated with a better myocardial performance, greater Do(2) and [OV0312]o(2), lower blood lactate concentration and Pco(2) gap, and less anatomic injury.
Halothane Depresses Glutamatergic Neurotransmission to Brain Stem Inspiratory Premotor Neurons in a Decerebrate Dog Model
Authors: Stucke Astrid G. , Zuperku Edward J. , Tonkovic-Capin Viseslav , Tonkovic-Capin Mislav , Hopp Francis A. , Kampine John P. , Stuth Eckehard A. E.
Published: November 2003

Background

Inspiratory bulbospinal neurons in the caudal ventral medulla are premotor neurons that drive phrenic motoneurons and ultimately the diaphragm. Excitatory drive to these neurons is mediated by N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors and modulated by an inhibitory gamma-aminobutyric acid(A) (GABA(A))ergic input. The authors investigated the effect of halothane on these synaptic mechanisms in decerebrate dogs.

Methods

Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABA(A) receptor blocker bicuculline and the glutamate agonists AMPA and NMDA. Complete blockade of the GABA(A)ergic mechanism by bicuculline allowed differentiation between the effects of halothane on overall GABA(A)ergic inhibition and on overall glutamatergic excitation. The neuronal responses to exogenous AMPA and NMDA were used to estimate the anesthetic effect on postsynaptic glutamatergic neurotransmission.

Results

Halothane, 1 MAC, depressed the spontaneous activity of 21 inspiratory neurons by 20.6 +/- 18.0% (mean +/- SD; P = 0.012). Overall glutamatergic excitation was depressed 15.4 +/- 20.2% (P = 0.001), while overall GABA(A)ergic inhibition did not change. The postsynaptic responses to exogenous AMPA and NMDA were also depressed by 18.6 +/- 35.7% (P = 0.03) and 22.2 +/- 26.2% (P = 0.004), respectively.

Conclusion

Halothane, 1 MAC, depressed the activity of inspiratory premotor neurons by a reduction of glutamatergic excitation. Overall inhibitory drive did not change. The postsynaptic AMPA and NMDA receptor response was significantly reduced. These findings contrast with studies in expiratory premotor neurons in which overall inhibition was significantly increased by halothane and there was no reduction in the postsynaptic glutamate receptor response.
Mitochondrial Adenosine Triphosphate–regulated Potassium Channel Opening Acts as a Trigger for Isoflurane-induced Preconditioning by Generating Reactive Oxygen Species
Authors: Tanaka Katsuya , Weihrauch Dorothee , Ludwig Lynda M. , Kersten Judy R. , Pagel Paul S. , Warltier David C.
Published: November 2003

Background

Whether the opening of mitochondrial adenosine triphosphate-regulated potassium (K(ATP)) channels is a trigger or an end effector of anesthetic-induced preconditioning is unknown. We tested the hypothesis that the opening of mitochondrial K(ATP) channels triggers isoflurane-induced preconditioning by generating reactive oxygen species (ROS) in vivo.

Methods

Pentobarbital-anesthetized rabbits were subjected to a 30-min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive a vehicle (0.9% saline) or the selective mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD) alone 10 min before or immediately after a 30-min exposure to 1.0 minimum alveolar concentration (MAC) isoflurane. In another series of experiments, the fluorescent probe dihydroethidium was used to assess superoxide anion production during administration of 5-HD or the ROS scavengers N-acetylcysteine or N-2-mercaptopropionyl glycine (2-MPG) in the presence or absence of 1.0 MAC isoflurane. Myocardial infarct size and superoxide anion production were measured using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively.

Results

Isoflurane (P < 0.05) decreased infarct size to 19 +/- 3% (mean +/- SEM) of the left ventricular area at risk as compared to the control (38 +/- 4%). 5-HD administered before but not after isoflurane abolished this beneficial effect (37 +/- 4% as compared to 24 +/- 3%). 5-HD alone had no effect on infarct size (42 +/- 3%). Isoflurane increased fluorescence intensity. Pretreatment with N-acetylcysteine, 2-MPG, or 5-HD before isoflurane abolished increases in fluorescence, but administration of 5-HD after isoflurane only partially attenuated increases in fluorescence produced by the volatile anesthetic agent.

Conclusions

The results indicate that mitochondrial K(ATP) channel opening acts as a trigger for isoflurane-induced preconditioning by generating ROS in vivo.
Nerve Stimulators Used for Peripheral Nerve Blocks Vary in Their Electrical Characteristics
Authors: Hadzic Admir , Vloka Jerry , Hadzic Nihad , Thys Daniel M. , Santos Alan C.
Published: November 2003

Background

Nerve stimulation with a low-intensity electrical current has become a vital part of the performance of peripheral nerve blockade. The purpose of this study was to compare the accuracy and characteristics of peripheral nerve stimulators used in clinical practice in the United States.

Methods

Fifteen peripheral nerve stimulators were fitted with fresh batteries and set to deliver currents ranging from 0.1 to 4.0 mA into a series of high-tolerance resistance loads ranging from 1 to 100 komega. The current output, stimulus duration, morphology, frequency, and maximum voltage output were studied using a factory-calibrated oscilloscope.

Results

All peripheral nerve stimulators performed uniformly well when set to deliver currents of 1.0 mA or more into a standard resistance load of 1 or 2 komega. However, at lower currents, the median error (%) increased from 2.4 (-5-144%) at 0.5 mA to 10.4 (-24-180%) at 0.1 mA into a 1 komega load. The morphology of the stimulus was characterized by a regular monophasic square pulse at current outputs of up to 1 mA and at a resistance of 1 komega. The stimulus waveform became particularly distorted as the impedance load was increased. The duration of the default stimulus set by the manufacturer varied from 34.8 to 460 micros among the peripheral nerve stimulators tested. The maximum voltage output ranged from 7.4 to 336 Volts.

Conclusions

Nerve stimulators used for regional anesthesia vary greatly in accuracy of current output and in manufacturer-selected electrical characteristics (e.g., current duration, stimulating frequency, maximum voltage output).
Does the Suggested Lightwand Bent Length Fit Every Patient?
Authors: Chen Tsai-Hsin , Tsai Shen-Kou , Lin Chen-Jung , Lu Cheng-Wei , Tsai Tsung-Po , Sun Wei-Zen
Published: November 2003

Background

To date, no study has explored the effect of bent length on lightwand intubation. For successful intubation in daily practice, the authors found that bent length should be approximated to the patient's thyroid prominence-to-mandibular angle distance (TMD), but some patients have a TMD much shorter than the suggested bent length range. The purposes of this study were to understand TMD distribution in adults and to test the influence of bent length on lightwand intubation.

Methods

The TMD, airway, and demographic data of 379 patients were collected. To test the bent length influence, patients were enrolled in group A (158 patients, TMD </= 5.5 cm) and group B (131 patients, TMD > 5.5 cm) and were intubated randomly using the lower (6.5 cm) and upper (8.5 cm) limits of the suggested range. Success rate and lightwand search time were compared.

Results

In group A, the success rate was 98.8% with 6.5-cm bent length and 78.2% with 8.5-cm bent length (P < 0.05). Search times were 5.7 +/- 2.90 and 8.9 +/- 5.80 s with 6.5- and 8.5-cm bent length, respectively (P < 0.01). In group B, there was no statistical difference in success rate and search time between 6.5- and 8.5-cm bent length.

Conclusion

The suggested range was suitable for patients in group B (TMD > 5.5 cm). However, in group A (</=5.5 cm), the large discrepancy between the upper limit of the suggested range and this TMD caused difficulty in lightwand intubation. A 6.5-cm bent length is more suitable than an 8.5-cm bent length in these patients.
Neural Mechanism of Propofol Anesthesia in Severe Depression
Authors: Ogawa Kenichi , Uema Takeshi , Motohashi Nobutaka , Nishikawa Masami , Takano Harumasa , Hiroki Masahiko , Imabayashi Etsuko , Ohnishi Takashi , Inoue Tomio , Takayama Yutaka , Takeda Masatoshi , Matsuda Hiroshi , Andoh Tomio , Yamada Yoshitsugu
Published: November 2003

Background

The precise neural mechanisms of propofol anesthesia in humans are still unknown. The authors examined the acute effects of propofol on regional cerebral blood flow (rCBF) using positron emission tomography in patients with severe depression.

Methods

In six severely depressed patients (mean age, 55.0 yr) scheduled for electroconvulsive therapy, anesthetic levels were monitored by electroencephalography, and rCBF was serially quantified in the awake, sedated, and anesthetized states. The authors used high-resolution positron emission tomography with 15O-labeled water and statistical parametric mapping 99 for imaging and analysis of the data.

Results

Global cerebral blood flow showed sharp decreases from the awake level during the administration of propofol, decreasing 26.8% in the sedated state and 54.4% in the anesthetized state. Moreover, a dose effect was seen in both parietal cortices and the left lateral prefrontal region with larger regions of relative decrease in rCBF at higher propofol doses. At the higher dose, the values of rCBF in the pulvinar nucleus of the thalamus, the pontine tegmentum, and the cerebellar cortex were also affected. Meanwhile, there were few changes of relative rCBF in the basal frontal lobes during both sedated and anesthetized states.

Conclusions

As in earlier studies using normal subjects, pronounced suppression in rCBF in the brain stem reticular formation, the thalamus, and the parietal association cortex occurred even in severely depressed patients. However, previously reported decreases in rCBF in the basal frontal lobe were absent in depressed patients.
Hypothermia Does Not Alter Somatosensory Evoked Potential Amplitude and Global Cerebral Oxygen Extraction during Marked Sodium Nitroprusside–induced Arterial Hypotension
Authors: Kottenberg-Assenmacher Eva , Armbruster Wolf , Bornfeld Norbert , Peters Jürgen
Published: November 2003

Background

To prevent neurologic damage, monitoring cerebral function by somatosensory evoked potentials is used in selected settings. Excision of intraocular melanoma provides a unique opportunity to assess independently during anesthesia the effects on median nerve somatosensory evoked potentials (MN-SSEPs) and cerebral oxygen extraction of sodium nitroprusside-evoked arterial hypotension with and without hypothermia.

Methods

Median nerve somatosensory evoked potentials, arterial pressure, jugular venous bulb oxygen saturation (Sjo(2)) and lactate concentration, and arterial-jugular bulb oxygen content difference were assessed during propofol-remifentanil anesthesia under sodium nitroprusside-evoked arterial hypotension (mean arterial pressure, 40 mmHg) with and without surface hypothermia (32 degrees C) in 11 otherwise healthy patients undergoing resection of choroidal melanoma.

Results

Hypothermia alone did not affect peak-to-peak amplitude of N20/P25 but prolonged cortical latency of N20 (22.6 +/- 2.2 vs. 25.9 +/- 2.5 ms, P < 0.05), cervical latency of N13 (14.3 +/- 1.2 vs. 15.7 +/- 1.6 ms, P < 0.05), and central conduction time (8.3 +/- 1.4 vs. 10.2 +/- 1.6 ms, P < 0.05). Evoked arterial hypotension did not depress MN-SSEP N20/P25 amplitude either with or without hypothermia (-0.31 vs. -0.28 microV, P > 0.05) or alter latency (0.08 vs. 0.1 ms, P > 0.05). Furthermore, hypotension with or without hypothermia did not change Sjo(2), arterial-jugular bulb oxygen content difference, or lactate concentration.

Conclusions

Thus, hypothermia to 32 degrees C does not alter MN-SSEP amplitude and global cerebral oxygen extraction during marked sodium nitroprusside-induced arterial hypotension with a mean arterial pressure of 40 mmHg but prolongs MN-SSEP latencies during propofol-remifentanil anesthesia in individuals without cerebrovascular disease.
Peri-MAC Depression of a Nociceptive Withdrawal Reflex Is Accompanied by Reduced Dorsal Horn Activity with Halothane but not Isoflurane
Authors: Jinks Steven L. , Martin John T. , Carstens Earl , Jung Sung-Won , Antognini Joseph F.
Published: November 2003

Background

Anesthetics act in the spinal cord to suppress movement evoked by a noxious stimulus, although the exact site is unknown.

Methods

This study investigated sensorimotor processing in hind limb withdrawal reflexes, and effects of two general anesthetics, halothane and isoflurane, on simultaneously recorded responses of single dorsal horn neurons and hind limb withdrawal force, elicited by graded noxious thermal hind paw stimulation in rats. Minimum alveolar anesthetic concentration (MAC) needed to block gross movement to a supra-maximal mechanical stimulus was determined for each animal.

Results

Between 0.9 and 1.1 MAC, halothane and isoflurane greatly reduced or abolished withdrawal force (79 and 89% reduction, respectively). Halothane (0.75-1.4 MAC) depressed heat-evoked neuronal responses in a concentration-related manner (41% reduction between 0.9 and 1.1 MAC averaged across all stimulus temperatures, P < 0.05) and decreased stimulus-response function slopes, with corresponding reductions in withdrawal force. In contrast, isoflurane did not reduce neuronal responses in the 0.75-1.4 MAC range and slightly facilitated responses (by 16%) when concentration increased from 0.9 to 1.1 MAC, despite a concurrent withdrawal force reduction. Anesthetic depression of heat-evoked withdrawal force correlated well with MAC determination using a supra-maximal mechanical stimulus. At sub-MAC anesthetic concentrations, some units exhibited firing rate changes that preceded and paralleled moment-to-moment changes in force during a given withdrawal.

Conclusions

Halothane reduces noxious-evoked movement at least partly via depression of dorsal horn neurons, whereas isoflurane suppresses movement by an action at more ventral sites in the spinal cord.