bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal Nitric Oxide Synthase Mediates Halothane-induced Cerebral Microvascular Dilation
Authors: Staunton Michael , Drexler Cathy , Schmid Phillip G. , Havlik Heather S. , Hudetz Antal G. , Farber Neil E. 
Published: November 2003

Background
The causes of volatile anesthetic-induced cerebral vasodilation include direct effects on smooth muscle and indirect effects via changes in metabolic rate and release of mediators from vascular endothelium and brain parenchyma. The role of nitric oxide and the relative importance of neuronal and endothelial nitric oxide synthase (nNOS and eNOS, respectively) are unclear.

Methods
Rat brain slices were superfused with oxygenated artificial cerebrospinal fluid. Hippocampal arteriolar diameters were measured using computerized videomicrometry. Vessels were preconstricted with prostaglandin F2alpha (PGF2alpha; halothane group) or pretreated with 7-nitroindazole sodium (7-NINA, specific nNOS inhibitor, 7-NINA + halothane group) or N-nitro-L-arginine methylester (L-NAME; nonselective NOS inhibitor, L-NAME + halothane group) and subsequently given PGF2alpha to achieve the same total preconstriction as in the halothane group. Increasing concentrations of halothane were administered and vasodilation was calculated as a percentage of preconstriction.

Results
Halothane caused significant, dose-dependent dilation of hippocampal microvessels (halothane group). Inhibition of nNOS by 7-NINA or nNOS + eNOS by L-NAME similarly attenuated halothane-induced dilation at 0.6, 1.6, and 2.6% halothane. The dilation (mean +/- SEM) at 1.6% halothane was 104 +/- 10%, 65 +/- 6%, and 51 +/- 9% in the halothane, 7-NINA + halothane and L-NAME + halothane groups, respectively. The specificity of 7-NINA was confirmed by showing that acetylcholine-induced dilation was not inhibited by 7-NINA but was converted to constriction by L-NAME.

Conclusions
At clinically relevant concentrations, halothane potently dilates intracerebral arterioles. This dilation is mediated, in part, by neuronally derived nitric oxide. Endothelial NOS does not play a major role in halothane-induced dilation of hippocampal microvessels.
Effect of Spinal Morphine after Long-term Potentiation of Wide Dynamic Range Neurones in the Rat
Authors: Rygh Lars Jørgen , Green Mark , Athauda Nuwan , Tjølsen Arne , Dickenson Anthony H. 
Published: November 2003

Background
Studies have shown that long-term increase in the excitability of single wide dynamic range neurones in the spinal dorsal horn of rats may be induced after tetanic stimulation to the sciatic nerve. This sensory event is possibly an in vivo counterpart of long-term potentiation, described in the brain. This study investigated whether this phenomenon occurs in the halothane-anesthetized rat and whether the antinociceptive effects of spinally administered morphine are altered when tested on the enhanced activity.

Methods
Single unit extracellular recordings were made in three different groups of halothane-anesthetized rats (n = 6 in each group). In group 1, the evoked neuronal responses of wide dynamic range neurones by a single electrical stimulus to the peripheral nerve were recorded every 4 min, for 1 h before (baseline) and for 3 h after brief high-frequency conditioning stimulation of the sciatic nerve. In group 2, morphine was applied onto the spinal cord after long-term potentiation had been established. Increasing concentrations of morphine were added until the C fiber-evoked responses were abolished; this was followed by naloxone reversal. In group 3, the same protocol as in group 2 was used except a waiting period substituted for the electrical conditioning.

Results
The C fiber-evoked responses were significantly increased (P < 0.001) after conditioning compared with baseline and those in control animals. Further, significantly higher concentrations of morphine (P = 0.008) were needed to abolish the C fiber-evoked responses in tetanized animals than in control animals. Naloxone reversed the effects of morphine to the predrug potentiated baseline in group 2, showing that opioids do not block the maintenance of spinal long-term potentiation.

Conclusions
Long-term potentiation of C fiber-evoked responses also can be induced in halothane-anesthetized rats, and morphine seems to have less potency during such conditions. These data suggest that long-term potentiation-like mechanisms may underlie some forms of hyperalgesia associated with a reduced effect of morphine.
Sevoflurane Does Not Inhibit Human Platelet Aggregation Induced by Thrombin
Authors: Nozuchi Shinji , Mizobe Toshiki , Aoki Hiroshi , Hiramatsu Noriko , Kageyama Kyoko , Amaya Fumimasa , Uemura Koichi , Fujimiya Tatsuya 
Published: November 2003

Background
Sevoflurane reportedly inhibits adenosine diphosphate-induced platelet aggregation by suppressing thromboxane A2 formation. The increase in intracellular calcium concentration that fosters platelet aggregation, however, is also induced by other cell signaling pathways, such as activation of the production of inositol 1,4,5-triphosphate by thrombin. The current study aimed to clarify the net influence of sevoflurane on thrombin-induced platelet aggregation.

Methods
Washed platelets were stimulated by thrombin after incubation with 0.5, 1.0, or 1.5 mM sevoflurane, halothane, or isoflurane. Aggregation curves were measured by an aggregometer. Intracellular calcium concentration was measured fluorometrically using fura-2. Calcium mobilization via plasma membrane calcium channels and the dense tubular system was assessed differentially. Intracellular inositol 1,4,5-triphosphate was measured by radioimmunoassay.

Results
Halothane significantly suppressed aggregation ratios at 5 min compared with those in controls (89 +/- 7%) to 71 +/- 10% (1.0 mM) and 60 +/- 11% (1.5 mM) and the increase in intracellular calcium concentration (controls, 821 +/- 95 nM vs. 440 +/- 124 nM [1.0 mM] or 410 +/- 74 nM [1.5 mM]). Halothane also significantly inhibited release of calcium from the dense tubular system (controls, 220 +/- 48 nM vs. 142 +/- 31 nM [1.0 mM]). Neither sevoflurane nor isoflurane produced a net change in aggregation ratios, intracellular calcium concentration, or calcium mobilization. Halothane (1 mM) significantly suppressed inositol 1,4,5-triphosphate concentrations, whereas neither 1 mM isoflurane nor 1 mM sevoflurane had any effect.

Conclusions
Although sevoflurane has been reported to inhibit human platelet aggregation induced by weak agonists such as adenosine diphosphate, it does not inhibit human platelet aggregation induced by strong agonists such as thrombin.
Hypoxic Brain Tissue following Subarachnoid Hemorrhage
Authors: Hoffman William E. , Wheeler Peggy , Edelman Guy , Charbel Fady T. , Torres Norman J. , Ausman James I. 
Published: November 2003

Background
Subarachnoid hemorrhage can lead to cerebral ischemia and irreversible brain injury. The purpose of this study was to determine whether subarachnoid hemorrhage produces changes in brain tissue oxygen pressure, carbon dioxide pressure, or pH during surgery for cerebral aneurysm clipping.

Methods
After institutional review board approval and patient consent, 30 patients undergoing craniotomy for cerebral aneurysm clipping were studied, 15 without and 15 with subarachnoid hemorrhage. Patients with subarachnoid hemorrhage were prospectively separated into groups with modest (Fisher grade 1 or 2; n = 8) and severe bleeds (Fisher grade 3; n = 7). After a craniotomy, a probe was inserted into cortex tissue supplied by the artery associated with the aneurysm. Baseline measures were made in the presence of a 4% end-tidal desflurane level. The end-tidal desflurane level was increased to 9% before clipping of the aneurysm, and a second tissue measurement was made.

Results
The median time of surgery after subarachnoid hemorrhage was 2 days, ranging from 1 to 13 days. During baseline anesthesia, brain tissue oxygen pressure was 17+/-9 mm Hg (mean +/- SD) in control patients, 13+/-9 mm Hg in those with Fisher grade 1 or 2 hemorrhage, and 7+/-6 mm Hg in those with Fisher grade 3 hemorrhage (P<0.05 compared with control). Brain tissue pH was 7.10+/-0.10 in control patients, 7.14+/-0.13 in those with Fisher grade 1 or 2 hemorrhage, and 6.95+/-0.18 in those with with Fisher grade 3 hemorrhage (P<0.05). At a 9% end-tidal desflurane level, brain tissue oxygen pressure increased to 19+/-9 mm Hg and brain tissue pH increased to 7.11+/-0.11 in patients with Fisher grade 3 hemorrhage (P<0.05 for both increases).

Conclusion
These results show that subarachnoid hemorrhage can significantly decrease brain tissue oxygen pressure and pH related to the severity of the bleed. Increasing the desflurane concentration to 9% increased brain tissue oxygen pressure in all patients and brain tissue pH in patients with subarachnoid hemorrhage with baseline acidosis.
Long-lasting Hyperalgesia Induced by Fentanyl in Rats
Authors: Célèrier Evelyne , Rivat Cyril , Jun Yan , Laulin Jean-Paul , Larcher Agnès , Reynier Patrick , Simonnet Guy 
Published: November 2003

Background
It has been reported that mu-opioid receptor activation leads to a sustained increase in glutamate synaptic effectiveness at the N-methyl-D-aspartate (NMDA) receptor level, a system associated with central hypersensitivity to pain. One hypothesis is that postoperative pain may result partly from the activation of NMDA pain facilitatory processes induced by opiate treatment per se. The authors tested here the effectiveness of the opiate analgesic fentanyl for eliciting a delayed enhancement in pain sensitivity.

Methods
The consequences of four bolus injections (every 15 min) of fentanyl (20-100 microg/kg per injection, subcutaneously) on immediate (for several hours) and long-term (for several days) sensitivity to nociceptive stimuli in the rat (paw-pressure vocalization test) were evaluated. The effects of the combination of the NMDA-receptor antagonist ketamine (10 mg/kg, subcutaneously) with fentanyl also were assessed.

Results
Fentanyl administration exhibited a biphasic time-dependent effect: first, an early response (for 2-5 h) associated with a marked increase in nociceptive threshold (analgesia), and second, a later response associated with sustained lowering of the nociceptive threshold (5 days for the longest effect) below the basal value (30% of decrease for the maximal effect) indicative of hyperalgesia. The higher the fentanyl dose used, the more pronounced was the fentanyl-induced hyperalgesia. Ketamine pretreatment, which had no analgesic effect on its own, enhanced the earlier response (analgesia) and prevented the development of long-lasting hyperalgesia.

Conclusions
Fentanyl activates NMDA pain facilitatory processes, which oppose analgesia and lead to long-lasting enhancement in pain sensitivity.
Intrathecally Administered cGMP-dependent Protein Kinase Iα Inhibitor Significantly Reduced the Threshold for Isoflurane Anesthesia
Authors: Tao Yuan-Xiang , Hassan Aalya , Johns Roger A. 
Published: November 2003

Background
Inhalational anesthetics have been shown to inhibit the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Previous studies indicated that inhibition of the NO-cGMP pathway decreased the level of consciousness and augmented anesthesia, analgesia, or sedation. The current study investigated the possible involvement of cGMP-dependent protein kinases (PKGs) as major effectors for the NO-cGMP pathway in the anesthetic state.

Methods
After initial baseline determination of the minimum alveolar concentration (MAC), a selective cGMP-dependent protein kinase Ialpha inhibitor, Rp-8-p-CPT-cGMPS, or an NO donor, (NOC-12), were injected intrathecally. Ten minutes later, MAC measurement was repeated. The rats also were evaluated for the presence of locomotor dysfunction by intrathecal administration of Rp-8-p-CPT-cGMPS and NOC-12 in conscious rats.

Results
Rp-8-p-CPT-cGMPS at 25, 50, 100, and 200 microg/10 microl produced a significant decrease from isoflurane control MAC of -4+/-3.1%, 16+/-4.5%, 30+/-5.0%, and 21+/-2.2%, respectively, which was not accompanied by significant changes in either blood pressure or heart rate. In contrast, NOC-12 at 100 microg/10 microl caused an increase from isoflurane control MAC of 23+/-5.8%, which was accompanied by significant decrease in blood pressure but not in heart rate. Rp-8-p-CPT-cGMPS (100 microg/10 microl) produced a significant reversal of isoflurane MAC increase induced by NOC-12 (100 microg/10 microl), which was accompanied by significant reversal of the reduction of blood pressure induced by NOC-12. Locomotor activity was not changed.

Conclusions
The results indicate that cGMP-dependent protein kinase Ialpha inhibitor not only markedly reduces MAC for isoflurane, but also completely blocks the NO-induced increase in isoflurane MAC, which suggests that cGMP-dependent protein kinase Ialpha may mediate the action for the NO-cGMP pathway in anesthetic mechanisms at the spinal cord level.
Propofol-induced Modifications of Cardiomyocyte Calcium Transient and Sarcoplasmic Reticulum Function in Rats
Authors: Guenoun Thierry , Montagne Olivier , Laplace Monique , Crozatier Bertrand 
Published: November 2003

Background
Propofol is considered to be an anesthetic agent with few or no negative inotropic effects. This study evaluated a possible direct depressant effect of propofol on sarcoplasmic reticulum Ca2+ accumulation and cardiomyocytes.

Methods
The effects of propofol on intracellular Ca2+ transients were evaluated in isolated rat cardiomyocytes using a microfluorometric technique with Indo-1. Sarcoplasmic reticulum function was also assessed by measuring the oxalate-stimulated Ca2+ uptake from homogenates of rat ventricles.

Results
The Ca2+ uptake capacity of the sarcoplasmic reticulum was decreased by propofol (10(-4) M). Large concentrations of propofol decreased the rate of decrease of the intracellular Ca2+ transient, which resulted in an increase of diastolic Ca2+ when the diastolic interval was decreased. The increased diastolic Ca2+ also resulted in a decrease in Ca2+ transient. This effect appeared for lower doses (10(-5) M) after a short diastolic pause rather than after a long (2- to 3-min) rest (appearing at 10(-4) M).

Conclusions
For doses more than 10(-5) M, propofol induces a Ca2+ uptake capacity impairment of the sarcoplasmic reticulum. This is probably responsible for a slowing of the decrease of the Ca2+ transient, which in turn increases the diastolic Ca2+ for high heart rate. These diastolic modifications may participate in the slight negative inotropic effect of the drug.
Primate Pleuroesophageal Tissue Barrier Frequency Response and Esophageal Pressure Waveform Bandwidth in Health and Acute Lung Injury
Authors: Hartford Craig G. , van Schalkwyk Johan M. , Rogers Geoffrey G. , Turner Martin J. 
Published: November 2003

Background
Dynamic intraesophageal pressure (Pes) is used to estimate intrapleural pressure (Ppl) to calculate lung compliance and resistance. This study investigated the nonhuman primate Ppl-Pes tissue barrier frequency response and the dynamic response requirements of Pes manometers.

Methods
In healthy monkeys and monkeys with acute lung injury undergoing ventilation, simultaneous Ppl and Pes were measured directly to determine the Ppl-Pes tissue barrier amplitude frequency response, using the swept-sine wave technique. The bandwidths of physiologic Pes waveforms acquired during conventional mechanical ventilation were calculated using digital low-pass signal filtering.

Results
The Ppl-Pes tissue barrier is amplitude-uniform within the bandwidth of conventional Pes waveforms in healthy and acute lung injury lungs, and does not significantly attenuate Ppl-Pes signal transmission between 1 and 40 Hz. At Pes frequencies higher than conventional clinical regions of interest the Ppl-Pes barrier resonates significantly, is pressure amplitude dependent at low-pressure offsets, and is significantly altered by acute lung injury. Allowing for 5% or less Pes waveform error, the maximum Pes bandwidths during conventional ventilation were 1.9 Hz and 3.4 Hz for physiologic and extreme-case waveforms in healthy lungs and 4.6 Hz and 8.5 Hz during acute lung injury.

Conclusions
In monkeys, the Ppl-Pes tissue barrier has a frequency response suitable for Ppl estimation during low-frequency mechanical ventilation, and Pes manometers should have a minimum uniform frequency response up to 8.5 Hz. However, the Ppl-Pes tissue barrier adversely affects the accurate estimation of dynamic Ppl at high frequencies, with varied airway pressure amplitudes and offsets, such as the Ppl encountered during high-frequency oscillatory ventilation.
Comparison of Blood-conservation Strategies in Cardiac Surgery Patients at High Risk for Bleeding
Authors: Nuttall Gregory A. , Oliver William C. , Ereth Mark H. , Santrach Paula J. , Bryant Sandra C. , Orszulak Thomas A. , Schaff Hartzell V. 
Published: November 2003

Background
Aprotinin and tranexamic acid are routinely used to reduce bleeding in cardiac surgery. There is a large difference in agent price and perhaps in efficacy.

Methods
In a prospective, randomized, partially blinded study, 168 cardiac surgery patients at high risk for bleeding received either a full-dose aprotinin infusion, tranexamic acid (10-mg/kg load, 1-mg x kg(-1) x h(-1) infusion), tranexamic acid with pre-cardiopulmonary bypass autologous whole-blood collection (12.5% blood volume) and reinfusion after cardiopulmonary bypass (combined therapy), or saline infusion (placebo group).

Results
There were complete data in 160 patients. The aprotinin (n = 40) and combined therapy (n = 32) groups (data are median [range]) had similar reductions in blood loss in the first 4 h in the intensive care unit (225 [40-761] and 163 [25-760] ml, respectively; P = 0.014), erythrocyte transfusion requirements in the first 24 h in the intensive care unit (0 [0-3] and 0 [0-3] U, respectively; P = 0.004), and durations of time from end of cardiopulmonary bypass to discharge from the operating room (92 [57-215] and 94 [37, 186] min, respectively; P = 0.01) compared with the placebo group (n = 43). Ten patients in the combined therapy group (30.3%) required transfusion of the autologous blood during cardiopulmonary bypass for anemia.

Conclusions
The combination therapy of tranexamic acid and intraoperative autologous blood collection provided similar reduction in blood loss and transfusion requirements as aprotinin. Cost analyses revealed that combined therapy and tranexamic acid therapy were the least costly therapies.
Approximate Entropy as an Electroencephalographic Measure of Anesthetic Drug Effect during Desflurane Anesthesia
Authors: Bruhn Jörgen , Röpcke Heiko , Hoeft Andreas 
Published: November 2003

Background
The authors hypothesized that the electroencephalogram (EEG) during higher anesthetic concentrations would show more "order" and less "randomness" than at lower anesthetic concentrations. "Approximate entropy" is a new statistical parameter derived from the Kolmogorov-Sinai entropy formula which quantifies the amount of regularity in data. The approximate entropy quantifies the predictability of subsequent amplitude values of the EEG based on the knowledge of the previous amplitude values. The authors investigated the dose-response relation of the EEG approximate entropy during desflurane anesthesia in comparison with spectral edge frequency 95, median frequency, and bispectral index.

Methods
Twelve female patients were studied during gynecologic laparotomies. Between opening and closure of the peritoneum, end-tidal desflurane concentrations were varied between 0.5 and 1.6 minimum alveolar concentration (MAC). The EEG approximate entropy, median EEG frequency, spectral edge frequency 95, and bispectral index were determined and the performance of each to predict the desflurane effect compartment concentration, obtained by simultaneous pharmacokinetic-pharmacodynamic modeling, was compared.

Results
Electroencephalogram approximate entropy decreased continuously over the observed concentration range of desflurane. The performance of the approximate entropy (prediction probability PK = 0.86 +/- 0.06) as an indicator for desflurane concentrations is similar to spectral edge frequency 95 (PK = 0.86 +/- 0.06) and bispectral index (PK = 0.82 +/- 0.06) and is statistically significantly better than median frequency (PK = 0.78 +/- 0.06).

Conclusions
The amount of regularity in the EEG increases with increasing desflurane concentrations. The approximate entropy could be a useful EEG measure of anesthetic drug effect.
Population Pharmacokinetics of Propofol
Authors: Schüttler Jürgen , Ihmsen Harald 
Published: November 2003

Background
Target-controlled infusion is an increasingly common type of administration for propofol. This method requires accurate knowledge of pharmacokinetics, including the effects of age and weight. The authors performed a multicenter population analysis to quantitate the effects of covariates.

Methods
The authors analyzed 4,112 samples of 270 individuals (150 men, 120 women, aged 2-88 yr, weighing 12-100 kg). Population pharmacokinetic modeling was performed using NONMEM (NONMEM Project Group, University of California, San Francisco, CA). Inter- and intraindividual variability was estimated for clearances and volumes. The effects of age, weight, type of administration and sampling site were investigated.

Results
The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3).

Conclusions
Pharmacokinetics of propofol can be well described by a three-compartment model. Inclusion of age and weight as covariates significantly improved the model. Adjusting pharmacokinetics to the individual patient should improve the precision of target-controlled infusion and may help to broaden the field of application for target-controlled infusion systems.