bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripheral Nerve Injury Alters the α2Adrenoceptor Subtype Activated by Clonidine for Analgesia
Authors: Duflo Frédéric , Li Xinhui , Bantel Carsten , Pancaro Carlo , Vincler Michelle , Eisenach James C.
Published: November 2003

Background

Previous studies suggest that the alpha adrenoceptor subtype is the target for spinally administered alpha -adrenergic agonists, clonidine, for pain relief. However, ST 91, a preferential alpha adrenoceptor subtype agonist, induces antinociception, and intrathecally administered alpha antisense oligodeoxynucleotide decreases antinociception induced by clonidine in the rat, suggesting non-A sites may be important as well. Therefore, the authors examined the subtype of alpha adrenoceptor activated by clonidine and ST 91 in normal rats and those with nerve injury-induced hypersensitivity.

Methods

The same mechanical stimulus was applied to normal rats and those following spinal nerve ligation, and the effect of intrathecal clonidine and ST 91 on withdrawal threshold to the stimulus was determined. To further examine subtypes, animals were spinally pretreated with vehicle, BRL 44408 (an alpha subtype-preferring antagonist), and ARC 239 (an alpha subtype-preferring antagonist).

Results

In normal animals, clonidine's effect was diminished by pretreatment with either antagonist, whereas ST 91's antinociceptive effect was solely blocked by pretreatment with ARC 239. In nerve-injured animals, the antihypersensitivity action of both clonidine and ST 91 was blocked by administration of ARC 239, whereas BRL 44408 was ineffective.

Conclusions

These data agree with previous studies supporting that the alpha adrenoceptor is important to the antinociceptive effect of clonidine in normal animals. Nerve injury alters this and results in a total reliance on alpha adrenoceptors.
Isoflurane Alters Angiotensin II–Induced Ca2+Mobilization in Aortic Smooth Muscle Cells from Hypertensive Rats
Authors: Samain Emmanuel , Bouillier Hélène , Rucker-Martin Catherine , Mazoit Jean-Xavier , Marty Jean , Renaud Jean-François , Dagher Georges
Published: November 2003

Background

Angiotensin II (AngII) is a potent vasoconstrictor involved in the short-term control of arterial blood pressure. Isoflurane was reported to decrease vascular tone through an alteration of vascular smooth muscle cell vasomotor response to several agonists, but its effect on AngII signaling is not known. On the other hand, vascular response to AngII is altered in hypertension. In this study, the authors tested the hypothesis that (1) isoflurane alters AngII-induced intracellular Ca mobilization in aortic vascular smooth muscle cell from Wistar Kyoto and spontaneously hypertensive rats, and (2) this effect could be associated with an alteration of the organization of microtubular network, reported to be involved in AngII signaling.

Methods

The effect of 0.5-3% isoflurane was studied (1) on AngII (10 m)-induced intracellular Ca mobilization, intracellular Ca release from internal stores, and Ca influx in Fura-2 loaded cultured aortic vascular smooth muscle cell isolated from 6-week-old Wistar Kyoto and spontaneously hypertensive rats, using fluorescent imaging microscopy; and (2) on the organization of cytoskeletal elements, using immunofluorescence labeling.

Results

In both stains, isoflurane decreased in a concentration-dependent manner AngII-induced intracellular Ca mobilization, Ca release from internal stores, and Ca influx through nifedipine-insensitive Ca channels. This effect occurred at a lower concentrations of isoflurane in Wistar Kyoto rats than in spontaneously hypertensive rats. In both strains, the effect of isoflurane on AngII- Ca mobilization was abolished by impairment with nocodazole, vinblastine, or paclitaxel of microtubules polymerization. Isoflurane directly altered tubular network organization in a concentration-dependent and reversible manner.

Conclusions

Isoflurane decreased AngII-induced Ca mobilization at clinically relevant concentrations, suggesting that vascular response to AngII could be altered during isoflurane anesthesia. The hypertensive strain was found less sensitive than the normotensive one. In both strains, the isoflurane effect was associated with a microtubular network interaction.
Dexmedetomidine Increases the Cocaine Seizure Threshold in Rats
Authors: Whittington Robert A. , Virag Laszlo , Vulliemoz Yvonne , Cooper Thomas B. , Morishima Hisayo O.
Published: November 2003

Background

Central alpha adrenoceptors have been demonstrated to play an important role in the control of seizure activity; moreover, alpha adrenoceptors have been linked to electroencephalogram changes associated with cocaine. The purpose of this study was to determine if dexmedetomidine, a highly selective alpha -adrenoceptor agonist, alters the threshold for cocaine-induced seizure activity in rats.

Methods

Sprague-Dawley rats received a cocaine infusion (1.25 mg x kg(-1) x min(-1)) followed 15 min later by the coinfusion of either dexmedetomidine (20-microg/kg intravenous bolus followed by an infusion of 1 microg x kg(-1) x min(-1), CD group, n = 8) or an equal volume of saline (CS group, n = 8). Dexmedetomidine or saline were coinfused with cocaine until the onset of cocaine-induced seizures. Dopamine concentrations in the nucleus accumbens were measured by microdialysis paired with chromatography. To determine if changes in extracellular dopamine were related to the seizures, dopamine (1 microm) was continuously delivered to the nucleus accumbens in a separate group (DACD group, n = 6) retrograde microdialysis. These rats then received an intravenous cocaine infusion followed by dexmedetomidine in the same manner as the CD group.

Results

Dexmedetomidine significantly increased the dose of cocaine necessary to produce seizures. Seizures occurred at 25.0 +/- 7.7 and 49.3 +/- 14.8 min in CS and CD, respectively (P < 0.001). The ratio of the percent increase in accumbal dopamine to the cocaine dose at the onset of seizure activity was significantly lower in CD, 39.9 +/- 16.5, compared to CS, 82.2 +/- 46.5 (P = 0.04). Intraaccumbal administration of dopamine prevented the effects of dexmedetomidine on the cocaine seizure threshold.

Conclusions

These data suggest that dexmedetomidine increases the cocaine-induced seizure threshold possibly a mechanism related to the attenuation of the extracellular dopaminergic neurotransmitter response to cocaine.
Differential Effects of Bupivacaine on Intracellular Ca2+Regulation
Authors: Zink Wolfgang , Graf Bernhard M. , Sinner Barbara , Martin Eike , Fink Rainer H. A. , Kunst Gudrun
Published: November 2003

Background

Bupivacaine produces skeletal muscle damage in clinical concentrations. It has been suggested that this may be caused by an increased intracellular level of [Ca2+]. Therefore, the aim of this study was to investigate direct intracellular effects of bupivacaine on Ca2+ release from the sarcoplasmic reticulum (SR), on Ca2+ uptake into the SR, and on Ca2+ sensitivity of the contractile proteins.

Methods

Saponin skinned muscle fibers from the extensor digitorum longus muscle of BALB/c mice were examined according to a standardized procedure described previously. For the assessment of effects on Ca2+ uptake and release from the SR, bupivacaine was added to the loading solution and the release solution, respectively. Force transients and force decays were monitored, and the position of the curve relating relative isometric force free [Ca2+] was evaluated in the presence or absence of bupivacaine.

Results

Bupivacaine induces Ca2+ release from the SR. In addition, the Ca2+ loading procedure is suppressed, resulting in smaller caffeine-induced force transients after loading in the presence of bupivacaine. The decay of caffeine-induced force transients is reduced by bupivacaine, and it also shifts [Ca2+]-force relation toward lower [Ca2+].

Conclusions

These data reveal that bupivacaine does not only induce Ca2+ release from the SR, but also inhibits Ca2+ uptake by the SR, which is mainly regulated by SR Ca2+ adenosine triphosphatase activity. It also has a Ca2+ -sensitizing effect on the contractile proteins. These mechanisms result in increased intracellular [Ca2+] concentrations and may thus contribute to its pronounced skeletal muscle toxicity.
Does the A118G Polymorphism at the μ-opioid Receptor Gene Protect against Morphine-6-Glucuronide Toxicity?
Authors: Lötsch Jörn , Zimmermann Michael , Darimont Jutta , Marx Claudia , Dudziak Rafael , Skarke Carsten , Geisslinger Gerd
Published: November 2003

Background

Some, but not all, patients with renal dysfunction suffer from side effects after morphine administration because of accumulation of the active metabolite morphine-6-glucuronide (M6G). The current study aims to identify genetic causes that put patients at risk for, or protect them from, opioid side effects related to high plasma M6G. Candidate genetic causes are the single nucleotide polymorphism (SNP) A118G of the mu-opioid-receptor gene (OPRM1), which has recently been identified to result in decreased potency of M6G, and mutations in the MDR1-gene coding P-glycoprotein, of which morphine and M6G might be a substrate.

Methods

Two men, aged 87 and 65 yr, with renal failure (creatinine clearance of 6 and 9 ml/min) received 30 mg/day oral morphine for pain treatment. Both patients had sufficient analgesia from morphine. However, while one patient tolerated morphine well despite high plasma M6G of 1735 nM, in the patient with M6G plasma concentrations of 941 nM it caused severe sleepiness and drowsiness. Patients were genotyped for known SNPs of the OPRM1 and MDR1 genes.

Results

The patient who tolerated morphine well despite high plasma M6G was a homozygous carrier of the mutated G118 allele of the mu-opioid-receptor gene, which has been previously related to decreased M6G potency. In contrast, the patient who suffered from side effects was "wild-type" for this mutation. No other differences were found between the OPRM1 and MDR1 genes.

Conclusions

The authors hypothesize that the A118G single nucleotide polymorphism of the mu-opioid-receptor is among the protective factors against M6G-related opioid toxicity. The observation encourages the search for pharmacogenetic reasons that cause interindividual variability of the clinical effects of morphine.
Early Effects of Acid-Base Management during Hypothermia on Cerebral Infarct Volume, Edema, and Cerebral Blood Flow in Acute Focal Cerebral Ischemia in Rats
Authors: Kollmar Rainer , Frietsch Thomas , Georgiadis Dimitrios , Schäbitz Wolf-Rüdiger , Waschke Klaus F. , Kuschinsky Wolfgang , Schwab Stefan
Published: November 2003

Background

Although the frequency for the use of moderate hypothermia in acute ischemic stroke is increasing, the optimal acid-base management during hypothermia remains unclear. This study investigates the effect of pH- and alpha-stat acid-base management on cerebral blood flow (CBF), infarct volume, and cerebral edema in a model of transient focal cerebral ischemia in rats.

Methods

Twenty Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h during normothermic conditions followed by 5 h of reperfusion during hypothermia (33 degrees C). Animals were artificially ventilated with either alpha- (n = 10) or pH-stat management (n = 10). CBF was analyzed 7 h after induction of MCAO by iodo[(14)C]antipyrine autoradiography. Cerebral infarct volume and cerebral edema were measured by high-contrast silver infarct staining (SIS).

Results

Compared with the alpha-stat regimen, pH-stat management reduced cerebral infarct volume (98.3 +/- 33.2 mm(3) vs. 53.6 +/- 21.6 mm(3); P > or = 0.05 mean +/- SD) and cerebral edema (10.6 +/- 4.0% vs. 3.1 +/- 2.4%; P > or = 0.05). Global CBF during pH-stat management exceeded that of alpha-stat animals (69.5 +/- 12.3 ml x 100 g(-1) x min(-1) vs. 54.7 +/- 13.3 ml x 100 g(-1) x min; P > or = 0.05). The regional CBF of the ischemic hemisphere was 62.1 +/- 11.2 ml x 100 g(-1) x min(-1) in the pH-stat group versus 48.2 +/- 7.2 ml x 100 g(-1) x min(-1) in the alpha-stat group ( P> or = 0.05).

Conclusions

In the very early reperfusion period (5 h), pH-stat management significantly decreases cerebral infarct volume and edema as compared with alpha-stat during moderate hypothermia, probably by increasing CBF.
Ketamine Stereoselectively Affects Vasorelaxation Mediated by ATP-sensitive K+Channels in the Rat Aorta
Authors: Dojo Mayuko , Kinoshita Hiroyuki , Iranami Hiroshi , Nakahata Katsutoshi , Kimoto Yoshiki , Hatano Yoshio
Published: November 2003

Background

The effect of ketamine on vasodilation mediated by adenosine triphosphate (ATP)-sensitive K(+) channels has not been studied. The present study was designed to determine whether ketamine might stereoselectively affect vasorelaxation induced by an ATP-sensitive K(+) channel opener in the isolated rat aorta.

Methods

Rings of the rat aorta with or without endothelium were suspended for isometric force recording. During contraction to phenylephrine (3 x 10(-7) M), vasorelaxation in response to an ATP-sensitive K(+) channel opener levcromakalim (10(-8) to 10(-5) M) or a nitric oxide donor sodium nitroprusside (10(-10) to 10(-5) M) was obtained. Glibenclamide (10(-5) M), S(+) ketamine (10(-4) M), or ketamine racemate (10(-5) to 10(-4) M) was applied 15 min before addition of phenylephrine.

Results

Vasorelaxation induced by levcromakalim was completely abolished by an ATP-sensitive K(+) channel antagonist glibenclamide (10(-5) M) in the aorta with or without endothelium. Ketamine racemate (3 x 10(-5) to 10(-4) M) significantly inhibited this vasorelaxation in a concentration-dependent fashion, whereas S(+) ketamine did not affect the relaxation. However, the highest concentration of ketamine racemate and S(+) ketamine used in the present study did not alter vasorelaxation in response to sodium nitroprusside in the aorta without endothelium.

Conclusion

In the isolated rat aorta, clinically relevant concentrations of ketamine racemate can inhibit relaxation induced by an ATP-sensitive K(+) channel opener, whereas S(+) ketamine did not produce any inhibitory effect on this vasorelaxation. These results suggest that ketamine stereoselectively alters vasodilation ATP-sensitive K(+) channels in the conduit artery.
Myeloperoxidase-associated Tyrosine Nitration after Intratracheal Administration of Lipopolysaccharide in Rats
Authors: Hataishi Ryuji , Kobayashi Hirosuke , Takahashi Yuko , Hirano Seishiro , Zapol Warren M. , Jones Rosemary C.
Published: November 2003

Background

Previous studies have shown that lipopolysaccharide-induced inflammation in the lung results in tyrosine nitration. The objective of this study was to evaluate the contribution of myeloperoxidase and peroxynitrite pathway to the tyrosine nitration in lipopolysaccharide-administered lungs of rats that were otherwise untreated or leukocyte-depleted by cyclophosphamide or received inhaled nitric oxide (NO).

Methods

The authors analyzed the immunoreactivity of inducible nitric oxide synthase (iNOS), nitrotyrosine (a product of the myeloperoxidase or peroxynitrite pathway), and chlorotyrosine (a byproduct of the myeloperoxidase pathway) by use of specific antibodies. The number of neutrophils in bronchoalveolar lavage fluid (BALF) and levels of myeloperoxidase activity in lung homogenates were also measured.

Results

Lipopolysaccharide enhanced the immunoreactivity of iNOS, nitrotyrosine, and chlorotyrosine in alveolar wall cells, alveolar macrophages, and neutrophils. Leukocyte depletion by cyclophosphamide and inhibition of leukocyte accumulation in the lungs by NO inhalation did not eliminate the increase in iNOS immunoreactivity in alveolar macrophages after lipopolysaccharide treatment, but nitrotyrosine and chlorotyrosine were not produced in these cells. Tyrosine nitration in response to lipopolysaccharide was associated with increases in neutrophil count in BALF and in myeloperoxidase activity in lung homogenates, whereas NO inhalation suppressed the neutrophil count in BALF and reduced tyrosine nitration and chlorination.

Conclusions

These findings suggest that myeloperoxidase pathway has a role in tyrosine nitration in the lungs of lipopolysaccharide-treated rats, and that NO inhalation during early phase of inflammation does not increase but rather decreases tyrosine nitration and chlorination, possibly by reducing neutrophil sequestration.
Cost-efficacy of Rofecoxib versus Acetaminophen for Preventing Pain after Ambulatory Surgery
Authors: Issioui Tijani , Klein Kevin W. , White Paul F. , Watcha Mehernoor F. , Skrivanek Gary D. , Jones Stephanie B. , Hu Jie , Marple Bradley F. , Ing Caleb
Published: November 2003

Background

Nonsteroidal antiinflammatory drugs are commonly administered as part of a multimodal regimen for pain management in the ambulatory setting. This randomized, double-blinded, placebo-controlled study was designed to compare the analgesic effect of oral rofecoxib, a cyclooxygenase-2 inhibitor, and acetaminophen when administered alone or in combination prior to outpatient otolaryngologic surgery.

Methods

A total of 143 healthy outpatients undergoing elective otolaryngologic surgery were assigned to one of four study groups: group 1 = control (500 mg vitamin C); group 2 = 2 g acetaminophen; group 3 = 50 mg rofecoxib; or group 4 = 2 g acetaminophen and 50 mg rofecoxib. The first oral dose of the study medication was taken 15-45 min before surgery, and a second dose of the same medication was administered on the morning after surgery. Recovery times, side effects, and the need for rescue analgesics were recorded. Follow-up evaluations were performed at 24 and 48 h after surgery to assess postdischarge pain, analgesic requirements, nausea, and patient satisfaction with their postoperative pain management and quality of recovery. Peak pain scores and the need for rescue analgesic medication were used as the endpoints for estimating efficacy of the study drugs, while cost to achieve complete satisfaction with analgesia was used in the cost-effectiveness analysis.

Results

Premedication with rofecoxib (50 mg) was significantly more effective than either placebo or acetaminophen (2 g) in reducing the peak postoperative pain, the need for analgesic medication, and improving the quality of recovery and patient satisfaction. Moreover, the addition of acetaminophen failed to improve its analgesic efficacy. An expenditure for rofecoxib of 16.76 US dollars (95% confidence interval, 7.89 to 21.03 US dollars) and 30.24 US dollars (95% confidence interval, 5.25 to 54.20 US dollars) would obtain complete satisfaction with pain control in one additional patient who would not have been satisfied if placebo or acetaminophen, respectively, had been administered prior to surgery.

Conclusions

Rofecoxib, 50 mg administered orally, decreased postoperative pain and the need for analgesic rescue medication after otolaryngologic surgery. The addition of 2 g oral acetaminophen failed to improve its analgesic efficacy.
Dose Response of Intrathecal Adenosine in Experimental Pain and Allodynia
Authors: Eisenach James C. , Curry Regina , Hood David D.
Published: November 2003

Background

Intrathecal adenosine reduces areas of mechanical hypersensitivity and provides analgesia in patients with neuropathic pain. Adenosine also causes side effects, yet its dose response for either efficacy or side effects has not been examined in double blind studies. We studied two doses of intrathecal adenosine in humans with experimental hypersensitivity and the ability of the adenosine receptor antagonist, aminophylline, to reverse adenosine's effects.

Methods

Following Internal Review Board approval and written informed consent, 35 volunteers were studied. Five volunteers were studied to confirm the stability of a new method of inducing hypersensitivity with capsaicin. The remaining 30 volunteers received, in a randomized, double-blind manner, saline, or adenosine, 0.5 or 2.0 mg, by intrathecal injection 40 min after areas of allodynia and hyperalgesia were established from capsaicin. Two hr later, volunteers were randomized to receive intravenous saline or aminophylline, 5 mg/kg.

Results

Topical capsaicin with intermittent heating resulted in stable areas of allodynia and hyperalgesia. Intrathecal adenosine, but not saline, reduced areas of allodynia and hyperalgesia from capsaicin, with no differences between doses. Side effects occurred in 1, 2, and 6 volunteers receiving saline, 0.5 mg and 2.0 mg adenosine, respectively. Aminophylline failed to reverse adenosine's effects.

Conclusions

There is no difference in efficacy to experimental hypersensitivity between the largest approved dose of intrathecal adenosine and a dose 25% this size, but side effects are more common with the larger dose. Failure of aminophylline to reverse adenosine's effects could reflect inadequate concentrations at receptors in the spinal cord after intravenous injection.
PACU Bypass after Outpatient Knee Surgery Is Associated with Fewer Unplanned Hospital Admissions but More Phase II Nursing Interventions
Authors: Williams Brian A. , Kentor Michael L. , Williams John P. , Vogt Molly T. , DaPos Stacey V. , Harner Christopher D. , Fu Freddie H.
Published: November 2003

Background

The authors recently proposed a recovery scoring system for outpatients receiving regional anesthesia (RA) or general anesthesia (GA). This scoring system was designed to allow qualifying patients to be directly routed to the phase II (step-down) recovery unit instead of the traditional postanesthesia care unit (PACU). We report PACU bypass rates using these criteria, and the extent to which PACU bypass was associated with (1) required nursing interventions in the step-down recovery unit, and (2) successful same-day discharge.

Methods

Day-of-surgery outcomes were studied for 894 outpatients undergoing outpatient sports medicine surgery on the lower extremity. We determined PACU-bypass rates, nursing interventions in the step-down recovery unit for common symptoms, and unplanned hospital admissions. Using logistic regression, we analyzed step-down nursing interventions based on PACU requirement versus PACU bypass, and anesthesia techniques used (GA vs. not, peripheral nerve blocks vs. not).

Results

Eighty-seven percent (778/894) of all patients bypassed PACU. Of PACU-bypass patients, 241/778 (31%) required step-down nursing interventions. Of patients requiring PACU, only 19/116 (16%) required additional interventions in step-down (P < 0.001). PACU-bypass patients were almost three times more likely (odds ratio 2.9,P < 0.001) to require at least one nursing intervention in the step-down unit, when compared with patients requiring PACU. Fewer unplanned admissions were required by patients who bypassed PACU (odds ratio = 0.3,P = 0.007).

Conclusions

For outpatient lower extremity surgery, applying our PACU-bypass criteria led to an 87% PACU bypass rate with no reportable adverse events.
Positive Experimental Demonstration of the Negative Brain “Protective” Effects of Anesthetics following Cardiac Arrest
Authors: Michenfelder John D. , Raja Srinivasa N.
Published: November 2003

The cerebral metabolic effects of a massive dose of thiopental (177 mg/kg) were investigated in seven dogs. The systemic circulation was supported with an extracorporeal circuit. At an infusion rate of 2 mg/kg/min, cerebral oxygen consumption (CMR(O(2))) decreased progressively until cerebral electrical silence was produced. This occurred after a mean dose of 72 mg/kg, which caused a mean decrease in CMR(O(2)) to 58% of the control value (measured at 1.5% halothane inspired). Thereafter, despite continued at 4 mg/kg/min, CMR(O(2)) did not decrease further. The oxygen-glucose index never changed during the infusion period and, at the termination of the infusion, brain assays for ATP, phosphocreatine, lactate, and pyruvate revealed normal concentrations. It is concluded that there was no alteration in normal cerebral metabolic pathways, that cerebral metabolic effects of thiopental are secondary to functional effects, that thiopental would provide no cerebral protection during hypoxia sufficient to abolish cerebral function, and that thiopental does not uncouple oxidative phosphorylation.
Synchronous Rhythmical Vasomotion in the Human Cutaneous Microvasculature during Nonpulsatile Cardiopulmonary Bypass
Authors: Podgoreanu Mihai V. , Stout Robert G. , El-Moalem Habib E. , Silverman David G.
Published: November 2003

Background

The origin, control mechanisms, and functional significance of oscillations in microvascular flow are incompletely understood. Although the traditional belief has been that only low-frequency oscillations (0.04-0.10 Hz) can originate at the microvascular level, recent evidence in healthy volunteers has suggested that high-frequency oscillations (> 0.10 Hz) also may have a microvascular origin (as opposed to being mechanically transmitted respiratory-induced variations in stroke volume). The current study determined if such oscillations would emerge in the absence of cardiac and respiratory activity during nonpulsatile cardiopulmonary bypass (NP-CPB).

Methods

Forehead and finger laser Doppler flow, arterial pressure, and core temperature were simultaneously recorded in eight patients during NP-CPB. Analyses included time- domain indices, frequency-domain indices (auto power spectral density), and a measure of regularity (approximate entropy) for standardized time segments.

Results

Nonpulsatile cardiopulmonary bypass was associated with the emergence of rhythmical oscillations in laser Doppler flow, with characteristic frequencies for the forehead (0.13 +/- 0.03 Hz) and finger (0.07 +/- 0.02 Hz). Forehead vasomotion became progressively synchronized, with a gain in high-frequency spectral power from 17.5 (minute 1) to 89.1 (minute 40) normalized units, and a decrease in approximate entropy from 1.2 (before NP-CPB) to less than 0.5 (minute 40).

Conclusions

The emergence of forehead microvascular oscillations at greater than 0.10 Hz (characteristic of parasympathetic frequency response), in the absence of cardiac and respiratory variability, demonstrates their peripheral origin and provides insights into parasympathetic vasoregulatory mechanisms. The progressive synchronization of forehead vasomotion during NP-CPB, suggestive of increased coupling among microvascular biologic oscillators, may represent a microcirculatory homeostatic response to systemic depulsation, with potential implications for end-organ perfusion.
The Minimum Alveolar Concentration of Xenon in the Elderly Is Sex-dependent
Authors: Goto Takahisa , Nakata Yoshinori , Morita Shigeho
Published: November 2003

Background

The minimum alveolar concentration (MAC) of xenon in the elderly has not been determined. Moreover, because xenon inhibits the activity of the N-methyl-D-aspartate receptors, and because N-methyl-D-aspartate receptor antagonists such as ketamine and MK-801 exert sex-dependent actions, we hypothesized that the MAC of xenon would also be sex-dependent.

Methods

Forty-eight patients of both sexes (24 patients of each sex), who were aged 65 yr or older and were undergoing elective laparotomy, were anesthetized with inhalational induction of xenon. Those who demonstrated marked agitation received supplemental propofol intravenously. After tracheal intubation, the end-tidal concentration of xenon was maintained at 45 (women only), 50, 55, 60, 65, 70, or 75% (men only) for at least 15 min before skin incision. These concentrations were randomly allocated to four patients of each sex. Each patient was monitored for the presence or absence of any purposeful bodily movement for 1 min following skin incision. The MAC of xenon was calculated separately for men and women using logistic regression analysis.

Results

The MAC of xenon was 69.3% (95% CI, 63.0-75.6%) for men and 51.1% (44.6-57.6%) for women. The two 95% confidence intervals did not overlap, indicating a statistically significant difference (P < 0.05).

Conclusions

The MAC of xenon in the elderly is higher in men than in women.
Biphasic Effects of Isoflurane on the Cardiac Action Potential
Authors: Suzuki Akihiro , Aizawa Kei , Gassmayr Susanne , Bosnjak Zeljko J. , Kwok Wai-Meng
Published: November 2003

Background

The mechanism underlying isoflurane modulation of cardiac electrophysiology is not well understood. In the present study, the authors investigated the effects of isoflurane on the cardiac action potential (AP) characteristics. The results were correlated to modulation of the L-type calcium (I(Ca,L)), the delayed-rectifier potassium (I(Kdr)), and the inward-rectifier potassium (I(Kir)) currents.

Methods

Single ventricular myocytes were enzymatically isolated from guinea pig hearts. The current clamp and whole cell voltage clamp configurations of the patch clamp technique were used to monitor the cardiac AP and ionic currents, respectively. A dynamic AP voltage protocol that mimicked changes in membrane potential during an AP was used to monitor the I(Ca,L), I(Kdr) and I(Kir).

Results

Isoflurane produced a concentration-dependent, biphasic effect on the AP duration (APD). At 0.6 mm (1.26 vol%), isoflurane significantly increased APD50 and APD90 by 50.0 +/- 7.6% and 48.9 +/- 7.2%, respectively (P < 0.05; n = 6). At 1.0 mm (2.09 vol%), isoflurane had no significant effect on APD (n = 6). In contrast, at 1.8 mm (3.77 vol%), isoflurane decreased APD50 and APD90 by 38.3 +/- 5.4% and 32.2 +/- 5.5%, respectively (P < 0.05; n = 7). The inhibitory effects of isoflurane on I(Kdr) chord conductance were greater than those on I(Ca,L) (P < 0.05; n = 6/group). Both I(Ca,L) inactivation and I(Kdr) activation kinetics were accelerated by isoflurane. Isoflurane had no significant effects on I(Kir) chord conductance (n = 6).

Conclusion

At the lower anesthetic concentration, the prolongation of the APD may be the result of the dominant inhibitory effects of isoflurane on I(Kdr). At the higher concentration, the shortening of the APD may be caused by the inhibitory effects on I (Ca,L) combined with the isoflurane-induced acceleration of I(Ca,L) inactivation kinetics. Because I(Kdr) is significantly inhibited by isoflurane, I(Kir) appears to be the major repolarizing current, which is minimally affected by isoflurane.
Comparison of Predicted Induction Dose with Predetermined Physiologic Characteristics of Patients and With Pharmacokinetic Models Incorporating those Characteristics as Covariates
Authors: Kazama Tomiei , Morita Koji , Ikeda Takehiko , Kurita Tadayoshi , Sato Shigehito
Published: November 2003

Background

The relationship between patient characteristics and anesthesia induction dose at a high administration rate is unclear. This study was designed to investigate the relation between induction dose and patient characteristics and to compare it to the predicted induction dose using the previously reported pharmacokinetic model.

Methods

Diluted propofol (0.5 mg/ml) dose required to reach loss of consciousness, when infused at an infusion rate per lean body mass (LBM) of 150 mg x kg(-1) x h(-1) (high rate), was determined in 82 patients, ages 10-85 yr. Cardiac output, blood volume, central blood volume (CBV), and hepatic blood flow were measured with indocyanine green pulse spectrophotometry. Stepwise multiple linear regression models were used to investigate the relations between the patient characteristics and induction dose. These were compared with our previously reported parameters at the rate of 40 mg x kg(-1) x h(-1) (low rate) and with predicted induction doses with two previously reported pharmacokinetic models.

Results

Significant factors for predicting the induction dose at a high rate were age, LBM, and CBV. Induction dose with one pharmacokinetic model was 1.5 times that of the measured one and the other was half that of the measured one at a high rate. At a low rate, one pharmacokinetic model provided an accurate induction dose.

Conclusions

The prediction of induction dose from physiologic characteristics of patients provides reasonable accuracy at both high and low administration rates of propofol. A previously reported pharmacokinetic model that incorporated patient characteristics provides the same accurate induction dose at a low rate.
Response Surface Modeling of Remifentanil–Propofol Interaction on Cardiorespiratory Control and Bispectral Index
Authors: Nieuwenhuijs Diederik J.F. , Olofsen Erik , Romberg Raymonda R. , Sarton Elise , Ward Denham , Engbers Frank , Vuyk Jaap , Mooren Rene , Teppema Luc J , Dahan Albert
Published: November 2003

Background

Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans.

Methods

The effect of steady-state concentrations of remifentanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentration range: propofol studies, 0-2.6 microg/ml; remifentanil studies, 0-2.0 ng/ml). Respiratory experiments consisted of ventilatory responses to three to eight increases in end-tidal Pco2 (Petco2). Invasive blood pressure, heart rate, and bispectral index were monitored concurrently. The nature of interaction was assessed by response surface modeling using a population approach with NONMEM. Values are population estimate plus or minus standard error.

Results

A total of 94 responses were obtained at various drug combinations. When given separately, remifentanil and propofol depressed cardiorespiratory variables in a dose-dependent fashion (resting V(i) : 12.6 +/- 3.3% and 27.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; V(i) at fixed Petco of 55 mmHg: 44.3 +/- 3.9% and 57.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; blood pressure: 9.9 +/- 1.8% and 3.7 +/- 1.1% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting V(i)). The effects of both drugs on heart rate and blood pressure were modest, with additive interactions when combined. Over the dose range studied, remifentanil had no effect on bispectral index even when combined with propofol (inert interaction).

Conclusions

These data show dose-dependent effects on respiration at relatively low concentrations of propofol and remifentanil. When combined, their effect on respiration is strikingly synergistic, resulting in severe respiratory depression.
Intracranial Pressure and Cerebral Hemodynamic in Patients with Cerebral Tumors
Authors: Petersen Kurt D. , Landsfeldt Uffe , Cold Georg Emil , Petersen Carsten B. , Mau Søren , Hauerberg John , Holst Peter , Olsen Karsten Skovgaard
Published: November 2003

Background

A critical point during craniotomy is opening of dura, where a high intracranial pressure (ICP) results in swelling of cerebral tissue. Controlled studies concerning ICP, degree of dural tension, and degree of cerebral swelling are therefore warranted.

Methods

In an open-label study, 117 patients with supratentorial cerebral tumors were randomized to propofol-fentanyl (group 1), isoflurane-fentanyl (group 2), or sevoflurane-fentanyl anesthesia (group 3). Normo- to moderate hypocapnia was applied, with a target level of arterial carbon dioxid tension of 30-40 mmHg. Mean arterial blood pressure was stabilized with intravenous ephedrine (2.5-5 mg) if necessary. Subdural ICP, mean arterial blood pressure, cerebral perfusion pressure (CPP), arteriovenous oxygen difference (AVDo2), internal jugular vein oxygen saturation were monitored before and after a 10-min period of hyperventilation, and the carbon dioxide reactivity was calculated. Furthermore, the tension of dura before and during hyperventilation and the degree of cerebral swelling during hyperventilation and after opening of the dura were estimated by the neurosurgeon.

Results

No differences were found between groups with regard to demographics, neuroradiologic examination, positioning of the head, and time to ICP measurement. Before and during hyperventilation, ICP was significantly lower and mean arterial blood pressure and CPP significantly higher in group 1 compared with groups 2 and 3 (P < 0.05). The tension of dura before and during hyperventilation was significantly lower in group 1 compared with group2 (P < 0.05), but not significantly different from group 3. In group 1, cerebral swelling after opening of dura was significantly lower compared with groups 2 and 3 (P < 0.05). Furthermore, AVDo was significantly higher and jugular vein oxygen saturation and carbon dioxide reactivity were significantly lower in group 1 compared with groups 2 and 3 (P < 0.05). No significant differences with regard to ICP, CPP, AVDo, carbon dioxide reactivity, and jugular vein oxygen saturation were found between patients anesthetized with isoflurane and sevoflurane.

Conclusions

The study indicates that before as well as during hyperventilation, subdural ICP and AVDo2 are lower and CPP higher in propofol-anesthetized patients compared with patients anesthetized with isoflurane or sevoflurane. These findings were associated with less tendency for cerebral swelling after opening of dura in the propofol group. The carbon dioxide reactivity in patients anesthetized with isoflurane and sevoflurane was significantly higher than in the propofol group. The differences in subdural ICP between the groups are presumed to be caused by differences in the degree of vasoconstriction elicited by the anesthetic agents, but autoregulatory mechanisms caused by differences in CPP cannot be excluded.
Despite In Vitro Increase in Cyclic Guanosine Monophosphate Concentrations, Intracarotid Nitroprusside Fails to Augment Cerebral Blood Flow of Healthy Baboons
Authors: Joshi Shailendra , Hartl Roger , Sun Lena S. , Libow Adam D. , Wang Mei , Pile-Spellman John , Young William L. , Connolly E. Sander , Hirshman Carol A.
Published: November 2003

Background

During cerebral angiography, intracarotid infusion of sodium nitroprusside (SNP), an endothelium-independent nitric oxide donor, fails to increase cerebral blood flow (CBF) of human subjects. A confounding effect of intracranial pathology or that of radiocontrast could not be ruled out in these experiments. The authors hypothesized that, if nitric oxide was a significant regulator of CBF of primates, then intracarotid SNP will augment CBF of baboons.

Methods

In studies, CBF (intraarterial (133)Xe technique) was measured in healthy baboons during isoflurane anesthesia at (1) baseline and during (2) induced hypertension with intravenous phenylephrine, (3) concurrent infusions of intravenous phenylephrine and intracarotid SNP, and (4) intracarotid verapamil (positive control drug). In studies, the authors measured tissue cyclic guanosine monophosphate (cGMP) by radioimmunoassay after incubating vascular rings obtained from freshly killed baboons (1) with increasing concentrations of SNP and (2) after SNP exposure following preincubation with the radiocontrast agent, iohexhol.

Results

In the studies, coinfusion of intravenous phenylephrine and intracarotid SNP did not increase CBF. However, intracarotid verapamil significantly increased CBF (from 26 +/- 7 to 43 +/- 11 ml x 100 g(-1) x min(-1); P < 0.0001) without a change in mean arterial pressure. In the studies, incubation of intracranial arterial rings in SNP resulted in dose-dependent increases in cGMP concentrations. A similar increase in cGMP content was evident despite iohexhol preincubation.

Conclusions

Collectively, these results suggest that, in healthy baboons, intracarotid SNP does not decrease arteriolar resistance, although SNP could affect proximal arterial tone, as demonstrated by the increase in cGMP content of these vessels.
The α2-Adrenoceptor Agonist Dexmedetomidine Converges on an Endogenous Sleep-promoting Pathway to Exert Its Sedative Effects
Authors: Nelson Laura E. , Lu Jun , Guo Tianzhi , Saper Clifford B. , Franks Nicholas P. , Maze Mervyn
Published: November 2003

Background

The authors investigated whether the sedative, or hypnotic, action of the general anesthetic dexmedetomidine (a selective alpha -adrenoceptor agonist) activates endogenous nonrapid eye movement (NREM) sleep-promoting pathways.

Methods

c-Fos expression in sleep-promoting brain nuclei was assessed in rats using immunohistochemistry and hybridization. Next, the authors perturbed these pathways using (1) discrete lesions induced by ibotenic acid, (2) local and systemic administration of gamma-aminobutyric acid receptor type A (GABA ) receptor antagonist gabazine, or (3) alpha2-adrenoceptor antagonist atipamezole in rats, and (4) genetic mutation of the alpha -adrenoceptor in mice.

Results

Dexmedetomidine induced a qualitatively similar pattern of c-Fos expression in rats as seen during normal NREM sleep, a decrease in the locus ceruleus (LC) and tuberomammillary nucleus (TMN) and an increase in the ventrolateral preoptic nucleus (VLPO). These changes were attenuated by atipamezole and were not seen in mice lacking functional alpha2a-adrenoceptors, which do not show a sedative response to dexmedetomidine. Bilateral VLPO lesions attenuated the sedative response to dexmedetomidine, and the dose-response curve to dexmedetomidine was shifted right by gabazine administered systemically or directly into the TMN. VLPO lesions and gabazine pretreatment altered c-Fos expression in the TMN but in not the LC after dexmedetomidine administration, indicating a hierarchical sequence of changes.

Conclusions

The authors propose that endogenous sleep pathways are causally involved in dexmedetomidine-induced sedation; dexmedetomidine's sedative mechanism involves inhibition of the LC, which disinhibits VLPO firing. The increased release of GABA at the terminals of the VLPO inhibits TMN firing, which is required for the sedative response.
Thermogenesis Inhibition in Brown Adipocytes Is a Specific Property of Volatile Anesthetics
Authors: Ohlson Kerstin B.E. , Lindahl Sten G.E. , Cannon Barbara , Nedergaard Jan
Published: November 2003

Background

This investigation examined the possibility that the inhibitory effect of halothane on nonshivering thermogenesis (heat production) in brown adipocytes is not a universal effect of all anesthetic agents but related to the type of anesthetic.

Methods

Brown adipocytes from hamster were isolated with a collagenase digestion method and incubated with anesthetic agents. The rate of oxygen consumption was measured with an oxygen electrode. The effect of clinically relevant (and higher) doses of anesthetics of different classes on basal and norepinephrine-induced thermogenesis (oxygen consumption) was tested.

Results

Two distinct groups of anesthetics could be distinguished: thermogenesis inhibitors and noninhibitors. Thermogenesis inhibitors include volatile anesthetics such as halothane (IC(50), 1.1 mm), ether (IC(50), 20 mm), and chloroform (IC(50), 2.2 mm) (nominal concentrations), but also tribromoethanol (IC(50), 0.6 mm), all inducing inhibition of norepinephrine-induced thermogenesis without affecting the EC for norepinephrine. Thermogenesis noninhibitors include the nonvolatile anesthetics pentobarbital, propofol, ketamine, and urethane, the inhalation anesthetic nitrous oxide, and, notably, also the volatile nonanesthetics (nonimmobilizers) 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane; none of these compounds had any effect on norepinephrine-induced thermogenesis at any concentration tested.

Conclusions

There are two distinct classes of anesthetics with regard to effects on thermogenesis, thermogenesis inhibitors and thermogenesis noninhibitors. The results are important for the interpretation of studies in thermal biology in general; specifically, they indicate that conclusions concerning regulation of nonshivering thermogenesis during anesthesia depend on the type of anesthetic used. Of clinical importance is that the volatile anesthetics are inhibitory for nonshivering thermogenesis and thus for an alternative heat production when myorelaxants prevent shivering. As the distinction between thermogenesis inhibitors and thermogenesis noninhibitors corresponds to the distinction between volatile and nonvolatile anesthetics, it may be related to the mode of action of the volatile anesthetics.
Neuroprotective Effect of Urinary Trypsin Inhibitor against Focal Cerebral Ischemia–Reperfusion Injury in Rats
Authors: Yano Toshiyuki , Anraku Sakiko , Nakayama Ryosuke , Ushijima Kazuo
Published: November 2003

Background

Acute inflammatory reactions cause neuronal damage in cerebral ischemia-reperfusion. Urinary trypsin inhibitor (UTI), a serine protease inhibitor, is cytoprotective against ischemia-reperfusion injury in the liver, intestine, kidney, heart, and lung through its antiinflammatory activity. Neuroprotective action of UTI on transient global cerebral ischemia has been documented. This is the first study to determine whether UTI is neuroprotective against transient focal cerebral ischemia.

Methods

Adult male Wistar rats were randomly assigned to the following treatment groups: 0.9% saline (control, n = 9); 100,000 U/kg UTI (n = 9); and 300,000 U/kg UTI (n = 9). Treatments were performed intravenously 10 min before right middle cerebral artery occlusion for 2 h and subsequent reperfusion. Ninety-six hours after the onset of reperfusion, the motor neurologic deficit and the cerebral infarct size were evaluated. Furthermore, immunohistochemical staining for myeloperoxidase and nitrotyrosine to count infiltrating neutrophils and nitrated cells, respectively, was performed on the brain sections.

Results

Infarct volume in the 300,000 U/kg UTI group was smaller than in the 100,000 U/kg UTI and saline control groups (P < 0.05). Treatment with 300,000 U/kg UTI showed a trend to improve neurologic outcome but did not reach statistical significance (P = 0.0693). The significant decrease in neutrophil infiltration was observed in the ischemic hemisphere treated with 300,000 U/kg UTI compared with saline control (P < 0.05). Nitrotyrosine deposition in the ischemic hemisphere was significantly reduced in the 300,000 U/kg UTI group compared with saline control and 100,000 U/kg UTI groups (P < 0.05).

Conclusions

Intravenous pretreatment with 300,000 U/kg UTI reduces focal ischemia-reperfusion injury in the rat brain, potentially opening a novel therapeutic avenue for the treatment of cerebral ischemia.