bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypothermia in Barbiturate-anesthetized Rats Suppresses Natural Killer Cell Activity and Compromises Resistance to Tumor Metastasis
Authors: Ben-Eliyahu Shamgar , Shakhar Guy , Rosenne Ella , Levinson Yuri , Beilin Benzion
Published: November 2003

Background

Clinical studies have implicated surgery in promoting infections and compromising immune functions, including natural killer cell activity. Animal studies indicate that surgery-induced suppression of natural killer cell activity also promotes tumor metastasis. Hypothermia, a common surgical complication, has been suggested to underlie some of the deleterious consequences of surgery. This study evaluated the effect of hypothermia on the activity and number of blood natural killer cells and on host susceptibility to metastasis. The involvement of adrenergic mechanisms was also considered.

Methods

Fischer-344 rats remained awake in their cages (control group) or were anesthetized with 70 mg/kg thiopental and maintained for 2.5 h at core body temperatures of 30-32 degrees C (hypothermia group) or 38 degrees C (normothermia group). Thereafter, at several time points, blood was drawn so natural killer cell activity could be assessed, or rats were injected with syngeneic MADB106 tumor cells that metastasize only to the lungs. Lungs were removed 9 h later for assessment of lung tumor retention, or 4 weeks later for counting of metastases.

Results

Normothermic anesthesia reduced natural killer cell activity (lytic units at 30% specific killing, mean +/- SEM) to 39+/-6.2% of control levels and hypothermia further reduced it to 15+/-6.6%. These changes were not accompanied by alterations in the numbers of circulating natural killer cells. Hypothermia increased tumor retention to 250% of control levels, and the number of metastases increased from 1.1+/-0.4 to 4.7+/-1.2. Normothermia had no significant effects on this index. Nadolol (0.4 mg/kg), a beta-adrenergic antagonist, significantly attenuated the effect of hypothermia on tumor retention.

Conclusions

Hypothermia under thiopental anesthesia suppresses natural killer cell activity and compromises host resistance to metastatic formation, possibly via adrenergic mechanisms. Such suppression may place patients with metastasizing tumors or dormant viral infections at greater risk for complications after intraoperative hypothermia.
Interregional Differences in the Systolic and Diastolic Response of Nonischemic Myocardium to Remote Coronary Occlusion
Authors: Marsch Stephan C. U. , Muñoz Hernan R. , Dalmas Serge , Foëx Pierre
Published: November 2003

Background

Previous work showed a twofold increase in stiffness of nonischemic myocardium at the base during ischemia of the left anterior wall. Whether the diastolic response of nonischemic myocardium to remote ischemia depends on the localization of the ischemic or the nonischemic area is unknown.

Methods

In dogs with open chests, regional function in ischemic and nonischemic myocardium was assessed (sonomicrometry) before and 5 min after occlusion of the left anterior descending coronary artery (LAD; n = 7) or the left circumflex coronary artery (LCX; n = 7).

Results

In nonischemic myocardium at the base, left anterior descending and left circumflex coronary artery occlusion both resulted in a twofold increase in chamber stiffness, whereas contractility and peak lengthening rate remained unchanged. In nonischemic myocardium of the posterior wall, left anterior descending coronary artery occlusion resulted in a significant (P<0.05 vs. control, P<0.05 vs. base) increase (mean+/-SD) in chamber stiffness (25+/-6%), contractility (17+/-5%), and peak lengthening rate (28+/-6%). In nonischemic myocardium at the apex, left circumflex coronary artery occlusion resulted in a significant (P<0.05 vs. control, P<0.05 vs. base) increase in chamber stiffness (15+/-5%), contractility (16+/-4%), and peak lengthening rate (19+/-6%).

Conclusions

Stiffening of remote nonischemic myocardium occurs regardless of the localization of the ischemic and nonischemic area. The systolic and diastolic responses of nonischemic myocardium are not necessarily homogenous but may vary among different regions.
Unintended Inhalation of Nitric Oxide by Contamination of Compressed Air
Authors: Benzing Albert , Loop Torsten , Mols Georg , Geiger Klaus
Published: November 2003

Background

Compressed air from a hospital's central gas supply may contain nitric oxide as a result of air pollution. Inhaled nitric oxide may increase arterial oxygen tension and decrease pulmonary vascular resistance in patients with acute lung injury and acute respiratory distress syndrome. Therefore, the authors wanted to determine whether unintentional nitric oxide inhalation by contamination of compressed air influences arterial oxygen tension and pulmonary vascular resistance and interferes with the therapeutic use of nitric oxide.

Methods

Nitric oxide concentrations in the compressed air of a university hospital were measured continuously by chemiluminescence during two periods (4 and 2 weeks). The effects of unintended nitric oxide inhalation on arterial oxygen tension (n = 15) and on pulmonary vascular resistance (n = 9) were measured in patients with acute lung injury and acute respiratory distress syndrome by changing the source of compressed air of the ventilator from the hospital's central gas supply to a nitric oxide-free gas tank containing compressed air. In five of these patients, the effects of an additional inhalation of 5 ppm nitric oxide were evaluated.

Results

During working days, compressed air of the hospital's central gas supply contained clinically effective nitric oxide concentrations (> 80 parts per billion) during 40% of the time. Change to gas tank-supplied nitric oxide-free compressed air decreased the arterial oxygen tension by 10% and increased pulmonary vascular resistance by 13%. The addition of 5 ppm nitric oxide had a minimal effect on arterial oxygen tension and pulmonary vascular resistance when added to hospital-supplied compressed air but improved both when added to tank-supplied compressed air.

Conclusions

Unintended inhalation of nitric oxide increases arterial oxygen tension and decreases pulmonary vascular resistance in patients with acute lung injury and acute respiratory distress syndrome. The unintended nitric oxide inhalation interferes with the therapeutic use of nitric oxide.
Evaluation of Interaction between Gabapentin and Ibuprofen on the Formalin Test in Rats
Authors: Yoon Myung Ha , Yaksh Tony L.
Published: November 2003

Background

Gabapentin is active in the regulation of facilitated pain states evoked by tissue injury. The mechanism of this action is believed to be through a specific binding site, likely at the spinal level. Nonsteroidal antiinflammatory drugs have a comparable behavioral profile, although their actions are believed to be mediated by cyclooxygenase inhibition at the spinal level. This study was undertaken to determine the nature of the interaction of these two mechanistically distinct antihyperalgesic agents in rats in a model of facilitated processing, the formalin test.

Methods

The effects of intraperitoneal gabapentin and ibuprofen were examined on flinching behavior and cardiovascular response (mean arterial blood pressure [MABP] and heart rate measured in the tail artery) evoked by the injection of formalin (5%; 50 microl). Their interaction was characterized using an isobolographic analysis.

Results

Injection of formalin into the hind paw caused a biphasic flinching and parallel increases in MABP. Gabapentin and ibuprofen produced a limited effect on the flinching in phase 1, but both drugs produced dose-dependent suppression of the flinching observed during phase 2 (gabapentin ED50 = 88 mg/kg; ibuprofen ED50 = 19 mg/kg). Gabapentin similarly showed a dose-dependent suppression of the MABP and heart rate response only during phase 2; ibuprofen showed dose-dependent reduction of MABP response in both phases. The isobolographic analysis carried out using equipotent dose ratios in phase 2 revealed an additive interaction between the two drugs. Neither gabapentin nor ibuprofen affected the baseline cardiovascular measures.

Conclusion

Gabapentin and ibuprofen independently alter the facilitated state as measured by somatomotor and autonomic response. Together these agents interact in an additive fashion if delivered concurrently. This combination may prove useful in managing postinjury pain states in humans.
Local Anesthetics Inhibit Muscarinic Receptor-mediated Activation of Extracellular Signal-regulated Kinases in Rat Pheochromocytoma PC12 Cells
Authors: Tan Zhiming , Dohi Shuji , Ohguchi Kenji , Nakashima Shigeru , Nozawa Yoshinori
Published: November 2003

Background

Because protein phosphorylation is a key mechanism for controlling cellular functions and extracellular signal-regulated kinase (ERK) plays a role in cellular signal transduction, the authors wanted to determine whether local anesthetics interfere with biochemical signaling molecules.

Methods

Protein tyrosine phosphorylation and ERK activation induced by carbachol, an agonist for muscarinic acetylcholine receptors, were examined in rat pheochromocytoma PC12 cells, a model for investigating signal transduction. Carbachol-induced tyrosine-phosphorylated proteins of 44 and 42 kd were determined by Western blot analysis and identified as activated ERK1 and ERK2 using anti-ERK antibody. The ERK activation was blocked by preincubation with atropine or an M3 muscarinic acetylcholine receptor antagonist 4-diphenyacetooxy-1, 1-dimethylpiperidinium, indicating that is was mediated by M3 muscarinic acetylcholine receptor activation. Then, in the presence of local anesthetic, the carbachol-induced tyrosine phosphorylation and ERK activation were evaluated. The effects of three Na+ current-modifying reagents on carbachol-induced ERK activation were also evaluated.

Results

Procaine (10(-4) to 10(-3) M) inhibited carbachol-induced tyrosine phosphorylation and ERK activation in a concentration-dependent manner. Although tetracaine, lidocaine, and bupivacaine similarly suppressed carbachol-induced tyrosine phosphorylation and ERK activation, neither tetrodotoxin, veratridine, nor ouabain affected the carbachol-induced ERKs activation. Both ERKs were also activated by 4beta-phorbol 12-myristate 13-acetate, an activator of protein kinase C, and fluoroaluminate (AlF4-), respectively, but procaine did not affect ERK activation induced by these two substances. The inhibition of carbachol-induced ERK activation by procaine was not modified by a phosphatase inhibitor, calyculin A.

Conclusions

The current results indicate that local anesthetics inhibit the activity of the signal-transducing molecule(s) leading to M3 muscarinic acetylcholine receptor-mediated ERK activation in PC12 cells. Such action is unlikely to be a result of the drug's action on Na+ channels or on the electrochemical gradients of the neuronal cell membrane.
Direct Inhibition of the N-methyl-D-aspartate Receptor Channel by High Concentrations of Opioids
Authors: Yamakura Tomohiro , Sakimura Kenji , Shimoji Koki
Published: November 2003

Background

Electrophysiologic and receptor binding studies showed that some opioids have noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist properties.

Methods

The effects and mechanisms of action of various opioid compounds were examined on four kinds of heteromeric NMDA receptor channels, namely the epsilon1/zeta1, epsilon2/zeta1, epsilon3/zeta1, and epsilon4/zeta1 channels, expressed in Xenopus oocytes. Furthermore, the action sites of opioids on NMDA receptor channels were investigated by site-directed mutagenesis.

Results

Meperidine inhibited four kinds of channels to a similar extent with inhibitor concentrations for half-control response (IC50s) of 210-270 microM. Morphine, fentanyl, codeine, and naloxone also inhibited NMDA receptor channels with affinities comparable to meperidine. Opioid inhibition exhibited voltage dependence and was quite effective at negative potentials. Opioids also shifted the inhibition curve of Mg2+ to the right. Furthermore, replacement of the conserved asparagine residue with glutamine in the channel-lining segment M2 of the zeta1 subunit, which constitutes the block sites of Mg2+ and ketamine, reduced the sensitivity to opioids, whereas that of the epsilon2 subunit barely affected the opioid sensitivity.

Conclusions

These results, together with previous findings, suggest that the low-affinity NMDA receptor antagonist activity is a common characteristic of various opioid compounds, and that the inhibition is a result of channel-block mechanisms at the site, which partially overlaps with those of Mg2+ and ketamine. This antagonist property of opioids may be clinically significant in the spinal cord following epidural or intrathecal administration, after which the cerebrospinal fluid concentrations of some opioids reach the high micromolar level.
Intrathecal Adenosine Interacts with a Spinal Noradrenergic System to Produce Antinociception in Nerve-injured Rats
Authors: Gomes Josenilia A. , Li Xinhui , Pan Hui-Lin , Eisenach James C.
Published: November 2003

Background

Adenosine analogs produce antinociception in animal models of acute pain, reduce hypersensitivity in models of inflammatory and nerve-injury pain, and stimulate neurotransmitter release in the brain. Adenosine itself is entering clinical trials for analgesia, and the current study examined the effect, mechanisms of action, and interaction with noradrenergic systems of intrathecal adenosine in a rat model of neuropathic pain.

Methods

The left L5 and L6 spinal nerve roots were ligated and, 1 week later, an intrathecal catheter was inserted in male rats. Withdrawal threshold to mechanical stimulation of the left hind paw was determined before and after surgery, confirming mechanical hypersensitivity. The effects of intrathecal adenosine, clonidine, and their combination on withdrawal threshold were determined, and reversal of the effects of adenosine by adenosine and alpha2-adrenergic antagonists and by destruction of noradrenergic nerve terminals was tested. Finally, spinal cord slices were perfused in vitro with the adenosine agonist 5'-N-ethylcarboxamide adenosine, and norepinephrine release was measured.

Results

Intrathecal adenosine and clonidine reduced hypersensitivity and interacted in an additive manner. The effects of adenosine were blocked by intrathecal injection of A1 but not A2 adenosine receptor antagonists, by an alpha2-adrenergic antagonist, and by destruction of spinal noradrenergic nerve terminals. Perfusion of spinal cord slices with 5'-N-ethylcarboxamide adenosine resulted in a concentration-dependent increase in norepinephrine release.

Conclusion

These data support clinical examination of intrathecal adenosine alone and with clonidine in the treatment of chronic pain states that include a component of mechanical hypersensitivity and suggest that, after nerve injury, adenosine acts to reduce hypersensitivity through spinal norepinephrine release.
Anticoagulation Monitoring during Cardiac Surgery
Authors: Despotis George J. , Gravlee Glenn , Filos Kriton , Levy Jerrold , Fisher Dennis M.
Published: November 2003

The literature does not consistently support the importance of anticoagulation monitoring techniques during CPB. This is best reflected by studies that have evaluated the impact of the ACT method on blood loss and transfusion outcomes. Inconsistent findings from studies that evaluated the impact of ACT monitoring may be related to either suboptimal study design (i.e., retrospective, unblinded, nonrandomized) or possibly the diagnostic inprecision of the ACT method used in these studies. There are a small number of well-controlled studies, some of which suggest that bleeding and transfusion outcomes can be improved by refining heparin monitoring techniques, either by sustaining better anticoagulation during CPB or by optimizing protamine doses (i.e., when empiric protocols result in excessive protamine doses). More well-controlled studies are needed to better define the importance of anticoagulation management during CPB.
Forty-hertz Midlatency Auditory Evoked Potential Activity Predicts Wakeful Response during Desflurane and Propofol Anesthesia in Volunteers
Authors: Dutton Robert C. , Smith Warren D. , Rampil Ira J. , Chortkoff Ben S. , Eger Edmond I
Published: November 2003

Background

Suppression of response to command commonly indicates unconsciousness and generally occurs at anesthetic concentrations that suppress or eliminate memory formation. The authors sought midlatency auditory evoked potential indices that successfully differentiated wakeful responsiveness and unconsciousness.

Methods

The authors correlated midlatency auditory evoked potential indices with anesthetic concentrations permitting and suppressing response in 22 volunteers anesthetized twice (5 days apart), with desflurane or propofol. They applied stepwise increases of 0.5 vol% end-tidal desflurane or 0.5 microg/ml target plasma concentration of propofol to achieve sedation levels just bracketing wakeful response. Midlatency auditory evoked potentials were recorded, and wakeful response was tested by asking volunteers to squeeze the investigator's hand. The authors measured latencies and amplitudes from raw waveforms and calculated indices from the frequency spectrum and the joint time-frequency spectrogram. They used prediction probability (PK) to rate midlatency auditory evoked potential indices and concentrations of end-tidal desflurane and arterial propofol for prediction of responsiveness. A PK value of 1.00 means perfect prediction and a PK of 0.50 means a correct prediction 50% of the time (e.g., by chance).

Results

The approximately 40-Hz power of the frequency spectrum predicted wakefulness better than all latency or amplitude indices, although not all differences were statistically significant. The PK values for approximately 40-Hz power were 0.96 during both desflurane and propofol anesthesia, whereas the PK values for the best-performing latency and amplitude index, latency of the Nb wave, were 0.86 and 0.88 during desflurane and propofol (P = 0.10 for -40-Hz power compared with Nb latency), and for the next highest, latency of the Pb wave, were 0.82 and 0.84 (P < 0.05). The performance of the best combination of amplitude and latency variables was nearly equal to that of approximately 40-Hz power. The approximately 40-Hz power did not provide a significantly better prediction than anesthetic concentration; the PK values for concentrations of desflurane and propofol were 0.91 and 0.94. Changes of 40-Hz power values of 20% (during desflurane) and 16% (during propofol) were associated with a change in probability of nonresponsiveness from 50% to 95%.

Conclusions

The approximately 40-Hz power index and the best combination of amplitude and latency variables perform as well as predictors of response to command during desflurane and propofol anesthesia as the steady-state concentrations of these anesthetic agents. Because clinical conditions may limit measurement of steady-state anesthetic concentrations, or comparable estimates of cerebral concentration, the approximately 40-Hz power could offer advantages for predicting wakeful responsiveness.
Positive End-expiratory Pressure Improves Respiratory Function in Obese but not in Normal Subjects during Anesthesia and Paralysis
Authors: Pelosi Paolo , Ravagnan Irene , Giurati Gabriella , Panigada Mauro , Bottino Nicola , Tredici Stefano , Eccher Giuditta , Gattinoni Luciano
Published: November 2003

Background

Morbidly obese patients, during anesthesia and paralysis, experience more severe impairment of respiratory mechanics and gas exchange than normal subjects. The authors hypothesized that positive end-expiratory pressure (PEEP) induces different responses in normal subjects (n = 9; body mass index < 25 kg/m2) versus obese patients (n = 9; body mass index > 40 kg/m2).

Methods

The authors measured lung volumes (helium technique), the elastances of the respiratory system, lung, and chest wall, the pressure-volume curves (occlusion technique and esophageal balloon), and the intraabdominal pressure (intrabladder catheter) at PEEP 0 and 10 cm H2O in paralyzed, anesthetized postoperative patients in the intensive care unit or operating room after abdominal surgery.

Results

At PEEP 0 cm H2O, obese patients had lower lung volume (0.59 +/- 0.17 vs. 2.15 +/- 0.58 l [mean +/- SD], P < 0.01); higher elastances of the respiratory system (26.8 +/- 4.2 vs. 16.4 +/- 3.6 cm H2O/l, P < 0.01), lung (17.4 +/- 4.5 vs. 10.3 +/- 3.2 cm H2O/l, P < 0.01), and chest wall (9.4 +/- 3.0 vs. 6.1 +/- 1.4 cm H2O/l, P < 0.01); and higher intraabdominal pressure (18.8 +/-7.8 vs. 9.0 +/- 2.4 cm H2O, P < 0.01) than normal subjects. The arterial oxygen tension was significantly lower (110 +/- 30 vs. 218 +/- 47 mmHg, P < 0.01; inspired oxygen fraction = 50%), and the arterial carbon dioxide tension significantly higher (37.8 +/- 6.8 vs. 28.4 +/- 3.1, P < 0.01) in obese patients compared with normal subjects. Increasing PEEP to 10 cm H2O significantly reduced elastances of the respiratory system, lung, and chest wall in obese patients but not in normal subjects. The pressure-volume curves were shifted upward and to the left in obese patients but were unchanged in normal subjects. The oxygenation increased with PEEP in obese patients (from 110 +/-30 to 130 +/- 28 mmHg, P < 0.01) but was unchanged in normal subjects. The oxygenation changes were significantly correlated with alveolar recruitment (r = 0.81, P < 0.01).

Conclusions

During anesthesia and paralysis, PEEP improves respiratory function in morbidly obese patients but not in normal subjects.
Effect of the Frequency of Transcutaneous Electrical Nerve Stimulation on the Postoperative Opioid Analgesic Requirement and Recovery Profile
Authors: Hamza Mohamed A. , White Paul F. , Ahmed Hesham E. , Ghoname El-sayed A.
Published: November 2003

Background

Transcutaneous electrical nerve stimulation (TENS) at either an acupoint or dermatome corresponding to the surgical incision produces comparable decreases in postoperative opioid requirements and opioid-related side effects. However, the effect of the frequency of the electrical stimulus on the postoperative analgesic response to TENS therapy has not been studied.

Methods

One hundred women undergoing major gynecological procedures with a standardized general anesthetic technique were enrolled in the study. Patients were randomly assigned to four groups: group I, patient-controlled analgesia (PCA) plus sham TENS (no stimulation); group II, PCA plus low-frequency (2-Hz) TENS; group m, PCA plus high-frequency (100-Hz) TENS; group IV, PCA plus mixed-frequency (2- and 100-Hz) TENS. The PCA device was programmed to deliver 2-3 mg intravenous boluses of morphine with a lockout interval of 10 min. The TENS device was used every 2 h during the day. Standard 100-mm visual analog scales were used to assess pain, sedation, fatigue, and nausea at specific intervals after surgery.

Results

Mixed frequency (2 and 100 Hz) of stimulation decreased morphine requirements by 53% compared with the sham group; low (2-Hz) and high (100-Hz) frequencies produced 32% and 35% decreases, respectively. All three "active" TENS groups reduced the duration of PCA therapy, as well as the incidence of nausea, dizziness, and itching.

Conclusions

TENS decreased postoperative opioid analgesic requirements and opioid-related side effects when utilized as an adjunct to PCA after lower abdominal surgery. Use of TENS at mixed (2- and 100-Hz) frequencies of stimulation produced a slightly greater opioid-sparing effect than either low (2-Hz) or high (100 Hz) frequencies alone.
Evaluation of Tracheal Intubation Difficulty in Patients with Cervical Spine Immobilization
Authors: Smith Charles E. , Pinchak Anna B. , Sidhu Tejbir S. , Radesic Brian P. , Pinchak Alfred C. , Hagen Joan F.
Published: November 2003

Background

The WuScope is a rigid, fiberoptic laryngoscope designed to facilitate tracheal intubation without the need for head extension. The study evaluated the WuScope in anesthetized patients with neck immobilization.

Methods

Patients were randomized to one of two groups: those receiving fiberoptic laryngoscopy (WuScope, n = 43) and those receiving conventional laryngoscopy (Macintosh blade, n = 44). Manual in-line stablization of the cervical spine was done during intubation. Seven parameters of intubation difficulty were measured (providing an intubation difficulty scale score): number of operators, number of attempts, number of techniques, Cormack view, lifting force, laryngeal pressure, and vocal cord position.

Results

Successful intubation occurred in 95% of patients in the fiberoptic group and in 93% of patients in the conventional group. There were no differences in number of attempts. In the fiberoptic group, 79% of patients had an intubation difficulty scale score of 0, representing an ideal intubation: that is, one performed by the first operator on the first attempt using the first technique with full glottic visualization. Only 18% of patients in the conventional group had an intubation difficulty scale score of 0 (P < 0.001). More patients had Cormack grade 3 or 4 views with conventional than with fiberoptic laryngoscopy (39 vs. 2%, P < 0.001). Intubation times in patients with one attempt were slightly longer in the fiberoptic (median, 25th-75th percentiles: 30, 23-53 s) compared with the conventional group (24, 17-30 s, P < 0.05). Corresponding times in patients requiring > one attempt were 155 (range, 112-201) s and 141 (range, 95-186) s in the fiberoptic and conventional groups, respectively (P value not significant).

Conclusions

Compared with conventional laryngoscopy, tracheal intubation using the fiberoptic laryngoscope was associated with lower intubation difficulty scale scores and better views of the laryngeal aperture in patients with cervical imnmobilization. However, there were no differences in success rates or number of intubation attempts.
Compound A Uptake and Metabolism to Mercapturic Acids and 3,3,3-Trifluoro-2-fluoromethoxypropanoic Acid during Low-flow Sevoflurane Anesthesia
Authors: Kharasch Evan D. , Jubert Carole
Published: November 2003

Background

Sevoflurane is degraded during low-flow anesthesia to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether ("compound A"), which causes renal necrosis in rats but is not known to cause nephrotoxicity in surgical patients. Compound A is metabolized to glutathione S-conjugates and then to cysteine S-conjugates, which are N-acetylated to mercapturic acids (detoxication pathway), or metabolized by renal beta-lyase to reactive intermediates (toxification pathway) and excreted as 3,3,3-trifluoro-2-fluoromethoxypropanoic acid. This investigation quantified compound A metabolites in urine after low-flow sevoflurane administration, to assess relative flux via these two pathways.

Methods

Patients (n = 21) with normal renal function underwent low-flow (11 min) sevoflurane anesthesia designed to maximize compound A formation. Inspiratory, expiratory, and alveolar compound A concentrations were quantified. Urine mercapturic acids and 3,3,3-trifluoro-2-fluoromethoxypropanoic acid concentrations were measured by gas chromatography and mass spectrometry.

Results

Sevoflurane exposure was 3.7 +/- 2.0 MAC-h. Inspired compound A maximum was 29 +/- 14 ppm; area under the inspired concentration versus time curve (AUCinsp) was 78 +/- 58 ppm x h. Compound A dose, calculated from pulmonary uptake, was 0.39 +/- 0.35 mmol (4.8 +/- 4.0 micromol/kg) and correlated with AUCinsp (r2 = 0.84, P < 0.001). Mercapturic acids excretion was complete after 2 days, whereas 3,3,3-trifluoro-2-fluoromethoxypropanoic acid excretion continued for 3 days in some patients. Total (3-day) mercapturates and fluoromethoxypropanoic acid excretion was 95 +/- 49 and 294 +/- 416 micromol, respectively (1.2 +/- 0.6 and 3.6 +/- 5.0 micromol/kg).

Conclusion

Compound A doses during 3.7 MAC-h, low-flow sevoflurane administration in humans are substantially less than the threshold for renal toxicity in rats (200 micromol/kg). Compound A metabolites quantification may provide a biomarker for compound A exposure and relative metabolism via toxification and detoxication pathways. Compared with previous investigations, relative metabolic flux (fluoromethoxypropanoic acid/mercapturates) through the toxification pathway was sixfold greater in rats than in humans. Species differences in dose and metabolism may influence compound A renal effects.
High Thoracic Epidural Anesthesia Does Not Inhibit Sympathetic Nerve Activity in the Lower Extremities
Authors: Magnúsdóttir Helga , Kirnö Klaus , Ricksten Sven-Erik , Elam Mikael
Published: November 2003

Background

Sympathetic nerve activity was recorded in the leg during high thoracic epidural anesthesia with a segmental sensory blockade of the upper thoracic dermatomes to test the hypothesis that the sympathetic blockade accompanying thoracic epidural anesthesia includes caudal parts of the sympathetic nervous system.

Methods

Experiments were performed on 10 patients scheduled for thoracotomy. An epidural catheter was inserted at the T3-T4 or T4-T5 interspace. In the main protocol (seven patients), blood pressure, heart rate, and skin temperature (big toe, thumb) were continuously monitored, and multiunit postganglionic sympathetic nerve activity was recorded with a tungsten microelectrode in a muscle-innervating fascicle of the peroneal nerve. After baseline data collection, muscle sympathetic nerve activity was recorded for an additional 45-min period after epidural injection of 4-6 ml bupivacaine, 5 mg/ml. In an additional three patients, the effects of thoracic epidural anesthesia on skin-innervating sympathetic nerve activity were qualitatively assessed.

Results

Activation of thoracic epidural anesthesia caused no significant changes in peroneal muscle sympathetic nerve activity (n = 7), blood pressure, or heart rate. Skin temperature increased significantly in the hand 15 min after activation of the blockade, from 32.7 +/- 2.4 degrees C to 34.4 +/- 1.5 degrees C (mean +/- SD), whereas no changes were observed in foot temperature. The sensory blockade extended from T1 (C4-T2) to T8 (T6-T11).

Conclusions

A high thoracic epidural anesthesia with adequate sensory blockade of upper thoracic dermatomes may be achieved without blockade of caudal parts of the sympathetic nervous system. This finding differs from that of earlier studies that used indirect methods to evaluate changes in sympathetic nerve activity.
Pharmacokinetics and Pharmacodynamics of Rapacuronium in Patients with Cirrhosis
Authors: Duvaldestin Philippe , Slavov Velislav , Rebufat Yves
Published: November 2003

Background

Delayed elimination kinetics of steroidal neuromuscular blocking agents have been observed in patients with cirrhosis. Like other steroidal muscle relaxants, rapacuronium may, in part, be eliminated by the liver. To determine the influence of liver disease on its neuromuscular blocking effect, we studied the pharmacokinetics and pharmacodynamics of rapacuronium in patients with cirrhosis.

Methods

Sixteen patients undergoing elective surgery or endoscopy with general anesthesia, eight with cirrhosis and eight with normal liver function, were studied. Anesthesia was induced with fentanyl 2 microg/kg and thiopental 5-7 mg/kg and maintained with 60% nitrous oxide and 0.6-0.8% isoflurane in oxygen and repeated doses of fentanyl 1 microg/kg. Rapacuronium 1.5 mg/kg was administered intravenously before tracheal intubation. Thumb adduction force evoked by supramaximal ulnar nerve stimulation was recorded in 16 patients. Venous blood was sampled at frequent intervals for 8 h. Rapacuronium and its breakdown product Org 9488 were measured in plasma by high-pressure liquid chromatography. Values are reported as median (range).

Results

The central volume of distribution was increased to 131 (104-141) ml/kg in patients with cirrhosis (P < 0.01), compared with 75 (47-146) ml/kg in controls. The total apparent volume of distribution was also increased (P < 0.05) to 331 (284-488) ml/kg in patients with cirrhosis, compared with 221 (124-285) ml/kg in controls. The elimination half-life was 88 (77-102) min in controls and 90 (76-117) min in patients with cirrhosis. Plasma clearance was increased (P < 0.05) to 6.9 (6.1-8.9) ml x min(-1) x kg(-1) in patients with cirrhosis, compared with 5.3 (4.2-8.4) ml x min(-1) x kg(-1) in controls. Rapacuronium neuromuscular blocking effect was similar between the two groups. Onset time was 65 (40-110) s in controls and of 60 (52-240) s in patients with cirrhosis. Time to return to 90% of thumb adduction force control value was of 49 (28-80) min in controls and 47 (28-71) min in patients with cirrhosis.

Conclusion

The neuromuscular blocking effect of a single bolus dose of rapacuronium in patients with cirrhosis is not different from that of patients with normal hepatic function. No decrease in plasma clearance of rapacuronium was observed in patients with cirrhosis.
The Analgesic Action of Nitrous Oxide Is Dependent on the Release of Norepinephrine in the Dorsal Horn of the Spinal Cord
Authors: Zhang Chousheng , Davies Frances M. , Guo Tian-Zhi , Maze Mervyn
Published: November 2003

Background

The authors and others have demonstrated that supraspinal opiate receptors and spinal alpha2 adrenoceptors are involved in the analgesic mechanism for nitrous oxide (N2O). The authors hypothesize that activation of opiate receptors in the periaqueductal gray results in the activation of a descending noradrenergic pathway that releases norepinephrine onto alpha2 adrenoceptors in the dorsal horn of the spinal cord.

Methods

The spinal cord was transected at the level of T3-T4 in rats and the analgesic response to 70% N2O in oxygen was determined by the tail flick latency test. In a separate experiment in rats a dialysis fiber was positioned transversely in the dorsal horn of the spinal cord at the T12 level. The following day, the dialysis fiber was infused with artificial cerebrospinal fluid at a rate of 1.3 microl/min, and the effluent was sampled at 30-min intervals. After a 60-min equilibration period, the animals were exposed to 70% N2O in oxygen. The dialysis experiment was repeated in animals that were pretreated with naltrexone (10 mg/kg, intraperitoneally) before N2O. In a third series, spinal norepinephrine was depleted with n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine (DSP-4), and the analgesic response to 70% N2O in oxygen was determined.

Results

The analgesic effect of N2O was prevented by spinal cord transection. After exposure to N2O, there was a fourfold increase in norepinephrine released in the first 30-min period, and norepinephrine was still significantly elevated after 1 h of exposure. The increased norepinephrine release was prevented by previous administration of naltrexone. Depletion of norepinephrine in the spinal cord blocked the analgesic response to N2O.

Conclusions

A descending noradrenergic pathway in the spinal cord links N2O-induced activation of opiate receptors in the periaqueductal gray, with activation of alpha2 adrenoceptors in the spinal cord. N2O-induced release of norepinephrine in the dorsal horn of the spinal cord is blocked by naltrexone, as is the analgesic response. Spinal norepinephrine is necessary for the analgesic response to the N2O.
Pancreatitis-associated Protein Protects the Lung from Leukocyte-induced Injury
Authors: Heller Axel , Fiedler Fritz , Schmeck Joachim , Lück Vanessa , Iovanna Juan L. , Koch Thea
Published: November 2003

Background

Severe pancreatitis is often complicated by shock and acute lung failure. Little is known about the pathophysiologic impact of the 16.6-kD lectine, named pancreatitis-associated protein (PAP), which is expressed during pancreatitis and which reduces mortality in a rat model with severe pancreatitis. Therefore, the aim of this study was to investigate the effects of PAP on the pulmonary vasculature after leukocyte activation with N-formyl-Met-Leu-Phe (fMLP).

Methods

The experiments were performed in buffer-perfused isolated rabbit lungs. Mean pulmonary artery pressure, weight gain, and thromboxane A2 synthesis of the lungs were monitored. PAP was obtained by affinity chromatography of pancreas juice from pancreatitic rats. The authors tested whether treatment with PAP (260 microg/l, n = 9; or 500 microg/l, n = 6) before fMLP injection (10(-6) M) influences mean pulmonary artery pressure and edema formation. Lungs that were treated only with fMLP (n = 6) served as controls. Additional experiments in which PAP was applied were performed to study whether PAP (260 microg/l, n = 3; 500 microg/l, n = 3; 1,000 microg/l, n = 3) itself effects lung vasculature.

Results

Application of fMLP resulted in an increase of mean pulmonary artery pressure (+/- SD) from 8 +/- 2 mmHg up to 26 +/-13 mmHg (P < 0.01) at a flow of 150 ml/min. Pretreatment with PAP reduced the peak pressure developed after fMLP to 15 +/- 7 mmHg (PAP 260 microg/l; P < 0.05) and to 9 +/- 4 mmHg (PAP 500 microg/l), respectively. In addition, the fMLP-induced lung weight gain of 9 +/- 7 g in the controls was prevented by pretreatment with PAP after 150 min in either concentration. In parallel to the attenuated pressure increase, thromboxane A2 release was significantly suppressed in the 260-microg/l (200 +/- 220 pmol x ml(-1) x min(-1); P < 0.01) and 500-microg/l (285 +/- 70 pmol x m(-1) x min(-1); P < 0.05) PAP groups compared with controls (1,138 +/- 800 pmol x ml(-1) x mi(-1)). Treatment with PAP alone in either concentration did not induce any changes in mean pulmonary artery pressure, weight gain, or thromboxane A2 release.

Conclusion

Clinically relevant concentrations of PAP prevented fMLP-induced vasoconstriction and edema formation in the lung. These findings point toward a protective effect of PAP on polymorphonuclear neutrophil leukocyte-mediated lung injury.
Sevoflurane Reduces Myocardial Infarct Size and Decreases the Time Threshold for Ischemic Preconditioning in Dogs
Authors: Toller Wolfgang G. , Kersten Judy R. , Pagel Paul S. , Hettrick Douglas A. , Warltier David C.
Published: November 2003

Background

Recent evidence indicates that volatile anesthetics exert protective effects during myocardial ischemia and reperfusion. The authors tested the hypothesis that sevoflurane decreases myocardial infarct size by activating adenosine triphosphate-sensitive potassium (K(ATP)) channels and reduces the time threshold of ischemic preconditioning necessary to protect against infarction.

Methods

Barbiturate-anesthetized dogs (n = 75) were instrumented for measurement of aortic and left ventricular pressures and maximum rate of increase of left ventricular pressure and were subjected to a 60-min left anterior descending (LAD) coronary artery occlusion followed by 3-h reperfusion. In four separate groups, dogs received vehicle or the K(ATP) channel antagonist glyburide (0.1 mg/kg intravenously), and 1 minimum alveolar concentration sevoflurane (administered until immediately before coronary artery occlusion) in the presence or absence of glyburide. In three additional experimental groups, sevoflurane was discontinued 30 min (memory) before the 60-min LAD occlusion or a 2-min LAD occlusion as an ischemic preconditioning stimulus was used with or without subsequent sevoflurane (with memory) pretreatment. Regional myocardial perfusion and infarct size were measured with radioactive microspheres and triphenyltetrazolium staining, respectively.

Results

Vehicle (23 +/- 1% of the area at risk; mean +/- SEM) and glyburide (23 +/- 2%) alone produced equivalent effects on myocardial infarct size. Sevoflurane significantly (P < 0.05) decreased infarct size (13 +/- 2%). This beneficial effect was abolished by glyburide (21 +/- 3%). Neither the 2-min LAD occlusion nor sevoflurane followed by 30 min of memory were protective alone, but together, sevoflurane enhanced the effects of the brief ischemic stimulus and profoundly reduced infarct size (9 +/- 2%).

Conclusion

Sevoflurane reduces myocardial infarct size by activating K(ATP) channels and reduces the time threshold for ischemic preconditioning independent of hemodynamic effects in vivo.
Effects of Hypoxia–Reoxygenation on Microvascular Endothelial Function in the Rat Hippocampal Slice
Authors: Staunton Michael , Drexler Cathy , Dulitz Michael G. , Ekbom Dale C. , Schmeling William T. , Farber Neil E.
Published: November 2003

Background

Cerebral ischemia and hypoxia may cause injury to both neuronal and vascular tissue. The direct effects of hypoxia on endothelial function in intraparenchymal cerebral arterioles are unknown. Using a modification of the rat brain slice preparation, allowing continuous imaging of these previously inaccessible vessels, microvessel dilation was evaluated before and after a brief hypoxic episode.

Methods

Rat brain slices were superfused with oxygenated artificial cerebrospinal fluid. Hippocampal arterioles were visualized using computerized videomicroscopy, and their diameters (range, 12-27 microm) were measured using image analysis. After preconstriction with prostaglandin F2alpha and controlled pH and carbon dioxide tension, graded concentrations of either acetylcholine (endothelium-dependent vasodilation) or sodium nitroprusside (endothelium-independent vasodilation) were given before and after a 10-min period of hypoxia.

Results

Sodium nitroprusside (100 microM) caused similar dilation before and after hypoxia (mean +/- SEM: 9.6 +/- 0.6% vs. 13.0 +/- 0.9%). Acetylcholine (100 microM) caused significantly less dilation (P < 0.05) after hypoxia (mean +/- SEM: 9.3 +/- 1.8% vs. 3.6 +/- 1.2%). The decreased acetylcholine-induced dilation after hypoxia was not reversed by pretreatment with L-arginine (1 mM), the precursor of nitric oxide (mean +/- SEM: 8.8 +/- 1.3% vs. 4.4 +/- 0.7%).

Conclusions

Even brief periods of hypoxia may cause endothelial dysfunction in intraparenchymal cerebral arterioles. This does not seem to be related to a deficiency of the nitric oxide substrate, L-arginine. Endothelial dysfunction and impaired endothelium-dependent dilation of microvessels may decrease oxygen delivery and increase neuronal injury during cerebral hypoxia-reoxygenation.
Effects of Crystalloid and Colloid Preload on Blood Volume in the Parturient Undergoing Spinal Anesthesia for Elective Cesarean Section
Authors: Ueyama Hiroshi , He Yan-Ling , Tanigami Hironobu , Mashimo Takashi , Yoshiya Ikuto
Published: November 2003

Background

The role of crystalloid preloading to prevent hypotension associated with spinal anesthesia in parturients during cesarean section has been challenged. Direct measurement of blood volume should provide insight regarding the volume-expanding effects. The aim of the current study was to clarify the effects of volume preload with either crystalloid or colloid solution on the changes in blood volume of parturients undergoing spinal anesthesia for cesarean section.

Methods

Thirty-six healthy parturients scheduled for elective cesarean section during spinal anesthesia were allocated randomly to one of three groups receiving 1.5 l lactated Ringer's solution (LR; n = 12), 0.5 l hydroxyethylstarch solution, 6% (0.5 l HES; n = 12), and 1.0 l hydroxyethylstarch solution, 6% (1.0 l HES; n = 12), respectively. Blood volume and cardiac output were measured before and after volume preloading with indocyanine green (ICG), and the indocyanine green blood concentrations were monitored by noninvasive pulse spectrophotometry.

Results

After volume preload, the blood volume significantly increased in all three groups (P < 0.01). The volume of infused solution remaining in the vascular space in the LR, 0.5-l HES, and 1.0-l HES groups were 0.43+/-0.20 l, 0.54+/-0.14 l, and 1.03+/-0.21 l, respectively, corresponding to 28% of lactated Ringer's solution and 100% of hydroxyethylstarch solution infused. Significant increases in cardiac output were observed in the 0.5-l and 1.0-l HES groups (P < 0.01). A significant correlation between the percentage increase in blood volume and that of cardiac output was observed by volume preloading (r2 = 0.838; P < 0.001). The incidence of hypotension was 75% for the LR group, 58% for the 0.5-l HES group, and 17% for the 1.0-l HES group, respectively.

Conclusions

The incidence of hypotension developed in the 1.0-l HES group was significantly lower than that in the LR and 0.5-l HES groups, showing that greater volume expansion results in less hypotension. This result indicates that the augmentation of blood volume with preloading, regardless of the fluid used, must be large enough to result in a significant increase in cardiac output for effective prevention of hypotension.
Effect of Dobutamine on Splanchnic Carbohydrate Metabolism and Amino Acid Balance after Cardiac Surgery
Authors: Ensinger Hermann , Rantala Arto , Vogt Josef , Georgieff Michael , Takala Jukka
Published: November 2003

Background

As a predominant beta-adrenergic agonist, dobutamine may modify blood flow distribution and increase metabolic demands. The authors investigated the effect of a dobutamine-induced increase in cardiac output on splanchnic and femoral blood flow and metabolism in patients after cardiac surgery.

Methods

Seventeen stable patients were randomized to receive dobutamine or placebo (n = 8 per group, one dropout). After baseline measurement for systemic, splanchnic, and femoral blood flow (by dye dilution); oxygen consumption; gastric mucosal pressure of carbon dioxide (Pco2); total and splanchnic glucose production (by stable isotope tracer dilution); and regional lactate and amino acid balance, patients received either dobutamine, at a dosage (6 microg x kg(-1)min(-1)) sufficient to increase cardiac index by at least 25%, or placebo. A second set of measurements was performed 60 min after the start of dobutamine or placebo infusion.

Results

Dobutamine increased cardiac index (3.0+/-0.6 to 4.4+/-1.0 l x min(-1)m(-2), mean +/- SD; P < 0.05), splanchnic blood flow (from 0.8+/-0.2 to 1.0 + 0.2 l x min(-1)m(-2); P < 0.05), femoral blood flow (from 0.2+/-0.1 to 0.3+/-0.1 l x min(-1)m(-2); P < 0.05), and the arterial-gastric mucosal Pco2 gap (from 11.4+/-9.5 to 11.9+/-8.0 mmHg; P < 0.05). Dobutamine increased systemic oxygen consumption (from 132+/-14 to 146+/-13 ml x min(-1) x m(-2); P < 0.05) but not splanchnic or femoral oxygen consumption. Splanchnic glucose production and lactate and amino acid balance did not change.

Conclusion

After coronary artery bypass surgery, dobutamine increased systemic and regional blood flow and decreased systemic and regional oxygen extraction. Dobutamine did not affect splanchnic glucose production or lactate or amino acid balance. This suggests that dobutamine increases splanchnic blood flow without a concomitant increase in hepatosplanchnic metabolism.