bluuebunny/crossref_metadata_2025 huggingface dataset:
Capsaicin-evoked Mechanical Allodynia and Hyperalgesia Cross Nerve Territories
Authors: Sang Christine N. , Gracely Richard H. , Max Mitchell B. , Bennett Gary J.
Published: November 2003

Background

The finding in some patients with neuropathic pain that mechanical allodynia (pain evoked by light touch) and hyperalgesia (supranormal pain evoked by painful stimuli) extend beyond the territory of a single nerve or spinal sensory root (extraterritorial pain) often prompts a diagnosis of psychiatric illness. The hypothesis that focal nociceptive input in a single nerve territory can result in allodynia and hyperalgesia in a nerve territory adjacent to the input was investigated in normal human subjects.

Methods

On separate days, 13 healthy volunteers each received left radial and ulnar nerve blocks. After block of either nerve, sensation remaining for three classes of afferents (A beta low-threshold mechanoreceptors, A delta nociceptors, and C polymodal nociceptors) allowed inference of the nerve territory of the adjacent nerve, and the area of overlapping innervation. On a third day, 1,000 micrograms intradermal capsaicin was administered into a site such that C-nociceptor input was confined to the ulnar nerve territory. Areas of brush allodynia and pinprick hyperalgesia were determined.

Results

Spread of brush allodynia beyond all three borders of the ulnar nerve territory occurred in 9 of 13 patients (for these subjects, range 5-28 mm), whereas spread of pinprick hyperalgesia beyond all borders of the ulnar nerve territory occurred in 12 of 13 subjects (range 1-31 mm). Spread of brush allodynia beyond the A beta border of the ulnar nerve territory occurred in 10 of 13 subjects (range 4-35 mm); and spread of pinprick hyperalgesia beyond the A delta border of the ulnar nerve territory occurred in 12 of 13 subjects (range 1-31 mm).

Conclusions

It is concluded that activation of C-nociceptors evokes a state of central sensitization that may manifest itself by the appearance of extraterritorial pain abnormalities.
Induction of Anesthesia and Tracheal Intubation with Sevoflurane in Adults
Authors: Muzi M. , Robinson B.J. , Ebert T.J. , O'Brien T.J.
Published: November 2003

Background

The speed, quality, and cost of mask induction of anesthesia and laryngeal mask airway insertion or tracheal intubation were studied in young non-premedicated volunteers given high inspired concentrations of sevoflurane (6 to 7%).

Methods

Twenty healthy persons who were 19 to 32 years old participated three times, received 6 l/min fresh gas flow, and were randomized to receive 6 to 7% sevoflurane in 66% nitrous oxide/28% oxygen by face mask until tracheal intubation (treatment 1) or until laryngeal mask airway insertion (treatment 3), or 6 to 7% sevoflurane without nitrous oxide to tracheal intubation (treatment 2). Participants exhaled to residual volume and took three vital capacity breaths of the gas mixture; thereafter ventilation was manually assisted. The time of exposure to the inhaled gas was varied for consecutive participants. It was either increased or decreased by 30-sec increments based on the failure or success of the preceding volunteer's response to laryngoscopy and intubation after a preselected exposure time. Failure was defined as poor jaw relaxation, coughing or bucking, or inadequate vocal cord relaxation.

Results

Loss of the lid-lash reflex in unpremedicated young volunteers was achieved in 1 min and did not differ among groups. Average time (and 95% confidence interval) for acceptable conditions for LMA insertion was achieved in 1.7 (0.7 to 2.7) min, and all participants had an immediate return of spontaneous ventilation. The time for acceptable tracheal intubating conditions after manual hyperventilation by mask was 4.7 (3.7 to 5.7) min and 6.4 (5.1 to 7.7) min in treatments 1 and 2, respectively. There were no cases of increased secretions or laryngospasm. The incidence of breath holding and expiratory stridor ("crowing") was 7.5% and 25%, respectively, during treatment 1 and 15% and 40%, respectively, during treatment 2.

Conclusions

The induction of anesthesia to loss of lid reflex in young non-premedicated adults approaches the speed of intravenous induction techniques. No untoward airway responses were noted during mask induction of anesthesia with a three-breath technique. In response to intubation, no adverse airway responses, including jaw tightness, laryngospasm, and excessive coughing or bucking, occurred in participants whose duration of mask administration of sevoflurane met the appropriate times (as determined in this study).
Hypothermia and Isoflurane Similarly Inhibit Glutamate Release Evoked by Chemical Anoxia in Rat Cortical Brain Slices
Authors: Eilers Helge , Bickler Philip E.
Published: November 2003

Background

Accumulation of the excitatory neurotransmitter glutamate in ischemic brain tissue contributes to neuronal cell death. Volatile anesthetics at clinically relevant concentrations are neuroprotective in in vivo models of brain ischemia and reduce glutamate release in vivo and in vitro, but they appear to have weaker neuroprotective effects than hypothermia. The purpose of this study was to determine whether isoflurane reduces glutamate release in hypoxic brain slices, how large this effect is compared to that of hypothermia, and if it is diminished by hyperthermia.

Methods

Glutamate released from rat cortical brain slices during chemical anoxia (100 microM NaCN) was measured continuously with a fluorescence assay. The release rate was compared at three temperatures (28 degrees C, 37 degrees C, and 39 degrees C) with and without isoflurane at concentrations equipotent to 1 minimum alveolar concentration. At the same three temperatures, glutamate release rates before and after exposure to isoflurane were compared.

Results

Isoflurane reduced glutamate release from brain slices during chemical anoxia at 37 degrees C (19.6%, P < 0.01) and at 39 degrees C (25.4%, P < 0.01), but not at 28 degrees C. The reduction in glutamate release with hypothermia was similar to that with isoflurane. Hyperthermia (39 degrees C) caused greater glutamate release under basal and anoxic conditions than normo- and hypothermia. Isoflurane caused a slight increase in basal glutamate release rates, although this effect was smaller than the increase caused by hyperthermia.

Conclusions

In a brain slice model of cerebral anoxia, 1 minimum alveolar concentration isoflurane decreases glutamate release to a similar extent that hypothermia (28 degrees C) does. The increased glutamate release with hyperthermia (39 degrees C) is not prevented by isoflurane.
Riluzole Anesthesia
Authors: MacIver M. Bruce , Amagasu Shanti M. , Mikulec Anthony A. , Monroe Frances A.
Published: November 2003

Background

Riluzole (RP 54274) is an experimental benzothiazole with anesthetic properties, but little is known about its synaptic or cellular actions.

Methods

The authors investigated riluzole effects on synaptic response of CA 1 pyramidal neurons in rat hippocampal brain slices. Electrophysiologic recordings of population spikes (PS), excitatory postsynaptic potentials (EPSP), and fiber volleys were studied. Paired pulse stimulation (120 ms interpulse interval) was used to measure effects on gamma-amino butyric acid (GABA)-mediated synaptic inhibition, and stimulus trains (33 Hz) were used to test for use-dependent effects.

Results

Synaptically evoked PS discharge was blocked in a concentration-dependent manner by riluzole (2.0-20 microM), similar to effects produced by other anesthetics. Paired pulse inhibition was not altered by riluzole. In contrast, 20 microM thiopental produced a marked increase in paired pulse inhibition. Riluzole (5.0 microM) produced a 46.6 +/- 19.8% depression of glutamate-mediated EPSPs, which could account for most of the mate-mediated EPSPs, which could account for most of the depression of PS discharge (54.2 +/- 12.6%) produced by this concentration. Riluzole produced a 36 +/- 17% depression of fiver volley amplitudes, which, based on input/output analysis, could completely account for the depression of EPSPs. The depression of fiber volley amplitudes showed a marked use-dependence; the second and subsequent action potentials in a train were progressively depressed by riluzole to a greater extent than the first action potential.

Conclusions

Riluzole produced a potent block of excitatory synaptic transmission via depression of presynaptic conduction in glutamatergic nerve fibers. The use-dependent depression observed resembled that produced by some local anesthetics on nerve conduction and sodium channels. The presynaptic action, together with a lack of effect on gamma-amino butyric acid-mediated inhibition, provides a unique mechanism of action for a general anesthetic.
Sympathetic Nervous System Does Not Mediate Reflex Pupillary Dilation during Desflurane Anesthesia
Authors: Larson Merlin D. , Tayefeh Farzin , Sessler Daniel I. , Daniel Malcolm , Noorani Mimi
Published: November 2003

Background

Pupil size is determined by an interaction between the sympathetic and parasympathetic divisions of the autonomic nervous system. Noxious stimulation dilates the pupil in both unanesthetized and anesthetized humans. In the absence of anesthesia, dilation is primarily mediated by the sympathetic nervous system. In contrast, pupillary dilation in cats given barbiturate or cloralose anesthesia is mediated solely by inhibition of the midbrain parasympathetic nucleus. The mechanism by which noxious stimuli dilate pupils during anesthesia in humans remains unknown. Accordingly, the authors tested the hypothesis that the pupillary dilation in response to noxious stimulation during desflurane anesthesia is primarily a parasympathetic reflex.

Methods

In six volunteers, the alpha-I adrenergic receptors of the iris musculature were blocked by unilateral administration of topical dapiprazole; six other volunteers were given unilateral topical tropicamide to block the muscarinic receptors in the iris. Desflurane anesthesia was subsequently induced in all volunteers. Sympathetic nervous system activation, with reflex dilation of the pupil, was produced by noxious electrical stimulation during 4% and 8% end-tidal desflurane, and by a rapid 4%-to-8% step-up in the desflurane concentration. Pupil diameter and the change in pupil size induced by a light stimulus (light reflex amplitude) were measured with infrared pupillometry.

Results

Dapiprazole drops produced a Horner's miosis, but pupils were equally small after induction of anesthesia. Pupillary dilation after noxious stimulation and desflurane step-up was identical in the unblocked and dapiprazole-blocked pupils. After tropicamide administration, the pupil was dilated and the light reflex was completely inhibited. Noxious stimulation nonetheless produced a slight additional dilation.

Conclusions

During desflurane anesthesia, pupillary dilation in response to noxious stimulation or desflurane step-up is not mediated by the sympathetic nervous system (as it is in unanesthetized persons). Although inhibition of the pupillo-constrictor nucleus may be the cause of this dilation, the mechanism remains unknown.
Effects of Sevoflurane with and without Nitrous Oxide on Human Cerebral Circulation
Authors: Cho Sungsam , Fujigaki Toru , Uchiyama Yasue , Fukusaki Makoto , Shibata Osamu , Sumikawa Koji
Published: November 2003

Background

This study was designed to evaluate the effects of sevoflurane with and without nitrous oxide on human middle cerebral artery (MCA) flow velocity, cerebrovascular carbon dioxide reactivity, and autoregulation compared with the awake state using transcranial Doppler ultrasonography.

Methods

In 14 patients, the time-mean middle cerebral artery flow velocity (Vmca) was measured when the end-tidal carbon dioxide level was approximately 30, 40, and 50 mmHg under the following conditions: (1) awake; (2) with 2% (1.2 MAC) sevoflurane; and (3) with 1.2 MAC sevoflurane-60% nitrous oxide. In six other patients, the cerebrovascular autoregulation during anesthesia was determined using intravenous phenylephrine to increase blood pressure.

Results

Sevoflurane (1.2 MAC) significantly decreased Vmca compared with the awake value at each level of end-tidal carbon dioxide, whereas 1.2 MAC sevoflurane-60% nitrous oxide did not exert significant influence. The Vmca in normocapnic patients decreased from 69 cm/s to 55 cm/s with 1.2 MAC sevoflurane and then increased to 70 cm/s when nitrous oxide was added. Sevoflurane (1.2 MAC) with and without 60% nitrous oxide had a negligible effect on cerebrovascular carbon dioxide reactivity. A phenylephrine-induced increase of mean arterial pressure did not influence Vmca during anesthesia.

Conclusions

Sevoflurane (1.2 MAC) reduced Vmca compared with the awake condition, whereas the addition of nitrous oxide caused Vmca to increase toward the values obtained in the awake condition. The cerebrovascular carbon dioxide reactivity and autoregulation were well maintained during 1.2 MAC sevoflurane with and without 60% nitrous oxide.
Effects of Motion on the Performance of Pulse Oximeters in Volunteers
Authors: Barker Steven J. , Shah Nitin K.
Published: November 2003

Background

Pulse oximetry is considered a standard of care in both the operating room and the postanesthetic care unit, and it is widely used in all critical care settings. Pulse oximeters may fail to provide valid pulse oximetry data in various situations that produce low signal-to-noise ratio. Motion artifact is a common cause of oximeter failure and loss of accuracy. This study compares the accuracy and data dropout rates of three current pulse oximeters during standardized motion in healthy volunteers.

Methods

Ten healthy volunteers were monitored by three different pulse oximeters: Nellcor N-200, Nellcor N-3000, and Masimo SET (prototype). Sensors were placed on digits 2, 3, and 4 of the test hand, which was strapped to a mechanical motion table. The opposite hand was used as a stationary control and was monitored with the same pulse oximeters and an arterial cannula. Arterial oxygen saturation rate varied from 100% to 75% by changing the inspired oxygen concentration. While pulse oximetry was both constant and changing, the oximeter sensors were connected before and during motion. Oximeter errors and dropout rates were digitally recorded continuously during each experiment.

Results

If the oximeter was functioning before motion began, the following are the percentages of time when the instrument displayed a pulse oximetry value within 7% of control: N-200 = 76%, N-3000 = 87%, and Masimo = 99%. When the oximeter sensor was connected after the beginning of motion, the values were N-200 = 68%, N-3000 = 47%, and Masimo = 97%. If the alarm threshold was chosen as pulse oximetry less than 90%, then the positive predictive values (true alarms/ total alarms) are N-200 = 73%, N-3000 = 81%, and Masimo = 100%. In general, N-200 had the greatest pulse oximetry errors and N-3000 had the highest dropout rates.

Conclusions

The mechanical motions used in this study significantly affected oximeter function, particularly when the sensors were connected during motion, which requires signal acquisition during motion. The error and dropout rate performance of the Masimo was superior to that of the other two instruments during all test conditions. Masimo uses a new paradigm for oximeter signal processing, which appears to represent a significant advance in low signal-to-noise performance.
Mechanism of Myocardial Protection by Isoflurane
Authors: Kersten Judy R. , Schmeling Todd J. , Hettrick Douglas A. , Pagel Paul S. , Gross Garrett J. , Warltier David C.
Published: November 2003

Background

The mechanism of the protective actions of volatile anesthetics in ischemic myocardium has not been clearly elucidated. The role of myocardial adenosine triphosphate-regulated potassium (KATP) channels in isoflurane-induced enhancement of recovery of regional contractile function after multiple brief occlusions and reperfusion of the left anterior descending coronary artery (LAD) was studied in dogs anesthetized with barbiturates.

Methods

Dogs (n = 32) were instrumented to measure left ventricular and aortic blood pressure, cardiac output, LAD coronary blood flow velocity, and subendocardial segment length. Regional myocardial perfusion was measured using radioactive microspheres. Hemodynamics and percentage segment shortening (%SS) in the LAD perfusion territory were evaluated after instrumentation was complete; after pretreatment with the KATP channel antagonist, glyburide (0.05 mg/kg-1) or drug vehicle (polyethylene glycol in ethyl alcohol; control experiments); and in the presence or absence of 1 MAC isoflurane administered for 30 min before and during five 5-min occlusions and reperfusion of the LAD in four experimental groups. Isoflurane was discontinued at the onset of the final reperfusion period. Measurements of hemodynamics, %SS, and myocardial perfusion were repeated at several intervals during 180 min after reperfusion of the LAD.

Results

Left anterior descending coronary artery occlusion caused regional dyskinesia during each 5-min occlusion in each dog. Control and glyburide-pretreated dogs demonstrated poor recovery of %SS by 180 min after reperfusion (2 +/- 10 and 7 +/- 6% of baseline, respectively). In contrast, dogs anesthetized with isoflurane exhibited complete recovery of function (%SS) by 180 min after reperfusion (82 +/- 8% of baseline). Enhanced recovery of regional contractile function by isoflurane was abolished by pretreatment with glyburide 180 min after reperfusion (16 +/- 10% of baseline). Improvement of functional recovery of stunned myocardium by isoflurane, and the blockade of this action by glyburide, was not associated with changes in hemodynamics or regional myocardial perfusion.

Conclusions

The results indicate that isoflurane prevents decreased systolic shortening caused by multiple episodes of ischemia and reperfusion. These actions result in improved recovery of contractile function of postischemic, reperfused myocardium and are mediated by isoflurane-induced activation of KATP channels.
Clonidine, but Not Morphine, Delays the Development of Thermal Hyperesthesia Induced by Sciatic Nerve Constriction Injury in the Rat
Authors: Yamamoto Tatsuo , Nozaki-Taguchi Natsuko
Published: November 2003

Background

It has been shown that the spinal facilitation induced by the injury discharge evoked by a nerve constriction injury is crucial in the development of thermal hyperesthesia. Both opioids and alpha 2 agonists have been reported to prevent the development of spinal facilitation evoked by the small afferent input to the spinal cord. Moreover, it has been reported that the thermal hyperesthesia induced by a nerve constriction injury is sympathetically maintained and that spinally administered alpha 2 agonists can modulate the sympathetic outflow from the spinal cord. The current study investigated the effect of spinally administered morphine and clonidine, an alpha 2 agonist, on the development of thermal hyperesthesia induced by nerve constriction injury in the rat.

Methods

A model of thermal hyperesthesia induced by a constriction injury created by making four loose ligatures around the rat sciatic nerve was used to examine the development of thermal hyperesthesia. Morphine, clonidine, and idazoxan were administered intrathecally or intraperitoneally 20 min before (pretreatment study) or 20 min after (posttreatment study) the nerve injury.

Results

Pretreatment, but not posttreatment, with intrathecal clonidine significantly delayed the development of thermal hyperesthesia in a dose-dependent manner, and this delay in onset produced by clonidine was 3 days after the nerve injury. This effect of clonidine's was completely antagonized by the coadministration of idazoxan with clonidine. Intrathecal morphine had no effect on the development of thermal hyperesthesia in this study.

Conclusions

Spinal alpha 2 receptors, but not opioid receptors, may play an important role in the development of thermal hyperesthesia induced by a nerve constriction injury. This suggested that the activation of spinal alpha 2 receptor may reduce the sympathetic outflow and this reduction of sympathetic outflow may be the key mechanism that delays the development of thermal hyperesthesia.
Inhibition of Endogenous Nitric Oxide Synthase Potentiates Nitrovasodilators in Experimental Pulmonary Hypertension
Authors: Kavanagh Brian P. , Thompson John S. , Pearl Ronald G.
Published: November 2003

Background

The role of endogenous nitric oxide (NO) in the regulation of pulmonary vascular tone is complex. Inhibition of endogenous NO synthase, potentially through upregulation of guanylyl cyclase, results in an increase in potency of nitrovasodilators in the systemic circulation. This study considered whether inhibition of endogenous NO synthase would increase the potency of nitrovasodilators, but not of cyclic adenosine monophosphate-dependent vasodilators, in the pulmonary vasculature.

Methods

We used the isolated buffer-perfused rabbit lung. Preparations were randomized to receive either pretreatment with NG-nitro-L-arginine methyl ester (or L-NAME, an inhibitor of endogenous NO synthase) or no pretreatment. Stable pulmonary hypertension was then produced by infusing the thromboxane A2 analog U46619. The dose-response characteristics of two nitrovasodilators, sodium nitroprusside and nitroglycerin, and two nonnitrovasodilators, prostaglandin E2 and 5'-N-ethylcarboxamidoadenosine, were studied.

Results

Inhibition of endogenous NO synthase caused no significant changes in baseline pulmonary artery pressure but did significantly reduce the U46619 infusion rate required to produce pulmonary hypertension. Pretreatment with L-NAME (vs. no L-NAME) resulted in significantly lower values of the log median effective dose with sodium nitroprusside and nitroglycerin. In contrast, pretreatment with L-NAME resulted in no changes in the dose-response characteristics of the cyclic adenosine monophosphate-mediated, NO-independent vasodilators prostaglandin E1 and 5'-N-ethylcarboxamidoadenosine.

Conclusions

These data suggest that endogenous NO synthase is not an important regulator of basal pulmonary tone in this model but is an important modulator of pulmonary vascular responses to vasoconstriction and to nitrovasodilators. The pulmonary vasodilator effects of nitrovasodilators, but not of nonnitrovasodilators, may depend on the level of activity of NO synthase.
Halothane and Diazepam Inhibit Ketamine-induced c-fos Expression in the Rat Cingulate Cortex
Authors: Nakao Shin-ichi , Adachi Takehiko , Murakawa Masahiro , Shinomura Tetsutaro , Kurata Jiro , Shichino Tsutomu , Shibata Masatoshi , Tooyama Ikuo , Kimura Hiroshi , Mori Kenjiro
Published: November 2003

Background

Ketamine, a noncompetitive N-methyl-D-aspartate antagonist, has psychotomimetic side effects. Recent studies have shown that noncompetitive N-methyl-D-aspartate antagonists cause morphologic damage to the cingulate and retrosplenial cortices and induce c-fos protein (c-Fos) in the same regions. Although benzodiazepines are effective in preventing these side effects, the neural basis of the drug interactions has not been established.

Methods

The effects of diazepam and halothane on c-Fos expression induced by ketamine were studied. Diazepam (1 and 5 mg/kg) or vehicle were administered subcutaneously, followed 7 min later by 100 mg/kg ketamine given intraperitoneally. Halothane (1.0 and 1.8%), was administered continuously from 10 min before ketamine administration until brain fixation. Two hours after ketamine injection, rats were perfused and their brains fixed and extracted. Brain sections were prepared in a cryostat and c-Fos expression was detected using immunohistochemical methods.

Results

Ketamine induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices, thalamus, and neocortex. Diazepam suppressed the ketamine-induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices in a dose-dependent manner, leaving the thalamus and neocortex less affected. Halothane suppressed the ketamine-induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices and the neocortex in a dose-dependent manner, leaving the thalamus relatively unaffected.

Conclusion

Halothane and diazepam inhibited ketamine-induced c-Fos expression in the cingulate and retrosplenial cortices, leaving the thalamus relatively unaffected.
Volatile General Anesthetics Produce Hyperpolarization of Aplysia Neurons by Activation of a Discrete Population of Baseline Potassium Channels
Authors: Winegar Bruce D. , Owen David F. , Yost Spencer C. , Forsayeth John R. , Mayeri Earl
Published: November 2003

Background

The mechanism by which volatile anesthetics act on neuronal tissue to produce reversible depression is unknown. Previous studies have identified a potassium current in invertebrate neurons that is activated by volatile anesthetics. The molecular components generating this current are characterized here in greater detail.

Methods

The cellular and biophysical effects of halothane and isoflurane on neurons of Aplysia californica were studied. Isolated abdominal ganglia were perfused with anesthetic-containing solutions while membrane voltage changes were recorded. These effects were also studied at the single-channel level by patch clamping cultured neurons from the abdominal and pleural ganglia.

Results

Clinically relevant concentrations of halothane and isoflurane produced a slow hyperpolarization in abdominal ganglion neurons that was sufficient to block spontaneous spike firings. Single-channel studies revealed specific activation by volatile anesthetics of a previously described potassium channel. In pleural sensory neurons, halothane and isoflurane increased the open probability of the outwardly rectifying serotonin-sensitive channel (S channel). Halothane also inhibited a smaller noninactivating channel with a linear slope conductance of approximately 40 pS. S channels were activated by halothane with a median effective concentration of approximately 500 microM (0.013 atm), which increased channel activity about four times. The mechanism of channel activation involved shortening the closed-time durations between bursts and apparent recruitment of previously silent channels.

Conclusions

The results demonstrate a unique ability of halothane and isoflurane to activate a specific class of potassium channels. Because potassium channels are important regulators of neuronal excitability within the mammalian central nervous system, background channels such as the S channel may be responsible in part for mediating the action of volatile anesthetics.
Desflurane and Isoflurane Increase Lumbar Cerebrospinal Fluid Pressure in Normocapnic Patients Undergoing Transsphenoidal Hypophysectomy
Authors: Talke P. , Caldwell J. , Dodsont B. , Richardson C. A.
Published: November 2003

Background

Rapid emergence from anesthesia makes desflurane an attractive choice as an anesthetic for patients having neurosurgery. However, the data on the effect of desflurane on intracranial pressure in humans are still limited and inconclusive. The authors hypothesized that isoflurane and desflurane increase intracranial pressure compared with propofol.

Methods

Anesthesia was induced with intravenous fentanyl and propofol in 30 patients having transsphenoidal hypophysectomy with no evidence of mass effect, and it was maintained with 70% nitrous oxide in oxygen and a continuous 100 micrograms.kg-2.min-1 infusion of propofol. Patients were assigned to three groups randomized to receive only continued propofol infusion (n = 10), desflurane (n = 10), or isoflurane (n = 10) for 20 min. During the 20-min study period, each patient in the desflurane and isoflurane groups received, in random order, two concentrations (0.5 minimum alveolar concentration [MAC] and 1.0 MAC end-tidal) of desflurane or isoflurane for 10 min each. Lumbar cerebrospinal fluid (CSF) pressure, blood pressure, heart rate, and anesthetic concentrations were monitored continuously.

Results

Lumbar CSF pressure increased significantly in all patients receiving desflurane or isoflurane. Lumbar CSF pressure increased by 5 +/- 3 mmHg at 1-MAC concentrations of desflurane and by 4 +/- 2 mmHg at 1-MAC concentrations of isoflurane. Cerebral perfusion pressure decreased by 12 +/- 10 mmHg at 1-MAC concentrations of desflurane and by 15 +/- 10 mmHg at 1-MAC concentrations of isoflurane. Heart rate increased by 7 +/- 9 bpm with 0.5 MAC desflurane and by 8 +/- 7 bpm with 1.0 MAC desflurane, and by 5 +/- 11 bpm with 1.0 MAC isoflurane. Systolic blood pressure decreased in all but the patients receiving 1.0 MAC desflurane. To maintain blood pressure within predetermined limits, phenylephrine was administered to six of ten patients in the isoflurane group (range, 25 to 600 micrograms), two of ten patients in the desflurane group (range, 200 to 500 micrograms), and in no patients in the propofol group. Lumbar CSF pressure, heart rate, and systolic blood pressure did not change in the propofol group.

Conclusion

Desflurane and isoflurane, at 0.5 and 1.0 MAC, increase lumbar CSF pressure.
The Dose-Response Relation and Cost-effectiveness of Granisetron for the Prophylaxis of Pediatric Postoperative Emesis
Authors: Cieslak Gary D. , Watcha Mehernoor F. , Phillips Michael B. , Pennant John H.
Published: November 2003

Background

Postoperative nausea and vomiting (PONV) may delay discharge from hospital after ambulatory surgery. The antiserotonin agents, ondansetron and granisetron, provide effective prophylaxis against chemotherapy-induced and postoperative nausea and vomiting in adults, but are expensive. We determined the dose-response relation of granisetron and the financial impact of using this drug in preventing PONV after pediatric outpatient surgery.

Methods

In a randomized, double-blind, placebo-controlled study, 97 pediatric outpatients received a placebo or 10 or 40 micrograms.kg-1 granisetron intravenously during a standardized anesthetic. Episodes of postoperative retching, vomiting, and times to discharge readiness were recorded. A decision analysis tree was used to divide each study group into nine mutually exclusive subgroups, depending on the incidence of PONV, need for rescue therapy, and the side effects of antiemetics. Costs and probabilities were assigned to each subgroup, and the cost-effectiveness ratio was determined by dividing the sum of these weighted costs by the number of patients free from both PONV and antiemetic side effects.

Results

Granisetron (40 micrograms.kg-1 intravenously) was more effective than a placebo or 10 micrograms.kg-1 granisetron in decreasing the incidence and frequency of postoperative emesis, both in the ambulatory surgery center and during the first 24 h. Patients receiving 40 micrograms.kg-1 granisetron also had shorter times to discharge readiness compared with those receiving a placebo. Administering this dose of granisetron to all high-risk patients would cost the ambulatory care center an additional $99 (95% CI, range $89-$112) per emesis-free patient if nursing labor costs are excluded and $101 (95% CI, range $91-$113) if nursing costs are included.

Conclusions

In this study, 40 micrograms.kg-1 intravenous granisetron (but not 10 micrograms.kg-1) provided effective prophylaxis in children against PONV compared with a placebo, but at a high cost. The effective dose of granisetron for PONV prophylaxis is higher than the Food and Drug Administration-recommended dose for chemotherapy-induced emesis.
Statistical Modeling to Predict Elective Surgery Time
Authors: Wright Ian H. , Kooperberg Charles , Bonar Barbara A. , Bashein Gerard
Published: November 2003

Background

Accurate estimation of operating times is a prerequisite for the efficient scheduling of the operating suite. The authors, in this study, sought to compare surgeons' time estimates for elective cases with those of commercial scheduling software, and to ascertain whether improvements could be made by regression modeling.

Methods

The study was conducted at the University of Washington Medical Center in three phases. Phase 1 retrospectively reviewed surgeons' time estimates and the scheduling system's estimates throughout 1 yr. In phase 2, data were collected prospectively from participating surgeons by means of a data entry form completed at the time of scheduling elective cases. Data included the procedure code, estimated operating time, estimated case difficulty, and potential factors that might affect the duration. In phase 3, identical data were collected from five selected surgeons by personal interview.

Results

In phase 1, 26 of 43 surgeons provided significantly better estimates than did the scheduling system (P < 0.01), and no surgeon was significantly worse, although the absolute errors were large (34% of 157 min average case length). In phase 2, modeling improved the accuracy of the surgeons' estimates by 11.5%, compared with the scheduling system. In phase 3, applying the model from phase 2 improved the accuracy of the surgeons' estimates by 18.2%.

Conclusions

Surgeons provide more accurate time estimates than does the scheduling software as it is used in our institution. Regression modeling effects modest improvements in accuracy. Further improvements would be likely if the hospital information system could provide timely historical data and feedback to the surgeons.
Pharmacokinetic Model-driven Infusion of Fentanyl in Children
Authors: Ginsberg Brian , Howell Scott , Glass Peter S. A. , Margolis Judith O. , Ross Allison K. , Dear Guy de L. , Shafer Steven L.
Published: November 2003

Background

This study determined the accuracy of previously defined adult fentanyl pharmacokinetics in children having surgery; from this population, the pharmacokinetics of fentanyl were characterized in children when administered via a computerized assisted continuous-infusion device.

Methods

Twenty children between the ages of 2.7 and 11 y scheduled to undergo elective noncardiac surgery were studied. After induction, anesthesia was maintained with 60% nitrous oxide in oxygen supplemented with fentanyl (n = 10) or fentanyl plus isoflurane (n = 10). Fentanyl was administered via computerized assisted continuous-infusion to target concentrations determined by clinical requirements. Plasma fentanyl concentrations were measured and used to evaluate the performance of the fentanyl pharmacokinetics and then to determine a new set of pharmacokinetic parameters and the variance in the context-sensitive half-times simulated for these patients.

Results

The original adult fentanyl pharmacokinetics resulted in a positive bias (10.4%), indicating that measured concentrations were mostly greater than predicted. A two-compartment model with age and weight as covariates provided the optimal pharmacokinetic parameters. These resulted in a residual performance error of -1.1% and a median absolute performance error of 17.4%. The context-sensitive times determined from this pediatric population were considerably shorter than the context-sensitive times previously published for adults.

Conclusions

The pharmacokinetics of fentanyl administered by computerized assisted continuous-infusion differ between adults and children. The newly derived parameters are probably more suitable to determine infusion schemes of up to 4 h in children between the ages of 2 and 11 y.
Platelet Function and Adrenoceptors during and after Induced Hypotension using Nitroprusside
Authors: Dietrich Gerald V. , Heesen Michael , Boldt Joachim , Hempelmann Gunter
Published: November 2003

Background

Hypotension induced by sodium nitroprusside can minimize intraoperative blood loss. The release of endogenous catecholamines can influence adrenoceptors of platelets and thus might change the ability of platelets to aggregate.

Methods

Forty patients undergoing nasal septum, tympanoplastic, or sphenoid sinus surgery were randomly divided into two groups, those having controlled hypotension (A) and those serving as controls (B). Blood samples were drawn before the operation, after induction of anesthesia, 1 h after the start of the operation, and on the day after surgery.

Results

Epinephrine-induced platelet aggregation only increased in the controls on the day after surgery (A: from 49 +/- 25% to 47 +/- 29%; B: from 53 +/- 24% to 72 +/- 14%; mean +/- SD; P < 0.01). Spontaneous platelet aggregation increased in the controls from a median of 1.2 omega/h to 2.4 during the operation and 2.9 on the day after surgery but not after hypotension. On the day after surgery, alpha 2 receptors reached their maximum (A: 238 +/- 164; B: 234 +/- 80 per platelet). During the operation, the norepinephrine concentrations were significantly greater in group A (median, 419 pg/ml) than in group B (median, 217 pg/ml; P < 0.05). Blood loss was greater in the controls (A: 180 +/- 75; B: 379 +/- 120 ml; P < 0.05).

Conclusions

Controlled hypotension using sodium nitroprusside reduces epinephrine-induced and spontaneous platelet aggregation. Even on the day after hypotension, the usual postoperative reactive increase in platelet aggregation did not occur. These results may be explained by the direct effect of nitroprusside on platelets, the augmented stress response, lower shear stress on platelets due to the lower blood pressure, or the decreased blood loss compared with the controls.
Ketamine Attenuates and Reverses Morphine Tolerance in Rodents
Authors: Shimoyama Naohito , Shimoyama Megumi , Inturrisi Charles E. , Elliott Kathryn J.
Published: November 2003

Background

The development of tolerance complicates the use of morphine to manage persistent pain. N-methyl-D-aspartate receptor antagonists can attenuate or reverse morphine tolerance. The authors studied ketamine's ability to modulate morphine tolerance.

Method

Tolerance was produced in mice given morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after morphine to attenuate the development of tolerance was assessed. The ability of 10 mg/kg ketamine to reverse tolerance produced by the subcutaneous implantation of morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal morphine and the effects of the coadministration of 12 micrograms intraspinal ketamine were assessed.

Results

Morphine given subcutaneously produced a fivefold increase in the median effective (ED50) dose of morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED50 produced by morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED50, which was almost completely attenuated by the coadministration of intraspinal ketamine.

Conclusions

Systemically administered ketamine attenuates and reverses systemically induced morphine tolerance in mice, and intraspinal ketamine attenuates tolerance produced by intraspinal morphine in rats.
Interaction of Morphine and Clonidine on Gastrointestinal Transit in Mice
Authors: Puig M. M. , Pol O. , Warner W.
Published: November 2003

Background

Combinations of drugs are frequently used to achieve effective analgesia while minimizing side effects. Although the analgesic effects of morphine and clonidine seem to be synergistic, few studies have investigated other effects. Their role in inhibiting gastrointestinal transit was evaluated using different methods of analysis.

Methods

Percentage inhibition of transit induced by morphine, clonidine, or their combination was measured in mice that had been given an intragastric charcoal meal. Dose-response curves were obtained for each drug individually; for morphine:clonidine at 1:3, 1:1, and 1:0.33 ratios; and for morphine in the presence of 0.0138 mg/kg clonidine. The interaction was evaluated by isobolograms, combination indexes, and fixed-dose analysis.

Results

Each drug and their combinations inhibited transit in a dose-related manner. Combinations of morphine and clonidine produced interaction that depended on the ratio and level of response. The interaction analyzed by isobolograms and combination indexes showed that combinations in 1:1 and 1:3 proportions were synergistic at the median effective doses or less and were antagonistic at larger doses. Fixed-dose analysis using different ratios showed similar results. The effects of the combination (median effective dose at 1:1 ratio) were antagonized by efaroxan but not by naloxone, suggesting a predominant role of alpha-2-mediated effects.

Conclusions

Investigations into drug interactions should include several levels of response and combinations at different ratios. Isobolographic analysis permits the statistical evaluation of results without making assumptions about mechanisms of action of the drugs or their interactions. In this study, the combination of morphine and clonidine should produce synergy, antagonism, or no interaction depending on the relative doses and the level of effect.
Sevoflurane Inhibits Human Platelet Aggregation and Thromboxane A2Formation, Possibly by Suppression of Cyclooxygenase Activity
Authors: Hirakata Hideo , Ushikubi Fumitaka , Toda Hiroshi , Nakamura Kumi , Sai Satoko , Urabe Nobukata , Hatano Yoshio , Narumiya Shuh , Mori Kenjiro
Published: November 2003

Background

Halothane increases bleeding time and suppresses platelet aggregation in vivo and in vitro. A previous study by the authors suggests that halothane inhibits platelet aggregation by reducing thromboxane (TX) A2 receptor-binding affinity. However, no studies of the effects of sevoflurane on platelet aggregation have been published.

Methods

The effects of sevoflurane, halothane, and isoflurane were examined at doses of 0.13-1.4 mM. Human platelet aggregation was induced by adenosine diphosphate, epinephrine, arachidonic acid, prostaglandin G2, and a TXA2 agonist ([+]-9, 11-epithia-11, 12-methano-TXA2, STA2) and measured by aggregometry. Platelet TXB2 levels were measured by radioimmunoassay, and the ligand-binding characteristics of the TXA2 receptors were examined by Scatchard analysis using a [3H]-labeled TXA2 receptor antagonist (5Z-7-(3-endo-([ring-4-[3H] phenyl) sulphonylamino-[2.2.1.] bicyclohept-2-exo-yl) heptenoic acid, [3H]S145).

Results

Isoflurane (0.28-0.84 mM) did not significantly affect platelet aggregation induced by adenosine diphosphate and epinephrine. Sevoflurane (0.13-0.91 mM) and halothane (0.49-1.25 mM) inhibited secondary platelet aggregation induced by adenosine diphosphate (1-10 microM) and epinephrine (1-10 microM) without altering primary aggregation. Sevoflurane (0.13 mM) also inhibited arachidonic acid-induced aggregation, but not that induced by prostaglandin G2 or STA2, although halothane (0.49 mM) inhibited the latter. Sevoflurane (3 mM) did not affect the binding of [3H]S145 to platelets, whereas halothane (3.3 mM) suppressed it strongly. Sevoflurane (0.26 mM) and halothane (0.98 mM) strongly suppressed TXB2 formation by arachidonic acid-stimulated platelets.

Conclusions

The findings that sevoflurane suppressed the effects of arachidonic acid, but not those of prostaglandin G2 and STA2, suggest strongly that sevoflurane inhibited TXA2 formation by suppressing cyclooxygenase activity. Halothane appeared to suppress both TXA2 formation and binding to its receptors. Sevoflurane has strong antiaggregatory effects at subanesthetic concentrations (greater than 0.13 mM; i.e., approximately 0.5 vol/%), whereas halothane has similar effects at somewhat greater anesthetic concentrations (0.49 mM; i.e., approximately 0.54 vol/%). Isoflurane at clinical concentration (0.84 mM; i.e., approximately 1.82 vol/%) does not affect platelet aggregation significantly.
Effects of Proportional Assist Ventilation on Inspiratory Muscle Effort in Patients with Chronic Obstructive Pulmonary Disease and Acute Respiratory Failure
Authors: Ranieri Marco V. , Grasso Salvatore , Mascia Luciana , Martino Sergio , Tommasco Fiore , Brienza Antonio , Giuliani Rocco
Published: November 2003

Background

Acute respiratory failure may develop in patients with chronic obstructive pulmonary disease because of intrinsic positive end-expiratory pressure (PEEPi) and increased resistive and elastic loads. Proportional assist ventilation is an experimental mode of partial ventilatory support in which the ventilator generates flow to unload the resistive burden (flow assistance: FA) and volume to unload the elastic burden (volume assistance: VA) proportionally to inspiratory muscle effort, and PEEPi can be counterbalanced by application of external PEEP. The authors assessed effects of proportional assist ventilation and optimal ventilatory settings in patients with chronic obstructive pulmonary disease and acute respiratory failure.

Methods

Inspiratory muscles and diaphragmatic efforts were evaluated by measurements of esophageal, gastric, and transdiaphragmatic pressures. Minute ventilation and breathing patterns were evaluated by measuring airway pressure and flow. Measurements were performed during spontaneous breathing, continuous positive airway pressure, FA, FA+PEEP, VA, VA+PEEP, FA+VA, and FA+VA+PEEP.

Results

FA+PEEP provided the greatest improvement in minute ventilation (89 +/- 3%) and dyspnea (62 +/- 2%). The largest reduction in pressure time product per breath of the respiratory muscles and diaphragm (44 +/- 3% and 33 +/- 2%, respectively) also was observed during FA+PEEP condition. When VA was added to this setting, a reduction in respiratory rate (50 +/- 3%), an increase in inspiratory time (102 +/- 6%), and a further reduction in pressure time product per minute (65 +/- 2% and 64% for the respiratory muscles and diaphragm, respectively) was observed. However, values of pressure time product per liter of minute ventilation during FA+VA+PEEP did not differ with those observed during FA+PEEP condition. Worsening of patient-ventilator interaction and breathing asynchrony occurred when VA was implemented.

Conclusions

Application of PEEP to counterbalance PEEPi and FA to unload the resistive burden provided the optimal conditions in such patients. Ventilator over-assistance and patient-ventilator asynchrony was observed when VA was added to this setting. The clinical use of proportional assist ventilation should be based on continuous measurements of respiratory mechanics.